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Clinical and Developmental Immunology
Volume 2012 (2012), Article ID 831090, 7 pages
Impact of Temozolomide on Immune Response during Malignant Glioma Chemotherapy
1Brain Tumor Laboratory, Roger Williams Medical Center, 825 Chalkstone Avenue, Prior 222, Providence, RI 02908, USA
2Department of Neurological Surgery, Boston University School of Medicine, Boston, MA 02118, USA
Received 11 July 2012; Revised 10 September 2012; Accepted 20 September 2012
Academic Editor: Steven Eric Finkelstein
Copyright © 2012 Sadhak Sengupta et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Malignant glioma, or glioblastoma, is the most common and lethal form of brain tumor with a median survival time of 15 months. The established therapeutic regimen includes a tripartite therapy of surgical resection followed by radiation and temozolomide (TMZ) chemotherapy, concurrently with radiation and then as an adjuvant. TMZ, a DNA alkylating agent, is the most successful antiglioma drug and has added several months to the life expectancy of malignant glioma patients. However, TMZ is also responsible for inducing lymphopenia and myelosuppression in malignant glioma patients undergoing chemotherapy. Although TMZ-induced lymphopenia has been attributed to facilitate antitumor vaccination studies by inducing passive immune response, in general lymphopenic conditions have been associated with poor immune surveillance leading to opportunistic infections in glioma patients, as well as disrupting active antiglioma immune response by depleting both T and NK cells. Deletion of O6-methylguanine-DNA-methyltransferase (MGMT) activity, a DNA repair enzyme, by temozolomide has been determined to be the cause of lymphopenia. Drug-resistant mutation of the MGMT protein has been shown to render chemoprotection against TMZ. The immune modulating role of TMZ during glioma chemotherapy and possible mechanisms to establish a strong TMZ-resistant immune response have been discussed.
1. Introduction
Glioblastoma, or malignant glioma (MG), is the most aggressive adult brain cancer and accounts for more than 50% of all glioma cases diagnosed [1]. Despite research efforts, the average lifespan for a MG patient postdiagnosis is 14.6 months with most patients experiencing tumor relapse and outgrowth within 7 months of initial radiation therapy [2–4]. For these reasons, MG care remains largely palliative. Brain tumors constitute a unique class of tumors among the most difficult to treat because they are anatomically shielded by the blood-brain barrier, lack a lymphatic drainage system, and grow in a strongly immunosuppressive environment due mainly to tumor infiltration by regulatory T cells (Tregs) marked with the rapid proliferation of tumor cells [5–8].
The overall prognosis of MG has increased only slightly over the past 30 years. High-grade glioma outcome is generally dependent on factors such as age, histology, and extent of surgical resection. Other predictors of survival tend to be the tumor size and proliferation index overexpression [9, 10]. Current treatment options include surgery, radiation, and chemotherapy [11]. Surgery combined with radiotherapy and chemotherapy has proven to prolong patient survival [2, 12]. However, patients diagnosed with MG who are treated with traditional therapeutic methods often experience harmful side effects like loss of cognitive process from surgery, inflammatory responses from chemotherapy or even induction of secondary cancers from radiation therapy [13]. Temozolomide (TMZ), an oral alkylating chemotherapeutic agent, is now a part of postresection standard chemotherapy for MG treatment [14]. Although, radiotherapy followed by concomitant and adjuvant TMZ therapy showed promising results in patient survival [2], recent studies indicate a rather disconcerting outcome. Over 40% of patients undergoing chemotherapy and 55% of newly diagnosed cases do not benefit at all from TMZ therapy [15, 16]. Further, a limitation in the established treatment protocol is the tumor's location within the brain [5, 17]. As a result, novel strategies are continually being tested to improve patient survival, quality of life, and overall outcomes. Targeted immunotherapy has received a great deal of interest in recent years [5, 18]. Its appeal is in being able to utilize a tumor-specific cytotoxic agent that preferentially targets tumor cells, without causing damage to the surrounding brain tissue.
However, active immunotherapy in glioma patients faces a major roadblock when it is ready to be used for translational therapeutic purposes due to TMZ-induced lymphopenia [19, 20]. TMZ, like other chemotherapeutic drugs, comes with its own side effects that include moderate to severe lymphopenia or abnormally low levels of white blood cells. In this paper, we will discuss the role of TMZ during glioma chemotherapy and possible remedies to mitigate TMZ-induced lymphopenia during active MG immunotherapy.
2. Temozolomide
To date, the most widely used and effective chemotherapeutic drug for glioblastoma patients is temozolomide (TMZ). TMZ is a prodrug of the alkylating agent 5-(3 methyltriazen-1-yl) imidazole-4-carboximide (MTIC) [21]. Upon administration, TMZ spontaneously hydrolyzes at physiological pH to the active metabolite (MTIC). MTIC is then further hydrolyzed to the active methylating species, methylhydrazine [15, 22]. TMZ exerts its antitumor effects by methylating guanine at the N7 (70% of adducts) and O6 (5% of adducts) positions and adenine at the N3 position (9% of adducts) [22–24]. These adducts create DNA damage in tumor cells that result in apoptosis and cytotoxicity [25]. The base-excision repair mechanism repairs the N7 guanine and N3 adenine adducts; however, TMZ preferentially targets the middle guanine residue of GGG DNA sequences, which produces O6-methyl-guanine (O6MeG), the most potent killing adduct [26]. O6MeG preferentially pairs with thymine and leads to GC-AT transitions, beginning a cycle of DNA mismatch repair that leads to DNA double-stranded breaks and, ultimately, apoptosis of tumor cells [23].
