tbuckley/cabot-search huggingface dataset:
Abstract SY20-03: Metastatic latency and immune evasion by cancer stem cells
Authors: Joan Massague
Journal: Cancer Research (2016)

Abstract Metastasis frequently develops, years after the removal of a primary tumor, from a minority of disseminated cancer cells that survived as latent entities. An improved understanding of the location and survival mechanisms of disseminated cancer cells, and their ability to enter a quiescent state, evade immune surveillance, and retain tumor reinitiating capacity is needed in order to better prevent and treat metastasis. To this end, we developed latency competent cancer cell (LCC) models from early stage human lung and breast carcinoma cell lines and defined the mechanisms that prevent the outgrowth, support the long-term survival, and maintain the tumor-initiating potential of these cells during latent metastasis. LCC cells show stem cell-like characteristics and express Sox transcription factors, which are essential for their survival in host organs under restrictive conditions and for metastatic outgrowth under permissive conditions. Through autocrine suppression of WNT signaling and heightened TGF-β signaling, LCC cells self-impose a slow-cycling state with broad downregulation of NK cell activators. By actively entering quiescence, metastatic stem cells can evade innate immunity to remain latent for extended periods. By persistently reentering the proliferative state, these cells may evolve organ-specific colonization traits to take over the host stroma. Citation Format: Joan Massague. Metastatic latency and immune evasion by cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY20-03.
Thyroid Ophthalmopathy, Dermopathy, and Acropachy
Authors: Carlo Guerrero, Mark R Pittelkow
Journal: New England Journal of Medicine (2016)

A 56-year-old man was referred to a dermatologist for assessment of the progression of his thyroid dermopathy. Three years earlier, he had received a diagnosis of Graves’ disease with thyroid-associated ophthalmopathy and dermopathy.
Abstract 26: Sensitive step in cholesterol biosynthesis reveals role for sterol metabolites in regulating growth of EGFR/KRAS-dependent tumors
Authors: Linara Gabitova, Diana Restifo, Elizabeth Handorf, Kathy Q. Cai, Igor A. Astsaturov
Journal: Cancer Research (2016)

Abstract We identified SC4MOL and NSDHL, two enzymes in the cholesterol pathway and their substrates, meiosis activating sterols (MAS), as critical regulators of receptor signaling and trafficking in normal development and in cancer. Oncogenic transformation by EGFR or RAS increases the demand for cholesterol, suggesting a possibility for metabolic interference. To test this idea in vivo, we ablated Nsdhl in adult keratinocytes expressing KRASG12D. Strikingly, Nsdhl inactivation antagonized the growth of skin tumors, while having little effect on normal skin. Loss of Nsdhl induced the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, reduced the expression of low-density lipoprotein receptor (LDLR), decreased intracellular cholesterol and was dependent on the liver X receptor (LXR) α. Importantly, EGFR signaling opposed LXRα effects on cholesterol homeostasis, while an EGFR inhibitor synergized with LXRα agonists in killing cancer cells. Inhibition of SC4MOL or NSDHL, or activation of LXRα by sterol metabolites can be an effective strategy against carcinomas with activated EGFR-KRAS signaling. Citation Format: Linara Gabitova, Diana Restifo, Elizabeth Handorf, Kathy Q. Cai, Igor A. Astsaturov. Sensitive step in cholesterol biosynthesis reveals role for sterol metabolites in regulating growth of EGFR/KRAS-dependent tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 26.
Reflectance confocal microscopy (RCM) and melanocyte-specific immunostaining of histologic skin sections
Authors: Ingrida Vaisnoriene, Janina Didziapetriene, Violeta Zalgeviciene, Aida Laurinaviciene, Tomas Vaisnoras, Vytautas Kulvietis, Ricardas Rotomskis
Journal: Journal of the American Academy of Dermatology (2016)
Checkmate 205: Nivolumab (nivo) in classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and brentuximab vedotin (BV)—A phase 2 study.
Authors: Anas Younes, Armando Santoro, Pier Luigi Zinzani, John Timmerman, Stephen Maxted Ansell, Philippe Armand, Michelle A. Fanale, Voravit Ratanatharathorn, John Kuruvilla, Jonathon Brett Cohen, Graham P Collins, Kerry J. Savage, Marek Trněný, Kazunobu Kato, Benedetto Farsaci, Susan M. Parker, Scott J. Rodig, Margaret Ann Shipp, Andreas Engert
Journal: Journal of Clinical Oncology (2016)

