tbuckley/cabot-search huggingface dataset:
Systemic Consequences of Pulmonary Hypertension and Right-Sided Heart Failure
Authors: Stephan Rosenkranz, Luke S. Howard, Mardi Gomberg-Maitland, Marius M. Hoeper
Journal: Circulation (2020)

Pulmonary hypertension (PH) is a feature of a variety of diseases and continues to harbor high morbidity and mortality. The main consequence of PH is right-sided heart failure which causes a complex clinical syndrome affecting multiple organ systems including left heart, brain, kidneys, liver, gastrointestinal tract, skeletal muscle, as well as the endocrine, immune, and autonomic systems. Interorgan crosstalk and interdependent mechanisms include hemodynamic consequences such as reduced organ perfusion and congestion as well as maladaptive neurohormonal activation, oxidative stress, hormonal imbalance, and abnormal immune cell signaling. These mechanisms, which may occur in acute, chronic, or acute-on-chronic settings, are common and precipitate adverse functional and structural changes in multiple organs which contribute to increased morbidity and mortality. While the systemic character of PH and right-sided heart failure is often neglected or underestimated, such consequences place additional burden on patients and may represent treatable traits in addition to targeted therapy of PH and underlying causes. Here, we highlight the current state-of-the-art understanding of the systemic consequences of PH and right-sided heart failure on multiple organ systems, focusing on self-perpetuating pathophysiological mechanisms, aspects of increased susceptibility of organ damage, and their reciprocal impact on the course of the disease.
A Review Of Peanut Oral Food Challenges In Patients With No Or Minimal Sensitization To Ara H2
Authors: Michelle El-Hosni, Sofija Volertas, Neesha Patel, Emily Hautman, Marisa Coury, Marc McMorris, Alan Baptist, Georgiana Sanders, Malika Gupta
Journal: Journal of Allergy and Clinical Immunology (2020)
Long non-coding RNAs as a determinant of cancer drug resistance: Towards the overcoming of chemoresistance via modulation of lncRNAs
Authors: Wenxiao Jiang, Jun Xia, Shangdan Xie, Ruanmin Zou, Shuya Pan, Zhi-wei Wang, Yehuda G. Assaraf, Xueqiong Zhu
Journal: Drug Resistance Updates (2020)
A retrospective review of the effect of metformin in metastatic prostate cancer.
Authors: So Yi Lam, Chung-Shien Lee, Wingsze Liu, Cristina Sison, Emily Miao, Xinhua Zhu
Journal: Journal of Clinical Oncology (2020)

62 Background: Current treatments of metastatic prostate cancer are mainly hormone therapy and chemotherapy. The anticancer potential of metformin on metastatic prostate cancer remains obscure. In this study, we aim to investigate the significance of patients with prostate cancer taking metformin in addition to their current treatment. Methods: An IRB approved retrospective review of metastatic prostate cancer patients was conducted. Patients were categorized into metastatic castration resistant prostate cancer (mCRPC) or hormone-sensitive prostate cancer (mHSPC). Patients were further stratified to those who received metformin vs. those who did not. Progression free survival (PFS) was evaluated based on PCWG3 and RECIST criteria. 6-month (6MO) PSA response and overall survival (OS) were also evaluated in this study. Results: A total of 281 subjects were included for analysis with a mean age of 70±10. Patients were known to have either mHSPC (n = 205) or mCRPC (n = 75), and taking metformin (n = 66) or not (n = 215). There was no significant difference between metformin groups with respect to PSA response at 6MO (p &lt; 0.73). Among those with a recorded 6MO PSA response, 70.4% (38/54) had a response in the metformin group and 72.9% (140/192) had a response in the non-metformin group. Overall median PFS was estimated to be 17 months, with no significant difference in PFS between metformin groups (16.6 vs 17.3; p &lt; 0.88). Within the mHSPC group, metformin users had a lower risk of progression relative to non-users (HR = 0.89; 95% CI: 0.62 to 1.29). Within the mCRPC group, metformin users had a significantly higher risk of progression relative to non-users (HR = 2.65; 95% CI: 1.4 to 5.0). Median overall survival was estimated to be 81.5 months. There was a significant difference in survival time between metformin groups (148.5 vs 69.4; p &lt; 0.02). Conclusions: No significant differences were found in 6MO PSA response or PFS. There was a significant difference in OS amongst patients who were in the metformin group and those who were not.
Interleukin 1β-mediated HOXC10 Overexpression Promotes Hepatocellular Carcinoma Metastasis by Upregulating PDPK1 and VASP
Authors: Yunzhi Dang, Jie Chen, Weibo Feng, Chenyang Qiao, Weili Han, Yongzhan Nie, Kaichun Wu, Daiming Fan, Limin Xia
Journal: Theranostics (2020)

