Targeted Therapies and Utility of the Lung-molGPA in Non-Small-Cell Lung Cancer Patients with Brain Metastases.
Therapeutic advances have increased the survival of non-small-cell lung cancer (NSCLC) patients as well as the lifetime risk of being diagnosed with brain metastases (BM). Although BM have historically been associated with poor prognosis, it is unclear whether they remain a strong predictor of reduced survival. This study aimed to evaluate the prognostic value of BM and the utility of the Lung-molGPA. This single-center retrospective database analysis included 1,393 NSCLC patients with newly diagnosed BM who registered at the Instituto Nacional de Cancerología of Mexico (INCan) from 2010 to 2020. The Kaplan-Meier method and log-rank test were used for the survival analysis. Survival times were calculated from the date of NSCLC diagnosis (OS), or BM diagnosis, to the date of death or last follow-up. Cox proportional-hazards models were used to calculate the hazard ratio (HR) for death and the significance of the parameters evaluated. Out of 1,058 patients who underwent genetic testing for epidermal growth factor receptor (EGFR) mutations and/or anaplastic lymphoma kinase (ALK) rearrangements, 650 had a positive tumor mutational/rearrangement status (543 had EGFR mutations, 104 had ALK rearrangements, and 3 had both EGFR and ALK alterations). Median OS did not differ between patients with BM and without BM (17.7 months [95% CI, 15.4-19.0] vs. 16.6 months [95% CI, 14.3-19.0]; p = 0.362). In contrast, the presence of BM was associated with worse OS in patients with a negative tumor mutational status (HR: 1.225 [95% CI, 1.041-1.443]; p = 0.015), who did not receive TKI therapy (HR: 1.269 [95% CI, 1.082-1.488]; p = 0.003), or with non-adenocarcinoma histology (HR: 1.582 [95% CI, 1.118-2.238]; p = 0.01). The median survival after BM diagnosis was 4.27, 6.96, 14.68, and 18.89 months for adenocarcinoma patients with Lung-molGPA scores 0-1, 1.5-2, 2.5-3, and 3.5-4, respectively (p < 0.0001). For non-adenocarcinoma patients with Lung-molGPA scores 0-1, 1.5-2, and 2.5-3, the corresponding estimates were 0.95, 2.89, and 9.39 months, respectively (p < 0.0001). These results show that the prognosis of NSCLC patients with BM is no longer uniformly poor and should be individually assessed. Furthermore, the validity of the Lung-molGPA was confirmed in an independent population from a different geographical region.


Correction to: Nitrogen application and different water regimes at booting stage improved yield and 2-acetyl-1-pyrroline (2AP) formation in fragrant rice.
It was highlighted that the original article (Mo et al. 2019) contained an error in Fig. 1f which revealed the biosynthesis pathway of 2AP. This Correction article shows the correct Fig. 1 and incorrect Fig. 1. The original article has been updated.


Increased vigorous exercise and decreased sedentary activities are associated with decreased depressive symptoms in United States adults: Analysis of The National Health and Nutrition Examination Survey (NHANES) 2017-2020.
Depression is a major public health concern that affects over 4% of the global population. Identification of new nonpharmacologic recommendations will help decrease the burden of disease. The overarching of this study was to examine the association between physical activity and depressive symptoms in a large sample of adults in the United States. Presently, researchers utilized data from the National Health and Nutrition Examination Surveys (NHANES 2017-2020), which is a retrospective, complex, multistage, representative, and modern cohort of the United States. Adult patients ( > 18 years; N = 8091) with complete 9-item Patient Health Questionnaire (PHQ-9) information were included in the study. The PHQ-9 is a well-validated survey, per literature, scores ≥10 are considered to have clinically relevant depression. Univariable and multivariable logistic regression was fit for active and sedentary activities on clinical depression (PHQ-9 ≥ 10). The acquisition and analysis of the data within this study were approved by the National Center for Health Statistics Ethics Review Board. After adjusting for potential confounders like age, race, sex, and income, we found that increased vigorous exercise was associated with lower rates of depressive symptoms. Each extra day of vigorous exercise was associated with 11% decreased odds of depression (odd ratio [OR]: 0.89, confidence interval [CI]: 0.83-0.96, p < 0.01). Increased sedentary activity was associated with increased depression. Each extra hour per day of sedentary activity was associated with a 6% increase in odds of depression (OR: 1.06, (1.02-1.10, p < 0.01). To conclude, exercise appears to be protective against depressive symptoms; however, further prospective studies are required to ascertain whether exercise causes decreased depressive symptoms.


Selective and sensitive detection and detoxification of Pd2+ in living cells with a water-soluble fluorescent probe.
Due to the cytotoxic potential of even low doses of Pd2+, the development of its detection and detoxification strategies is highly demanding. In this paper, we developed a water-soluble fluorescent probe IMQU-8 with a new scaffold for Pd2+ sensing. IMQU-8 can detect Pd2+ with high selectivity and sensitivity and has a good detection limit of 2.5 nM under physiological conditions. Its sensing mechanism has been revealed through job plot experiments and HRMS, FT-IR, 1H NMR and DFT calculations, which demonstrated that the N atoms of the pyridyl group and imino group are crucial for Pd2+ sensing. Fluorescence lifetime assessment indicated that IMQU-8 and IMQU-8-Pd have almost identical fluorescence lifetimes, implying that IMQU-8 undergoes static quenching toward Pd2+. Additionally, IMQU-8 has been successfully applied to image Pd2+ in living cells. Since IMQU-8 and its coordinated complex IMQU-8-Pd exhibit low toxicity, IMQU-8 has been applied for the detoxification of Pd2+ in living cells.


Current-use flame retardants: Maternal exposure and neurodevelopment in children of the CHAMACOS cohort.
Flame retardants are commonly used in consumer products found in U.S. households. Restrictions on the use of polybrominated diphenyl ether flame retardants have resulted in increased use of replacement chemicals, including Firemaster 550® (FM 550®) and organophosphate flame retardants (PFRs): tris(1,3- dichloro-2-propyl) phosphate (TDCIPP); tris(chloropropyl) phosphate (TCIPP); tris(2-chloroethyl) phosphate (TCEP); and triphenyl phosphate (TPHP). Animal research suggests that PFRs may affect neurodevelopment through noncholinergic mechanisms similar to some organophosphate (OP) pesticides. Despite the widespread presence of these compounds in home environments, and their structural similarity to neurotoxic OP pesticides, understanding of human exposure and health effects of PFRs is limited. We measured four urinary PFR metabolites from pregnant women in the CHAMACOS birth cohort study (n = 310) and assessed neurodevelopment of their children at age 7. Metabolites of TDCIPP (BDCIPP: bis(1,3-dichloro-2-propyl) phosphate) and TPHP (DPHP: diphenyl phosphate) were detected in >75% of urine samples, and isopropylphenyl phenyl phosphate (ip-PPP), a metabolite of one component of FM 550®, was detected in 72% of urine samples. We observed decreases of 2.9 points (95% Confidence Interval (CI): -6.3, 0.5) and 3.9 points (95% CI: -7.3,-0.5) in Full-Scale intelligence quotient and Working Memory, respectively, for each ten-fold increase in DPHP in adjusted regression models (n = 248). Decreases in Full-Scale IQ and Working Memory were greater in models of the molar sum of the PFR metabolites compared to the DPHP models. This is the first study to examine PFR and FM 550® exposures and potential neurodevelopmental outcomes in pregnant women and children. Additional research is warranted.


Schisandrin B ameliorates high-glucose-induced vascular endothelial cells injury by regulating the Noxa/Hsp27/NF-κB signaling pathway.
To address the molecular mechanism of the anti-inflammation effects of schisandrin B (Sch B) in atherosclerosis, we examined injured HMEC-1, HBMEC, and HUVEC-12 cells induced by high glucose (HG). Western blot was performed to detect the levels of the proteins Hsp27, Noxa, TLR5, p-IκBα, and p-p65 in HG-induced cells, while ELISA was used to analyze the inflammatory cytokines TNF-α, IL-6, MCP-1, and IL-1β in cells with Hsp27 or Noxa stable expression. Overexpression of Hsp27 upregulated the inflammatory cytokines and the release of IκBα, promoted transportation of p65 into the nucleus, and lastly, affected the inflammation process, while Sch B counteracted the upregulation. In addition, the effect of Noxa overexpression, which is different from Hsp27 overexpression, was consistent with that of Sch B treatment. Sch B may inhibit the inflammatory cascade and alleviate the injury to HMEC-1, HBMEC, and HUEVC-12 cells caused by HG by regulating the Noxa/Hsp27/NF-κB signaling pathway.


Complications of pelvic resections.
The authors report on complications that occurred with 63 pelvic resections. There were 43 complications: 13 infections, seven cases of nerve palsy, 12 cases of vascular or visceral damage, six mechanical and five aesthetic complications. Infection and vascular and visceral damage were more frequent in anterior arch resections, neurological damage in iliac wing resections, and mechanical complications in periacetabular resections. The treatment and outcome of the complications are reported.


Gastric and duodenal squamous cell carcinoma: metastatic or primary?
Either metastatic or primary squamous cell carcinoma in the gastrointestinal tract is extremely rare, with very few cases reported in the literature. In this paper, we report a case in which the patient presented with dysphagia during the course of radiotherapy for recurrent lung cancer in a mediastinal lymph node. Although the dysphagia mimicked radiation esophagitis, the ultimate cause proved to be gastric and duodenal metastases from primary lung squamous cell carcinoma. Taking into account the value of identification of metastatic or primary SCC in the stomach and duodenum on the prognosis and treatment options, it is imperative that the correct diagnosis be established. This report is followed by a discussion of the differential diagnosis between metastatic and primary squamous cell carcinoma in the stomach and duodenum.


Sense of coherence, health locus of control, and quality of life in obese adults: physical limitations and psychological normalcies.
To assess differences between overweight and normal-weight adults in sense of coherence (SOC), health locus of control (HLOC), and health-related quality of life (HQOL). Cross-sectional population study (Augsburg, Germany). Random sample aged 25-74 (N=947). Body mass index (BMI) was categorized into four groups (normal-weight: 18.5-25; pre-obesity: 25-29.9; moderate obesity: 30-34.9; severe obesity: > or =35). The associations between obesity classification and SOC-13T, MHLOC-Scales, and SF-12 summary scores were estimated via analysis of covariance. Adjusted for age and socio-economic status, no differences across BMI-groups related to SOC, internal HLOC, external HLOC-'chance', and SF-12-'mental health'. HLOC-'doctors' was marginally elevated in obese women. Larger differences pertained to SF-12-'physical health' in that it was considerably reduced in obese women and severely obese men. In this adult population sample, obesity is not associated with SOC, HLOC, and HQOL in terms of mental health, but is associated with poorer physical health, which was reported by all groups of obese women, and by severely obese men. These results underline the need to treat and prevent obesity to restore and promote physical HQOL, and to distinguish moderate vs. severe obesity in obesity research.


