tbuckley/cabot-search huggingface dataset:
Hepatic Slug epigenetically promotes liver lipogenesis, fatty liver disease, and type 2 diabetes
Authors: Yan Liu, Haiyan Lin, Lin Jiang, Qingsen Shang, Lei Yin, Jiandie D. Lin, Wen-Shu Wu, Liangyou Rui
Journal: Journal of Clinical Investigation (2020)

De novo lipogenesis is tightly regulated by insulin and nutritional signals to maintain metabolic homeostasis. Excessive lipogenesis induces lipotoxicity, leading to nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. Genetic lipogenic programs have been extensively investigated, but epigenetic regulation of lipogenesis is poorly understood. Here, we identified Slug as an important epigenetic regulator of lipogenesis. Hepatic Slug levels were markedly upregulated in mice by either feeding or insulin treatment. In primary hepatocytes, insulin stimulation increased Slug expression, stability, and interactions with epigenetic enzyme lysine-specific demethylase-1 (Lsd1). Slug bound to the fatty acid synthase (Fasn) promoter where Slug-associated Lsd1 catalyzed H3K9 demethylation, thereby stimulating Fasn expression and lipogenesis. Ablation of Slug blunted insulin-stimulated lipogenesis. Conversely, overexpression of Slug, but not a Lsd1 binding-defective Slug mutant, stimulated Fasn expression and lipogenesis. Lsd1 inhibitor treatment also blocked Slug-stimulated lipogenesis. Remarkably, hepatocyte-specific deletion of Slug inhibited the hepatic lipogenic program and protected against obesity-associated NAFLD, insulin resistance, and glucose intolerance in mice. Conversely, liver-restricted overexpression of Slug, but not the Lsd1 binding-defective Slug mutant, had the opposite effects. These results unveil an insulin/Slug/Lsd1/H3K9 demethylation lipogenic pathway that promotes NAFLD and type 2 diabetes.
Durability of Cross-Protection by Different Schedules of the Bivalent HPV Vaccine: The CVT Trial
Authors: Sabrina H Tsang, Joshua N Sampson, John Schussler, Carolina Porras, Sarah Wagner, Joseph Boland, Bernal Cortes, Douglas R Lowy, John T Schiller, Mark Schiffman, Troy J Kemp, Ana Cecilia Rodriguez, Wim Quint, Mitchell H Gail, Ligia A Pinto, Paula Gonzalez, Allan Hildesheim, Aimée R Kreimer, Rolando Herrero
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Background The Costa Rica HPV Vaccine Trial has documented cross-protection of the bivalent HPV vaccine against HPV31/33/45 up to 7 years after vaccination, even with one dose of the vaccine. However, the durability of such protection remains unknown. Here, we evaluate the efficacy of different schedules of the vaccine against HPV31/33/45 out to 11 years postvaccination, expanding to other nontargeted HPV types. Methods We compared the rates of HPV infection in vaccinated women with the rates in a comparable cohort of unvaccinated women. We estimated the average vaccine efficacy (VEavg) against incident infections and tested for a change in VE over time. Results Among 3-dose women, we observed statistically significant cross-protection against HPV31/33/45 (VEavg = 64.4%, 95% confidence interval [CI] = 57.7% to 70.0%). Additionally, we observed borderline, statistically significant cross-protection against HPV35 (VEavg = 23.2%, 95% CI = 0.3% to 40.8%) and HPV58 (VEavg = 21.2%, 95% CI = 4.2% to 35.3%). There was no decrease in VE over time (two-sided Ptrend &amp;gt; .05 for HPV31, -33, -35, -45, and -58). As a benchmark, VEavg against HPV16/18 was 82.0% (95% CI = 77.3% to 85.7%). Among 1-dose women, we observed comparable efficacy against HPV31/33/45 (VEavg = 54.4%, 95% CI = 21.0% to 73.7%). Acquisition of nonprotected HPV types was similar between vaccinated and unvaccinated women, indicating that the difference in HPV infection rates was not attributable to differential genital HPV exposure. Conclusions Substantial cross-protection afforded by the bivalent vaccine against HPV31/33/45, and to a lesser extent, HPV35 and HPV58, was sustained and remained stable after 11 years postvaccination, reinforcing the notion that the bivalent vaccine is an effective option for protection against HPV-associated cancers.
Targeting Hepatic Glutaminase 1 Ameliorates Non-alcoholic Steatohepatitis by Restoring Very-Low-Density Lipoprotein Triglyceride Assembly
Authors: Jorge Simon, Maitane Nuñez-García, Pablo Fernández-Tussy, Lucía Barbier-Torres, David Fernández-Ramos, Beatriz Gómez-Santos, Xabier Buqué, Fernando Lopitz-Otsoa, Naroa Goikoetxea-Usandizaga, Marina Serrano-Macia, Rubén Rodriguez-Agudo, Maider Bizkarguenaga, Imanol Zubiete-Franco, Virginia Gutiérrez-de Juan, Diana Cabrera, Cristina Alonso, Paula Iruzubieta, Manuel Romero-Gomez, Sebastiaan van Liempd, Azucena Castro, Ruben Nogueiras, Marta Varela-Rey, Juan Manuel Falcón-Pérez, Erica Villa, Javier Crespo, Shelly C. Lu, Jose M. Mato, Patricia Aspichueta, Teresa C. Delgado, María Luz Martínez-Chantar
Journal: Cell Metabolism (2020)
Randomized phase III trial of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) or gemcitabine and cisplatin (GC) as perioperative chemotherapy for muscle invasive urothelial bladder cancer (MIUBC): Preliminary results of the GETUG/AFU V05 VESPER trial on toxicity and pathological responses.
Authors: Stephane Culine, Gwenaelle Gravis, Aude Flechon, Michel Soulie, Laurent Guy, Brigitte Laguerre, Nicolas Mottet, Florence Joly, Yves Allory, Valentin Harter, Christian Pfister
Journal: Journal of Clinical Oncology (2020)

