tbuckley/cabot-search huggingface dataset:
Results of a Phase I/II Study of the Combination of 5-aza-2′-Deoxycytidine (DAC) and Valproic Acid (VPA) in Patients (pts) with Leukemia.
Authors: Guillermo Garcia-Manero, Hagop Kantarjian, Blanca Sanchez-Gonzalez, Stefan Faderl, Srdan Verstovsek, Farhad Ravandi, Michael Ryttling, Jorge Cortes, William Wierda, Koyu Hoshino, Hui Yang, Claritsa Santos-Malave, Jackie Fiorentino, Elias Jabbour, Gary Rosner, Jean-Pierre Issa
Journal: Blood (2004)
CD4+ T Cell Help Is Required for the Formation of a Cytolytic CD8+ T Cell Subset that Protects against Chronic Infection and Cancer
Authors: Ryan Zander, David Schauder, Gang Xin, Christine Nguyen, Xiaopeng Wu, Allan Zajac, Weiguo Cui
Journal: Immunity (2019)

Although CD4+ T cell "help" is crucial to sustain antiviral immunity, the mechanisms by which CD4+ T cells regulate CD8+ T cell differentiation during chronic infection remain elusive. Here, using single-cell RNA sequencing, we show that CD8+ T cells responding to chronic infection were more heterogeneous than previously appreciated. Importantly, our findings uncovered the formation of a CX3CR1-expressing CD8+ T cell subset that exhibited potent cytolytic function and was required for viral control. Notably, our data further demonstrate that formation of this cytotoxic subset was critically dependent on CD4+ T cell help via interleukin-21 (IL-21) and that exploitation of this developmental pathway could be used therapeutically to enhance the killer function of CD8+ T cells infiltrated into the tumor. These findings uncover additional molecular mechanisms of how "CD4+ T cell help" regulates CD8+ T cell differentiation during persistent infection and have implications toward optimizing the generation of protective CD8+ T cells in immunotherapy.
Limited expression of TLR9 on T cells and its functional consequences in patients with nonalcoholic fatty liver disease
Authors: Nadia Soledad Alegre, Cecilia Claudia Garcia, Luis Ariel Billordo, Beatriz Ameigeiras, Daniel Poncino, Javier Benavides, Luis Colombato, Alejandra Claudia Cherñavsky
Journal: Clinical and Molecular Hepatology (2019)

Toll-like receptors (TLRs) modulate T cell responses in diverse diseases. Co-stimulation of T cell activation via TLR9 induces production of interferon gamma (IFN-γ), priming of which is critical for differentiation of pro-inflammatory macrophages. These macrophages have a crucial role in nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the expression of TLR9 protein on T cells and the consequences of TLR9-mediated triggering of these cells in patients with NAFLD.Our study included 34 patients with simple steatosis, 34 patients with nonalcoholic steatohepatitis, eight patients with NAFLD who met general diagnostic criteria but lacked histological diagnosis, and 51 control subjects. We used a synthetic TLR9 ligand to co-stimulate T cells. We measured TLR9 expression in liver and peripheral T cells and CD69 and IFN-γ as phenotypic markers of T cell activation and differentiation by flow cytometry.TLR9 expression on liver and peripheral T cells was lowest in patients with simple steatosis and was positively associated with anthropometric, biochemical, and histopathological features of NAFLD. In vitro co-stimulation of T cells from patients with simple steatosis induced a limited number of IFN-γ-producing CD8+ T cells. At baseline, these patients showed a low frequency of circulating type 1 CD8+ cells.The positive associations between TLR9 and anthropometric, clinical, and histological features and the crucial role of IFN-γ-in NAFLD suggest that limited TLR9 expression and production of IFN-γ play a protective role in patients with simple steatosis.
Ubrogepant for the Treatment of Migraine
Authors: David W. Dodick, Richard B. Lipton, Jessica Ailani, Kaifeng Lu, Michelle Finnegan, Joel M. Trugman, Armin Szegedi
Journal: New England Journal of Medicine (2019)