Signaling pathways implicated in alpha-melanocyte stimulating hormone-induced lipolysis in 3T3-L1 adipocytes.
Melanocortins, besides their central roles, have also recently been reported to regulate adipocyte metabolism. In this study, we attempted to characterize the mechanism underlying alpha-melanocyte-stimulating hormone (MSH)-induced lipolysis, and compared it with that of the adrenocorticotrophin hormone (ACTH) in 3T3-L1 adipocytes. Similar to ACTH, MSH treatment resulted in the release of glycerol into the cell supernatant. The activity of hormone-sensitive lipase, a rate-limiting enzyme, which is involved in lipolysis, was significantly increased by MSH treatment. In addition, a variety of kinases, including protein kinase A (PKA) and extracellular signal-regulated kinase (ERK) were also phosphorylated as the result of MSH treatment, and their specific inhibitors caused a reduction in MSH-induced glycerol release and HSL activity, indicating that MSH-induced lipolysis was mediated by these kinases. These results suggest that PKA and ERK constitute the principal signaling pathways implicated in the MSH-induced lipolytic process via the regulation of HSL in 3T3-L1 adipocytes.


Trichotillomania in early childhood--a report of two cases with a peculiar habit.
Trichotillomania in early childhood is considered a benign habit disorder in contrary to older children and adults where trichotillomania is associated with greater psychopathology. We present two cases of trichotillomania in young children, both using a pacifier to pull out their hair.


T-588 enhances neurite outgrowth and choline acetyltransferase in cultured rat spinal ventral horn neurons.
T-588(R(-)-1-(benzo(b)thiophen-5yl)-2-[2(N,N-diethylamino)ethoxy]ethanol hydrochloride) is a novel compound which has been shown to exhibit a wide range of neurotrophic effects both in vivo and in vitro. This compound can slow the motor deterioration of wobbler mouse motor neuron disease. However, it is not known whether this compound has a trophic effect on spinal motor neurons. We have studied the effect of T-588 on neurite outgrowth and choline acetyltransferase(ChAT) activity in primary explant cultures of ventral spinal cord of fetal rats(VSCC). Cultures were treated with T-588 from day 1 to 1 week. T-588 treated VSCC, compared with control VSCC, had a significant neurite promoting effect at ranged between 10(-8) molar(M) and 10(-5) M, with 2.3 to 5.3 fold increased over that of control VSCC. In T-588 treated VSCC, ChAT activity was increased 1.5 times over that of control at 10(-6), and 10(-5) M respectively. Our data showing T-588 has neurotrophic action on VSCC and suggests a potential use of T-588 in treating diseases that involve degeneration and death of spinal motor neurons, such as motor neuropathy and motor neuron disease.


Failure of type 1 herpesvirus to develop resistance to ribavirin.
Exposure (10 passages) of type 1 herpesvirus to ribavirin or idoxuridine in Vero cells results in resistance to idoxuridine, but not to ribavirin.


Sequential endocardial resection for the surgical treatment of refractory ventricular tachycardia.
The optimal surgical therapy for refractory ventricular tachycardia is controversial. The usual operation involves induction of tachycardia and endocardial mapping during normothermic cardiopulmonary bypass, followed by systemic hypothermia, aortic cross-clamping, and resection of the identified site of origin of the tachycardia. Our initial experience with this technique in 20 patients (mean age 60 years, mean ejection fraction 29%, mean number of failed antiarrhythmic drugs three) resulted in five (25%) surgical deaths, three caused by ventricular tachycardia and two by respiratory or heart failure. Electrophysiologic study showed that 11 of 15 survivors were free from ventricular tachycardia after operation, for a success rate in the survivors of 73%. Most failures occurred in patients with multiple tachycardia morphologies that were not eradicated by initial resection. Thereafter, the technique of sequential endocardial resection was used. After completion of endocardial mapping, directed normothermic endocardial resection is performed; more attempts to induce ventricular tachycardia are made and followed by further mapping and resection until tachycardia can no longer be induced. Fifty patients (mean age 59 years, mean ejection fraction 33%, mean number of failed antiarrhythmic drugs three) were treated by this method, with a mean of two resections per patient (range one to six). Mean perfusion time in the sequential resection group (101 +/- 28 minutes) was not significantly different from that of the earlier patients (101 +/- 40 minutes). There were four (8%) surgical deaths, one caused by persistent arrhythmia and three caused by respiratory or heart failure. Electrophysiologic study after operation showed that 40 of 46 survivors (87%) were free of ventricular tachycardia. Symptoms in the six with inducible tachycardia on postoperative electrophysiologic study were well controlled with medication. These data suggest that sequential endocardial resection guided by intraoperative mapping is a highly effective operative approach for patients with ventricular tachycardia.


Unmasking the immune recognition of prostate cancer with CTLA4 blockade.
Although cancer cells can be immunogenic, tumour progression is associated with the evasion of immunosurveillance, the promotion of tumour tolerance and even the production of pro-tumorigenic factors by immune cells. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) represents a crucial immune checkpoint, the blockade of which can potentiate anti-tumour immunity. CTLA4-blocking antibodies are now an established therapeutic approach for malignant melanoma, and clinical trials with CTLA4-specific antibodies in prostate cancer have also shown clinical activity. This treatment may provide insights into the targets that the immune system recognizes to drive tumour regression, and could potentially improve both outcome and toxicity for patients with prostate cancer.


Patients with olfactory loss exhibit pronounced adaptation to chemosensory stimuli: an electrophysiological study.
Pronounced chemosensory adaptation affects many patients with olfactory loss. The study aimed to investigate adaptation to olfactory and trigeminal nasal stimuli in patients with olfactory loss in comparison to controls using electrophysiological measures. Thirty-four patients with olfactory loss (mean age ± SD = 59 ± 16 years) and 17 healthy volunteers (mean age ± SD = 50 ± 14 years) were recruited. Sniffin' sticks test was used for evaluation of olfactory function and EEG-derived chemosensory event-related potentials were recorded. Intranasal stimuli were presented using high-precision, computer-controlled stimulators based on the principles of air-dilution olfactometry. Data were analyzed in two different approaches according to the relatively short or long inter-stimulus interval. A decreased peak amplitude or a prolonged latency was considered as an expression of adaptation. The majority of participants (88%) responded reliably to chemosensory stimulation. Patients with olfactory loss exhibited pronounced olfactory and trigeminal adaptation within the long-term design, without such effects in healthy controls. Odor sensitivity correlated with both olfactory and trigeminal amplitude changes: the worse the olfactory sensitivity, the more pronounced chemosensory adaptation. The results help to explain the patients' complaints in terms of the fast adaptation towards chemosensory stimuli, for example during eating and drinking. The differences in adaptation in patients with olfactory loss and healthy controls could serve as a clinical criterion to gauge olfactory dysfunction.


The carbohydrate specificity of conglutinin and its homology to proteins in the hepatic lectin family.
Inhibition experiments with D-mannose oligosaccharides establish that conglutinin recognises terminal alpha 1----2 mannobiosyl units present in the glycopeptide of the alpha-chain of the complement component C3b. On the basis of its three domain structure and the homology of its N-terminal amino-acid sequence to that of the dog pulmonary surfactant protein, it is proposed that conglutinin is a member of the hepatic lectin family.


Cell death mechanisms during follicular atresia in Dipetalogaster maxima, a vector of Chagas' disease (Hemiptera: Reduviidae).
In this work we have analyzed the involvement of cell death pathways during the process of follicular atresia in the hematophagous insect vector Dipetalogaster maxima. Standardized insect rearing conditions were established to induce a gradual follicular degeneration stage by depriving females of blood meal during post-vitellogenesis. We first characterized the morpho-histological and ultrastructural changes of the ovarian tissue at early and late follicular atresia by light and transmission electron microscopy. Apoptosis was investigated by DAPI nuclear staining, TUNEL labeling and the detection of active caspase-3 by immunofluorescence. Autophagy was assessed by the measurement of acid phosphatase activity in ovarian homogenates and monitored by the detection of the specific marker of autophagic compartments, LC3. High levels of acid phosphatase activity were detected at all atretic stages. However, follicular cells of follicles undergoing incipient degeneration in early atresia exhibited features of apoptosis such as chromatin condensation, DNA fragmentation and the presence of active caspase-3. The ultrastructural findings and the increased levels of LC3-II found at late follicular atresia supported the relevance of autophagy at this atretic stage, although the extent of autophagosome formation demonstrated that this cell death pathway also occurred at early atresia. In late atresia, follicular cells also displayed more drastic changes compatible with necrosis. Taken together, results showed that apoptosis, autophagy and necrosis were operative during follicular atresia in D. maxima. Moreover, it was shown that the relevance of these cell death mechanisms correlates with the time elapsed since the onset of the degenerative process.


Group B streptococcal cellulitis.
We have described a 2-week-old infant with cellulitis in the left submandibular region due to beta hemolytic Streptococcus, group B, and presented 16 additional cases compiled from the literature.


Herbal hepatotoxicity.
There is appropriate concern about the potential risk for hepatotoxicity from herbal products because they are unregulated and therefore not standardized with regard to their contents. This is particularly the case for the crude herbals that are commonly formulated as a mixture, so that their ingredients may be ambiguous and even contain harmful contaminants. Presented here is an overview of the more commonly recognized herbal products that have been reported to be associated with liver injury. Although many of them are clearly implicated, there are some, particularly those identified solely through an occasional case report, for which the relationship is uncertain.