7535 Background: cHL is characterized by amplification at 9p24.1, causing overexpression of PD-1 ligands. Thus, cHL may be uniquely sensitive to PD-1 blockade. Nivo is a fully human IgG4 immune checkpoint inhibitor targeting PD-1 that showed promising results in a phase 1b study (NCT01592370) in pts with relapsed/refractory cHL (Ansell SM et al NEJM 2015;372:311–9), who currently have limited treatment options. Methods: This study evaluated the efficacy and safety of nivo in pts with cHL who had received BV after failed ASCT, as Cohort B of the larger Phase 2 Checkmate 205 study (NCT02181738). Nivo was given at 3 mg/kg IV q2w. Response was assessed by independent radiologic review committee (IRRC) and investigators (Inv), using 2007 IWG criteria. Primary endpoint was IRRC ORR. Results: The main characteristics of 80 treated cHL pts were: median age 37 y, median (range) 4 prior regimens (3–15). 90% of pts had drug-related AEs: 25% G3–4, 1% G5 (multi-organ failure). Most common drug-related AEs were fatigue (25%), infusion reaction (IR; 20%) and rash (16%). Most common SAEs were pyrexia, tumor progression, arrhythmia, IR, septic meningitis, and pneumonia ( ≤ 4% each). Select immune-related AEs, all G1–2, occurred in 26%. At database lock (DBL; October 2015), median (range) follow-up was 8.9 mo (1.9–11.7). 64% of pts remained on therapy; main reason for discontinuation was disease progression (16%). IRRC ORR (95% CI) was 66% (54.8–76.4); CR and PR rates were 8.8% (3.6–17.2) and 57.5% (45.9–68.5), respectively. Inv ORR, a pre-specified secondary endpoint, was 73% (61.4–81.9); CR and PR rates were 27.5% (18.1–38.6) and 45.0% (33.8–56.5). 62% (33/53) of IRRC responders remained in response at DBL. 6 pts elected to stop nivo and undergo stem cell transplant, all of these pts were alive at data cut-off. IRRC 6-mo PFS was 77%; OS was 99%. In 43 pts who had no prior BV response, nivo treatment resulted in an IRRC ORR of 72% (31/43). Conclusions: Nivo demonstrated a high response rate, long-lasting responses, and an acceptable safety profile in pts with cHL after ASCT and BV, including pts with no prior BV response. PFS and OS are encouraging in this heavily pretreated population. Clinical trial information: NCT02181738.
Full house
Authors: Jorge Zimbron
Journal: BMJ (2007)

Winyard argues that the BMA is being “ambiguous” in criticising both the medical training application service (MTAS) fiasco and the changes in immigration policy.1 He implies that it is incongruent to do so, as stopping immigration is necessary for the system to run adequately. Although this is somewhat true, the BMA is not lobbying for the rights of future immigrants, but for the rights of current immigrants who have been unfairly forced into exile by the new immigration rules. The BMA deserves nothing but praise for this.

He also mentions that the United Kingdom currently has “the worst of all worlds,” as it invests in expanding medical schools but still recruits people from overseas, only to fail to give them all a job down the line. But this is actually quite clever. In the end, what you get is a surplus of intelligent, well intentioned, overqualified people with no transferable skills, thousands of pounds in debt, desperately looking for a job in the one company that has the monopoly for employing their services. It's the best of all worlds, really, and any company in the private sector would kill for this.

The way forward is clear. The house is full, so please shut all the doors. All of them. Not only permit-free training, but highly skilled migrant programmes, professional and linguistic assessment board tests, and all entry to UK medical schools by overseas students aspiring to stay in the UK. The fact that all these structures still offer false hope (and charge heavily for the privilege) is nothing but cruel. But what about those already inside? Would it be too much to let them stay? Even if it means a little more competition? After all, they did help to build the house.
Pathological Basis for Deficient Excitatory Drive to Cortical Parvalbumin Interneurons in Schizophrenia
Authors: Daniel W. Chung, Kenneth N. Fish, David A. Lewis
Journal: American Journal of Psychiatry (2016)

