tbuckley/cabot-search huggingface dataset:
PAK4 Phosphorylates Fumarase and Blocks TGFβ-Induced Cell Growth Arrest in Lung Cancer Cells
Authors: Tao Chen, Ting Wang, Wenhua Liang, Qin Zhao, Qiujing Yu, Chun-Min Ma, Lingang Zhuo, Dong Guo, Ke Zheng, Chengzhi Zhou, Shupei Wei, Wenhua Huang, Juhong Jiang, Jing Liu, Shiyue Li, Jianxing He, Yuhui Jiang, Nanshan Zhong
Journal: Cancer Research (2019)

The metabolic activity of fumarase (FH) participates in gene transcription linking to tumor cell growth. However, whether this effect is implicated in lung cancer remains unclear. Here, we show TGFβ induces p38-mediated FH phosphorylation at Thr 90, which leads to a FH/CSL (also known as RBP-Jκ)/p53 complex formation and FH accumulation at p21 promoter under concomitant activation of Notch signaling; in turn, FH inhibits histone H3 Lys 36 demethylation and thereby promotes p21 transcription and cell growth arrest. In addition, FH is massively phosphorylated at the Ser 46 by PAK4 in non-small cell lung cancer (NSCLC) cells, and PAK4-phosphorylated FH binds to 14-3-3, resulting in cytosolic detention of FH and prohibition of FH/CSL/p53 complex formation. Physiologically, FH Ser 46 phosphorylation promotes tumorigenesis through its suppressive effect on FH Thr 90 phosphorylation-mediated cell growth arrest in NSCLC cells and correlates with poor prognosis in patients with lung cancer. Our findings uncover an uncharacterized mechanism underlying the local effect of FH on TGFβ-induced gene transcription, on which the inhibitory effect from PAK4 promotes tumorigenesis in lung cancer. SIGNIFICANCE: Fumarase counteracts CSL via its metabolic activity to facilitate TGFβ-induced cell growth arrest, an effect largely blocked by PAK4-mediated phosphorylation of fumarase.
Abstract 14585: Testosterone and Estradiol Mediate Discrete Effects on High-density Lipoprotein Particle Size and Sterol Efflux Capacity in Healthy Men
Authors: Katya B Rubinow, Tomas Vaisar, Jing Chao, Jay W Heinecke, Stephanie T Page
Journal: Circulation (2017)

Introduction: Exogenous testosterone decreases serum levels of high-density lipoprotein cholesterol (HDL-C) in men, but whether this reflects altered HDL function is uncertain. Hypothesis: Testosterone-mediated changes in serum HDL-C do not predict changes in HDL cholesterol efflux capacity (CEC). Methods: Healthy men (n=45, 19-55 years of age) were rendered medically castrate with the GnRH antagonist acyline for 4 weeks and administered either 1) placebo gel, 2) low-dose testosterone gel (1.62%, 1.25 g), 3) full replacement dose testosterone gel (5 g) or 4) full replacement dose testosterone gel with an aromatase inhibitor. At baseline and end-of-treatment, serum total and ABCA1-specific CEC were quantified, and HDL particle size and concentration were measured through calibrated ion mobility analysis. Results: As expected, a significant time-by-group interaction was observed for serum levels of HDL-C (p=0.01 in overall RM-ANOVA), with significant increases in HDL-C evident after both complete and partia...
Nivolumab (NIVO) + low-dose ipilimumab (IPI) in previously treated patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Long-term follow-up.
Authors: Michael J. Overman, Sara Lonardi, Ka Yeung Mark Wong, Heinz-Josef Lenz, Fabio Gelsomino, Massimo Aglietta, Michael Morse, Eric Van Cutsem, Raymond S. McDermott, Andrew G Hill, Michael B. Sawyer, Alain Hendlisz, Bart Neyns, Magali Svrcek, Ajlan Atasoy, Huanyu Zhao, Ming Lei, Scott Kopetz, Thierry Andre
Journal: Journal of Clinical Oncology (2019)