Rationale: Metastasis and recurrence are the primary reasons for the high mortality rate of human hepatocellular carcinoma (HCC) patients. However, the exact mechanism underlying HCC metastasis remains unclear. The Homeobox (HOX) family proteins, which are a highly conserved transcription factor superfamily, play important roles in cancer metastasis. Here, we report a novel role of HOXC10, one of the most upregulated HOX genes in human HCC tissues, in promoting HCC metastasis. Methods: The expression of HOXC10 and its functional targets was detected by immunohistochemistry in two independent human HCC cohorts. Luciferase reporter and chromatin immunoprecipitation assays were used to measure the transcriptional regulation of target genes by HOXC10. The effect of HOXC10-mediated invasion and metastasis were analyzed by Transwell assays and by an orthotopic metastasis model. Results: Elevated expression of HOXC10 was positively correlated with the loss of tumor encapsulation and with higher tumor-nodule-metastasis (TNM) stage and poor prognosis in human HCC. Overexpression of HOXC10 promoted HCC metastasis by upregulating metastasis-related genes, including 3-phosphoinositide-dependent protein kinase 1 (PDPK1) and vasodilator-stimulated phosphoprotein (VASP). Knockdown of PDPK1 and VASP inhibited HOXC10-enhanced HCC metastasis, whereas upregulation of PDPK1 and VASP rescued the decreased metastasis induced by HOXC10 knockdown. Interleukin-1β (IL-1β), which is the ligand of IL-1R1, upregulated HOXC10 expression through the c-Jun NH2-terminal kinase (JNK)/c-Jun pathway. HOXC10 knockdown significantly reduced IL-1β-mediated HCC metastasis. Furthermore, Anakinra, a specific antagonist of IL-1R1, inhibited IL-1β-induced HOXC10 upregulation and HCC metastasis. In human HCC tissues, HOXC10 expression was positively correlated with PDPK1, VASP and IL-1R1 expression, and patients with positive coexpression of HOXC10/PDPK1, HOXC10/VASP or IL-1R1/HOXC10 exhibited the poorest prognosis. Conclusions: Upregulated HOXC10 induced by IL-1β promotes HCC metastasis by transactivating PDPK1 and VASP expression. Thus, our study implicates HOXC10 as a prognostic biomarker, and targeting this pathway may be a promising therapeutic option for the clinical prevention of HCC metastasis.
Synonymous Site-to-Site Substitution Rate Variation Dramatically Inflates False Positive Rates of Selection Analyses: Ignore at Your Own Peril
Authors: Sadie R Wisotsky, Sergei L Kosakovsky Pond, Stephen D Shank, Spencer V Muse
Journal: Molecular Biology and Evolution (2020)