437 Background: The optimal perioperative chemotherapy regimen for patients (pts) with MIUBC is not defined. Methods: Between February 2013 and February 2018, 494 pts were randomized in 28 French centres and received either 4 cycles of GC every 3 weeks or 6 cycles of dd-MVAC every 2 weeks before surgery (neoadjuvant group) or after surgery (adjuvant group). The primary endpoint was the progression-free survival at 3 years. Secondary endpoints included toxicity, pathological responses and overall survival. Results: In the neoadjuvant group, 218 pts received dd-MVAC and 219 pts GC. The median number of cycles was 6 (0-6) and 4 (1-4), respectively. 60% of pts received 6 cycles in the dd-MVAC arm, 84% received 4 cycles in the GC arm. 199 pts (91%) and 198 (90%) pts underwent surgery, respectively. Complete pathologic responses (ypT0pN0) were observed in 84 (42%) and 71 (36%) pts, respectively (p=0.02). An organ-confined status (&lt;ypT3pN0) was obtained in 154 (77%) and 124 (63%) pts, respectively (p=0.002). In the adjuvant group (57 pts), the median number of cycles was 5 (1-6) and 4 (1-4), respectively. 40% of pts received 6 cycles in the dd-MVAC arm, 60% received 4 cycles in the GC arm. Most of CTCAE grade ≥ 3 toxicities concerned hematological toxicities. At least one of these where reported for 125 (50%) pts in the dd-MVAC group and 134 (54%) pts in the GC group (p=NS). Gastrointestinal (GI) grade ≥ 3 disorders were more frequently observed in the dd-MVAC arm (p&lt;0.0001) as well as grade ≥ 3 asthenia (p&lt;0.00001). Four deaths (3 in the dd-MVAC) occurred during chemotherapy. Conclusions: Complete pathological responses and organ-confined status were more frequently observed in the dd-MVAC arm. Toxicity was manageable with more severe asthenia and GI side effects in the dd-MVAC arm. Clinical trial information: 2012-000563-25.
Antibody-mediated inhibition of syndecan-4 dimerisation reduces interleukin (IL)-1 receptor trafficking and signalling
Authors: Lars Godmann, Miriam Bollmann, Adelheid Korb-Pap, Ulrich König, Joanna Sherwood, Denise Beckmann, Katja Mühlenberg, Frank Echtermeyer, James Whiteford, Giulia De Rossi, Thomas Pap, Jessica Bertrand
Journal: Annals of the Rheumatic Diseases (2020)

