tbuckley/cabot-search huggingface dataset:
Transcriptomic Heterogeneity of Androgen Receptor Activity Defines a <i>de novo</i> low AR-Active Subclass in Treatment Naïve Primary Prostate Cancer
Authors: Daniel E. Spratt, Mohammed Alshalalfa, Nick Fishbane, Adam B. Weiner, Rohit Mehra, Brandon A. Mahal, Jonathan Lehrer, Yang Liu, Shuang G. Zhao, Corey Speers, Todd M. Morgan, Adam P. Dicker, Stephen J. Freedland, R. Jeffery Karnes, Sheila Weinmann, Elai Davicioni, Ashley E. Ross, Robert B. Den, Paul L. Nguyen, Felix Y. Feng, Tamara L. Lotan, Arul M. Chinnaiyan, Edward M. Schaeffer
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The heterogeneity of androgen receptor (AR)-activity (AR-A) is well-characterized in heavily treated metastatic castration-resistant prostate cancer (mCRPC). However, the diversity and clinical implications of AR-A in treatment-naïve primary prostate cancer is largely unknown. We sought to characterize AR-A in localized prostate cancer and understand its molecular and clinical implications. Experimental Design: Genome-wide expression profiles from prostatectomy or biopsy samples from 19,470 patients were used, all with independent pathology review. This was comprised of prospective discovery (n = 5,239) and validation (n = 12,728) cohorts, six retrospective institutional cohorts with long-term clinical outcomes data (n = 1,170), and The Cancer Genome Atlas (n = 333). Results: A low AR-active subclass was identified, which comprised 9%–11% of each cohort, and was characterized by increased immune signaling, neuroendocrine expression, and decreased DNA repair. These tumors were predominantly ERG and basal subtype. Low AR-active tumors had significantly more rapid development of recurrence or metastatic disease across cohorts, which was maintained on multivariable analysis [HR, 2.61; 95% confidence interval (CI), 1.22–5.60; P = 0.014]. Low AR-active tumors were predicted to be more sensitive to PARP inhibition, platinum chemotherapy, and radiotherapy, and less sensitive to docetaxel and androgen-deprivation therapy. This was validated clinically, in that low AR-active tumors were less sensitive to androgen-deprivation therapy (OR, 0.41; 95% CI, 0.21–0.80; P = 0.008). Conclusions: Leveraging large-scale transcriptomic data allowed the identification of an aggressive subtype of treatment-naïve primary prostate cancer that harbors molecular features more analogous to mCRPC. This suggests that a preexisting subgroup of patients may have tumors that are predisposed to fail multiple current standard-of-care therapies and warrant dedicated therapeutic investigation.
Efficacy and Safety of Rovalpituzumab Tesirine in Third-Line and Beyond Patients with DLL3-Expressing, Relapsed/Refractory Small-Cell Lung Cancer: Results From the Phase II TRINITY Study
Authors: Daniel Morgensztern, Benjamin Besse, Laurent Greillier, Rafael Santana-Davila, Neal Ready, Christine L. Hann, Bonnie S. Glisson, Anna F. Farago, Afshin Dowlati, Charles M. Rudin, Sylvestre Le Moulec, Satwant Lally, Sreeni Yalamanchili, Jürgen Wolf, Ramaswamy Govindan, David P. Carbone
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Although extensive-stage small-cell lung cancer (SCLC) is highly responsive to first-line therapy, virtually all patients develop resistance with short survival. Rovalpituzumab tesirine (Rova-T) is an antibody–drug conjugate targeting delta-like 3 protein (DLL3). This open-label, single-arm, phase II study (TRINITY) assessed safety and efficacy of Rova-T in patients with DLL3-expressing SCLC in the third-line and beyond (3L+) setting. Patients and Methods: Patients with DLL3-expressing SCLC (determined by mouse antibody immunohistochemistry [IHC] assay), and ≥2 prior regimens, received 0.3 mg/kg Rova-T once every 6 weeks for two cycles. During study, a rabbit antibody IHC assay was developed and used for the final analysis, with DLL3-positive and DLL3-high defined as ≥25% and ≥75% of tumor cells positive for DLL3, respectively. The primary endpoints were objective response rate (ORR) and overall survival (OS). Results: Among 339 patients enrolled, 261 (77%) had two prior lines of therapy and 78 (23%) had ≥3. DLL3-high and DLL3-positive tumors by rabbit IHC were seen in 238 (70%) and 287 (85%) patients, respectively. The remaining 52 (15%) were DLL3-negative only by rabbit IHC or had missing results. ORR was 12.4%, 14.3%, and 13.2% in all, DLL3-high, and DLL3-positive patients, respectively. Median OS was 5.6 months in all patients and 5.7 months in DLL3-high patients. The most common adverse events (AE) were fatigue, photosensitivity reaction, and pleural effusion. Grade 3–5 AEs were seen in 213 (63%) patients. Conclusions: Rova-T is the first targeted agent in SCLC to use DLL3, a novel biomarker. However, results demonstrate modest clinical activity in 3L+ SCLC, with associated toxicities.