Forest ditch maintenance impoverishes the fauna of aquatic invertebrates: Opportunities for mitigation.
One of the main factors causing biodiversity loss in wetlands is drainage, nevertheless, even drained areas may provide habitat for aquatic fauna in the form of drainage ditches. Assemblages in ditches are regularly disturbed by ditch maintenance, but the extent of these disturbances and mitigation possibilities are poorly documented. We conducted an experimental study in three commercially managed forest plots in eastern Estonia, aiming to find out how ditch network maintenance (DNM) affects the diversity and assemblages of aquatic macroinvertebrates in ditches and remnant pools, and whether this effect can be alleviated by constructing mitigation waterbodies. For comparison we also collected data from natural pools in three undrained forest plots. Before DNM, ditches supported greater number of higher taxa compared to remnant and natural pools and more strictly aquatic taxa, whereas natural pools in undrained plots supported more Trichoptera shredders. After DNM, the diversity in remnant pools decreased. Moreover, majority of the pools dried out, which resulted in further reduction of the richness and abundance of macroinvertebrates. In ditches the diversity dropped immediately after DNM, but recovered in two to three years. Nevertheless, plot-scale richness and abundance did not completely recover. Assemblage shift in ditches took place right after DNM and remained distinct after the four year survey period. Mitigation pools provided habitat for several taxa (especially Odonata) uncommon in other waterbodies in drained and undrained plots. Our results show that DNM in forests substantially impoverishes habitat availability and reduces the abundance and diversity of aquatic macroinvertebrates. We recommend retaining uncleaned sections in ditches and constructing mitigation pools as tools for supporting wetland biodiversity in drained forests.


In situ synthesis of polypyrrole on graphite felt as bio-anode to enhance the start-up performance of microbial fuel cells.
This study introduces an effective method to deposit polypyrrole (PPy) on graphite felt (GF) as anode to improve the start-up performance of microbial fuel cells (MFCs). The results of scanning electron microscope (SEM) and electrochemical testing reveal that polypyrrole is able to improve the electrical conductivity and surface roughness, which is beneficial to the microorganism attachment and growth. It shows that microorganisms grow faster on polypyrrole-modified anode than on unmodified anode. It takes ca. 5 days for polypyrrole-modified anode to reach a reproducible voltage platform, while it takes 11 days for unmodified anode. Moreover, the maximum power density of microbial fuel cells with polypyrrole-modified anode was 919 mW m-2, which were 2.3 times of that with unmodified anode. This research revealed that polypyrrole modification can improve the start-up performance of microbial fuel cells. It is considered as a feasible, economical and sustainable anode.


The safety and efficacy of remimazolam tosylate combined with propofol in upper gastrointestinal endoscopy: A multicenter, randomized clinical trial.
Hypotension is the most common adverse event under propofol-mediated sedation and is possible to cause varying degrees of damage to patients. Whereas remimazolam has a poorer sedative effect than propofol. The aim of this study was to explore the advantages of the combination of remimazolam tosylate and propofol. 304 patients were divided into the remimazolam tosylate group (RT group), the propofol group (P group), and the remimazolam tosylate plus propofol group(R+T group). The primary outcome was the incidence of hypotension. Secondary outcomes included the results of sedation and recovery. The safety results mainly include the incidence of Hypotension, adverse respiratory events, postoperative nausea and vomiting, hiccup, cough, body movement and bradycardia. The incidence of hypotension was 56.7% in the P group, 12.6% in the RT group, and 31.3% in the R+P group, three groups of pairwise comparisons showed statistical differences, with P< 0.001. The incidence of body movement was significantly higher in the RT group (26.1%) than in the P group (10.3%) and the R+P group (12.5%), P = 0.004. The endoscopist satisfaction was higher in the P (3.87±0.44) and R+P (3.95±0.22)groups than in the RT(3.53±0.84) group. The incidence of adverse events, in descending order, was P group, RT group, and R+P group (93.8%vs.61.3%vs.42.7%). Co-administration had fewer adverse events than propofol monotherapy, also had a better sedative effect and higher endoscopist satisfaction than remimazolam monotherapy. Clinical trial registration number: NCT05429086.


Iophendylate (pantopaque) and MR imaging of the spine.
Residual iophendylate in the spinal subarachnoid space may closely resemble certain spinal canal tumors on MR imaging of the spine. A knowledge of the appearance on MR imaging scans of iophendylate is essential to differentiate it from spinal tumors.


[T4 rectal carcinoma. Surgical and multimodal therapy].
In locally advanced rectal cancer with infiltration of neighbouring organs (uT4), resectability and local control are difficult to achieve. Combined preoperative radiochemotherapy may result in increased resectability and reduced local recurrence rates. Thirty-four patients with biopsy-proven locally advanced rectal cancer were treated by preoperative radiochemotherapy. All tumours had been staged as uT4 lesions by endorectal ultrasound or computed tomography. Radiotherapy was applied in standard blocks, 5 x 1.8 Gy up to 45 Gy. Chemotherapy consisted of two cycles of 5-fluorouracil (300-350 mg/m2/day) and leucovorin (50 mg). In 20 patients, additional thermotherapy was carried out using the Sigma 60 applicator BSD 2000 once a week prior to radiotherapy. Surgery was performed 4-6 weeks after radiochemotherapy. Postoperatively, all patients received four cycles of 5-fluorouracil and leucovorin. Treatment-induced toxicity occurred in 26% of the patients (WHO grade III (n = 6) and IV (n = 3)). The resectability rate was 76% (26/34 patients) (R0 resectability n = 21; 62%). The pathological complete response rate was 6% (n = 2) and the partial response rate was 47% (n = 16). A local failure was observed in six patients after median time of 16 months (range 7-36 months). Patients with R0 resection achieved a 5-year disease-free survival rate of 55% and a survival rate of 71%. The overall 5-year survival rate for all patients with advanced uT4 rectal cancer was 49%. Our data on preoperative combined treatment in locally advanced T4 rectal cancer revealed encouraging downstaging, local control, and survival rates.


Iron uptake by cultured lens epithelial cells.
Transferrin and Fe concentrations increase in the intraocular fluids in pathological conditions and the lens accumulates Fe during ocular inflammation. Tissues take up Fe from transferrin by two mechanisms, receptor-medicated endocytosis of diferric transferrin and a process occurring at the cell membrane which may be mediated by an oxido-reductase. However, Fe metabolism, transport and storage have not been previously investigated in the lens. This study was designed to characterize the uptake of Fe from transferrin by lens epithelial cells in culture. Primary, secondary and tertiary cultures of canine lens epithelial cells and cultures obtained from cataractous lenses were studied. Uptake of 59Fe from transferrin by these cultured cells was measured. Transferrin receptor populations were determined in receptor-binding assays. There was a distinct relationship between the amount of Fe-transferrin added and the amount of Fe taken up, which was linear for the primary cultures but significantly reduced for the secondary, tertiary and cataract cultures (252 +/- 21, 169 +/- 14, 153 +/- 14 and 96 +/- 2 ng Fe/mg protein, respectively). Transferring receptor expression in lens cell cultures was reduced 10-fold within 2 days of addition of serum to cells grown in low-Fe, serum-free medium for 1 week. The reduction of Fe uptake by the subcultured and cataract cell lines probably reflects a decrease in transferrin receptor expression and in the activity of an alternative pathway for Fe transferrin uptake occurring over time. This reduced Fe uptake may result from long-term exposure to relatively high Fe concentration in the media. A reduction in the expression of the transferrin receptor after incubation with high concentrations of Fe supports this conclusion.


Establishment of an efficient early flowering-assisted CRISPR/Cas9 gene-editing system in Arabidopsis.
Ectopic expression of the florigen FT gene along with the Cas9 cassette promotes fast reproduction of the T1 transgenic plants, and the late-flowering phenotype serves as a convenient marker for transgene-free plants screening in T2 segregation population.


Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4.
T cell trafficking into the lung is critical for lung immunity, but the mechanisms that mediate T cell lung homing are not well understood. Here, we show that lung dendritic cells (DCs) imprint T cell lung homing, as lung DC-activated T cells traffic more efficiently into the lung in response to inhaled antigen and at homeostasis compared with T cells activated by DCs from other tissues. Consequently, lung DC-imprinted T cells protect against influenza more effectively than do gut and skin DC-imprinted T cells. Lung DCs imprint the expression of CCR4 on T cells, and CCR4 contributes to T cell lung imprinting. Lung DC-activated, CCR4-deficient T cells fail to traffic into the lung as efficiently and to protect against influenza as effectively as lung DC-activated, CCR4-sufficient T cells. Thus, lung DCs imprint T cell lung homing and promote lung immunity in part through CCR4.


Melatonin: A look at protozoal and helminths.
Melatonin is a pleiotropic neurohormone found in different animal, plant, and microorganism species. It is a product resulting from tryptophan metabolism in the pineal gland and is widely known for its ability to synchronize the circadian rhythm to antitumor functions in different types of cancers. The molecular mechanisms responsible for its immunomodulatory, antioxidant and cytoprotective effects involve binding to high-affinity G protein-coupled receptors and interactions with intracellular targets that modulate signal transduction pathways. In vitro and in vivo studies have reported the therapeutic potential of melatonin in different infectious and parasitic diseases. In this review, the protective and pathophysiological roles of melatonin in fighting protozoan and helminth infections and the possible mechanisms involved against these stressors will be discussed.


Morphological and molecular identification of Tetratrichomonas flagellates from the giant anteater (Myrmecophaga tridactyla).
A tetratrichomonad flagellate found in the diarrhoeic faeces of a 5 years-old male giant anteater (Myrmecophaga tridactyla) was characterised by morphological and genetic analysis. This protozoan presents four anterior flagella of unequal length and a recurrent flagellum attached to the undulating membrane without a free end portion, and a broad axostyle projection. Numerous vacuoles of different sizes containing bacteria and digestion products were found. The complete sequence of the DNA coding for the 16S rRNA-ITS1-5.8S rRNA-ITS2 region was also obtained in order to compare this isolate with other tetratrichomonad species. The sequence obtained was identical to others previously obtained by other researchers from bovines and turtles (Geochelone sp.). It is not easily explainable how the same organism could be found in such different hosts and locations; however these results indicate that some tetratrichomonad species could have a wide host range and could survive in a wide range of environmental conditions.


Challenges for the dental radiology clinic in times of the COVID-19 pandemic.
This letter addresses the challenges for the dental radiology clinic in times of the COVID-19 pandemic. It highlights the use of teleradiography and mobile devices, as well as the proper care in disinfecting these equipments. As there are still no specific therapies for COVID-19, biosafety measures that promote containment and prevent the spread of the virus are crucial to stop the outbreak and control a possible new infectious peak.