A 2005 study by the European Organization for the Research and Treatment of Cancer and the National Cancer Institute of Canada Clinical Trials Group (EORTC/NCIC) launched TMZ as the new standard of care for MG when a significant improvement was demonstrated in both overall median survival (12.1 months in the standard radiotherapy cohort versus 14.6 months in the TMZ-treated cohort) and 2-year survival (10% versus 27%) [2]. These findings refuted long-held reservations regarding the widespread use and safety of TMZ. TMZ is currently licensed by FDA (in USA) and EMA (in EU) to treat MG concurrently with radiation, followed by an adjuvant maintenance period of TMZ treatment [19]. It is also licensed as a therapy for refractory anaplastic astrocytoma (in USA) as well as recurrent MG (in EU) and is approved for use in metastatic melanoma patients in over 20 countries [19]. A major benefit of TMZ is its ability to penetrate the blood-brain barrier, with almost 100% bioavailability. However, as the current standard of chemotherapeutic care, TMZ is associated with only 2.5 months of additional survival for patients when compared to treatment with radiation therapy alone [17]. In recent studies, it has been confirmed that patients with methylated promoter of DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) fare significantly better in TMZ response with a median survival of 21.7 months [27].
3. MGMT and Its Role in TMZ Resistance
The most important prognostic factor for survival and predictive biomarker for TMZ response is the methylation status of MGMT. MGMT is a DNA repair protein that repairs the O6MeG lesion created by TMZ. MGMT irreversibly binds to and degrades O6MeG adducts from DNA [26, 28]. MGMT encodes human alkyl guanine transferase, which transfers the methyl group from O6MeG to an internal cysteine residue, simultaneously repairing DNA and counteracting the cytotoxicity of TMZ and other alkylating agents [25, 29–31]. When O6MeG is repaired by MGMT, cells become either resistant to O6MeG-triggered apoptosis or die due to N-alkylation lesions like 3-methyladenine, 3-methylguanine, and apurinic sites created as side products of N-methylpurine hydrolysis. Depletion of MGMT by O6-benzylguanine (O6-BG, a specific MGMT inhibitor) prevents TMZ-induced apoptosis [26]. It has been widely documented that the level of MGMT activity is correlated with tumor cell resistance to the methylating chemotherapeutic drugs [32–37]. Kitange et al. compared five primary xenograft models of TMZ resistance and found significant upregulation of MGMT expression in resistant MG xenograft lines, where MGMT was proven mechanistically linked to TMZ resistance. O6-BG restored TMZ sensitivity only in those lines that overexpressed MGMT [38]. Epigenetic silencing by promoter methylation (reviewed by Riemenschneider et al. [39]) and MGMT depletion [26, 40] provides relief from TMZ resistance in MG.
4. Role of TMZ in Inducing Lymphopenia and Its Role Immune Response during Glioma Chemotherapy
While lower expression of MGMT is desired in glioma cells for better TMZ efficacy, successful immune response in MG patients depends upon the functional efficiency of MGMT in conferring resistance to TMZ cytotoxicity. Although TMZ has proven to be generally well tolerated among patients, it is known to induce lymphopenia or abnormally low levels of white blood cells. An initial report of TMZ-induced lymphopenia was reported by Brock et al. [41] and has been confirmed by others in recent years [42–46]. Bone marrow cells are particularly vulnerable to TMZ due to lower MGMT activity than tumors, resulting in myelosuppression [23, 31, 47].
It has been observed that TMZ selectively targets the human monocytes but not dendritic cells that are derived from these monocytes [48]. MGMT levels decline during maturation of monocytes into dendritic cells (DCs) [49] which was contradictory to the established fact that low MGMT levels were required for TMZ sensitivity. The concept of selective affinity of TMZ towards monocytes was further confirmed in an animal experiment where either GL261 mouse glioma cells in a syngeneic model or U87 human glioma in a xenograft model were treated with systemic application of anti-CCL2 monoclonal antibody (MAb). Cotreatment of these animals with TMZ significantly prolonged their survival (8/10) [50]. Malignant glioma secretes CCL2 or monocyte chemoattractant protein-1 (MCP-1) to stimulate monocytes to migrate to the tumor site where they are converted into immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs) and facilitates tumor growth [51–53]. While anti-CCL2 MAb prevented the migration of the monocytes to the tumor site, TMZ probably played a role in surveillance and killing of monocytes that reached the tumor site, thereby mitigating immune suppression. In a recent report, Bauer et al. have attributed the selective apoptosis of monocytes by TMZ to ATM/ATR pathway-induced p53 activation, rather than any active role played by MGMT [54]. In another recent study, peripheral blood mononuclear cells (PBMCs) of 25 MG patients were tested for immune modulation prior to and 4 weeks after radiation therapy-temozolomide (RT-TMZ) treatment [55]. The authors observed measurable decrease in tumor-infiltrating CD8 CTLs and NK cells and proportional increase in functional Tregs. Further, they also observed that monocytes retained their ability to differentiate into DCs after RT-TMZ treatment. Yet again, in an animal model study by Banissi et al., low-dose metronomic administration of TMZ, but not standard regimen, demonstrated a decrease in circulating Tregs in a glioma rat model [56]. Results from this study were completely opposite to the above-discussed human study but corroborated with earlier findings of pan-CD4+ lymphopenia in TMZ-treated melanoma patients [57]. Blockade of CD25 or IL2-receptor alpha chain by monoclonal antibodies during TMZ-induced lymphopenia selectively abrogated Tregs in mice and humans and correlated with enhanced immunity in patients with MG [58, 59]. The Treg reduction was associated with a significant expansion of vaccine-stimulated antitumor effector T cells. Several studies in both mice [60] and humans [61, 62] have shown that it may be possible to exploit this timeframe of lymphopenia in order to amplify immune response since lymphodepletion has been shown to decrease competition at the surface of antigen-presenting cells, therefore improving cytokine availability, which, in turn, amplifies T-cell activity and depletes Tregs [44]. Reardon and his colleagues have succinctly remarked that lymphodepletion resets host's immune system and thus eliminates host's tolerance to autologous tumor antigens. Efficacy of antitumor vaccines can thus be enhanced by vaccination immediately after lymphodepleting chemotherapy [63]. In as study with glioma patients, who were vaccinated with autologous tumor-lysate-loaded DCs after RT-TMZ therapy, increased frequency of interferon-gamma-positive CD4+ T cells was observed [64]. TMZ chemotherapy also increased cross-priming of tumor antigen-specific CD4+ and CD8+ T cells in an animal model and suppressed Treg activation when TMZ-treated animals were vaccinated with tumor-antigen pulsed DCs [65].