Abstract Most molecular evolutionary studies of natural selection maintain the decades-old assumption that synonymous substitution rate variation (SRV) across sites within genes occurs at levels that are either nonexistent or negligible. However, numerous studies challenge this assumption from a biological perspective and show that SRV is comparable in magnitude to that of nonsynonymous substitution rate variation. We evaluated the impact of this assumption on methods for inferring selection at the molecular level by incorporating SRV into an existing method (BUSTED) for detecting signatures of episodic diversifying selection in genes. Using simulated data we found that failing to account for even moderate levels of SRV in selection testing is likely to produce intolerably high false positive rates. To evaluate the effect of the SRV assumption on actual inferences we compared results of tests with and without the assumption in an empirical analysis of over 13,000 Euteleostomi (bony vertebrate) gene alignments from the Selectome database. This exercise reveals that close to 50% of positive results (i.e., evidence for selection) in empirical analyses disappear when SRV is modeled as part of the statistical analysis and are thus candidates for being false positives. The results from this work add to a growing literature establishing that tests of selection are much more sensitive to certain model assumptions than previously believed.
Phase II trial of a novel immunotherapy combination of pembrolizumab and HER2 bi-armed activated T cells (BATs) in metastatic castrate resistant prostate cancer.
Authors: Meera Patel, Lawrence G. Lum, Abhinav Deol, Archana Thakur, Elisabeth I. Heath, Wei Chen, Kimberlee Dobson, Joseph A. Fontana, Ulka N. Vaishampayan
Journal: Journal of Clinical Oncology (2020)

97 Background: Immune checkpoint inhibitors (ICI) have demonstrated only modest efficacy in metastatic castrate resistant prostate cancer (mCRPC). Anti-HER2 and Anti-CD3 bispecific antibody armed activated T cells (HER2 BATs) demonstrated efficacy in prostate cancer cell lines, irrespective of HER2 expression status. Safety and preliminary responses in refractory mCRPC were noted in a phase I trial with HER2 BATs. Preclinical synergy was noted in prostate cancer with ICI and BATs. We conducted a phase II study with pembrolizumab and HER2 BATs that would potentially transform immune cells to exhibit cytotoxicity against prostate cancer. Methods: mCRPC patients with 0-1 performance status (PS) and normal liver, kidney and marrow function, pre or post docetaxel chemotherapy were eligible. Primary endpoint was 6 month progression free survival. Patients underwent apheresis for mononuclear cell collection which was shipped to the University of Virginia for manufacturing of HER2 BATs, which were infused twice weekly for 4 weeks. Pembrolizumab was administered every 21 days for a maximum duration of 6 months starting 1 week prior to HER2 BATs infusion. Progression was determined by clinical evaluation, PSA, and radiologic assessment at 3 and 6 months and every 6 months thereafter. Results: Twelve patients have been enrolled on the study of which one withdrew consent. Median age was 69 years (Range 57 to 76 years). Five of 11 patients had prior docetaxel chemotherapy. Eight of 11 patients had bone and lymph node metastases, 1 had lymph node metastases only, and 2 had peritoneal metastasis. Median PSA was 111ng/ml [Range 5.2 - 378 ng/ml]. Five and 6 patients had PS of 0 and 1 respectively. The regimen was well tolerated with no unexpected toxicities. To date 3 of 6 patients have completed study treatment and remain progression free at 6 months, 1 death occurred due to an unrelated cause, and 2 patients progressed at 12 weeks of therapy. Two patients demonstrated an 88% and 36% PSA decline. Immune correlates will be presented. Conclusions: The combination regimen of pembrolizumab and BATs appears to be worthy of future exploration in a larger trial in mCRPC. Clinical trial information: NCT03406858.
Covid-19: surge in cases in Italy and South Korea makes pandemic look more likely
Authors: Michael Day
Journal: BMJ (2020)

Covid-19: surge in cases in Italy and South Korea makes pandemic look more likely Michael Day London, UK A surge in cases of covid-19 in northern Italy on 24 February heightened fears that the emerging infection has passed the tipping point and the world is on the brink of a pandemic.By 25 February a seventh person infected with covid-19 died in Italy.He was an 80 year old heart patient, who died at the Sacco hospital in Milan.Italian civil protection officials said 219 people had now tested positive for the virus.
A phase II trial of regorafenib for advanced urothelial cancer (aUC) following prior chemotherapy.
Authors: Gurudatta Naik, Ulka N. Vaishampayan, Lisle Nabell, Mollie R. De Shazo, Lakshminarayanan Nandagopal, Petros Grivas, Charity Morgan, Pamela Hardwick, Guru Sonpavde
Journal: Journal of Clinical Oncology (2020)