635 Background: In the phase II CheckMate-142 trial, NIVO + low-dose IPI (1 mg/kg) provided meaningful clinical benefit in previously treated MSI-H/dMMR mCRC pts after a median follow-up of 13.4 mo. Here, we present long-term follow-up (median 25.4 mo) of these pts. Methods: Pts received NIVO 3 mg/kg + low-dose IPI Q3W (4 doses) followed by NIVO 3 mg/kg Q2W until disease progression. Primary endpoint was investigator (INV)-assessed objective response rate (ORR; RECIST v1.1). Results: Of 119 treated pts, 76% had ≥ 2 prior lines of therapy. ORR and disease control rates (DCR) were 58 and 81%, respectively (Table). Complete response (CR) rate increased with long-term follow-up from 3 (13.4 mo) to 6% (25.4 mo). Median duration of response (DOR) was not reached, with 68% of responses ongoing at data cutoff. At 24 mo, progression-free survival (PFS) and overall survival (OS) rates were 60 and 74%, respectively; OS rates were 96, 56, and 29% in pts with CR or partial response (PR), stable disease (SD), and progressive disease (PD), respectively. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 31% of pts; 10% (grade 3–4) and 13% (any grade) of pts had TRAEs leading to discontinuation. Conclusions: Long-term follow-up with NIVO + low-dose IPI provides durable clinical benefit with deepening of response and a manageable safety profile with no new safety signals, demonstrating long-term benefit of NIVO + low-dose IPI for previously treated pts with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]
Abstract 20740: Experimental Sleep Restriction, Energy Balance and Weight Gain: Implications for Visceral Adiposity
Authors: Naima Covassin, Prachi Singh, Shelly K McCrady-Spitzer, Erik K St Louis, Andrew D Calvin, James A Levine, Virend K Somers
Journal: Circulation (2017)

Introduction: Chronic sleep deficiency is a burgeoning phenomenon and its detrimental consequences for cardiometabolic health and especially obesity risk are increasingly apparent. Nevertheless, ca...
A phase 1 trial of ibrutinib plus palbociclib in previously treated mantle cell lymphoma
Authors: Peter Martin, Nancy L. Bartlett, Kristie A. Blum, Steven Park, Kami Maddocks, Jia Ruan, LeAnn Ridling, Christopher Dittus, Zhengming Chen, Xiangao Huang, Giorgio Inghirami, Maurizio DiLiberto, Selina Chen-Kiang, John P. Leonard
Journal: Blood (2019)
Delayed Hematologic Recovery in AML Patients after Induction Chemotherapy Is Associated with Inferior Relapse-Free Survival and Persistence of Preleukemic Mutations
Authors: Tracy Murphy, Jinfeng Zou, Georgina S Daher-Reyes, Vikas Gupta, Caroline J McNamara, Mark D. Minden, Aaron D Schimmer, Hassan Sibai, Karen W.L. Yee, Tracy L. Stockley, Suzanne Kamel-Reid, Dawn Maze, Scott Bratman, Andre Schuh, Steven M Chan
Journal: Blood (2018)
The importance of supporting NHS staff and patients through the complaints process
Authors: Andrew Medlock
Journal: BMJ (2019)

A complaint can be stressful and anxiety inducing for everyone involved, including healthcare professionals, and we should never underestimate the effect a complaint can have on them.1

NHS staff must be fully supported throughout the complaints process so that it doesn’t damage their confidence, trigger mental health problems, or result in the overmanagement of patients.

Exemplary complaint handling services in …
Comparative analysis of staging systems in AL amyloidosis
Authors: Eli Muchtar, Terry M. Therneau, Dirk R. Larson, Morie A. Gertz, Martha Q. Lacy, Francis K. Buadi, David Dingli, Suzanne R. Hayman, Prashant Kapoor, Wilson Gonsalves, Taxiarchis V. Kourelis, Rahma Warsame, Amie Fonder, Miriam Hobbs, Yi Lisa Hwa, Nelson Leung, Stephen Russell, John A. Lust, Yi Lin, Ronald S. Go, Steven Zeldenrust, Robert A. Kyle, S. Vincent Rajkumar, Shaji K. Kumar, Angela Dispenzieri
Journal: Leukemia (2019)
Distinct Cancer-Promoting Stromal Gene Expression Depending on Lung Function
Authors: Brian J. Sandri, Laia Masvidal, Carl Murie, Margarita Bartish, Svetlana Avdulov, LeeAnn Higgins, Todd Markowski, Mark Peterson, Jonas Bergh, Ping Yang, Charlotte Rolny, Andrew H. Limper, Timothy J. Griffin, Peter B. Bitterman, Chris H. Wendt, Ola Larsson
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Chronic obstructive pulmonary disease is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that lung stromal cells activate pathological gene expression programs that support oncogenesis.
Alexithymia reversion in psoriasis
Authors: F. Sampogna, L. Puig, P. Spuls, G. Girolomoni, M.A. Radtke, B. Kirby, M. Brunori, P. Bergmans, P. Smirnov, J. Rundle, A. Castiglia, F. Lavie, C. Paul
Journal: British Journal of Dermatology (2019)