Of splice and men: what does the distribution of IKAP mRNA in the rat tell us about the pathogenesis of familial dysautonomia?
Familial dysautonomia (FD) is the best-known and most common member of a group of congenital sensory/autonomic neuropathies characterized by widespread sensory and variable autonomic dysfunction. As opposed to the sensory/motor neuropathies, little is known about the causes of neuronal dysfunction and loss in the sensory/autonomic neuropathies. FD involves progressive neuronal degeneration, has a broad impact on the operation of many of the body's systems, and leads to a markedly reduced quality of life and premature death. In 2001, we identified two mutations in the IKBKAP gene that result in FD. IKBKAP encodes IKAP, a member of the putative human holo-Elongator complex, which may facilitate transcription by RNA polymerase II. Whether or not the Elongator plays this role is moot. The FD mutation found on >99.5% of FD chromosomes does not cause complete loss of function. Instead, it results in a tissue-specific decrease in splicing efficiency of the IKBKAP transcript; cells from patients retain some capacity to produce normal mRNA and protein. To better understand the relationship between the genotype of FD patients and their phenotype, we have used in situ hybridization histochemistry to map the IKAP mRNA in sections of whole rat embryos. The mRNA is widely distributed. Highest levels are in the nervous system, but substantial amounts are also present in peripheral organs.


Surgical correction of ulnar drift in the rheumatoid hand.
A new technique for the correction of ulnar drift is described which has been used by the author in selected cases during the past 5 years. Results of this technique during a 2 year period are compared with those treated by prosthetic joint replacement alone, or a combination of the two methods.


Endothelin, astrocytes and glaucoma.
It has become increasingly clear that astrocytes may play an important role in the genesis of glaucoma. Astrogliosis occurs in response to ocular stress or the presence of noxious stimuli. Agents that appear to stimulate reactive gliosis are becoming increasingly clear. One class of agents that is emerging is the endothelins (ETs; specifically, ET-1). In this review we examine the interactions of ET-1 with astrocytes and provide examples where ET-1 appears to contribute to activation of astrocytes and play a role in the neurodegenerative effects that accompany such reactivation resulting in astrogliosis. These actions are presented in the context of glaucoma although information is also presented with respect to ET-1's role in the central nervous system and brain. While much has been learned with respect to ET-1/astrocyte interactions, there are still a number of questions concerning the potential therapeutic implications of these findings. Hopefully this review will stimulate others to examine this potential.


A single-center retrospective analysis of patency rates of intraluminal versus subintimal endovascular revascularization of long femoropopliteal occlusions.
The evaluation of patency rates of intraluminal versus subintimal endovascular revascularization of long femoropopliteal (FP) lesions. Chronic total occlusions (CTO) of the FP artery in peripheral interventions are crossed either with a support catheter-guidewire based technique or subintimal dissection and re-entry device assisted approach. Both techniques have a high procedural success rate, but their long term patency is not well studied. There is also lack of comparative data addressing the patency of long non-CTO vs. CTO occlusions. We performed a single center retrospective analysis, studying the patency rates in 215 patients (254 limbs) with TASC C and D FP lesions treated with stents. There were 3 patient groups: without CTO (non-CTO); CTO crossed using support catheter and guide-wire (CTO-SW) and CTO crossed with a re-entry device (CTO-RE). There were 155 limbs in CTO-SW group; 50 in CTO-RE group and 49 in non-CTO. Lesion length (mean±SD) was 251.81±7.48mm in CTO-SW group; 280±13.18mm in CTO-RE group and 248.77±13.31 in non-CTO group (p=non-significant). In-stent restenosis (ISR) at a mean follow-up of 19.26±16.14months did not differ between groups occurring in 23 (47%) limbs in non-CTO; 66 (42%) in CTO-SW; and 24 (48%) in CTO-RE. Smoking and stent fracture were predictors of ISR by multivariate analysis. In patients with long FP lesions, ISR rates were similar between patients with and without CTO. In the CTO group mid-term vessel patency was not affected by the crossing technique utilized.


Different adverse effects of air pollutants on dry eye disease: Ozone, PM2.5, and PM10.
To date, there have been no well-organized clinical studies evaluating which air pollutants affect dry eye disease (DED). In this study, we investigated changes in the clinical parameters of DED according to exposure to outdoor air pollutants, including PM2.5 (particulate matter with an aerodynamic diameter of less than 2.5 μm), PM10 (less than 10 μm), and ozone. A prospective observational study was conducted on 43 DED patients who had used the same topical eye drop treatment between 2016 and 2018 in South Korea. Ocular surface discomfort index (OSDI) score, tear film break-up time (TBUT), corneal fluorescein staining score (CFSS), and tear secretion were measured during each visit. Air pollution data of ambient PM10, PM2.5, and ozone, based on the patients' address, were obtained, and mean concentrations were computed for one day, one week, and one month before the examination. The relationships between air pollutants and DED were analyzed in single- and multi-pollutant models adjusted for demographic and clinical factors. In the multi-pollutant model, the OSDI score was positively correlated with ozone and PM2.5 exposure [ozone: β(exposure for 1 day/1 week) = 0.328 (95% CI: 0.161-0.494)/0.494 (0.286-0.702), p < 0.001/<0.001, per 1 ppb increase; PM2.5: β(1 day/1 week) = 0.378 (0.055-0.699)/0.397 (0.092-0.703), p = 0.022/ = 0.011, per 1 μg/m3 increase], and tear secretion decreased with increased ozone exposure [ozone: β(1 week/1 month) = -0.144 (-0.238 to -0.049)/-0.164 (-0.298 to -0.029), p = 0.003/ = 0.017, per 1 ppb increase]. Interestingly, increased PM10 exposure was only associated with decreased TBUT [β(1 day/1 week/1 month) = -0.028(-0.045 to -0.011)/-0.029(-0.046 to -0.012)/-0.023(-0.034 to -0.006), p = 0.001/ = 0.001/ = 0.018, per 1 μg/m3 increase]. Tear secretion and CFSS were not associated with PM10 exposure. Increased ozone and PM2.5 exposure led to aggravated ocular discomfort, and increased PM10 concentration aggravated tear film stability in patients with DED. Thus, each air pollutant may aggravate DED via different mechanisms of action.


Deciphering the Electronic Transitions of Thiophene-Based Donor-Acceptor-Donor Pentameric Ligands Utilized for Multimodal Fluorescence Microscopy of Protein Aggregates.
Anionic pentameric thiophene acetates can be used for fluorescence detection and diagnosis of protein amyloid aggregates. Replacing the central thiophene unit by benzothiadiazole (BTD) or quinoxaline (QX) leads to large emission shifts and basic spectral features have been reported [Chem. Eur. J. 2015, 21, 15133-13137]. Here we present new detailed experimental results of solvent effects, time-resolved fluorescence and examples employing multi-photon microscopy and lifetime imaging. Quantum chemical response calculations elucidate how the introduction of the BTD/QX groups changes the electronic states and emissions. The dramatic red-shift follows an increased conjugation and quinoid character of the π-electrons of the thiophene backbone. An efficient charge transfer in the excited states S1 and S2 compared to the all-thiophene analogue makes these more sensitive to the polarity and quenching by the solvent. Taken together, the results guide in the interpretation of images of stained Alzheimer disease brain sections employing advanced fluorescence microscopy and lifetime imaging, and can aid in optimizing future fluorescent ligand development.


Dietary energy density was associated with diet quality in Brazilian adults and older adults.
Cross-sectional and longitudinal studies present association of low dietary energy density with higher intake of vitamins, minerals and dietary fiber, lower intake of fat, and better balance of macronutrients. The objective of this study was to verify the relationship between dietary energy density and diet quality measured by an index of diet quality. This study used data from 496 adults and 445 older adults of cross-sectional population-based survey from São Paulo conducted in 2008-2009, Brazil. Dietary intake data was assessed by two 24-h dietary recalls. Dietary energy density values were calculated based on foods only method. Dietary energy density and revised Brazilian Health Eating Index and its components, were estimated by usual intake using Multiple Source Method. The relationship between dietary energy density and the total revised Brazilian Health Eating Index and its components were assessed by Gaussian family log-link model for each age group. The analyses showed an inverse association between dietary energy density and total revised Brazilian Health Eating Index in adults (T2:β = 0.96, p < 0.001; T2:β = 0.86, p < 0.001) and older adults (T2:β = 0.96, p < 0.001; T2:β = 0.90, p < 0.001), and an inverse association between dietary energy density and nine of twelve revised Brazilian Health Eating Index components in adult and/or older adults groups. Dietary energy density was associated with diet quality in Brazilian adults and older adults regardless of sex, per capita household income, body mass index, physical activity level, current smoking habits status, alcohol beverage drinking status and usual energy intake (kilocalories) from beverages.


Rate of conversion from mild cognitive impairment to dementia in a Thai hospital-based population: A retrospective cohort.
Mild cognitive impairment (MCI) is the state between normal cognition and dementia. This study objective was to estimate an average 1-year rate of conversion from MCI to dementia and explore the associated factors of conversion in a hospital-based cohort. A retrospective cohort study of participants with MCI was conducted in a tertiary care hospital in Thailand. Two hundred fifty participants, 50 years of age or older, were enrolled. An average 1-year conversion rate from MCI to dementia was 18.4%. MCI patients who converted to dementia were likely older (P < .001), predominantly female (P = .028), vitamin D deficient (P = .012), and associated with lower Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores during first assessments (P < .001, P < .001 respectively) and follow-up assessments (P < .045, P < .001 respectively). We conducted two models of multivariate analysis, using binary logistic regression. In the first model, adjusted for age, sex, education, vitamin D deficiency, and first assessment MMSE scores, we found that underlying vitamin D deficiency (odds ratio [OR] = 3.13, 95% confidence interval [CI] 1.04 to 9.44) and first assessment MMSE scores (OR = 0.83, 95% CI 0.73 to 0.93) were significantly associated with conversion to dementia. In the second model, adjusted for age, sex, education, vitamin D deficiency and first assessment MoCA scores, only first assessment MoCA scores (OR = 0.58, 95% CI 0.45 to 0.76) were significantly associated with conversion to dementia. The 1-year conversion rate from MCI to dementia was 18.4%. MMSE and MoCA were useful tools to assess baseline cognitive status in MCI patients and predict dementia progression. The association between vitamin D deficiency and risk of conversion from MCI to dementia requires further investigations.