498 Background: Salvage therapy options for aUC following platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) have modest activity. Regorafenib is a multitargeted TKI that targets VEGF and Tie2 receptors among others, which is approved for multiple malignancies. Both VEGF and Tie2 inhibitors have preliminarily exhibited activity in aUC. Hence, a rationale was made to evaluate regorafenib in aUC progressing following chemotherapy. Methods: We conducted a single arm, non-randomized Phase II study (NCT02459119) of regorafenib for aUC following chemotherapy. All patients (pts) started at 120 mg po qd for one cycle (28 days) before escalating to 160 mg po qd in the absence of intolerable regorafenib related toxicities. Pts who had progressed after 1-3 prior chemotherapy regimens and exhibited measurable disease by RECIST 1.1 were selected. The primary objectives was progression free survival at 6 months (PFS-6) and the secondary objectives were objective response rates (ORR), overall survival (OS) and toxicities. PFS6 of ≥20% was considered of interest and the target accrual was 32 evaluable pts. The treatment was continued until progression or intolerable adverse events. Results: We enrolled 17 pts across 3 institutions (UAB, Wayne State and Cleveland Clinic) between May 2015 and May 2019. Of these, 14 patients were male (82%) and the median age was 67 years. Pts received a median of 2 prior therapies including chemotherapy. 9 pts had received a prior ICI. 13 pts (76.5%) experienced treatment related adverse events (AE), and 7 pts (41.2%) had grade 3 toxicities including–anemia, thrombocytopenia, myalgia, hypophosphatemia, abdominal pain and fatigue. Treatment was discontinued for patients who suffered grade 3 myalgia and abdominal pain. There were no treatment related deaths. 3 patients attained PFS6 (18%) who also displayed minor regressions and 1 of them had received a prior ICI. Conclusions: Although the trial was halted for slow accrual, regorafenib appeared to demonstrate activity in heavily pretreated pts with aUC who had received chemotherapy or ICI. Further evaluation may be warranted in less heavily pretreated pts and in combination with rational agents with non-overlapping toxicities. Clinical trial information: NCT02459119.
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study
Authors: Xiaobo Yang, Yuan Yu, Jiqian Xu, Huaqing Shu, Jia'an Xia, Hong Liu, Yongran Wu, Lu Zhang, Zhui Yu, Minghao Fang, Ting Yu, Yaxin Wang, Shangwen Pan, Xiaojing Zou, Shiying Yuan, You Shang
Journal: The Lancet Respiratory Medicine (2020)
Phase III study of pembrolizumab (pembro) plus enzalutamide (enza) versus placebo plus enza for metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-641.
Authors: Julie Nicole Graff, Joseph Burgents, Li Wen Liang, Arnulf Stenzl
Journal: Journal of Clinical Oncology (2020)