Alexithymia means the inability to identify and express emotions. This condition is more common in people with chronic inflammatory diseases such as arthritis and inflammatory bowel disease. This international team previously showed, in the ‘Epidemiological Study In Patients With Recently DiagnosEd PSOriasis’ (EPIDEPSO), that alexithymia also affects adults with severe psoriasis; those affected are more likely to suffer from anxiety and depression and have a high risk of alcohol dependency and unemployment. An important question is whether alexithymia is a fixed personality trait, or a state which can improve if the psoriasis gets better: perhaps some psoriasis patients block their recognition of emotion as a defence against feeling stigmatised. To answer this, the authors followed up 467 of the original EPIDEPSO patients a year after starting systemic medication (i.e. it works on the whole body, rather than just being applied to the skin) or ultra‐violet light treatment. The prevalence of alexithymia reduced significantly from 26.7% to 18.8% and this improvement was most evident in patients younger than 40 years, who had suffered anxiety and depression, with psoriasis of recent onset, on visible areas, or that responded well to treatment. Patients who were clear or almost clear of psoriasis at follow‐up showed the greatest improvement in alexithymia. Hazardous alcohol use reduced by almost 3‐fold after 1 year. Although improvement in alexithymia was related to improvement in psoriasis, the authors acknowledge that the assessment tools they used are not perfect and that they have not established cause and effect. Nonetheless, they conclude that patients with alexithymia and severe psoriasis require psychological counselling as well as active psoriasis treatment.
Factors Associated With Unplanned Reoperation After Above-Knee Amputation
Authors: Jeffrey B. Edwards, Mathew D. Wooster, Thanh Tran, Paul A. Armstrong, Neil Moudgill, Murray L. Shames, James D. Brooks
Journal: JAMA Surgery (2019)

Above-knee amputation (AKA) is typically a last-resort procedure in patients who are not candidates for limb salvage.Unplanned reoperation has been identified as a risk factor for increased morbidity and hospital readmission after vascular surgery.
Two-Year Survival Comparing Web-Based Symptom Monitoring vs Routine Surveillance Following Treatment for Lung Cancer
Authors: Fabrice Denis, Ethan Basch, Anne-Lise Septans, Jaafar Bennouna, Thierry Urban, Amylou C. Dueck, Christophe Letellier
Journal: JAMA (2019)

This study reports 2-year survival outcomes among patients with advanced nonprogressive stage IIA to IV lung cancer randomized to symptom monitoring during chemotherapy via web-based patient-reported outcomes vs standard scheduled imaging after treatment to detect symptomatic recurrence.
Abstract 15439: AAV-Containing Exosomes as a Novel Vector to Improve AAV-Mediated Myocardial Gene Delivery in Resistance to Neutralizing Antibody
Authors: Yaxuan Liang, Prabhu Mathiyalagan, Erik Kohlbrenner, Elena Chepurko, Dongtak Jeong, Delaine Ceholski, Nicole Dubois, Roger Hajjar, Susmita Sahoo
Journal: Circulation (2017)

Introduction: Heart failure is a major cause of morbidity and mortality. Adeno-associated virus (AAV)-based gene therapy delivering the sarcoplasmic reticulum calcium ATPase (SERCA2a) to cardiomyoc...
Open and Endovascular Management of Aortic Aneurysms
Authors: Nicholas J. Swerdlow, Winona W. Wu, Marc L. Schermerhorn
Journal: Circulation Research (2019)

Aneurysmal disease can affect any segment of the aorta, from the aortic root to the aortic bifurcation. The treatment of aortic aneurysms has evolved dramatically in the past 3 decades, with the introduction of endovascular aneurysm repair using stent grafts causing a major paradigm shift in the field of aortic aneurysm surgery. While the technical details of the management of aortic aneurysms vary greatly depending on the location of an aneurysm, the principles remain the same. Successful aortic aneurysm treatment depends on either open replacement or endovascular exclusion of the aneurysmal segment with healthy artery proximal and distal to the repair. Major aortic branches of the arch and visceral segment add additional technical complexity to aneurysms involving these regions. Even as endovascular repair becomes the primary treatment modality for most aortic aneurysms, open repair remains an essential treatment modality in many circumstances. Additionally, long-term results of endovascular repair suggest that younger patients with long life expectancy and low-perioperative risk may benefit more from open repair. Therefore, technical expertise in both endovascular and open treatment is necessary for a comprehensive aortic aneurysm surgery practice.
Abstract 19768: Cerebral Vasomotor Reactivity Test During Targeted Temperature Management is Feasible for Prognostication After Out of Hospital Cardiac Arrest
Authors: Sung Eun Lee, Minjung K Chae, Ji Man Hong
Journal: Circulation (2017)