Ubrogepant is an oral, small-molecule calcitonin gene-related peptide receptor antagonist for acute migraine treatment.We conducted a randomized trial to evaluate the efficacy, safety, and side-effect profile of ubrogepant. We assigned adults with migraine, with or without aura, in a 1:1:1 ratio to receive an initial dose of placebo, ubrogepant at a dose of 50 mg, or ubrogepant at a dose of 100 mg for treatment of a single migraine attack, with the option to take a second dose. The coprimary efficacy end points were freedom from pain at 2 hours after the initial dose and absence of the most bothersome migraine-associated symptom at 2 hours. Secondary end points included pain relief (at 2 hours), sustained pain relief (from 2 to 24 hours), sustained freedom from pain (from 2 to 24 hours), and absence of symptoms associated with migraine (photophobia, phonophobia, and nausea) at 2 hours.A total of 1672 participants were enrolled; 559 were assigned to receive placebo, 556 to receive 50 mg of ubrogepant, and 557 to receive 100 mg of ubrogepant. The percentage of participants who had freedom from pain at 2 hours was 11.8% in the placebo group, 19.2% in the 50-mg ubrogepant group (P = 0.002, adjusted for multiplicity, for the comparison with placebo), and 21.2% in the 100-mg ubrogepant group (P<0.001). The percentage of participants who had freedom from the most bothersome symptom at 2 hours was 27.8% in the placebo group, 38.6% in the 50-mg ubrogepant group (P = 0.002), and 37.7% in the 100-mg ubrogepant group (P = 0.002). Adverse events within 48 hours after the initial or optional second dose were reported in 12.8% of participants in the placebo group, in 9.4% in the 50-mg ubrogepant group, and in 16.3% in the 100-mg ubrogepant group. The most common adverse events were nausea, somnolence, and dry mouth (reported in 0.4 to 4.1%); these events were more frequent in the 100-mg ubrogepant group (reported in 2.1 to 4.1%). Serious adverse events reported within 30 days in the ubrogepant groups included appendicitis, spontaneous abortion, pericardial effusion, and seizure; none of the events occurred within 48 hours after the dose.A higher percentage of participants who received ubrogepant than of those who received placebo had freedom from pain and absence of the most bothersome symptom at 2 hours after the dose. The most commonly reported adverse events were nausea, somnolence, and dry mouth. Further trials are needed to determine the durability and safety of ubrogepant for acute migraine treatment and to compare it with other drugs for migraine. (Funded by Allergan; ClinicalTrials.gov number, NCT02828020.).
What is the evidence for interactions between filaggrin null mutations and environmental exposures in the aetiology of atopic dermatitis? A systematic review
Authors: H. Blakeway, V. Van‐de-Velde, V.B. Allen, G. Kravvas, L. Palla, M.J. Page, C. Flohr, R.B. Weller, A.D. Irvine, T. McPherson, A. Roberts, H.C. Williams, N. Reynolds, S.J. Brown, L. Paternoster, S.M. Langan
Journal: British Journal of Dermatology (2019)