TPS258 Background: The mechanisms of action of pembro, a PD-1 inhibitor, and enza, an androgen receptor inhibitor, may be synergistic in the treatment of patients (pts) with mCRPC. The phase 1b/2 KEYNOTE-365 (NCT02861573) study showed antitumor activity with pembro + enza in pts with mCRPC pretreated with abiraterone acetate. A phase 2 study (NCT02312557) of enza-pretreated patients with mCRPC showed that some pts had a profound and durable anticancer response to pembro + enza. Methods: KEYNOTE-641 (NCT03834493) is a randomized, double-blind, phase 3 trial to evaluate efficacy and safety of pembro + enza versus placebo + enza in pts with mCRPC. An estimated 1200 patients will be randomly assigned 1:1 to receive enza 160 mg/day + pembro 200 mg IV Q3W or enza 160 mg/day + placebo. Treatment will be stratified by prior abiraterone acetate treatment (yes/no), metastases location (bone only/liver/other), and prior docetaxel treatment for metastatic hormone-sensitive prostate cancer (yes/no). Adults (≥18 years) with histologically or cytologically confirmed mCRPC who experienced biochemical or radiographic progression, ECOG PS 0/1, and adequate organ function are eligible. Pts will be required to provide tissue for biomarker analysis. Intolerance to or progression while receiving prior abiraterone acetate therapy is permitted, but not required. Prior chemotherapy for mCRPC, checkpoint inhibition, or any treatment with a second-generation androgen receptor inhibitor is prohibited. Responses will be assessed by CT/MRI and radionuclide bone imaging per PCWG3-modified RECIST v1.1 Q9W during the first year and Q12W thereafter. Treatment will continue until progression, unacceptable toxicity, or consent withdrawal, with up to 2 years of pembro/placebo. Dual primary end points are OS and rPFS by blinded independent central review. Secondary end points are time to subsequent anticancer therapy or death, ORR, DOR, PSA response rate, PSA undetectable rate, time to PSA progression, time to pain progression, time to soft tissue progression, time to symptomatic skeletal-related event, and safety. Accrual began July 28, 2019. Clinical trial information: NCT03834493.
Risk-adjusted therapy for pediatric non-T cell ALL improves outcomes for standard risk patients: results of JACLS ALL-02
Authors: Daiichiro Hasegawa, Toshihiko Imamura, Keiko Yumura-Yagi, Yoshihiro Takahashi, Ikuya Usami, So-ichi Suenobu, Shinichiro Nishimura, Nobuhiro Suzuki, Yoshiko Hashii, Takao Deguchi, Akiko Moriya-Saito, Koji Kato, Yoshiyuki Kosaka, Masahiro Hirayama, Akihiro Iguchi, Hirohide Kawasaki, Hiroki Hori, Atsushi Sato, Tooru Kudoh, Tatsutoshi Nakahata, Megumi Oda, Junichi Hara, Keizo Horibe
Journal: Blood Cancer Journal (2020)

This study was a second multicenter trial on childhood ALL by the Japan Childhood Leukemia Study Group (JACLS) to improve outcomes in non-T ALL. Between April 2002 and March 2008, 1138 children with non-T ALL were enrolled in the JACLS ALL-02 trial. Patients were stratified into three groups using age, white blood cell count, unfavorable genetic abnormalities, and treatment response: standard risk (SR), high risk (HR), and extremely high risk (ER). Prophylactic cranial radiation therapy (PCRT) was abolished except for CNS leukemia. Four-year event-free survival (4yr-EFS) and 4-year overall survival (4yr-OS) rates for all patients were 85.4% ± 1.1% and 91.2% ± 0.9%, respectively. Risk-adjusted therapy resulted in 4yr-EFS rates of 90.4% ± 1.4% for SR, 84.9% ± 1.6% for HR, and 66.5% ± 4.0% for ER. Based on NCI risk classification, 4yr-EFS rates were 88.2% in NCI-SR and 76.4% in NCI-HR patients, respectively. Compared to previous trial ALL-97, 4yr-EFS of NCI-SR patients was significantly improved (88.2% vs 81.2%, log rank p = 0.0004). The 4-year cumulative incidence of isolated (0.9%) and total (1.5%) CNS relapse were significantly lower than those reported previously. In conclusion, improved EFS in NCI-SR patients and abolish of PCRT was achieved in ALL-02.
A study of obesity, BMI, smoking and alcohol as risk factors for psoriatic arthritis
Authors: A. Green, G. Shaddick, R. Charlton, J. Snowball, A. Nightingale, C. Smith, W. Tillett, N. McHugh
Journal: British Journal of Dermatology (2020)