Assessing a 12-month course of oral alendronate for adults with avascular necrosis of the hip: MANTIS RCT with internal pilot.
People with avascular necrosis of the hip have very limited treatment options currently available to stop the progression of this disease; this often results in the need for a hip replacement. There is some weak evidence that a class of drugs called bisphosphonates may delay the course of the disease, and this trial was commissioned and set up to provide robust evidence regarding the use of bisphosphonates in adults aged ≥ 18 years with this condition. The aim of the Managing Avascular Necrosis Treatments: an Interventional Study ( MANTIS ) trial was to evaluate the clinical effectiveness and cost-effectiveness of a 12-month course of alendronate in the treatment of avascular necrosis. This was a 66-month, definitive, multisite, two-arm, parallel-group, placebo-controlled, double-blind, randomised controlled trial, with an internal pilot phase. Eight secondary care NHS hospitals across the UK. Planned trial size - 280 adult patients with avascular necrosis. Participants in the intervention group received 70 mg of alendronate (an oral bisphosphonate) weekly for 12 months. The main outcomes were Oxford Hip Score at 12 months (short-term outcome) and the time to decision that a hip replacement is required at 36 months (long-term outcome). Twenty-one patients were recruited and randomised to receive either the intervention drug, alendronate, or a placebo-matched tablet. This trial was principally limited by low disease prevalence. Other limitations included the late disease stage at which participants were identified and the rapid progression of the disease. This trial was limited by a low recruitment rate. Avascular necrosis of the hip should be treated as a rare disease. Future trials would need to recruit many more sites and recruit over a longer time period, and, for this reason, a registry may provide a more effective means of collecting data pertaining to this disease. The MANTIS trial was terminated at the end of the pilot phase, because it did not meet its go/no-go criteria. The main issue was a poor recruitment rate, owing to a lower than expected disease prevalence and difficulties in identifying the condition at a sufficiently early stage. Those patients who were identified and screened either were too advanced in their disease progression or were already taking medication. We would not recommend that a short-term interventional study is conducted on this condition until its prevalence, geographic foci and natural history and better understood. The difficulty of acquiring this understanding is likely to be a barrier in most health-care markets. One means of developing this understanding would be the introduction of a database/registry for patients suffering from avascular necrosis of the hip. The trial is registered as ISRCTN14015902. This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 43. See the NIHR Journals Library website for further project information.


A patient perspective on the barriers to home dialysis.
People with End Stage Renal Disease rarely choose home dialysis therapies even though they can offer a range of Quality-of-Life (QOL) benefits such as improved convenience, mental health well-being, employment, reduced mortality and cost effectiveness. Attempts to increase usage of such self-caring modalities, have met with limited success, in part due to a lack of understanding of patient decision making and patient perceived barriers to such therapies. To explore the patient perspective on the main barriers to a range of self-care or home dialysis therapies, including Continuous Ambulatory Peritoneal Dialysis, Home Haemodialysis and Extended Home Haemodialysis. A longitudinal patient narrative approach is adopted. There are significant barriers to all aspects of informed decision making around home therapies, but many are based on perception. Creating decision aids and education programmes to tackle these perceived barriers, actively encouraging home therapy take up, focusing on QOL in clinical decision making, offering peer support and expanded in-centre self-care treatment options may increase awareness and uptake of self-care therapies.


Classical conditioning in 3-, 30-, and 45-month-old rabbits: behavioral learning and hippocampal unit activity.
Evidence has accumulated to suggest that the hippocampus is impaired by aging processes. Hippocampal multiple unit activity was examined in 3-, 30-, and 45-month-old rabbits during classical conditioning in the trace paradigm. Animals were trained daily with 126 paired trials of tone and airpuff. The 3-month-olds learned to a criterion of 8/9 CR's in a mean of 3.2 days, while the 30-month-olds took a mean of 9.4 days, and the 45-month-olds took a mean of 11.75 days. Neural unit activity in the hippocampus modeled the behavioral eyelid response but took much longer to develop in the older animals. Results suggest that rabbits as young as 2 1/2 years old show behavioral and correlated neural response deficits.


VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding.
Co-expression of NRP1 and (VEGFR-2) KDR on the surface of endothelial cells (EC) enhances VEGF165 binding to KDR and EC chemotaxis in response to VEGF165. Overexpression of NRP1 by prostate tumor cells in vivo results in increased tumor angiogenesis and growth. We investigated the molecular mechanisms underlying NRP1-mediated angiogenesis by analyzing the association of NRP1 and KDR. An intracellular complex containing NRP1 and KDR was immunoprecipitated from EC by anti-NRP1 antibodies only in the presence of VEGF165. In contrast, VEGF121, which does not bind to NRP1, did not support complex formation. Complexes containing VEGF165, NRP1, and KDR were also formed in an intercellular fashion by co-culture of EC expressing KDR only, with cells expressing NRP1 only, for example, breast carcinoma cells. VEGF165 also mediated the binding of a soluble NRP1 dimer to cells expressing KDR only, confirming the formation of such complexes. Furthermore, the formation of complexes containing KDR and NRP1 markedly increased 125I-VEGF165 binding to KDR. Our results suggest that formation of a ternary complex of VEGF165, KDR, and NRP1 potentiates VEGF165 binding to KDR. These complexes are formed on the surface of EC and in a juxtacrine manner via association of tumor cell NRP1 and EC KDR.


Increased arterial stiffness parameters in panic disorder patients in long term treatment period.
The relationship between mental stress and cardiovascular disease has been shown in several studies. Panic disorder (PD) is also associated with cardiovascular disease due to increased risk of myocardial infarction. The aim of this study is to evaluate the association between arterial stiffness parameters and depression/anxiety scores in patients with PD. The study population consisted of 25 patients with PD and 25 age-sex-matched healthy controls. Depression and anxiety levels were evaluated by Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI), respectively. Determination of arterial stiffness parameters was conducted using a Mobil-O-Graph arteriograph system that detected signals from the brachial artery. While baseline characteristics were similar between two groups, BDI and BAI scores were significantly higher in patients with PD (p < 0.005). The pulse wave velocity (PWV) and Augmentation Index (AIx) were also significantly higher in patients with PD (p = 0.001, p = 0.006). There was a moderate correlation between PWV and AIx with BAI scores (r = 0.442, p = 0.001, r = 0.441, p = 0.001). AIx was also positively correlated with BDI scores (r = 0.415, p = 0.03). We demonstrated a significant relationship between arterial stiffness parameters and anxiety/depression scores in patients with PD who receive antidepressant treatment.


Spatially resolved ultra-trace analysis of elements combining resonance ionization with a MALDI-TOF spectrometer.
A combined setup for spatially resolved mass analysis of trace amounts of elements and macromolecules is presented. Using a MALDI-TOF mass spectrometer, a laser spectroscopic setup for resonant ionization of neutral atoms has been implemented. This allows for an efficient and selective detection of trace elements by means of resonance ionization mass spectrometry (RIMS). The instrumental scheme is described, and methodological developments are presented. In a first application pure, laser desorption/ionization with TOF-MS was used to measure mass distributions of cosmic nanodiamonds. For further applications regarding the spatially resolved ultra-trace analysis of elements in solid samples, an implanted target was used to characterize both laser desorption/ionization and laser desorption/resonance ionization for the detection of trace elements within. A perspective of the setup is given and future investigations are outlined.


Postural adjustments preceding rapid arm movements in parkinsonian subjects.
The electromyographic (EMG) responses in postural (thigh and trunk) and agonist (shoulder) muscles were examined in standing parkinsonian subjects and healthy controls prior to visual reaction time and self-paced rapid arm flexion movements. Recruitment of postural muscles typically preceded arm displacement in normals, but was less frequent, of shorter duration, and characterized by multiple EMG bursts which extended to the agonist in parkinsonians. Moreover, parallel delays in EMG recruitment times relative to the visual signal for both postural and agonist muscles were observed in akinetic patients. These abnormalities suggest that the basal ganglia may serve a preparatory motor function, by linking synergistic muscles through a common selection process.


Sulfonamide derivatives of benzylamine block cholesterol biosynthesis in HepG2 cells: a new type of potent squalene epoxidase inhibitors.
Sulfonamide derivatives of ene-yne benzylamine 1 have been prepared and identified as a new class of potent SE inhibitors having demonstrated activity in HepG2 cells as cholesterol biosynthesis inhibitors.


Analysis of colorectal cancer morphology in relation to sex, age, location, and family history.
Studies of colorectal cancer (CRC) have suggested different mechanisms of carcinogenesis in men and women, young and old patients, right- and left sided tumors, and sporadic and familial tumors. These differences might be reflected in morphology. CRCs from 1613 patients operated on in 2004-2006 in Sweden were histologically reviewed. Morphology was examined in relation to sex, age groups, location, and family history. Tumors in the right colon were larger, of higher stage, more often poorly differentiated, more mucin-producing, more often had a peritumoral lymphocytic infiltrate and a high level of tumor-infiltrating lymphocytes (TILs), and more seldom had an infiltrating margin than tumors in the left colon and rectum (p < 0.0001 for most features). Young patients (<60 years) more seldom had multiple tumors but more often had perineural invasion, an infiltrative tumor margin, and high-stage tumors. Three features, TILs, medullary tumors, and invasive tumor margin, were related to sex. Only vascular invasion was related to familiality. Location is the factor that has the most influence on tumor morphology. The results support the idea that different carcinogenic mechanisms may be involved in the right and left colon. Age is the most important determinant for the presence of multiple tumors and is a crucial factor for the aggressiveness of the disease.


Effects of short term fasting on the expression of genes involved in lipid metabolism in chicks.
The aim of this study was to analyze the expression patterns of key genes involved in lipid metabolism in response to short term fasting in chicks (Gallus gallus). The mRNA level of the genes was analyzed after 0, 2, and 4 h of fasting in the liver and white adipose tissue. In the liver, the mRNA level of peroxisome proliferator-activated receptor α was significantly increased after 2 h of fasting. The mRNA levels of carnitine palmitoyltransferase 1a and acyl-CoA oxidase were significantly increased after 4 h of fasting. In contrast, the mRNA levels of sterol regulatory element-binding protein 1, acetyl-CoA carboxylase α, and fatty acid synthase were significantly decreased after 4 h of fasting. The mRNA levels of cholesterol metabolism-related genes such as 3-hydroxy-3-methylglutaryl-CoA reductase and cholesterol 7α-hydroxylase were significantly decreased after 4 h of fasting. In the white adipose tissue, the mRNA level of adipose triglyceride lipase was significantly increased after 4 h of fasting. In contrast, the mRNA levels of peroxisome proliferator-activated receptor γ and lipoprotein lipase were significantly decreased after 4 h of fasting. These results demonstrated that the gene expression of lipid metabolism-related genes is regulated by short term fasting in both the liver and WAT in chicks.