Background Epidemiological studies indicate that gene–environment interactions play a role in atopic dermatitis (AD). Objectives To review the evidence for gene–environment interactions in AD aetiology, focusing on filaggrin (FLG) loss-of-function mutations. Methods A systematic search from inception to September 2018 in Embase, MEDLINE and BIOSIS was performed. Search terms included all synonyms for AD and filaggrin/FLG; any genetic or epidemiological study design using any statistical methods were included. Quality assessment using criteria modified from guidance (ROBINS-I and Human Genome Epidemiology Network) for nonrandomized and genetic studies was completed, including consideration of power. Heterogeneity of study design and analyses precluded the use of meta-analysis. Results Of 1817 papers identified, 12 studies fulfilled the inclusion criteria required and performed formal interaction testing. There was some evidence for FLG–environment interactions in six of the studies (P-value for interaction ≤ 0·05), including early-life cat ownership, older siblings, water hardness, phthalate exposure, higher urinary phthalate metabolite levels (which all increased AD risk additional to FLG null genotype) and prolonged breastfeeding (which decreased AD risk in the context of FLG null genotype). Major limitations of published studies were the low numbers of individuals (ranging from five to 94) with AD and FLG loss-of-function mutations and exposure to specific environmental factors, and variation in exposure definitions. Conclusions Evidence on FLG–environment interactions in AD aetiology is limited. However, many of the studies lacked large enough sample sizes to assess these interactions fully. Further research is needed with larger sample sizes and clearly defined exposure assessment. Linked Comment: Park and Seo. Br J Dermatol 2020; 183:411.
Upregulation of PUM1 Expression in Preeclampsia Impairs Trophoblast Invasion by Negatively Regulating the Expression of the lncRNA HOTAIR
Authors: Yan Zhang, Xiao-Ying He, Shi Qin, Hui-Qin Mo, Xiao Li, Fan Wu, Jing Zhang, Xing Li, Lin Mao, Ya-Qing Peng, Yu-Na Guo, Yi Lin, Fu-Ju Tian
Journal: Molecular Therapy (2019)

Pumilio (PUM) proteins are members of a highly conserved RNA-binding protein family that posttranscriptionally regulate gene expression in many organisms. However, their roles in the placenta are unclear. In the present study, we report the requirement for the PUM homolog 1 (PUM1) gene in preeclampsia (PE). Immunofluorescence and immunohistochemical data showed that PUM1 was highly expressed in human placental villi from women with PE compared to healthy controls (HCs). Further, PUM1 overexpression repressed, and knockdown enhanced, the invasion and proliferation of trophoblasts. Interestingly, PUM1 knockdown promoted trophoblast invasion in a villous explant culture model, while PUM1 overexpression repressed these effects. Furthermore, lncRNA transcriptome sequencing coupled with RNA immunoprecipitation (RIP) revealed that PUM1 inhibits trophoblast invasion in PE by downregulating the expression of lncRNA HOTAIR. Moreover, PUM1 regulates HOTAIR expression via a posttranscriptional mechanism. Using RNA-protein pull-down and mRNA stability assays, we identified PUM1 as a specific binding partner that decreased the half-life of HOTAIR and lowered the steady-state level of HOTAIR expression, suggesting a novel posttranscriptional regulatory mechanism. Collectively, these findings identified a novel RNA regulatory mechanism, revealing a new pathway governing the regulation of PUM1/HOTAIR in trophoblast invasion in the pathogenesis of PE.
TBK1 Is a Synthetic Lethal Target in Cancer with <i>VHL</i> Loss
Authors: Lianxin Hu, Haibiao Xie, Xijuan Liu, Frances Potjewyd, Lindsey I. James, Emily M. Wilkerson, Laura E. Herring, Ling Xie, Xian Chen, Johnny Castillo Cabrera, Kai Hong, Chengheng Liao, Xianming Tan, Albert S. Baldwin, Kan Gong, Qing Zhang
Journal: Cancer Discovery (2019)

Abstract TANK binding kinase 1 (TBK1) is an important kinase involved in the innate immune response. Here we discover that TBK1 is hyperactivated by von Hippel-Lindau (VHL) loss or hypoxia in cancer cells. Tumors from patients with kidney cancer with VHL loss display elevated TBK1 phosphorylation. Loss of TBK1 via genetic ablation, pharmacologic inhibition, or a new cereblon-based proteolysis targeting chimera specifically inhibits VHL-deficient kidney cancer cell growth, while leaving VHL wild-type cells intact. TBK1 depletion also significantly blunts kidney tumorigenesis in an orthotopic xenograft model in vivo. Mechanistically, TBK1 hydroxylation on Proline 48 triggers VHL as well as the phosphatase PPM1B binding that leads to decreased TBK1 phosphorylation. We identify that TBK1 phosphorylates p62/SQSTM1 on Ser366, which is essential for p62 stability and kidney cancer cell proliferation. Our results establish that TBK1, distinct from its role in innate immune signaling, is a synthetic lethal target in cancer with VHL loss. Significance: The mechanisms that lead to TBK1 activation in cancer and whether this activation is connected to its role in innate immunity remain unclear. Here, we discover that TBK1, distinct from its role in innate immunity, is activated by VHL loss or hypoxia in cancer. See related commentary by Bakouny and Barbie, p. 348. This article is highlighted in the In This Issue feature, p. 327
Chronic diarrhea, bile acids, and Clostridia
Authors: Julian R.F. Walters, Julian R. Marchesi
Journal: Journal of Clinical Investigation (2019)