However, other studies have sharply contradicted the aforementioned optimistic views. In a recent study performed on pathologically verified malignant glioma patients who were treated with focal radiotherapy plus concomitant daily TMZ, patients often suffered from severe lymphopenia, analyzed by assessing adverse effects including decrease in white blood cell counts, lymphocyte counts, and neutrocyte counts. Eighty-two percent of the patients suffered one or more adverse effects; lymphopenia (68%) was the most frequent adverse effect, with 32% of patients suffering CTC grade 4 lymphopenia [66]. The significant and long-lasting lymphopenia induced by TMZ is the biggest concern associated with its use. Preferential CD4+ lymphopenia has been observed in melanoma patients that were treated with an extended dose of TMZ [57]. These patients were also reported to have a high incidence of opportunistic infections. In a similar study performed on children and adolescents with brain tumors, improvement in survival was also associated with a higher rate of virus infections [67]. Similarly, concomitant radiotherapy with TMZ increased the proportion of functional Tregs while depleting the incidence of NK cells in MG patients, suggesting an increased immunosuppressive environment [55]. In another recent study, a combined immunotherapy of mTOR suppression and TMZ administration resulted in robust depletion of CD4+, CD8+, NK, and B cells leading to increased opportunistic infections in the treated group [68].
Depletion of O6-alkylguanine-DNA alkyl transferase (AT/MGMT) activity in PBMCs of TMZ-treated patients has been directly linked to the cause of myelosuppression [47]. In this study, however, TMZ was sequentially administered with fotemustine. Fotemustine is a nitrosourea alkylating agent and uses the same working principle as TMZ. D'Atri et al. corroborated this result by showing that TMZ induced a rapid depletion of MGMT activity in a concentration-dependent manner [69].
5. P140KMGMT and Chemoprotection against TMZ
Overexpression of MGMT has not been successful in resisting TMZ cytotoxicity [47, 69]. This was also confirmed by Briegert et al. where they showed that high levels of MGMT did not confer human monocytes resistant to alkylating chemotherapy [49]. Transfer of drug resistance genes to hematopoietic stem cells offers the potential to protect cancer patients from drug-induced myelosuppression and to increase the number of gene-modified cells by in vivo selection [70]. Recent studies have shown promising effects of chemoprotection in hematopoietic cells by mutating the proline residue at 140 of the MGMT peptide to lysine (P140KMGMT). Introduction of other coding region polymorphisms like L84F has been shown to alter the stability of target cells rather than affecting TMZ sensitivity [71]. Mice transplanted with P140KMGMT-transduced cells showed significant resistance to the myelosuppressive effects of TMZ and O6-BG. Following drug treatment, transduced cells were seen in all peripheral blood lineages, and secondary transplant experiments proved that selection had occurred at the stem cell level [70]. Zielske et al. showed that myelosuppression can be mitigated by P140KMGMT gene transfer into hematopoietic stem cells and bone marrow transplantation in order to continue with TMZ dose escalation [72]. NOD/SCID mice xenotransplanted with P140KMGMT-overexpressing human CD34+ cells conferred chemoresistance against O6-BG and O6-BG and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) [73]. Overexpression of P140KMGMT increased the DNA-repair capacity of both primary human CD34+ cells and K562 cell lines [23]. Using a canine model, Neff et al. have shown that P140KMGMT-transfected CD34+ hematopoietic cells prevented myelosuppression after repeated treatment with TMZ and O6-BG [74]. Chemoprotection was also observed in dogs engrafted with P140KMGMT-transfected CD34+ cells when challenged with O6-BG and BCNU [75]. P140KMGMT-based gene therapy developed significant resistance to TMZ in immunocompetent NK-92 and TALL-104 cells and protected their ability to kill K562 leukemia cells. The modified cells developed significant resistance to TMZ compared to nonmodified cells, and genetic modification of these cells did not affect their ability to kill K562 cells [76]. Simultaneous overexpression of multidrug resistance 1 (MDR1) and P140KMGMT in CD34+ cells resulted in stable populations of MGMT+ cells upon exposure to O6BG/TMZ therapy [77].