Background: Neurological prognostication after cardiac arrest is a complex process requiring a multimodal approach. Recently, some reports presented that cerebral autoregulation (CA) was labile to hypoxic brain damage and impaired CA was correlated with neurologically poor outcome. The aim of this study was to determine whether vasomotor reactivity (VMR) test by transcranial doppler (TCD), reflecting cerebral hemodynamic status, was feasible for neurological prognostication in post cardiac arrest patients. Methods: From October 2015 to February 2017, a total of 21 patients with VMR tests as well as conventional tests, such as EEG and SEP were enrolled. Primary outcome was cerebral performance category scale (CPC) at discharge. The VMR test was done by a breath-holding method during 40 seconds with neuromuscular blockade and a pause in ventilation and recorded changes of mean flow velocity on monitored vessel by TCD measurements. The VMR test was done on the first day in 24 hours of ROSC. Other conventiona...
Direct Oral Anticoagulant Vs Vitamin K Antagonist As Anticoagulant Therapy in Patients with Inherited and Acquired Thrombophilia
Authors: Pável E Olivera, Desirée Campoy, César A Velasquez, Katia Flores, Gabriela S Ene, Tania Canals, Gonzalo Artaza, Maricel Subira, Sofía Vila, Jorge Sierra, Ramón Salinas
Journal: Blood (2018)
Gene Aberrations in Adult Patients with Ph-Negative ALL in the Czech Republic
Authors: Zuzana Vrzalova, Hana Jelinkova, Stepan Hrabovsky, Frantisek Folber, Cyril Salek, Jan Horacek, Marketa Zaliova, Jiri Stika, Martina Slavikova, Sarka Pospisilova, Michael Doubek
Journal: Blood (2018)
MDM2 and MDM4 Are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors
Authors: Thomas P. Howard, Taylor E. Arnoff, Melinda R. Song, Andrew O. Giacomelli, Xiaofeng Wang, Andrew L. Hong, Neekesh V. Dharia, Su Wang, Francisca Vazquez, Minh-Tam Pham, Ann M. Morgan, Franziska Wachter, Gregory H. Bird, Guillaume Kugener, Elaine M. Oberlick, Matthew G. Rees, Hong L. Tiv, Justin H. Hwang, Katherine H. Walsh, April Cook, John M. Krill-Burger, Aviad Tsherniak, Prafulla C. Gokhale, Peter J. Park, Kimberly Stegmaier, Loren D. Walensky, William C. Hahn, Charles W.M. Roberts
Journal: Cancer Research (2019)

Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. In this study, we screened several MRT cell lines with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries to identify potential drug targets specific for these cancers. We discovered MDM2 and MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin (MDM2-specific) and ATSP-7041 (MDM2/4-dual), we show that MRT cells were more sensitive than other p53 wild-type cancer cell lines to inhibition of MDM2 alone as well as dual inhibition of MDM2/4. These compounds caused significant upregulation of the p53 pathway in MRT cells, and sensitivity was ablated by CRISPR-Cas9-mediated inactivation of TP53. We show that loss of SMARCB1, a subunit of the SWI/SNF (BAF) complex mutated in nearly all MRTs, sensitized cells to MDM2 and MDM2/4 inhibition by enhancing p53-mediated apoptosis. Both MDM2 and MDM2/4 inhibition slowed MRT xenograft growth in vivo, with a 5-day idasanutlin pulse causing marked regression of all xenografts, including durable complete responses in 50% of mice. Together, these studies identify a genetic connection between mutations in the SWI/SNF chromatin-remodeling complex and the tumor suppressor gene TP53 and provide preclinical evidence to support the targeting of MDM2 and MDM4 in this often-fatal pediatric cancer. SIGNIFICANCE: This study identifies two targets, MDM2 and MDM4, as vulnerabilities in a deadly pediatric cancer and provides preclinical evidence that compounds inhibiting these proteins have therapeutic potential.
Abstract 15583: Serum Vitamin D Deficiency is Independently Associated With Greater Prevalence of Erectile Dysfunction: Results From the National Health and Nutrition Examination Survey (NHANES) 2001-2004
Authors: Youssef M Farag, Eliseo Guallar, Di Zhao, Rita R Kalyani, Seth S Martin, Pamela L Lutsey, Kevin L Billups, Erin D Michos
Journal: Circulation (2015)