Excessive fecal bile acid (BA) loss causes symptoms in a large proportion of people diagnosed with irritable bowel syndrome with diarrhea, a common functional bowel disorder. This BA diarrhea (BAD) results from increased hepatic synthesis of BAs, with impaired negative feedback regulation by the ileal hormone fibroblast growth factor 19 (FGF19). In this issue of the JCI, Zhao et al. investigated BA metabolism, including fecal BAs, serum BAs, and FGF19, in patients and controls. They identified associations between fecal bacterial BA metabolism and specific microbiota, especially Clostridium scindens. These findings have been tested in a mouse model using microbiota transplants and antibiotic treatment. This group of organisms has potential as a biomarker for BAD and to be a target for therapy.
Low Incidence of FIP1L1-PDGFRA in Eosinophilic Patients and Long-Term Experience with Imatinib Therapy.
Authors: Animesh D. Pardanani, Rhett P. Ketterling, Chin-Yang Li, Alexandra P. Wolanskyj, Michelle A. Elliott, John K. Camoriano, Joseph H. Butterfield, Gordon W. Dewald, Ayalew Tefferi
Journal: Blood (2005)
대한간학회 제 8 차 춘계학술대회 초록집 : 간이식 후 B 형 간염 재발방지를 위한 저용량 헤파빅 근주 및 라미부딘 병용효과
Authors: 한준열, 정규원, 선희식, 윤승규, 차상복, 장정원, 배시현, 최종영, 조세현, 박두호, 남순우, 이창돈, 양진모, 김동구
Journal: Clinical and Molecular Hepatology (2002)
Association of Sex With Toxic Effects, Treatment Adherence, and Oncologic Outcomes in the CAO/ARO/AIO-94 and CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trials of Rectal Cancer
Authors: Markus Diefenhardt, Ethan B. Ludmir, Ralf-Dieter Hofheinz, Michael Ghadimi, Bruce D. Minsky, Claus Rödel, Emmanouil Fokas
Journal: JAMA Oncology (2019)

This pooled analysis of data from phase 3 randomized clinical trials assesses the association of sex with toxic effects, treatment adherence, surgical procedures, and long-term outcomes after standard multimodal treatment in patients with rectal cancer.
Functional Characterization of Genes Driving Enhanced Biological Aggressiveness of Myeloma Cells: Identification of Novel and Understudied "Drivers" of Myeloma
Authors: Huihui Tang, Ryosuke Shirasaki, Ricardo De Matos Simoes, Sara Gandolfi, Olga Dashevsky, Sondra L. Downey-Kopyscinski, Brian Glassner, Michal Sheffer, Megan Bariteau, John G Doench, Constantine S. Mitsiades
Journal: Blood (2019)
Does chemotherapy improve survival in muscle-invasive bladder cancer (MIBC)? A systematic review and meta-analysis (MA) of randomized controlled trials (RCT).
Authors: Angelina Tjokrowidjaja, Chee Lee, Martin R. Stockler
Journal: Journal of Clinical Oncology (2013)