6. Future Directions
Targeted immunotherapy of MG using antigen-redirected chimeric T cells is one of the mechanisms of active immunotherapy of MG that has been successfully developed in recent years [78–83]. This approach of MG immunotherapy may be functionally precise but may be inhibited by concurrent myelosuppressive TMZ, which produces a survival benefit in MG [20]. TMZ-induced immunosuppression also leads to opportunistic infections in MG patients undergoing chemotherapy (reviewed by Kizilarslanoglu et al. [84]) [57, 67]. As evidenced from the available literature, P140KMGMT mutation is successful in blocking the TMZ-induced cytotoxic depletion of MGMT activity in transduced hematological cells. However, P140KMGMT mutation has yet to be used for the treatment of immunosuppressive side effects of TMZ chemotherapy in MG patients. Autologous T cells from MG patients currently undergoing chemotherapy can be genetically modified to express P140KMGMT and render them resistant to TMZ. This will have two major benefits. On one hand these cells will be viable against chemotherapeutic cytotoxicity. On the other hand, these viable cells will be efficient in establishing a strong immune response because of, and eventually overcoming the huge immune void eventually created by TMZ-induced lymphopenia.
This work has been supported by Roger Williams Medical Center Brain Tumor Research Fund.
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- Poverty | Compassion International Blog - http://blog.compassion.com -
What Do We Do?
Posted By Web Team On May 22, 2013 @ 12:08 am In Multimedia,Sponsors and Donors | No Comments
What do we do? Well, that's a great question!
The short answer is,
"Releasing children from poverty in Jesus' name."
But if someone were to ask you what we did, what would you say?
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URL to article: http://blog.compassion.com/what-do-we-do/
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subset: commoncrawl


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The t(11;22) chromosomal translocation specifically linked to Ewing sarcoma and primitive neuroectodermal tumor results in a chimeric molecule fusing the amino-terminus-encoding region of the EWS gene to the carboxyl-terminal DNA-binding domain encoded by the FLI-1 gene. As the function of the protein encoded by the EWS gene remains unknown, we investigated the putative role of EWS in RNA polymerase II (Pol II) transcription by comparing its activity with that of its structural homolog, hTAFII68. We demonstrate that a portion of EWS is able to associate with the basal transcription factor TFIID, which is composed of the TATA-binding protein (TBP) and TBP-associated factors (TAFIIs). In vitro binding studies revealed that both EWS and hTAFII68 interact with the same TFIID subunits, suggesting that the presence of EWS and that of hTAFII68 in the same TFIID complex may be mutually exclusive. Moreover, EWS is not exclusively associated with TFIID but, similarly to hTAFII68, is also associated with the Pol II complex. The subunits of Pol II that interact with EWS and hTAFII68 have been identified, confirming the association with the polymerase. In contrast to EWS, the tumorigenic EWS-FLI-1 fusion protein is not associated with either TFIID or Pol II in Ewing cell nuclear extracts. These observations suggest that EWS and EWS-FLI-1 may play different roles in Pol II transcription.
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I'm a Good Citizen #2
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text:
GEVALIA Pumpkin Spice Latte
GEVALIA Pumpkin Spice Latte combines the flavor of pumpkin pie spices including cinnamon, nutmeg and cloves with real milk creamer. Experience our authentic café style latte today.
- This package includes 8 Milk Creamer T DISCS and 8 GEVALIA Flavored ESPRESSO T DISCS; you use one of each for every special drink
- These T DISCS brew together to make an 11 fl oz mug of pumpkin spice latte
How to Make It
- Place your favorite (11 fl oz) mug on the cup stand.
- Shake the Milk Creamer T DISC and insert it into the brewer. When the green Auto light comes on, press the button.
- After a moment of brewing, the orange Stand-by light will display. Replace the Creamer T DISC with the Flavored Espresso T DISC. When the green Auto light comes on, press the button again.
- The espresso will brew through the foam, then you can enjoy a delicious mug of this coffee house classic.


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Manga-Inspired Slush Pile: Aya Takeo, Talking to Strangers, Red String
- Posted by Johanna on May 23, 2010 at 9:47 pm
- Category: Graphic Novel Reviews
All books were provided by the creators for review. I'm grouping these together due to their obvious manga influences.
Aya Takeo Volume 1
story by Lloyd Prentice
art by Sonia Leong
Sweatdrop Studios, $12.99 US
Although clearly and strongly manga-influenced in story and art, the book more closely resembles a Prestige Format comic. It's only 64 pages, at a relatively high price (probably due to being in color), and at a larger trim size than the usual manga digest. As such, it doesn't come off very well in comparison to the smaller, fatter, cheaper books its audience is familiar with.
It seems that Aya Takeo is a webcomic, and this collects its first year of strips. It's also science fiction, with aliens (resembling mechanical spiders) having taken Aya's lover captive. She's learned to fight as a result, while he's been battling to survive his slavery. The story is generic and slight, although the art is well-done and eye-catching. If you're interested, read it online for free. You'll want to continue, anyway, since the story only barely gets going in this issue.
Talking to Strangers
stories by Fehed Said; art by various
Sweatdrop Studios, $12.99 US
This volume, from the same publisher, is more what I expected: over 200 pages, black and white, smaller and thicker and solid in the hand. Fehed Said previously wrote The Clarence Principle, released through SLG Publishing. Here, he presents six stories illustrated by five artists: Nana Li, Wing Yun Man, Chloe Citrine, Sonia Leong, and Faye Yong.