Background: Erectile dysfunction (ED) and cardiovascular disease (CVD) share common risk factors. Furthermore, up to 80% of ED is from vascular causes, and thus ED may be a marker for subclinical CVD. Low serum 25-hydroxyvitamin D [25(OH)D] levels have been associated with increased CVD risk, perhaps mediated through hypertension and diabetes, but it is unclear if low serum 25(OH)D is associated with ED, independent of CVD risk factors. Methods: We performed a cross-sectional analysis of 3,486 men aged ≥20 years free of CVD who participated in NHANES 2001-2004. Serum 25(OH)D was measured by the DiaSorin radioimmunoassay. We defined vitamin D deficiency as a serum level of 25(OH)D &lt;20 ng/mL. Self-reported erectile function was assessed by a single question: “How would you describe your ability to get and keep an erection adequate for satisfactory intercourse?” We defined ED as those who answered “sometimes able” or “never able.” We assessed the relationship between serum 25(OH)D deficiency and prevalence of ED using logistic regression after adjusting for potential confounders. Results: The prevalence of vitamin D deficiency and of ED was 30% and 16.4%, respectively. Serum 25(OH)D levels were statistically significantly lower in men with vs those without ED (mean 22.9 vs 24.3 ng/mL, respectively; p=0.0007). Vitamin D deficient men had a significantly higher prevalence of ED compared to those without deficiency (age- and race-adjusted OR 1.53, 95% CI 1.17-2.00). This association was materially unchanged after adjusting for multiple lifestyle variables, comorbidities, and medication use (OR 1.32, 95% CI 1.02-1.74) [ Figure ]. Conclusion: In this cross-sectional analysis of a representative sample of U.S. men, vitamin D deficiency was associated with an increased prevalence of ED independent of CVD risk factors. Additional research is needed to evaluate if treating vitamin D deficiency results in an improvement of erectile function or prevents vascular events.
Evaluation of safety and tolerability of durvalumab (D) with or without tremelimumab (T) in patients (pts) with biliary tract cancer (BTC).
Authors: Tatsuya Ioka, Makoto Ueno, Do-Youn Oh, Yutaka Fujiwara, Jen-Shi Chen, Yuichiro Doki, Nobumasa Mizuno, Keunchil Park, Akinori Asagi, Manabu Hayama, Masahiro Nii, Keiko Komuro, Mariko Sugimoto, Gordana Vlahovic, Masafumi Ikeda
Journal: Journal of Clinical Oncology (2019)

387 Background: This Phase 1 study (NCT01938612) evaluated D (anti-PD-L1 mAb) and T (anti-CTLA-4 mAb) in Asian pts, in whom optimal dosing of D and T is undetermined. No dose-limiting toxicities were observed, and durable responses were seen in a dose escalation phase evaluating various D doses and regimens in Japanese pts (Iguchi, ASCO 2015). The study was subsequently expanded to larger cohorts of Asian pts with advanced solid tumors including BTC. Methods: Two regimens were selected for the expansion phase: D monotherapy (10 mg/kg q2w) and D+T (D 20 mg/kg + T 1.0 mg/kg q4w). One cohort of pts with advanced BTC was enrolled to receive D monotherapy followed by a separate cohort that received D+T with additional pts enrolled if efficacy was observed. Safety, response, and survival endpoints were based on investigator assessment. Results: Pts were enrolled to D (N = 42) or D+T (N = 65). Median age was 64 years for the D cohort and 62 years for the D+T cohort, the majority were male, and ECOG PS was 0 or 1: 64% and 36% for pts in the D cohort and 49% and 51% for pts in the D+T cohort, respectively. Median number of prior chemotherapy regimens was 2 for both cohorts. Treatment-related adverse events (trAE) of any grade occurred in 64% and 82% of pts in the D and D+T cohorts. Grade ≥ 3 trAEs occurred in 19% and 23% of pts in the D and D+T cohorts. trAEs led to discontinuation in 2 pts in the D cohort and 5 pts in the D+T cohort. A death due to trAE (drug-induced liver injury) was reported in the D+T cohort, none in the D cohort. In the D cohort, 2 pts had a partial response (PR) and 7 pts had a PR in the D+T cohort; disease control rate at 12 weeks was 16.7% and 32.2%, respectively. Median duration of response for the D cohort was 9.7 months and 8.5 months for the D+T cohort. Median overall survival was 8.1 (95% CI, 5.6-10.1) months and 10.1 (95% CI, 6.2-11.4) months for the D and D+T cohorts, respectively. Conclusions: Both D monotherapy and D+T combination therapy were tolerable for Asian pts with BTC, and no unexpected toxicities were observed with either regimen. Promising clinical benefit was observed with both D and D+T therapy. This study provides valuable information regarding these therapeutic regimens for future studies in pts with BTC. Clinical trial information: NCT01938612.