Deficient excitatory drive to parvalbumin-containing cortical interneurons is proposed as a key neural substrate for altered gamma oscillations and cognitive dysfunction in schizophrenia. However, a pathological entity producing such a deficit has not been identified. The authors tested the hypothesis that cortical parvalbumin interneurons receive fewer excitatory synaptic inputs in individuals with schizophrenia.Fluorescent immunohistochemistry, confocal microscopy, and post-image processing techniques were used to quantify the number of putative excitatory synapses (i.e., the overlap of vesicular glutamate transporter 1-positive [VGlut1+] puncta and postsynaptic density protein 95-positive [PSD95+] puncta) per surface area of parvalbumin-positive (PV+) or calretinin-positive (CR+) neurons in the dorsolateral prefrontal cortex from schizophrenia subjects and matched unaffected comparison subjects.Mean density of VGlut1+/PSD95+ puncta on PV+ neurons was 18% lower in schizophrenia, a significant difference. This deficit was not influenced by methodological confounds or schizophrenia-associated comorbid factors, not present in monkeys chronically exposed to antipsychotic medications, and not present in CR+ neurons. Mean density of VGlut1+/PSD95+ puncta on PV+ neurons predicted the activity-dependent expression levels of parvalbumin and glutamic acid decarboxylase 67 (GAD67) in schizophrenia subjects but not comparison subjects.To the authors' knowledge, this is the first demonstration that excitatory synapse density is lower selectively on parvalbumin interneurons in schizophrenia and predicts the activity-dependent down-regulation of parvalbumin and GAD67. Because the activity of parvalbumin interneurons is required for generation of cortical gamma oscillations and working memory function, these findings reveal a novel pathological substrate for cortical dysfunction and cognitive deficits in schizophrenia.
Abstract 3892: Unique pleural vs peritoneal mesothelioma exosomal signature: does mesothelial cell susceptibility to asbestos matter
Authors: Arti Shukla, Phillip Munson, Joyce K. Thompson, Julie Dragon, Maximilian B. MacPherson, Hector Peinado
Journal: Cancer Research (2016)

Abstract Malignant mesothelioma (MM) is a cancer of mesothelial cells of the pleura or peritoneum caused exclusively by asbestos exposure. It is a deadly cancer which is only diagnosed at terminal stages, possibly due to the long latency period of development and lack of biomarkers for early diagnosis. Both pleural and peritoneal mesothelial cells can develop MM in response to asbestos, however, pleural MM (85%) is more common than peritoneal MM (15%). To get an insight of this difference we first isolated exosomes from pleural (Hmeso, H2373) and peritoneal (ORT) MM cells and performed proteomic analysis. We found that 45 proteins are common and specific to MM cells derived from pleural cavity (Hmeso/H2373) while 86 proteins are specific to ORT cells lines derived from peritoneal cavity. On the other hand, the non-transformed mesothelial cell line, LP9, showed a completely different profile with 269 proteins secreted in exosomes not shared with MM models. This led us to hypothesize that mesothelial cells of two different locations may have different susceptibility to asbestos, accounting for differences observed in pleural and peritoneal MM. To test this hypothesis we exposed human primary pleural and peritoneal mesothelial cells to asbestos for 8 h, and performed massively parallel sequencing on the RNA. Gene expression analysis performed on the RNA-Seq data showed a higher magnitude of responses from pleural mesothelial cells as compared to peritoneal mesothelial cells for the same genes. In addition, at a p&amp;lt;0.05 and 2-fold threshold, unique genes expressed in pleural mesothelium were pro-inflammatory genes known to be involved in MM tumorigenesis. Taken together, results from our study suggest that exosomal cargo from pleural and peritoneal MM cells bear unique signatures which may be due to the different responses of pleural and peritoneal mesothelial cells to asbestos. Future directions involve assessing miRNA cargo from exosomes of pleural and peritoneal MM cells and identifying potential biomarker candidates. This work is supported by grants from NIH (RO1 ES021110), DoD (W81XWH-14-1-0199) and the University of Vermont Cancer Center/Lake Champlain Cancer Research Organization. Citation Format: Arti Shukla, Phillip Munson, Joyce K. Thompson, Julie Dragon, Maximilian B. MacPherson, Hector Peinado. Unique pleural vs peritoneal mesothelioma exosomal signature: does mesothelial cell susceptibility to asbestos matter. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3892.
Abstract 5160: Establishment of <i>in vitro</i> carcinogenic model of high-grade serous ovarian carcinoma using immortalized fallopian tubal secretory epithelial cell
Authors: Kohei Nakamura, Kentaro Nakayama, Tohru Kiyono, Noriyoshi Ishikawa, Masako Ishikawa, Hiroshi Katagiri, Toshiko Minamoto, Tomoka Ishibashi, Emi Sato, Kaori Sanuki, Hitomi Yamashita, Kouji Iida, Razia Sultana, Satoru Kyo
Journal: Cancer Research (2016)