The first is immensely creepy, thought-provoking with no clear resolution, using the metaphor of a boy buried alive to raise the issue of euthanasia. The next shows us a crazy shut-in obsessed by TV yet discovering romance (this is the second-best tale in the book), followed by another drawn metaphor, about a boy chained to a stone of worries, and then an abused child. Finally comes my favorite, the longest, a charming tale about a girl discovering a flower.
The art is each case is more than sufficient to meet the needs of the stories, with each style well-suited and adding new levels of detail. For example, the first is fine-lined, which feels delicate and poetic against the life-and-death subject matter. The second is a bit more comedic, which keeps the mood light instead of depressed when dealing with the agoraphobic.
Many of the stories try too hard to be meaningful — I'd like to see Said tackle more standard plots and characters, like the "Flowers" story, instead of his more frequent emotional and death symbols — but I'm tempted to keep the book just for the flower story. The little girl is so cute! You can read more in-depth reviews with art samples at the Forbidden Planet blog or Robot 6.
Red String Book 5
by Gina Biggs
Self-Published, $9.95 US
I haven't checked in on this long-running webcomic manga since the first book. Since then, Gina Biggs has returned to self-publishing (with book 4) and announced that Red String will run eight books in total — making this just past the halfway point.
I didn't recall any of the characters, but the situations and types were immediately obvious, since there are a bunch of girls in school, worried about boys and clubs and their future. The art's very attractive and the cast sufficiently distinct in both looks and personalities. I did recognize the core couple, who were promised to each other in childhood and yet still fell in love. This volume features some incredibly important steps in their relationship, with plenty of emotional soap opera. I fell right back into their story, eager to find out what happened next, and I quickly came to adore the young lesbians, new characters to me.
Most chapters end with a visual representation of a character's inner conflict. You know, like a devil and angel on the shoulders? Except in this case it might be "character's dream job" vs. "character's parent's business path for them", but still as cute little versions of themselves. It's a nice reminder of where we are in the story and what's at stake.
Like some artists in Japan, Biggs is creating her own doujinshi. When I got this book from her at C2E2, she also gave me two explicit minicomics she'd created. One expands on chapter 29, contained in this book, the other on chapter 37, which will be in the next volume. Both are romantic scenes that, in the bound volumes, "cut away" from anything explicit. The adult, 18-and-up material is contained in the minicomics, one male/female, the other girl/girl. It's a clever concept that serves the fans with convention-only (because of the age check) specials. If you aren't interested in happy porn comics, you can stick with the proper books. If you love the characters and want a little something extra, there it is… and it's well-done.
And One More Upcoming — Madam Samurai
I haven't seen this book yet, since it's due out next month, but the art for Madam Samurai sure looks pretty. It's by David Hitchcock, who previously did striking period work in Whitechapel Freak. Check out the previews and trailer at the MS website.
3 Responses to "Manga-Inspired Slush Pile: Aya Takeo, Talking to Strangers, Red String"
- Pushback on pushback « MangaBlog Says:
May 25, 2010 at 8:26 AM[…] of Comic and Alice 19th at Every Day Is Like Wednesday. Johanna Draper Carlson looks at some manga-influenced graphic novels (including Red String doujinshi!) at Comics Worth Reading. Bad Jew has two ultra-micro-mini reviews […]
- Filthy Figments Launches » Comics Worth Reading Says:
June 1, 2010 at 7:38 AM[…] a new, subscription-based, adults-only webcomic site by women. It's run by Gina Biggs (Red String). $5 a month gets you full access, which will include 30 new pages of content a month, updated […]
- Coming Up: Manga Due December 2010 » Comics Worth Reading Says:
October 18, 2010 at 9:34 PM[…] enjoyed reading Talking to Strangers (Sweatdrop Studios, OCT10 1118, $12.99, December 22) which was self-published earlier this year […]


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Discussing: Nuzgûl of the Month January 2012
Nuzgûl of the Month January 2012
Message: 54479
01 Jan 12 5:17 AM
Original Post
General Audience
The Nuzgûl of the Month January 2012, Alternate Perspectives, can be found here.
Take any scene that Tolkien wrote, from any of the books. Now turn it on its head: write it from some POV other than the one Tolkien gave us. Here are some examples:
* Bilbo's "unexpected party" in The Hobbit -- we pretty much get just Bilbo's perspective. What was one of the Dwarves thinking, or Gandalf, or the hobbit next door?
* The Nazgûl attack Frodo, Sam, and Pippin as they cross the Shire (just before they bump into Gildor). We get Frodo's thoughts, but what about the other hobbits', or the elves, or the Nazgûl, or an animal who oversaw the whole encounter?
* Faramir's interrogation of Frodo and Sam, but from his POV or one of his Rangers', or from Frodo's for that matter.
* Éowyn attacks the Witch-king, but through her own eyes. Or Théoden's. Anyone but Merry.
The idea is to find a scene that Tolkien tells us through one point of view, and tell that same scene from some other cahracter (canonical or original) who would have seen the same scene. I'm not sure this would work for all scenes, but there are several that are told pretty strongly from one POV or the other.
(Movieverse pieces are allowed, too, if you can find a scene that's shown through one particular character's eyes, or even several but not all characters. The nature of the medium makes it harder, but if you can find such a scene go ahead and have fun.)