4544 Background: There is strong evidence that neoadjuvant chemotherapy improves survival in MIBC but its uptake in clinical practice is variable. The benefits of adjuvant chemotherapy are controversial, especially with the recent presentation of 3 RCTs not included in previous MA.We sought to summarise the effects of chemotherapy, both neoadjuvant and adjuvant, on survival in MIBC. Methods: We included published summary data from recent MA and RCTs. Eligible RCTs compared the addition of chemotherapy, neoadjuvant or adjuvant, to local treatment versus local treatment alone. We searched CENTRAL, PubMed, MEDLINE, proceedings of ASCO and clinicaltrials.gov from 2004 to August 2012.The primary outcome was overall survival (OS). Disease-free survival (DFS) and adverse events (AE) were secondary outcomes. Pooled hazard ratios (HR), confidence intervals (CI) and p-values (p) were estimated with fixed effects model. Heterogeneity and subgroup effects were assessed with p-values for interaction. Results: We included 21 RCTs (n=3986), 12 of neoadjuvant (n=3047) and 9 adjuvant chemotherapy (n=939).The addition of chemotherapy significantly improved OS (HR 0.86, 95% CI 0.79 to 0.93, p=0.0004). Separate analyses of neoadjuvant therapy and adjuvant therapy yielded significant results in both subgroups (HR 0.89, 95% CI 0.81 to 0.98, p=0.02; HR 0.75, 95% CI 0.63 to 0.90, p=0.002; respectively; p-value for interaction 0.11). There were larger benefits in DFS (HR 0.77, 95% CI 0.71 to 0.84, p&lt;0.000001), which were also noted with the addition of neoadjuvant and adjuvant therapy (HR 0.80 95% CI 0.73 to 0.88, p&lt;0.00001; HR 0.67 95% CI 0.55 to 0.81, p&lt;0.0001; respectively; p-value for interaction 0.10). The most common AE of grade 3 or 4 were haematological, gastrointestinal and renal impairment with median frequencies of 33%, 15% and 2% respectively in neoadjuvant; and 15%, 21% and 27% in adjuvant trials. Conclusions: Meta-analysis of available randomized trials indicates that chemotherapy, both adjuvant and neoadjuvant, improves survival in MIBC. A direct comparison of these two strategies in a large scale randomised trial is needed to determine which is optimal.
Neutrophil Counts Could Predict the Response to Immunosuppressive Treatment with Antithymocyte Globulin and Cyclosporine in the Patients with Severe Aplastic Anemia
Authors: Myung Hee Chang, Dong Hwan Kim, Kyoung Ha Kim, Hee Kyung Ahn, Su Jin Lee, Jun Ho Jang, Kihyun Kim, Chul Won Jung
Journal: Blood (2008)
The Unfolded Protein Response Causes Prothrombotic Transformation of Pancreatic Cancer Linking Tumor Progression with Cancer-Associated Thrombosis
Authors: Oluwatoyosi Muse, Rushad Patell, Christian Peters, Sol Schulman, Emale Darzi, Calvin Schuster, Ling Huang, Shibani Mukherjee, Senthil Muthuswamy, Jeffrey I. Zwicker, Robert C. Flaumenhaft
Journal: Blood (2019)
Interactions between Myeloma Cells and Osteoclasts Are Controlled by Unique Histological Structures Involving Vascular Compartments.
Authors: Thomas L. Andersen, Katarzyna E. Skorzynska, Teis E. Sondergaard, Trine Plesner, Ellen Hauge, Juha Risteli, Torben Plesner, Jean-Marie Delaisse
Journal: Blood (2005)
Gender dysphoria: puberty blockers and loss of bone mineral density
Authors: Grant Ferguson, Peter Simm, Michele O'Connell, Ken C Pang
Journal: BMJ (2019)

Cohen and Barnes clearly articulate the ongoing debate on the effects of puberty blockers (gonadotrophin releasing hormone (GnRH) agonists) on bone mineral density in trans and gender diverse young people.1 Contention remains as to whether use of GnRH agonists in adolescents causes slow bone accrual, static accrual, or bone loss. Contributing to the confusion is that previous studies have focused on mean changes in …
Exaggerated acoustic startle reflex in Gulf War veterans with posttraumatic stress disorder
Authors: C A Morgan, C Grillon, S M Southwick, M Davis, D S Charney
Journal: American Journal of Psychiatry (1996)