Abstract High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in the world. Recent studies suggest that fallopian tubal secretory epithelial cells (FTSECs) are candidates for the origin of HGSOC. Several genetic alterations involved in the carcinogenesis have been reported in HGSOC, but their minimal requirement and the specific combinations remained unclear. To clarify these points, we established an in vitro stepwise carcinogenesis model using immortalized FTSECs with overexpressed cyclinD1/cdk4 and hTERT, in which we additionally mimicked selected genetic abnormalities frequently observed in clinical samples. Mutational analysis using clinical samples of HGSOCs identified frequent p53 mutations (96%). Furthermore, RAS/PI3K pathway is important signaling pathway and was deregulated in 45% of HGSOCs. PI3K/AKT pathway is also important pathway in HGSOCs. Thus, we introduced dominant negative form of p53 alone or in combination with oncogenic mutant KRAS allele into immortalized cells, but both failed to exhibit tumorigenic phenotypes. Additional introduction of genetic factors were attempted, and overexpression of c-Myc or phosphorylated Akt (p-Akt) were independently found to confer tumorigenic phenotypes. Importantly, all transformed FTSECs exhibited high-grade serous carcinomas that were grossly, histologically, and immunohistochemically similar to human HGSOCs. Thus, p53/KRAS/c-Myc or p53/KRAS/PI3K-AKT pathways were determined to be minimal required for carcinogenesis. The strength of our study is the use of immortalized FTSECs that have original characteristics of fallopian tube as well as the introduction of genetic mutations clinically observed in human HGSOCs. This experimental model provides a foundation for future studies of early events in carcinogenesis of HGSOCs and the identification of candidate targets for drug development and secreted biomarkers for early detection. It is also likely that a similar model can be broadly applied to studying the normal biology of other epithelial cells where precursor lesions and malignant counterparts are not entirely understood. Citation Format: Kohei Nakamura, Kentaro Nakayama, Tohru Kiyono, Noriyoshi Ishikawa, Masako Ishikawa, Hiroshi Katagiri, Toshiko Minamoto, Tomoka Ishibashi, Emi Sato, Kaori Sanuki, Hitomi Yamashita, Kouji Iida, Razia Sultana, Satoru Kyo. Establishment of in vitro carcinogenic model of high-grade serous ovarian carcinoma using immortalized fallopian tubal secretory epithelial cell. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5160.
Abstract LB-330: Somatic copy number alterations at oncogenic loci show diverse correlations with gene expression
Authors: Jason Roszik, Ching Jiun Wu, Alan E. Siroy, Alexander J. Lazar, Michael A. Davies, Scott Woodman, Lawrence N. Kwong
Journal: Cancer Research (2016)