Re: Nuzgûl of the Month January 2012
I must admit that I didn't write this story for this challenge, but then I also didn't set the Challenge to match the story Nevertheless, a happy coincidence, and my entry for this month is A brief doubt


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Our inventory of new Subaru vehicles is among the largest in the Cleveland region. With models like the Outback, Impreza, Legacy, WRX, and Forester to choose from, we are confident we have the vehicle for you. Visit Ganley Westside Subaru and receive a great low price on your next new Subaru car in Cleveland. Use the Power Search filters below to find exactly what you are looking for and then contact a salesperson by phone. When you are ready for a test drive, come visit us at 25730 Lorain Rd.
Besides our selection of Outback, Impreza, Legacy, Tribeca and Forester models, you will discover we have a large inventory of used cars for our Cleveland customers. So if you're looking for a used car, but don't know where to start, visit Ganley Westside Subaru at 25730 Lorain Rd and let us find the perfect used vehicle for you!
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Whether it is for hockey, fishing, snowmobiling or any sort of winter sport, those who venture onto the ice during the winter months face inherent danger. Frost bite. Hypothermia. Death. All of these can and do happen once someone breaks through the ice.
Jack Frost and his arctic wake of ice and snow were just too much for Saturday's Crystal Lake Winter Festival. Normally a welcome friend to a festival that requires plenty of snow and a frozen Crystal Lake, Saturday's weather conditions were deemed too dangerous by festival officials.
A house fire which started early Wednesday afternoon in Grattan Township was quickly extinguished by firefighters from Grattan Township Fire Department with the assistance of firefighters from Cannon Township and Belding. According to Grattan Township Fire Chief Kirk Bride, the cause of the fire at 12221 Belding Road is currently under investigation.
Organizers of this year's Winterfest couldn't have been happier with the weather Saturday. Like Goldilocks' third try at pilfered porridge, it was not too hot and not too cold. The bevy of sleds turning out for the BEVRA Snowmobile Races and classic sled show had plenty of frozen liquid on which to race, but those taking part in the polar plunge were in no immediate danger of freezing solid upon exiting the water.
Pick a road — any road — in Michigan, and one is bound to find themselves grumbling about the cracks, bumps and potholes they encounter along the way. It's fact more than argument that the mitten state is ranked as one of the worst in the nation for road quality.
A Montcalm County Housing Commission complex bathroom caught fire Monday afternoon, but the Howard City Fire Department quickly extinguished the blaze.
However, a separate fire started up early Tuesday morning, the cause of which is currently unknown.
One year ago, the Howard City Police Department merged with the Montcalm County Sheriff's Office. Next month, another village police department may do the same.


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User Reviews
Displaying 1 - 10 of 12 2011 Volkswagen Jetta reviews.
2011 Volkswagen Jetta SE w/ Conv and Sunroof
ProsI love this car and I am SO glad I went with it instead of the Chevy I was looking at. ConsThat I cant drive it all the time.
Its A Fantastic Car With A Lot To Offer, And In My Opinion Is The Best Of Its Class. — Performance- The VW Jetta is great in this department, on the automatic version it has drive, as well as a Sport setting which allows you to accelerate much faster by reeving up to the red line. It can accelerate from 0-60 pretty rapidly. The Volkswagen also keeps with the European sport tradition of having EXCELLENT handling. The car goes exactly where you want it to go and parallel parking it is extremely easy. Build Quality- Ever since ive had the VW (close to 7 months) it has needed absolutely no repairs what so ever. It drives like a dream. Before this car I had a 2001 Jetta, and to this day its only needed standard maintenance. Im expecting that the new Jetta will hold up the same. Appearance- The outside of the new Jetta looks amazing. The older Jettas, up untill this one, all looked friendly and playful. The new Jetta looks mean and ready for action. The interior is simply fantastic. It has a BMW/Merc quality interior. Something youd expect from a 1 series or an E class. Its very stilish, very simple, and very functional. All of the buttons click into place nicely and there are no loose ends. The heated seats work in a matter or 2 min and the air conditioner/ heater works amazingly well, warming or cooling the car completely in about 5 min or less. The touch screen radio/sat nav works very well, and has no glitches what so ever. The sunroof is a VERY nice touch ;) Cost of Ownership- like I said before, the only things you really have to do is replace the windshield wiper fluid and gas. The car just needs standard maintnence. It is VERY cheep to own and the gas milage is somewhere around 36mpg I believe. Fun Factor- The car is an absolute joy to drive. Compaired to my friends cars this thing is the fastest, and most well handling car out of them. Its a pure joy to drive a car in sports mode, knowing you can turn where you want and nothing is going to go wrong. When it accelerates from 0 you get a sort of butterfly effect in your stomach as the tires spin on the pavement and cause smoke. Best car Ive ever had. Primary Use: Sport/fun (spirited driving, track racing, off-roading, etc.)
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2011 Volkswagen Jetta SE w/ Conv and Sunroof
ProsNew style and is about 2 inches wider.Thumb controls and blue tooth. ConsChanged many conveniences and made it cheaper. A letter I wrote to VW about this is below.