Primary peptide sequences from squid muscle and optic lobe myosin IIs: a strategy to identify an organelle myosin.
The squid giant axon provides an excellent model system for the study of actin-based organelle transport likely to be mediated by myosins, but the identification of these motors has proven to be difficult. Here the authors purified and obtained primary peptide sequence of squid muscle myosin as a first step in a strategy designed to identify myosins in the squid nervous system. Limited digestion yielded fourteen peptides derived from the muscle myosin which possess high amino acid sequence identities to myosin II from scallop (60-95%) and chick pectoralis muscle (31-83%). Antibodies generated to this purified muscle myosin were used to isolate a potential myosin from squid optic lobe which yielded 11 peptide fragments. Sequences from six of these fragments identified this protein as a myosin II. The other five sequences matched myosin II (50-60%, identities), and some also matched unconventional myosins (33-50%). A single band that has a molecular weight similar to the myosin purified from optic lobe copurifies with axoplasmic organelles, and, like the optic lobe myosin, this band is also recognized by the antibodies raised against squid muscle myosin II. Hence, this strategy provides an approach to the identification of a myosin associated with motile axoplasmic organelles.


Thirty-month outcome after fractional flow reserve-guided versus conventional multivessel percutaneous coronary intervention.
We investigated the value of fractional flow reserve (FFR)-guided percutaneous coronary intervention (FFR-PCI) versus conventional PCI in patients with multivessel disease (MVD). Conventional PCI is performed by visual estimation of the stenosis. Deferral of PCI because of a FFR >or=0.75 is associated with low event rates. However, the value of FFR-PCI in patients with MVD is unknown. We prospectively enrolled 137 patients (312 vessels) with MVD to compare FFR-PCI and conventional PCI. In the FFR-PCI group, FFR of all vessels was performed, and PCI of stenoses with a FFR <0.75 was performed. In the conventional PCI group, patients underwent multivessel PCI by visual estimation of the stenoses. Procedural characteristics, event rates, and cost were compared between the 2 groups. In the FFR-PCI group, after FFR analysis in 57 patients (128 vessels), PCI was performed in 48 patients (53 vessels). In the conventional PCI group, 80 patients (184 vessels) underwent PCI. The average number of vessels per patient that underwent PCI and the cost of procedure were significantly greater in the conventional PCI group than in the FFR-PCI group (2.27 +/- 0.50 vs 1.12 +/- 0.30 vessels and 3,167 dollars +/- 1,194 dollars vs 2,572 dollars +/- 934 dollars, respectively; p <0.001). The 30-month Kaplan-Meier event-free survival estimate was significantly higher in the FFR-PCI group than in the conventional PCI group (89% vs 59%, p <0.01). In conclusion, the results of the present study have demonstrated that in patients with MVD, compared with conventional PCI, FFR-PCI significantly reduces the number of vessels undergoing PCI, the event rate, and the cost of the procedure.


Splenic marginal zone B cells in humans: where do they mutate their Ig receptor?
Human IgM+ IgD+ CD27+ B cells have mutated Ig genes and harbor a splenic marginal zone (MZ) phenotype. In this issue, the group of R. Küppers has studied the expression of the enzyme activation-induced cytidine deaminase (AID) in human spleen samples by immunocytochemistry and failed to detect a significant AID-expressing subset in the MZ region. The consequences on the possible origin of these cells are discussed.


Estrogen regulation of agonistic and proceptive responses in the golden hamster.
The role of estrogen in modulation of agonistic (attack-chase) and proceptive (vaginal-marking) responses of the female hamster toward a male was examined in relation to time course of induction and duration of response. In addition, the sex-specific nature of the vaginal-marking response was examined. Cycling females showed a significantly higher frequency of attack-chase when endogenous estrogen levels were minimal in comparison to that at peak estrogen levels during the estrous cycle. Removal of estrogen (ovariectomy) resulted in a significant increase in attack-chase scores compared to high endogenous estrogen. Addition of exogenous estrogen (Silastic capsule) resulted in a significant decrease in attack-chase scores compared to ovariectomized animals. The inverse effect was found for vaginal marking with the lowest frequency of vaginal marking at low endogenous estrogen levels or following ovariectomy. During high endogenous estrogen levels or following treatment with exogenous estrogen vaginal-marking scores were maximal. Maximal induction of vaginal-marking responses and reduction of attack-chase were found between 6 and 48 hr of estrogen treatment. Both behaviors then returned to the prehormonal treatment level. Failure to detect effects beyond 48 hr was not due to repeated testing, as animals lacking hormone, or animals first tested at 96 hr of estrogen exposure, showed no effect of the treatment. Males gonadectomized as adults never showed vaginal marking, whereas males gonadectomized neonatally showed a low level of vaginal marking which was increased significantly following estrogen treatment. Thus both attack-chase and vaginal marking in the presence of a male are modulated by estrogen. Further, since vaginal marking is estrogen sensitive in the neonatally gonadectomized male, expression of vaginal marking is determined by the hormonal environment during the neonatal period. However, peripheral feedback may be important for frequency of occurrence.


Synthesis, electronic properties and electropolymerisation of EDOT-capped sigma3-phospholes.
EDOT-capped sigma3-phosphole self-rigidifies due to an unprecedented P-O interaction and can be electropolymerised affording functionalizable polymers.


Does body mass index at diagnosis or weight change during therapy predict toxicity or survival in intermediate risk rhabdomyosarcoma? A report from the Children's Oncology Group Soft Tissue Sarcoma Committee.
Weight loss prevalence and its impact on toxicities and survival in intermediate risk rhabdomyosarcoma (IRMS) patients are unknown. We evaluated the association between weight change during therapy and number of toxicities, hospital days, infections, and overall survival and between baseline body mass index (BMI) and survival in patients treated on Children's Oncology Group trial D9803. Four hundred sixty-eight IRMS patients age ≥2 and <21 years treated on D9803 had required data. Regression models evaluated association between weight loss from baseline and toxicities, hospital days, infections, and survival. Kaplan-Meier curves and regression models evaluated baseline BMI percentile's association with survival. Thirty-five percent and 37% of patients had >5% weight loss at 12 and 24 weeks, respectively, with 16% and 19% losing >10% weight respectively. Greater than 10% weight loss at 24 weeks was associated with more toxicities and hospital days during subsequent therapy but not infection rate or survival. Baseline underweight patients (<5th percentile BMI) had borderline inferior survival compared with baseline average weight patients while there was no difference in survival seen between average weight and overweight or obese patients. Nearly one in five IRMS patients experienced >10% weight loss on therapy. This was associated with increased toxicity but not decreased survival compared with patients who had less weight loss. Baseline BMI percentile trended toward a significant association with survival. Future studies might investigate nutritional impact on quality of life and if weight loss is preventable by early nutritional intervention.


Subperineurial space of the sural nerve in various peripheral nerve diseases.
The size of the subperineurial space of the sural nerve has been evaluated quantitatively in 69 cases of various peripheral nerve diseases and in controls. A significant increase was found in beriberi neuropathy (6 cases) and idiopathic polyradiculoneuropathy (9 cases) as compared with the control (8 cases). On electron microscopy a few macrophages, fibroblast processes, collagen fibrils with a diameter of 50 nm, microfibrils with a diameter of 8 nm, and amorphous material were observed in both the enlarged subperineural space and the endoneurial intercellular space. They were less frequently observed in controls. No significant correlation was found between the size of subperineurial space and the density of myelinated fibers.


Moms in Proteomics: building a supportive and unified community together.
There is a growing need to recognize, support, and promote diversity within scientific disciplines. Moms in Proteomics was founded to connect mothers in proteomics, a field exemplifying the constituent elements of science, technology, engineering, and math (STEM) from academia to industry, share stories of successes and challenges, and build a community of mothers in highly productive and influential careers.


Soluble neural cell adhesion molecule in brain, cerebrospinal fluid and plasma in the developing rat.
Neural cell adhesion molecule (NCAM) is a glycoprotein found in neurons, glial cells and muscle cells. In this report we describe the polypeptide composition and amount of soluble NCAM in brain, cerebrospinal fluid (CSF) and plasma in rats of various ages. One-two percent of total NCAM in rat brain was shown to be buffer-soluble. Soluble NCAM in brain, extracted at pH 7.2, constituted an increasing relative proportion of total NCAM during development, whereas the concentration of soluble NCAM in both CSF and plasma decreased in the same period. By radioiodination of brain extracts, CSF, and plasma, soluble NCAM was found to be composed of up to five polypeptides with molecular weights (Mr) of 200,000, 170,000, 150,000, 115,000 and 80,000. The relative composition did not vary significantly with age. The major forms in brain were the polypeptides with Mr of 200,000 and 115,000, whereas in CSF all forms seemed to appear in equal amounts. In plasma the 200,000 and the 170,000 Mr polypeptides were not observed and here the major forms were the 150,000 and 115,000 Mr polypeptides.


Low-loss hollow-core silica/air photonic bandgap fibre.
Photonic bandgap structures use the principle of interference to reflect radiation. Reflection from photonic bandgap structures has been demonstrated in one, two and three dimensions and various applications have been proposed. Early work in hollow-core photonic bandgap fibre technology used a hexagonal structure surrounding the air core; this fibre was the first demonstration of light guided inside an air core of a photonic bandgap fibre. The potential benefits of guiding light in air derive from lower Rayleigh scattering, lower nonlinearity and lower transmission loss compared to conventional waveguides. In addition, these fibres offer a new platform for studying nonlinear optics in gases. Owing largely to challenges in fabrication, the early air-core fibres were only available in short lengths, and so systematic studies of loss were not possible. More recently, longer lengths of fibre have become available with reported losses of 1,000 dB km(-1). We report here the fabrication and characterization of long lengths of low attenuation photonic bandgap fibre. Attenuation of less than 30 dB km(-1) over a wide transmission window is observed with minimum loss of 13 dB km(-1) at 1,500 nm, measured on 100 m of fibre. Coupling between surface and core modes of the structure is identified as an important contributor to transmission loss in hollow-core photonic bandgap fibres.


Improved accuracy and reproducibility of spontaneous liposome leakage measurements by the use of supported lipid bilayer-modified quartz cuvettes.
Recent studies have revealed avid interactions between liposomes and several solid materials, such as quartz, polystyrene (PS) and poly(methyl methacrylate) (PMMA), commonly found in cuvettes used for spectroscopic measurements. These interactions risk leading to detrimental changes in liposome structure and integrity that, if overlooked, may compromise the measurements. In case of leakage experiments based on probing the spontaneous release of encapsulated hydrophilic markers, the liposome-cuvette interactions may result in the recording of erroneously high degrees of leakage. In the present study we investigate the possibilities of preventing unwanted liposome-cuvette interactions through the use of quartz cuvettes passivated with supported lipid bilayers (SLBs). The results show that this strategy leads to higher reproducibility and significantly improved accuracy of the leakage measurements. The usefulness of the method is validated in comparative experiments focused on how changes in temperature and lipid phase state, as well as inclusion of poly(ethylene glycol)-conjugated lipids (PEG-lipids), affect the release of liposome encapsulated carboxyfluorescein (CF).