Objective Syndecan-4 (sdc4) is a cell-anchored proteoglycan that consists of a transmembrane core protein and glucosaminoglycan (GAG) side chains. Binding of soluble factors to the GAG chains of sdc4 may result in the dimerisation of sdc4 and the initiation of downstream signalling cascades. However, the question of how sdc4 dimerisation and signalling affects the response of cells to inflammatory stimuli is unknown. Methods Sdc4 immunostaining was performed on rheumatoid arthritis (RA) tissue sections. Interleukin (IL)-1 induced extracellular signal-regulated kinases (ERK) phosphorylation and matrix metalloproteinase-3 production was investigated. Il-1 binding to sdc4 was investigated using immunoprecipitation. IL-1 receptor (IL1R1) staining on wild-type, sdc4 and IL1R1 knockout fibroblasts was performed in fluorescence-activated cell sorting analyses. A blocking sdc4 antibody was used to investigate sdc4 dimerisation, IL1R1 expression and the histological paw destruction in the human tumour necrosis factor-alpha transgenic mouse. Results We show that in fibroblasts, the loss of sdc4 or the antibody-mediated inhibition of sdc4 dimerisation reduces the cell surface expression of the IL-1R and regulates the sensitivity of fibroblasts to IL-1. We demonstrate that IL-1 directly binds to sdc4 and in an IL-1R-independent manner leads to its dimerisation. IL-1-induced dimerisation of sdc4 regulates caveolin vesicle-mediated trafficking of the IL1R1, which in turn determines the responsiveness to IL-1. Administration of antibodies (Ab) against the dimerisation domain of sdc4, thus, strongly reduces the expression IL1R1 on arthritic fibroblasts both in vitro and an animal model of human RA. Conclusion Collectively, our data suggest that Ab that specifically inhibit sdc4 dimerisation may support anti-IL-1 strategies in diseases such as inflammatory arthritis.
Fear of cancer recurrence among patients and survivors diagnosed with localized renal cell carcinoma.
Authors: Cristiane Decat Bergerot, Dena Battle, Errol James Philip, Paulo Gustavo Bergerot, Allan 'Ben' Smith, Kimryn Rathmell, Brian M. Shuch, Ithaar Derweesh, Eric Jonasch, Pavlos Msaouel, Sumanta K. Pal, Michael D. Staehler, Adam P. Stern
Journal: Journal of Clinical Oncology (2020)