Vw Of America — As a VW owner for nearly 2 decades now I had no reservations about buying a new 2011 VW Jetta SE 2.5 from a local reputable dealer without a test drive. After driving this car for approximately 3 weeks now I am forced by my overwhelming feeling of dismay to write this letter to you. Please allow me to explain. My most recent or previous VW was a 2009 Jetta SE 2.5. I was not only impressed with this car, but also liked its style and features which I was surprised to find in a car of this category. I also found it to be a very solid automobile. I found this out in a more personal manner after being slammed into by another car as I was backing out of my driveway during the worst winter the northeast experienced in close to 30 years. Needless to say my visibility was pretty poor due to all of the snow that had accumulated and I was hit so hard that the damages amounted to $7700 and a lower back injury. A couple of months after the accident I decided to upgrade to a new car. One, due to the accident, and two, because the mileage was quickly growing to where the warrantee would be exhausted. I did not hesitate for 1 minute to go and look at the new model Jetta, nor did I even think to consider another brand of vehicle. After sitting in the car I immediately informed the dealer I wanted one. I took delivery of my new 2011 Jetta SE 2.5 on June 30, 2011. I immediately noticed the ride was a bit more comfortable than my 2009 model, but I also began to notice things were missing as well. Even though other upgrades such as the Bluetooth and thumb controls, a radio unit that will probably take me a year to figure out how to work (because it's not user-friendly) there are also many downgrades. First and foremost I would like to point out potentially dangerous change that was made concerning the automatic traction control. There is no way to shut it off. I don't know about where the designers of this model live but where I live is called the "great northeast" for a reason. We get a lot of snow. I was stuck in the snow several times last winter and the only way to get out of being stuck and stranded was having the ability to turn off the traction control. The onboard computer does not know if the car is stuck in snow or skidding on a street. So it tries to adjust for the skidding, thus preventing a driver from getting unstuck from a snow bank. Other things I miss on my 2011 model from my 2009 model are as follows: 1) The center console lid used to crank up and pull forward providing a comfortable armrest. Now it's just a lid with no arm rest. This is an important feature to someone who drives a lot like I do. 2) The power seat for the driver side is totally manual now and to adjust the back of the seat there is a plastic handle that is very difficult to operate. 3) The button that used to unlock the gas door is now gone. The new gasoline doors are designed to open and close by pushing directly on them which in my opinion is cheap. 4) The buttons that operate the heated seats are new, but they only allow you three temperatures to choose from. The old design was more adjustable allowing you more than three settings. 5) My new car came with very cheap windshield wipers. More like the wipers I had in my 1997 Volkswagen golf. My 2009 car had very heavy-duty rubber wipers. I also noticed that all the other vehicles in the car lot had those heavy-duty rubber wipers and mine did not. 6) The engine and transmission timing seems to be off. The transmission up shifts too soon and also has to downshift hard when climbing a small hill. This is especially noticeable when the cruise control is set. 7) The leather seats in my 2009 Jetta used to be nice and slippery, allowing one to slide oneself left or right to get out of the vehicle nice and easy. Now you stick to the new leather seats as if they were cloth seats. Why should somebody spend the extra money for leather seats when they act more like cloth seats? 8) The trunk lid went from a nice solid carpeted piece of equipment with hydraulic pressure rods on each side to a bare lid with nothing but plastic covering it. Also, it takes more than one try at closing the lid to get it to lock. It may take a few attempts to finally get it closed and locked and it's still not a nice solid closing sound like my old car (the 2009 model). It sounds very cheap and it jiggles from side to side and goes back up when you first try to shut it unless your shutting it is right on the money. 9) I see that you installed an iPod attachment in the glove box. In the glove box? Why? Also, the cord for it is very short and the vehicles computer software for this item is not updated for the new iPod or iPhone's operating system so, it does not work. 10) You took away the fuel gauge needle and put in a digital fuel gauge system that does not allow one to actually estimate exactly when you're going to run out of fuel. The little bars disappear and when it gets down to two little bars left the gasoline light comes on. Also, this vehicle seems to use more gas than my old car (the 2009 model). I am filling up the gas tank more now than before. 11) A fabric type of air dam was installed to pop up when the sunroof is open. Why? All it does is catch bugs which makes it look nasty. It will probably have to be replaced soon due to its flimsy construction, costing the customer. I realize that some of these issues may be due to the car still breaking in as it only had 14 miles on it when I took delivery of it from the dealer. However, I also believe that many of these changes are due to the manufacturer trying to save money and be cost-effective but what you don't realize (or maybe you do) is that the customer is getting ripped off because, Volkswagen seems to be taking out things to save money and then increasing the price of the vehicle due to it being a new model and making money on both ends. Now this does not seem fair to me at all. Primary Use: Commuting to work |
2011 Volkswagen Jetta SE
ProsGreat car and plenty of pick. Inline 5 cyc engine is great. Fuel economy is good not as great as others in the same price but they sacrifice power. ConsPricey maintenance
Great Car For Most People — 2011 Jetta does lots of things well. Good on fuel economy, looks great, handles better and has a surprisingly spacious interior. I am 6'2 and am comfortable driving the car. The trunk is also a lot bigger than I thought it would be. Primary Use: Commuting to work |
2011 Volkswagen Jetta SE
ProsLooks great..! ConsCost too much for maintenance
2011 Volkswagen Jetta SE w/ Conv and Sunroof
ProsNice modern look, with large interior. rear seats are very comfortable. ConsCheaply made. My 2007 rabit is WAY better quality.