Abstract Somatic copy number alterations (SCNAs) affecting oncogenic drivers have a firmly established role in promoting cancer. However, no agreed-upon standard exists for calling locus-specific amplifications and deletions in each patient sample. Here, we report the correlative analysis of copy number amplitude and length with gene expression across 6,109 samples from The Cancer Genome Atlas (TCGA) dataset across 16 cancer types. Using specificity, sensitivity, and precision-based scores, we analyzed over 30 recurrently focally altered loci that had sufficient pan-cancer penetrance for robust statistical assessment. We were able to assign optimized amplitude and length cutoffs for nine recurrent SCNAs affecting known oncogenic drivers, using mRNA expression as a functional readout. These cutoffs captured the majority of SCNA-driven, highly-expression-altered samples. The majority of oncogenes required only amplitude cutoffs, as high amplitude samples were almost invariably focal; however, CDKN2A and PTEN uniquely required both amplitude and length cutoffs as primary predictors. For PTEN, these extended to downstream AKT activation. In contrast, the remaining 20+ assessed SCNA genes, particularly ones located peri-telomerically or in fragile sites, showed poor expression-copy number correlations. Finally, we describe several novel associations between copy number and gene expression that have implications for how SCNAs are assessed as harboring candidate cancer driver genes. Overall, our analyses identify optimized amplitude and length cutoffs as efficient predictors of gene expression changes for specific oncogenic SCNAs, yet warn against one-size-fits-all interpretations across all loci. Our results have implications for cancer data analyses and the clinic, where copy number and mutation data are increasingly used to personalize cancer therapy. Citation Format: Jason Roszik, Ching Jiun Wu, Alan E. Siroy, Alexander J. Lazar, Michael A. Davies, Scott Woodman, Lawrence N. Kwong. Somatic copy number alterations at oncogenic loci show diverse correlations with gene expression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-330.
Abstract 4544: FBW7 induces S-phase arrest caused by DNA double strand breaks through targeting SOX9 for proteasomal degradation
Authors: Xuehui Hong, Wenyu Liu, Ruipeng Song, Hiroyuki Inuzuka, Hatem E. Sabaawy, Katherine M. Morgan, Jamie J. Shah, Samuel F. Bunting, Xing Feng, Chi-Kwan Tsang, Zhiyuan Shen, X. F. Steven Zheng, LianXin Liu, Sharon R. Pine
Journal: Cancer Research (2016)

Abstract SOX9 encodes a transcription factor that governs cell fate specification throughout development and tissue homeostasis. Elevated SOX9 is implicated in the genesis or progression of many human tumors through increasing cell proliferation and epithelial-mesenchymal transition. We observed that, in response to UV irradiation or certain chemotherapeutic agents, SOX9 is actively and rapidly degraded by a ubiquitin pathway dependent mechanism across several different tumor types including lung cancer, colon cancer, osteosarcoma and melanoma, as well as normal human bronchial epithelial cells. We found that SOX9 is phosphorylated by GSK3β at Ser-236, facilitating the direct binding and degradation of SOX9 via the F box protein, FBW7α. We also determined that the de-ubiquitinase, USP28, stabilizes SOX9 under normal conditions by sequestering FBW7, but is released from FBW7 after UV irradiation, allowing FBW7 to bind SOX9 and target it for destruction. DNA damage-induced SOX9 degradation was independent of p53, ATM, ATR and MAPK pathways. Failure to deplete SOX9 attenuated the DNA damage-induced intra-S-phase checkpoint and increased long-term cell survival. Moreover, mutations within the FBW7 phosphodegron binding site of SOX9 prevented SOX9 degradation after DNA damage, and incurred resistance of non-small cell lung cancer (NSCLC) cells to cisplatin in vivo. We found that cancer patients with tumors expressing high Sox9 and low Fbw7 levels exhibit inferior survival. Our discovery reveals a novel function of SOX9 in the cellular response to DNA damage. Induced degradation of SOX9 may be part of the protection mechanisms to maintain genomic stability. This new regulatory mechanism of the FBW7-SOX9 axis in cancer could have diagnostic and therapeutic implications. Citation Format: Xuehui Hong, Wenyu Liu, Ruipeng Song, Hiroyuki Inuzuka, Hatem E. Sabaawy, Katherine M. Morgan, Jamie J. Shah, Samuel F. Bunting, Xing Feng, Chi-Kwan Tsang, Zhiyuan Shen, X. F. Steven Zheng, LianXin Liu, Sharon R. Pine. FBW7 induces S-phase arrest caused by DNA double strand breaks through targeting SOX9 for proteasomal degradation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4544.
<i>Smad7</i> gene delivery prevents muscle wasting associated with cancer cachexia in mice
Authors: Catherine E. Winbanks, Kate T. Murphy, Bianca C. Bernardo, Hongwei Qian, Yingying Liu, Patricio V. Sepulveda, Claudia Beyer, Adam Hagg, Rachel E. Thomson, Justin L. Chen, Kelly L. Walton, Kate L. Loveland, Julie R. McMullen, Buel D. Rodgers, Craig A. Harrison, Gordon S. Lynch, Paul Gregorevic
Journal: Science Translational Medicine (2016)

Muscle-directed Smad7 gene delivery prevents the loss of skeletal muscle mass and strength in mouse models of cachexia, an important contributor to poor prognosis in patients with advanced cancer.