649 Background: Fear of cancer recurrence (FCR) is considered one of the most pervasive and burdensome sources of distress for patients. Whereas it can be considered an adaptive response to real threats associated with diagnosis, treatment and disease, numerous studies have suggested that elevated levels can be dysfunctional. Despite this extensive body of research, little is known regarding FCR among individuals diagnosed with renal cell carcinoma (RCC). The current study sought to describe the prevalence of FCR among patients with RCC. Methods: Patients with localized RCC participated in an international survey from 07/19 to 09/19, through an online platform devised by a non-profit patient advocacy group (KCCure). Patients were assessed for FCR using the FCR-7, a 7-item measure, ranging from 0 to 28. A cutoff score of 17 indicates a moderate level of FCR, while a cutoff of 27 indicates severe level of FCR. Linear regression was used to determine the association between FCR and patients’ characteristics. Results: A total of 1150 patients participated in this survey, of which 412 had localized disease and were assessed for FCR. The majority were female (79%), with a median age of 54 years old (range, 30-80), and well-educated (58%). Patients were predominantly from US (85%), Canada (4%) and Germany (2%) and lived in suburban (48%) or rural areas (32%). More than half of participants were diagnosed with disease stage I (56%) and the remainder were divided between stage II (19%) and III (24%). More than half of patients (55%) reported a moderate or severe level of FCR. Younger patients (p=0.001) and those of female gender (p=0.004) were more likely to report higher levels of FCR. Conclusions: To our knowledge, this is the first study to quantify the degree of FCR among patients and survivors diagnosed with localized RCC. Importantly, high rates of FCR were associated with female gender and younger age, possibly driven by the fact that women may be more open to disclosing emotional symptoms and younger patients are still to pass through many life milestones and thus fear may be more pronounced. Targeted assessment and interventions are needed to address this highly prevalent form of distress among those diagnosed with RCC.
A tale of lineage plasticity: Intense neoadjuvant testosterone lowering therapy in localized prostate cancer (PCa) harboring high-risk genomic signatures.
Authors: Fatima Karzai, Ravi Amrit Madan, Adam G. Sowalsky, Marijo Bilusic, Guinevere Chun, Lisa M. Cordes, Scott C. Wilkinson, Nicholas Terrigino, Stephanie Harmon, Peter A. Pinto, Peter L. Choyke, Baris Turkbey, James L. Gulley, William L. Dahut
Journal: Journal of Clinical Oncology (2020)

368 Background: PCa is driven by androgen receptor (AR) signaling and neoadjuvant therapy with AR inhibitors offer an opportunity to improve cure rates in high-risk PCa particularly with utilization of multiparametric MRI (mpMRI). A loss of AR-regulated lineage characteristics and genomic loss of tumor suppressors RB1 and TP53 or mutations in DNA damage repair (DDR) genes can represent aggressive prostate variants. We conducted a feasibility study using mpMRI to evaluate tumor responses and resistance in newly diagnosed, high-risk PCa (NCT02430480). Methods: Pts were treated with androgen deprivation therapy (ADT) + enzalutamide (enza) 160 mg daily for 6 months (mos). Pts underwent 2 mpMRIs: baseline and post 6 mos treatment (trt). Post-trt mpMRI was followed by radical prostatectomy (RP). Primary endpoint: feasibility of mpMRI for localization and detection of PCa before and after ADT + enza. Results: 39 pts were enrolled on-study with 36 pts completing 6 mos trt and undergoing RP. Of 39 pts, 3 had disease progression. Conclusions: Neoadjuvant intense testosterone lowering therapy shows activity in PCa but a subset of pts not respond to AR-targeted therapies through lineage plasticity enabled by characteristic loss of RB1 and TP53 or due to genetic alterations. Identification of this high-risk patient population, along with development of treatment options, needs further investigation. Clinical trial information: NCT02430480. [Table: see text]
Effects of high-fat diet-induced gut microbiota dysbiosis: far beyond the gut
Authors: Tianyu Liu, Bangmao Wang, Hailong Cao
Journal: Gut (2020)

We read with great interest the attractive study by Ding N et al ,1 which reported that the dysbiosis of gut microbiota induced by high-fat diet (HFD) was one of the primary causes for the impaired sperm production and motility. It is likely mediated by elevated blood endotoxin, epididymal inflammation and the dysregulation of testicular gene expressions. We commend the authors for such a rigorous work on this critical issue. We would like to raise several concerns about this study.

According to the data in this study, metagenomic sequencing may be needed to further explore the mechanisms by which certain key bacteria disrupt spermatogenesis and sperm motility. Moreover, whether probiotics supplementation can modulate gut microbiota and improve spermatogenesis and sperm motility are also worthy of exploration.