Psoriatic Arthritis (PsA) is a progressive and often destructive joint disease affecting approximately 20% of people with psoriasis. PsA causes pain, swelling and joint stiffness and is accompanied by chronic skin disease and can lead to an impaired quality of life. It is helpful to understand the risk factors for developing PsA. The aim of this U.K. study was to examine the associations between obesity, changes in Body Mass Index (BMI), alcohol consumption, smoking status and the development of PsA in people with psoriasis. Data was collected from anonymised medical records and analysed. The authors found that increased risks of developing PsA were associated with an increased BMI, moderate drinking and ex-smoking status. In addition, reducing BMI over a 10-year period was associated with a reduction in the risk of developing PsA when compared to BMI remaining constant over the same period. In conclusion, while more studies are needed to investigate intentional weight loss on the risk of developing PsA, weight reduction amongst obese people with psoriasis may have the potential ability to prevent their excess risk of PsA while providing additional health benefits, including reduced cardiovascular and mortality risks. This is a summary of the study: Modifiable risk factors and the development of psoriatic arthritis in people with psoriasis
Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study
Authors: Sharon Chinthrajah, Natasha Purington, Sandra Andorf, Andrew Long, Katherine O'Laughlin, Shu-Chen Lyu, Monali Manohar Manohar, Scott Boyd, Robert Tibshirani, Holden Maecker, Kaori Mukai, Mindy Tsai, Manisha Desai, Stephen Galli, Kari Nadeau
Journal: Journal of Allergy and Clinical Immunology (2020)
Rucaparib for recurrent, locally advanced, or metastatic urothelial carcinoma (mUC): Results from ATLAS, a phase II open-label trial.
Authors: Petros Grivas, Yohann Loriot, Susan Feyerabend, Rafael Morales-Barrera, Min Yuen Teo, Nicholas J. Vogelzang, Enrique Grande, Yousef Zakharia, Nabil Adra, Ajjai Shivaram Alva, Andrea Necchi, Sumati Gupta, Debra Hannah Josephs, Alejo Rodriguez-Vida, Sandy Srinivas, Kenton Wride, Daleen Thomas, Rachel Dusek, Dale L. Nepert, Simon Chowdhury
Journal: Journal of Clinical Oncology (2020)

440 Background: ATLAS (NCT03397394) evaluated the efficacy/safety of the PARP inhibitor (PARPi) rucaparib in patients (pts) with previously treated locally advanced/unresectable UC or mUC. Methods: Pts with measurable disease who had progressed after 1–2 prior regimens (ie, platinum-based chemotherapy [PBC] and/or immune checkpoint inhibitors [ICI]) were enrolled regardless of tumor homologous recombination deficiency (HRD) status. Prior PARPi was not allowed. Pts received rucaparib 600 mg PO BID. Baseline tumor tissue or archival tissue ≤6 mo without intervening therapy was required; serial circulating tumor DNA samples were collected. Primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (defined as genomic loss of heterozygosity ≥10%) populations. Key secondary endpoints: progression-free survival (PFS) and safety. Clinical benefit rate (CBR) was defined as complete or partial response or stable disease (SD) lasting ≥16 weeks. Results: As of Oct 7, 2019, 97 pts were enrolled (median age 66 y [range, 39–87]); most were men (n=76, 78.4%) and had ECOG PS 1 (n=65, 67.0%). Sixty-six pts (68.0%) had both prior PBC and ICI. Twenty pts (20.6%) were HRD-positive, 30 (30.9%) were HRD-negative and 47 (48.5%) had unknown HRD status; 4 pts had a deleterious BRCA1/2 alteration. Median time on treatment was 54 d (range, 2–224). There were no confirmed responses. Of 96 evaluable pts, 27 (28.1%) had a best response of SD; CBR was 12.5% and median PFS was 1.8 mo. No relationship was observed between HRD status and clinical activity. Treatment was discontinued by 93 pts (95.9%), mainly due to radiologic or clinical progression (73.1%). Most frequent any grade treatment-emergent (any cause) adverse events were asthenia/fatigue (n=56, 57.7%), nausea (n=40, 41.2%), and anemia (n=34, 35.1%). Conclusions: Single agent rucaparib did not show activity in pts with previously treated advanced UC and enrollment was suspended at the first interim analysis. The safety profile was consistent with that observed in pts with ovarian cancer. Next generation sequencing–based characterization of the genomic landscape of mUC will be presented. Clinical trial information: NCT03397394.