Quarantine and COVID-19 pandemic: Multidimensional perception of people in quarantine in North Kerala.
Proper hand hygiene, face masks, social distancing, maintaining appropriate social distancing, and quarantine are the major strategies for the prevention of transmission of coronavirus disease (COVID-19) infection. The aim of the study was to determine and asses the knowledge, perceptions, health practices of quarantine and COVID-19 and to determine the psychosocial profile of people in quarantine. A descriptive cross-sectional study was done in quarantined individuals in a rural and urban setting in Malappuram district of Kerala from February 2021 to June 2021 by telephonic interview. Mental health status was assessed by Patient Health Questionnaire 9. Only half (49.6%) of the population has satisfactory knowledge about COVID-19 disease. Only 53.9% has satisfactory knowledge on preventive measures and this is significantly more in rural (62.9%) compared to urban (44.4%). Only 45.3% has satisfactory adherence on practice of preventive measures. Also nearly half (44.9%) of the participants were affected by factors such as fear of infection, frustration, inadequate supplies, inadequate communication and financial insecurity. Urban population (53.2%) were more affected compared to rural (37.1%). 31.6% of the participants were having any form of depression with PHQ 9. Pearson's correlation test revealed significant correlations between different factors and outcome variables. Predictors of 'Satisfactory Practice on preventive measures' and 'Any depression' were determined. Only half of the population has satisfactory knowledge and practice on preventive measures. Ensure health intervention programs to improve knowledge and adherence to practices. Strengthening of system to support their needs and psychosocial support should be provided.


Implications of the Hiroshima-Nagasaki genetic studies for the estimation of the human "doubling dose" of radiation.
Since 1946 a continuous effort to evaluate the potential genetic effects of the atomic bombs has been sustained. Observations on children born in Hiroshima and Nagasaki include sex ratio, congenital malformations, stillbirths, survival of liveborn infants, chromosomal abnormalities (sex chromosomal abnormalities and balanced chromosomal rearrangements), mutations altering protein structure or activity, and physical growth and development. There are no statistically significant differences between the children of parents who received increased amounts of radiation at the time of the bombings and those whose parents did not. However, the difference between the two sets of children is consistent with the hypothesis of a genetic effect of the exposure, but its magnitude suggests humans are not as sensitive to the genetic effects of radiation as projected from the mouse paradigm.


Cumulative human health risk analysis of trihalomethanes exposure in drinking water systems.
Chlorinated compounds on reaction with natural organic substances present in water leads to the formation of trihalomethanes (THMs), a major type of disinfection by-products (DBPs). Trihalomethanes (THMs) are the most widely investigated DBPs in drinking water systems because of their carcinogenic potential and subsequent adverse effects on human health. This study investigated the effect of gastro-intestinal absorption factor on human health risk assessment. Monitoring and analysis of water quality parameters and THMs levels in drinking water treatment plants revealed that the average values (306.5 μg/L) exceeded the recommended US EPA guidelines of 80 μg/L. Spearman rank (rho) correlation coefficient indicated that dissolved organic carbon is the major parameter influencing THMs formation. Monte Carlo simulations base risk assessment study was conducted for three different exposure pathways. The observed human health risk exposure effects due to THMs were below the recommended USEPA level (1.0 × 10-6) for both the drinking water treatment plants. Seasonal disparity on risk estimation analysis revealed higher risk in summer season followed by autumn which is principally due to high concentration of THMs in summers.


Control of mitochondrial integrity by Bcl-2 family members and caspase-independent cell death.
Programmed cell death (PCD) is essential for normal development and maintenance of tissue homeostasis in multicellular organisms. While it is now evident that PCD can take many different forms, apoptosis is probably the most well-defined cell death programme. The characteristic morphological and biochemical features associated with this highly regulated form of cell death have until recently been exclusively attributed to the caspase family of cysteine proteases. As a result, many investigators affiliate apoptosis with its pivotal execution system, i.e. caspase activation. However, it is becoming increasingly clear that PCD or apoptosis can also proceed in a caspase-independent manner and maintain key characteristics of apoptosis. Mitochondrial integrity is central to both caspase-dependent and-independent cell death. The release of pro-apoptotic factors from the mitochondrial intermembrane space is a key event in a cell's commitment to die and is under the tight regulation of the Bcl-2 family. However, the underlying mechanisms governing the efflux of these pro-death molecules are largely unknown. This review will focus on the regulation of mitochondrial integrity by Bcl-2 family members with particular attention to the controlled release of factors involved in caspase-independent cell death.


Observational study of potential risk factors of immersion pulmonary edema in healthy divers: exercise intensity is the main contributor.
The risk factors of pulmonary edema induced by diving in healthy subjects are not well known. The aim of the present study was to assess the parameters contributing to the increase in extravascular lung water after diving. This study was carried out in a professional diving institute. All divers participating in the teaching program from June 2012 to June 2014 were included in the study. Extravascular lung water was assessed using the detection of ultrasound lung comets (ULC) by chest ultrasonography. Clinical parameters and dive profiles were recorded using a questionnaire and a dive computer. One-hundred six divers were investigated after 263 dives. They used an open-circuit umbilical supplying compressed gas diving apparatus in 202 cases and a self-contained underwater breathing apparatus in 61 cases. A generalized linear mixed model analysis was performed which demonstrated that the dive induced a significant increase in ULC score (incidence rate ratio: 3.16). It also identified that the predictive variable of increased extravascular lung water after the dive was the exercise intensity at depth (z = 3.99, p < 0.0001). The other parameters studied such as the water temperature, dive profile, hyperoxic exposure, or anthropometric data were not associated with the increase in extravascular lung water after the dive. In this study, the exercise intensity was the main contributor to the increase in extravascular lung water in healthy divers. To improve the prevention of immersion pulmonary edema, the exercise intensity experienced during the dive should thus be adapted to the aerobic fitness level of the divers.


Characterization and chemical reactivity of room-temperature-stable MnIII-alkylperoxo complexes.
While alkylperoxomanganese(iii) (MnIII-OOR) intermediates are proposed in the catalytic cycles of several manganese-dependent enzymes, their characterization has proven to be a challenge due to their inherent thermal instability. Fundamental understanding of the structural and electronic properties of these important intermediates is limited to a series of complexes with thiolate-containing N4S- ligands. These well-characterized complexes are metastable yet unreactive in the direct oxidation of organic substrates. Because the stability and reactivity of MnIII-OOR complexes are likely to be highly dependent on their local coordination environment, we have generated two new MnIII-OOR complexes using a new amide-containing N5 - ligand. Using the 2-(bis((6-methylpyridin-2-yl)methyl)amino)-N-(quinolin-8-yl)acetamide (H6Medpaq) ligand, we generated the [MnIII(OO t Bu)(6Medpaq)]OTf and [MnIII(OOCm)(6Medpaq)]OTf complexes through reaction of their MnII or MnIII precursors with t BuOOH and CmOOH, respectively. Both of the new MnIII-OOR complexes are stable at room-temperature (t 1/2 = 5 and 8 days, respectively, at 298 K in CH3CN) and capable of reacting directly with phosphine substrates. The stability of these MnIII-OOR adducts render them amenable for detailed characterization, including by X-ray crystallography for [MnIII(OOCm)(6Medpaq)]OTf. Thermal decomposition studies support a decay pathway of the MnIII-OOR complexes by O-O bond homolysis. In contrast, direct reaction of [MnIII(OOCm)(6Medpaq)]+ with PPh3 provided evidence of heterolytic cleavage of the O-O bond. These studies reveal that both the stability and chemical reactivity of MnIII-OOR complexes can be tuned by the local coordination sphere.


[Significance of microsatellite instability in early gastric cancer treated by endoscopic submucosal dissection].
Microsatellite instability (MSI) is defined as a change of any length due to either insertion or deletion of repeating units, in a microsatellite within a tumor when compared to normal tissue. MSI is closely related with genetic instability, particularly in hereditary nonpolyposis colorectal cancer. MSI is found in 10-50% of all gastric cancers, suggesting that MSI may play an important role in carcinogenesis. The aim of this study was to investigate the relationship between microsatellite instability and clinicopathologic features in early gastric cancers (EGCs) treated by endoscopic submucosal dissection (ESD). We analyzed clinicopathological features of 95 specimens of EGCs including MSI, histologic type, mucin phenotype, p53, VEGF, location of cancer, depth of invasion, incidence of synchronous and metachronous cancer, age, and gender derived from 94 patients, treated by ESD during recent 19 months were analyzed in this study. According to microsatellite stability, MSI was observed in 13 (13.7%) cases of 95 specimens. The incidence of MSI was increased in patients with cancer at lower part of stomach and female gender. There was no significant relation between MSI and clinicopathologic features including histologic type, mucin phenotype, p53, VEGF, and depth of invasion. Our results demonstrate that there is no relationship between MSI and clinicopathologic features except tumor location and gender in ECGs treated by ESD. However, further studies are needed to evaluate the significance of MSI in EGCs.


False start: cotranslational protein ubiquitination and cytosolic protein quality control.
Maintaining proteostasis is crucial to cells given the toxic potential of misfolded proteins and aggregates. To this end, cells rely on a number of quality control pathways that survey proteins both during, as well as after synthesis to prevent protein aggregation, promote protein folding, and to target terminally misfolded proteins for degradation. In eukaryotes, the ubiquitin proteasome system plays a critical role in protein quality control by selectively targeting proteins for degradation. Recent studies have added to our understanding of cytosolic protein quality control, particularly in the area of cotranslational protein ubiquitination, and suggest that overlap exists across co- and post-translational protein quality control networks. Here, we review recent advances made in the area of cytoplasmic protein quality control with an emphasis on the pathways involved in cotranslational degradation of eukaryotic cytosolic proteins. Protein homeostasis, or proteostasis, encompasses the systems required by the cell for the generation and maintenance of the correct levels, conformational state, distribution, and degradation of its proteome. One of the challenges faced by the cell in maintaining proteostasis is the presence of misfolded proteins. Cells therefore have a number of protein quality control pathways to aid in folding or mediate the degradation of misfolded proteins. The ubiquitin proteasome system in particular plays a critical role in protein quality control by selectively targeting proteins for degradation. Nascent polypeptides can be ubiquitinated cotranslationally, however to what extent and how this is used by the cell as a quality control mechanism has, until recently, remained relatively unclear. The picture now emerging is one of two quality control networks: one that recognizes nascent polypeptides on stalled ribosomes and another that targets actively translating polypeptides that misfold, failing to attain their native conformation. These studies underscore the important balance between cotranslational protein folding and degradation in the maintenance of protein homeostasis. In this review we summarize recent advances made in the area of cytoplasmic protein quality control with an emphasis on pathways involved in cotranslational degradation of eukaryotic cytosolic proteins. This article is part of a Special Issue entitled: Can Proteomics Fill the Gap Between Genomics and Phenotypes?