Exaggerated startle reflex is reputed to be one of the cardinal symptoms of posttraumatic stress disorder (PTSD). The goal of this study was to assess the magnitude of the acoustic startle reflex in Gulf War veterans with PTSD.The eye-blink component of the startle reflex was measured in response to six blocks of pseudorandomized 40-msec white noise bursts of varying intensities (90, 96, 102, 108, and 114 dB) in 10 Gulf War veterans with PTSD, seven Gulf War veterans without PTSD, and 15 civilian subjects without PTSD.The magnitude of the first startle response, as well as the magnitude of startle response averaged across blocks of testing, was significantly greater in Gulf War veterans with PTSD than in veteran and civilian comparison groups.Consistent with some clinical studies investigating the startle response in Vietnam veterans with PTSD, this investigation provides evidence for exaggerated startle response in this disorder. Preclinical studies of shock sensitization of the startle response suggest that the higher levels of startle response seen in the PTSD subjects may reflect a sensitization of the fear/alarm response created by the stress of combat trauma.
Terminal Delirium in the Opera Kopernikus
Authors: Joshua Wales
Journal: JAMA (2019)

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Ifomide/pirarubicin/etoposide/carboplatin (ITEC) as second-line chemotherapy for hepatoblastoma.
Authors: Eiso Hiyama, Arata Kamimatsuse, Kaoru Ogura, Tomoro Hishiki, Kenichiro Watanabe, Michihiro Yano, Satoshi Kondo, Tatsuro Tajiri, Kohmei Ida, Fumiaki Sasaki
Journal: Journal of Clinical Oncology (2012)

9577 Background: The Japanese Study Group for Pediatric Liver Tumor is running cooperative treatment studies on hepatoblastoma (HBL) since 1991. The main aim in JPLT-1 study was to evaluate the efficacy of cisplatin/pirarubicin (CITA). A total of 145 cases were registered and their 5-year overall survival (OS) and event-free survival (EFS) were 73.4% and 66%, respectively (J Pediatr Surg 37: 851-6, 2002). Then, JPLT-2 protocol, in which CITA is kept as the first-line treatment, and ifomide, etoposide, pirarubicin, and carboplatin (ITEC) is the second-line regimen for CITA-resistant cases, was launched to evaluate the cure rate of risk-stratified HBL: standard risk HBL (a tumor involving three or fewer sectors of the liver) and high risk HBL (a tumor involving all sectors of the liver or with metastasis). Methods: In JPLT-2, 281 HBL cases were registered in JPLT-2 between 1999 and 2010, and 69 cases underwent ITEC protocol due to poor response to the CITA regimen. To evaluate the efficacy of the ITEC regimen, surgical resectability and outcome of these 69 patients who underwent this treatment. Results: These 69 cases were divided into 53 high-risk (metastatic, involvement of all sectors of the liver, vascular invasion and/or extra-hepatic intra-abdominal disease) and 16 standard-risk HBL (all others). All cases were initially treated with the CITA regimen and then underwent the ITEC regimen due to poor response to CITA. Complete resection of the liver tumor could be achieved in 48 patients (69.6%) consisting of 13 (81%) standard, 35 (66%) high- risk cases. The 5-year OS and EFS of the cases with standard risk HB were 96% and 76%, while that of the cases with high risk HB was 54% and 34%. The late phase complications in 281 cases were 3 cases with maldevelopment, 13 with cardiac complications, 20 with ototoxicity and 5 with second malignancies. Conclusions: As compared with the CITA-sensitive cases, ITEC regimen achieved similar rates of survival for CITA-resistant cases both in standard and high-risk HBL cases, indicating ITEC is effective as a second-line chemotherapeutic regimen for HBL.