Faecal microbiota transplantation (FMT) was performed in this study. …
Safety and efficacy of metformin in systemic lupus erythematosus: a multicentre, randomised, double-blind, placebo-controlled trial
Authors: Fangfang Sun, Hui Jing Wang, Zhe Liu, Shikai Geng, Hai Ting Wang, Xiaodong Wang, Ting Li, Laurence Morel, Weiguo Wan, Liangjing Lu, Xiangyu Teng, Shuang Ye
Journal: The Lancet Rheumatology (2020)
Mild traumatic brain injuries with minor intracranial hemorrhage: Can they Be safely managed in the community? – A cohort study
Authors: Sanjay Gupta, Haytham M A Kaafarani, Peter J Fagenholz, Myriam Tabrizi, Martin Rosenthal, Majed W El Hechi, George C Velmahos
Journal: International Journal of Surgery (2020)
UNISON: Nivolumab then ipilimumab + nivolumab in advanced nonclear cell renal cell carcinoma (ANZUP 1602).
Authors: Craig Gedye, David William Pook, Laurence Eliot Miles Krieger, Carole A. Harris, Jeffrey C. Goh, Ganessan Kichenadasse, Howard Gurney, Craig Underhill, Francis Parnis, Anthony M. Joshua, Thomas Ferguson, Felicia Roncolato, Michelle L. Harrison, Michelle Frances Morris, Stephen Begbie, Elizabeth J. Hovey, Mathew George, Prashanth Prithviraj, Elizabeth Chien Hern Liow, Ian D. Davis
Journal: Journal of Clinical Oncology (2020)

TPS768 Background: Renal cell carcinomas (RCC) are predominantly the clear cell (cc) subtype, with a unique biology, characterized by sensitivity to angiogenesis inhibition. However vascular endothelial growth factor-tyrosine kinase inhibitors elicit modest responses in people with rare variant non-clear cell (ncc) RCC. Immune checkpoint inhibitors (ICI) are active against many cancers, but people with rare variant nccRCC have been excluded from frontline trials despite experiencing a more aggressive disease course and poorer prognosis compared to those with ccRCC. UNISON (NCT03177239) aims to test 2 ideas; the activity of ICI in nccRCC, and the novel sequencing strategy of anti-programmed cell death protein (PD)1 immunotherapy, followed by the combination of anti-PD1 and anti-cytotoxic T-lymphocyte-associated protein (CTLA)4 blockade, in people failed by single agent treatment. Methods: This single-arm, two-part trial recruits people of good performance status suffering metastatic or locally advanced unresectable rare variant nccRCC, including but not limited to papillary (type 1/2), chromophobe, sarcomatoid, Xp11 translocation, collecting duct, and unclassified histological subtypes. Participants are offered fixed dose nivolumab at 240mg every two weeks in Part 1 of the trial. If they experience progressive disease, eligible participants may proceed to Part 2 consisting of nivolumab (3mg/kg) plus ipilimumab (1mg/kg) every 3 weeks for up to 4 doses. People experiencing disease control after single-agent or combined ICI are eligible to continue treatment for up to 1 year. UNISON is powered to distinguish a clinically non-relevant objective tumor response rate (OTRR) of 15% in people taking combination ICI whose cancers are refractory to single-agent PD1, versus a clinically-relevant OTRR of 30% at 5% level of significance with 80% power. 85 participants were recruited in Part 1, on the assumption that 55% of those entering Part 1 will be eligible for inclusion in Part 2. Enrolment commenced in November 2017 and was completed ahead of schedule in September 2019. Of the 48 participants projected to experience progression on anti-PD1 immunotherapy, 36 have so far commenced combination ICI in Part 2. Clinical trial information: NCT03177239.
Impact of overall survival (OS) as a function of facility caseload on feasibility of referral of radical prostatectomy (RP) to higher volume facilities.
Authors: Hamed Ahmadi, Afsaneh Barzi, Primo Lara, David I. Quinn, Eric A. Klein, Inderbir Gill, Sarmad Sadeghi
Journal: Journal of Clinical Oncology (2020)