Analysis of the Polycomb-related lncRNAs HOTAIR and ANRIL in bladder cancer.
Long non-coding RNAs (lncRNAs) have been claimed as key molecular players in gene expression regulation, being involved in diverse epigenetic processes. They are aberrantly expressed in various tumors, but their exact role in bladder cancer is still obscure. We have recently found a major role of the Polycomb repression complex in recurrence of non-muscle-invasive bladder cancer. Here, we report the xpression of Polycomb-related lncRNAs:antisense noncoding RNA in the INK4 locus (ANRIL) and HOX antisense intergenic RNA (HOTAIR) in these tumors. We studied a dataset of non-invasive bladder cancer samples by quantitative reverse transcription PCR (RT-qPCR) and analyzed also invasive bladder cancer samples using TCGA data. Our results showed that, while ANRIL seemed not to have a determining role, an increased HOTAIR expression appeared in recurrent and high-graded tumors associated with poor prognosis. In addition, through genome-wide transcriptome analyses, we observed that HOTAIR-EZH2-complex-regulated genes can efficiently discriminate between non-tumoral, recurrent, and non-recurrent bladder cancer samples. We also observed a significant correlation between EZH2 and HOTAIR expression levels. Using overexpression, knockdown, and pharmacological approaches in bladder cancer cell lines, we also observed that EZH2 regulates HOTAIR expression. Our findings indicate that HOTAIR expression has prognostic value for bladder cancer progression, recurrence, and survival and suggest that HOTAIR plays active roles in modulating the cancer epigenome, becoming an interesting candidate as a target for cancer diagnosis and therapy. The observed HOTAIR regulation by EZH2 and the possibility of modulating EZH2 activity with specific inhibitors open new possible paths to be explored in bladder cancer therapy.


Evidences for viral strain selection in late stages of HIV infection: an analysis of Vpu alleles.
One of the most studied topics about AIDS disease is the presence of different progression levels in patients infected by HIV. Several studies have shown that this progression is directly associated with host genetics, although viral factors are also known to play a role. Here we explore the contribution of Vpu protein in the evolution of viral population. The sequence variation of Vpu was analyzed during HIV infection in peripheral blood monocyte cells of 12 patients in different clinical stages of HIV-1 infection early and late stages of infections, separated by at least 4 years. The clustering analysis of Vpu sequences showed higher diversity of early alleles, non-random distribution of sequences, and viral evolution strains selection. Forty-two amino acid modifications were found in the multiple alignments of the 57 different alleles found for early stage were 23 modifications were found in the late stage dataset. Interestingly fourteen alteration of early stage were located in conserved site related with Vpu functions alterations while these alterations appear with less frequency in the late stage of infection. Moreover, late stage alleles tend to be similar with the Vpu wild type sequence, suggesting viral selection toward populations harboring more efficient variants during the course of infection. This would contribute to higher infectivity and viral replication actually observed at the aggressive late stages of infection. These data, in conjunction with in vitro experiments, will be important to elucidation of the physiological relevance of Vpu protein in the pathogenic mechanisms of AIDS.


Susceptibility to RPR 106,972, quinupristin/dalfopristin and erythromycin among recent clinical isolates of enterococci, staphylococci and streptococci from North American medical centres.
An orally administered streptogramin (RPR 106,972) and a parenteral streptogramin (quinupristin/dalfopristin) were evaluated against a collection of 2481 recent clinical isolates of gram-positive cocci. The isolates were gathered from ten North American medical centres during the winter months of 1996-1997. In spite of minor differences, both streptogramins had essentially identical spectra of activity which included many erythromycin-resistant isolates. Previously proposed interpretative criteria for quinupristin/dalfopristin disc diffusion susceptibility tests were confirmed.


ConCreT, a 2D convolutional neural network for taxonomic classification applied to viruses in the phylum Cressdnaviricota.
Taxonomic assignments allow scientists to communicate better with each other. In virology, taxonomy is continually improving towards a more precise and comprehensive framework. With the huge numbers of new viruses being described in metagenomic studies, automated taxonomy tools are urgently needed. A number of such tools have been proposed, and those applying machine learning (ML), mainly in the deep learning branch, stand out with accurate results. Still, there is a demand for tools that are less computationally intensive and that can classify viruses down to the ranks of genus and species. Cressdnaviruses are good subjects for testing such tools, due to their small, circular genomes and the existence of several families and genera with a highly imbalanced number of species. We developed a 2D convolutional neural network for virus taxonomy and tested it for classification of viruses from the phylum Cressdnaviricota. We obtained >98 % accuracy in the final pipeline tested, which we named ConCreT (Convolutional Neural Network for Cressdnavirus Taxonomy). The mixture of augmentation for more imbalanced groups with no augmentation for more balanced ones achieved the best score in the final test.


Survivin expression increases during aging and enhances the resistance of aged human fibroblasts to genotoxic stress.
Survivin, an important anti-apoptotic protein, is highly expressed in most cancers, which generally arise in cells of older individuals. We have shown here accumulation of survivin and phospho-survivin in aged normal human skin fibroblasts and mice organs. This age-related accumulation of survivin was due to protein stabilization through association with the molecular chaperone Hsp90 protein, which was also up-regulated during aging. Interestingly, Hsp90 binds preferentially to phospho-survivin, which explains its higher stability. In addition, we provide clear evidence that aged cells exhibit apoptosis resistance when challenged with UV light, cisplatin, γ-rays or H2O2 as compared to their younger counterparts. In response to γ-rays and H2O2, the levels of Bcl-2 and both forms of survivin were up-regulated in old cells, but not in their corresponding young ones. This repression of survivin and phospho-survivin in young cells is p53 dependent. Importantly, survivin inhibition/down-regulation with flavopiridol or specific shRNAs increased the apoptotic response of old fibroblasts to various genotoxic agents, and restored the pro-apoptotic Bax/Bcl2 ratio and the increase in the levels of cleaved caspase-3 and PARP in old cells. These results show the role of survivin in the age-dependent resistance of human fibroblasts, and provide new insights into the molecular mechanisms that underlie the complex relationship between aging, apoptosis, and cancer.


Executive function, approach sensitivity, and emotional decision making as influences on risk behaviors in young adults.
Relations among executive function, behavioral approach sensitivity, emotional decision making, and risk behaviors (alcohol use, drug use, and delinquent behavior) were examined in single female college students (N = 72). Hierarchical multiple regressions indicated a significant Approach Sensitivity x Working Memory interaction in which higher levels of alcohol use were associated with the combination of greater approach tendency and better working memory. This Approach Sensitivity x Working Memory interaction was also marginally significant for drug use and delinquency. Poor emotional decision making, as measured by a gambling task, was also associated with higher levels of alcohol use, but only for individuals low in inhibitory control. Findings point to the complexity of relations among aspects of self-regulation and personality and provide much needed data on neuropsychological correlates of risk behaviors in a nonclinical population.


The classification of delusional disorders.
Recognition of a delusion in a psychiatric illness places that illness in the broad category of psychotic disorders. The form and content of the delusion are, in themselves, however, insufficient to make a detailed diagnosis, and it is the context of the delusion within a particular disorder that is more pathognomonic. Among the large number of illnesses whose symptoms include delusions, there is a discrete group known as the delusional disorders. After many years of neglect, these are becoming of considerable interest to psychiatrists, and research to define their characteristics is on the rise. This article attempts to describe these illnesses, to indicate where possible their relationships to other psychiatric disorders, and to suggest promising areas of investigation.


Misincorporation of amino acid analogues into proteins by biosynthesis.
Despite astounding diversity in their structure and function, proteins are constructed from 22 protein or 'canonical' amino acids. Hundreds of amino acid analogues exist; many occur naturally in plants, some are synthetically produced or can be produced in vivo by oxidation of amino acid side-chains. Certain structural analogues of the protein amino acids can escape detection by the cellular machinery for protein synthesis and become misincorporated into the growing polypeptide chain of proteins to generate non-native proteins. In this review we seek to provide a comprehensive overview of the current knowledge on the biosynthetic incorporation of amino acid analogues into proteins by mammalian cells. We highlight factors influencing their incorporation and how the non-native proteins generated can alter cell function. We examine the ability of amino acid analogues, representing those commonly found in damaged proteins in pathological tissues, to be misincorporated into proteins by cells in vitro, providing us with a useful tool in the laboratory to generate modified proteins representing those present in a wide-range of pathologies. We also discuss the evidence for amino acid analogue incorporation in vivo and its association with autoimmune symptoms. We confine the review to studies in which the synthetic machinery of cell has not been modified to accept non-protein amino acids.


Dynamical correlation length and relaxation processes in a glass former.
We investigate the relaxation process and the dynamical heterogeneities of the kinetically constrained Kob-Andersen lattice glass model and show that these are characterized by different time scales. The dynamics is well described within the diffusing defect paradigm, which suggests that we relate the relaxation process to a reverse-percolation transition. This allows for a geometrical interpretation of the relaxation process and of the different time scales.


Successful treatment of a child with Schwartz-Jampel syndrome using rapid maxillary expansion and CPAP.
We reported an 8-year-old male patient with Schwartz-Jampel syndrome, severe obstructive sleep apnea, constricted maxilla and moderate tonsillar hypertrophy. The syndrome is characterized by myotonia, skeletal dysplasia, and facial dysmorphism. CPAP was initially prescribed, but he was not able to tolerate due to a high pressure setting. Rapid maxillary expansion alone reduced AHI to 10.4 events/h. When combined with CPAP, AHI is further reduced to 2.4 events/h. The patient has a better compliance with CPAP following rapid maxillary expansion therapy as the pressure setting decreased. This is the first report utilizing a combination of rapid maxillary expansion and CPAP therapy to successfully treat severe pediatric OSA.