Nice Sedan. Powerful And Roomy, Saddened By Cheap Construction. — First of all: I love my Jetta. Nice 2.5 liters engine, with MANUAL (YAY!) transmission is an absolute joy to drive. The overall quality of the car is, however, lower than the other car I drive (2007 VW Rabbit 2.5), which has many features that the Jetta doesn't have anymore. Rear vents, for example, or a temperature gauge (this was a cheap move, VW). The iPod connection is not in the center armrest with a docking station, anymore. Now it's only a cable dangling in the glove compartment, and the iPod rocks left and right with the turns. Result? I don't use it anymore. So, if you can get over the flaws due to a cheaper construction (VW had to kep costs down) and are willing to make some compromises, the Jetta is a great car. Though, with a few more bucks, it could have been a FANTASTIC car, just like the old one was. Primary Use: Family transportation |
2011 Volkswagen Jetta Base
ProsGreat handling, fun drive, interior and exterior live up to the Volkswagen name, fantastic trunk space. ConsFuel economy could be better
Fun And Practical At Once. — The signature Volkswagen vehicle, the Jetta is a lot of fun to drive. It handles spectacularly for a sedan, and the CVT engine makes for a unique driving experience. The interior room is decent, the sound system is engaging, and overall this is a good choice as a primary or secondary vehicle. Primary Use: Commuting to work |
2011 Volkswagen Jetta SE
ProsExcellent fuel consumption, almost no costs except for the car's cost, comfortable for long drives, handles well on the highway, small enough to easily fit into any parking spaces. ConsThe backseat is not very big so it is hard for long road trips seated in the backseat.
A Reliable Car Prepared For Any Obstacle. — Overall the car has the best bang for your buck than any car on the market because of the long list of pros. Additionally, the vehicle is able to perform with the utility of a much larger car because it has a spacious trunk that is able to hold any size object. Primary Use: Commuting to work |
2011 Volkswagen Jetta S
ProsI chose this vehicle because of the aggressive look. The reliability of VW in my experience of my wife owning three since we started dating is fantastic! The fuel economy is outstanding! 37.89 miles per gallon on a recent trip from Mass. to Manhattan back to Boston on 1 $41 fill up. Tons of leg room in the back. Tons of trunk space. Great in the snow! ConsA bit uncomfortable on long trips as the driver only.
Excellent! I Would Purchase This Vehicle Again. — Fuel economy is awesome! Up front comfort is lacking. Lots of leg room for all passengers, especially in the rear. The car looks great, aggressive styling gives it a sporty look. DIY's will appreciate the ease of maintenance. I feel very safe traveling with my family aboard. |
2011 Volkswagen Jetta SE
ProsHave fun to drive . ConsNon negative for me
Nice Car — I love this car . Look so cool. Seat so comfortable . I love classic style inside car . Yes, this car fun to drive !!! Exterior size car good too, its middle car , not small not so big ! On gas its not cost a lot . Trunk not small to . I like button to open trunk its easy to press on driver door . Primary Use: Commuting to work |
2011 Volkswagen Jetta SE PZEV w/ Conv
ProsIt's practical and affordable. ConsNot as spacious for the family.
Great For The Work Commute — Good car for newly wed couple with no kids. Great work commuter. Looks sporty with decent engine. With a child on the way and more to come this car will primarily be used for work commute. Love the Bluetooth and usage on a shorter road trip. Primary Use: Commuting to work |
Displaying 1 - 10 of 12 2011 Volkswagen Jetta reviews.
Reviews From Other Years
2014 Volkswagen Jetta Reviews
Excellent By Mannyhutch
Great daily driver, very good on gas, reliable, comfortable, this is a car that any person that has a long daily commute will enjoy, best part is going to the gas pump and not spending too much to fil... Read More
Great Daily Driver For The People Who Enjoy Driving By dustan
Overall a great car, I enjoy every drive. The car is comfortable and efficient all while being completely sexy. The car can get out of its own way well and it a blast to drive at highway speeds. The a... Read More
2013 Volkswagen Jetta Reviews
Very Happy With Car By Jcar
Super pleased with economy - I drive mostly highway, mostly 75-80 mph and average over 40 mpg. This is reason I bought the car - as I drive 120 miles to/from work. Great stereo, nice comfort, ve... Read More
Economical But Fun By Thorsten73
This car is a great family car that not only is a hybrid, but has a turbo for times that you need it. No problems, intuitive and great looking. I recommend this car to any small family looking for a ... Read More
2012 Volkswagen Jetta Reviews
Better Than I Could Have Ever Imagined! By SPoulin
I would definitely recommend this car to everyone and anyone asking! We love it!! Not only does it have incredible fuel economy, but the reliability as well as drivability of this vehicle is incredibl... Read More
Peppy By Deathjam4
Decent ride, handles really well and is very responsive. I have not owned the car for to long yet but it comes with a decent radio system and lots of space. best thing tho is unlike my old audi it ha... Read More
2010 Volkswagen Jetta Reviews
Great Value By Jonesb930
Overall I am happy that I purchased this car. I am at 100K and ready to trade it in but have been hesitating since it was such a great car overall. I have driven a newer model Passat during the last s... Read More
Great Economy Car By Jason
I drove this car for 5 years before I bought my challenger. I didn't realize how much you could actually spend on gas before I bought my challenger. I only went to the gas station once every 4-6 weeks... Read More
2009 Volkswagen Jetta Reviews
Fantastic Car! By csmtaylor
I really enjoyed owning this car! The look and comfort are great and the fuel milage on the highway averaged between 500 and 600 miles per tank. I plan on buying another Jetta TDI as soon as I find th... Read More
Cool Mom Car By RoanMissKitty
I would own another one for sure. I like my sun roof and it does pretty good in snow. I wish parts weren't so expensive and oil changes were cheaper. But, car is very reliable and I have not had any... Read More
People researching a 2011 Volkswagen Jetta contacted a dealer about
34% of the time
Honda Civic
6% of the time
Hyundai Elantra
6% of the time
Volkswagen Passat
6% of the time


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More reviews by christineneogoh
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My makeup lasts longer and it foundation and powder sticks better to my skin. I will definitely.repurchase!