363 Background: We recently reported a significant all-cause mortality (ACM) risk reduction associated with higher annual caseload for RP (PMID 31398279). Four volume groups (VG) were defined as VG1: &lt;50 th , VG2: 50 th -74 th , VG3: 75 th -89 th and VG4: top 10 percentile of caseload. The adjusted OS difference between VG1 and VG4 at 90 th percentile survivorship reached 13.2 months, HR 1.30 (p&lt;0.0001). Here we explore this economics of referral to VG4. Methods: Using a Markov model, we designed 4 scenarios (Sc) where 100,000 RPs were performed. In Sc 1 all RPs were performed at VG1; in Sc 2, 3 &amp; 4, all RPs were performed at VG2, 3 &amp;4 respectively. Subjects were followed for up to 20 years after RP. Survival and costs of care for each Sc were recorded. Probabilities of PSA recurrence (PSAR), development of metastatic disease (Met), cancer specific mortality (CSM) and ACM were adjusted for each VG according to the published HRs. Savings resulting from fewer recurrences, avoidance of salvage radiation therapy (SRT) and management of fewer Met were calculated. Standard discounting at 3% were applied to costs and benefits. Survival benefit and costs savings associated with making referrals from VG1, VG2, or VG3 centers to VG4 center were calculated. Using a willingness to pay (WTP) of $50K per life years gained (LYG), the maximum referral costs (MRC) were calculated. Results: Referral from a VG1 to a VG4 center was associated with highest OS benefit of 720 LYG at 20 years of follow up per 1000 referrals (PKR). Within a WTP of $50K, MRC of up to $37K was cost effective- Table. Conclusions: Given the survival benefit associated with performing RP at facility with high annual caseload, significant resources could be allocated to making a referral possible while still remaining within cost effectiveness boundaries.[Table: see text]
Impact of nadir PSA level and time to nadir during initial androgen deprivation therapy on prognosis in patients with metastatic castration-resistant prostate cancer.
Authors: Itsuto Hamano, Shingo Hatakeyama, Shintaro Narita, Masahiro Takahashi, Toshihiko Sakurai, Sadafumi Kawamura, Senji Hoshi, Toshiaki Kawaguchi, Shigeto Ishidoya, Jiro Shimoda, Hiromi Sato, Koji Mitsuzuka, Tatsuo Tochigi, Norihiko Tsuchiya, Yoichi Arai, Tomonori Habuchi, Chikara Ohyama
Journal: Journal of Clinical Oncology (2020)

241 Background: It is unknown whether the nadir prostate-specific antigen level (PSA nadir) and time to nadir (TTN) during initial androgen deprivation therapy (ADT) are prognostic factors in metastatic castration resistant prostate cancer (mCRPC) patients. Methods: We reviewed the Michinoku Urological Cancer Study Group database, including 321 mCRPC patients. Optimal cutoff values for PSA nadir and TTN on survival were calculated with the receiver operating characteristic (ROC) curve. Patients were stratified into unfavorable (higher PSA nadir and/or shorter TTN) and favorable (lower PSA nadir and longer TTN) groups. The inversed probability of treatment weighing (IPTW) adjusted Cox proportional hazard model was performed to evaluate the impact of the unfavorable group on overall survival (OS) after CRPC diagnosis. Results: Median age and follow-up period were 71 years and 35 months, respectively. ROC curve analysis demonstrated cutoffs of PSA nadir &gt;0.64 ng/mL and TTN &lt;7 months. The unfavorable group included 248 patients who had significantly shorter OS after mCRPC and CRPC-free survival. The Cox proportional and IPTW-adjusted multivariate analyses revealed that the unfavorable group had a negative impact on OS in mCRPC patients (hazards ratio [HR] 2.98, P &lt; 0.001). Conclusions: Higher PSA nadir and shorter TTN during the initial ADT are poor prognostic factors in patients with mCRPC.[Table: see text]
Antioxidant Gene Expression in Airway Smooth Muscle and Epithelial Cells is Upregulated by Synthetic Secoisolaricesinol Diglucoside (LGM2605)
Authors: Chioma Enweasor, Cameron Flayer, Angela Linderholm, Lisa Franzi, Thais Sielecki, Angela Haczku, Melpo Christofidou-Solomidou, Kyewon Park
Journal: Journal of Allergy and Clinical Immunology (2020)