Mediation of the Acute Stress Response by the Skeleton
Authors: Julian Meyer Berger, Parminder Singh, Lori Khrimian, Donald A. Morgan, Subrata Chowdhury, Emilio Arteaga-Solis, Tamas L. Horvath, Ana I. Domingos, Anna L. Marsland, Vijay Kumar Yadav, Kamal Rahmouni, Xiao-Bing Gao, Gerard Karsenty
Journal: Cell Metabolism (2019)
Author Correction: Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice
Authors: Jasper M. A. de Jong, Wenfei Sun, Nuno D. Pires, Andrea Frontini, Miroslav Balaz, Naja Z. Jespersen, Amir Feizi, Katarina Petrovic, Alexander W. Fischer, Muhammad Hamza Bokhari, Tarja Niemi, Pirjo Nuutila, Saverio Cinti, Søren Nielsen, Camilla Scheele, Kirsi Virtanen, Barbara Cannon, Jan Nedergaard, Christian Wolfrum, Natasa Petrovic
Journal: Nature Metabolism (2019)
Deciphering the cellular interplays underlying obesity-induced adipose tissue fibrosis
Authors: Geneviève Marcelin, Ana Letícia M. Silveira, Laís Bhering Martins, Adaliene V.M. Ferreira, Karine Clément
Journal: Journal of Clinical Investigation (2019)

Obesity originates from an imbalance between caloric intake and energy expenditure that promotes adipose tissue expansion, which is necessary to buffer nutrient excess. Patients with higher visceral fat mass are at a higher risk of developing severe complications such as type 2 diabetes and cardiovascular and liver diseases. However, increased fat mass does not fully explain obesity's propensity to promote metabolic diseases. With chronic obesity, adipose tissue undergoes major remodeling, which can ultimately result in unresolved chronic inflammation leading to fibrosis accumulation. These features drive local tissue damage and initiate and/or maintain multiorgan dysfunction. Here, we review the current understanding of adipose tissue remodeling with a focus on obesity-induced adipose tissue fibrosis and its relevance to clinical manifestations.
Efficacy of low dose pazopanib in advanced soft tissue sarcoma (STS): Experience from a dedicated sarcoma medical oncology clinic in India.
Authors: Santosh Kumar C, Sameer Rastogi, Ramjas Prajapati, Adarsh Barwad, Aditi Aggarwal, Ekta Dhamija, Rambha Panday, Anshul Gupta, Rimlee Dutta, SVS Deo, Parisa Manasa, Pankaj Kumar, Sorun Shishak
Journal: Journal of Clinical Oncology (2019)

e22555 Background: The approved dose of pazopanib in advanced STS is 800 mg/day and is not weight based. After initial patients who couldn’t tolerate pazopanib we started pazopanib at lower doses escalating to higher doses. There is already preliminary data about low dose pazopanib in asian patients. Methods: We retrospectively analysed the prospectively kept data base of patients with advanced non adipocytic STS who were treated with pazopanib at AIIMS sarcoma medical oncology clinic between September 2015 and February 2019. After start of pazopanib we get CT scan done every 3 monthly as institutional protocol. Statistical analysis was done by SPSS 23. Results: There were total of 66 patients with median age 40 yrs (17 – 81)and majority were males who (60). ECOG Performance status (PS) was PS 1 in 63% and PS 2 in 23%. Most common diagnosis was synovial sarcoma (22%), leiomyosarcoma (18 %), angiosarcoma (9%), MPNST(8%) and others (43%). Most of the patients received pazopanib as second line (59%) and third line (31%). 90% of patients received dose of 400 mg and remaining 10% of the patients received 600 mg of dose (in which it could be escalated after 1 month). Median weight was 63kg and median height in our patients was 160cm while the median BSA was 1.6. Dose escalation was attempted, but was not feasible due to toxicities. Out of total 66 patients, 57 were available for response assessment. RECIST responses were complete response (CR) was present in 2.9%, partial response (PR) in 17% , stable disease (SD) in 28%. The median progression free survival (PFS) was 5 months and median overall survival was 18 months after a median duration of follow up of 20 months. Grade 3 and grade 4 toxicities were present in 31% of the patients. Grade 3 hand foot syndrome (HFS) was present in 12% of patients.4.5% had hypertension. Other grade 3 and 4 toxicities were oral mucositis (6%) , transaminitis (4%) Cardiomyopathy (3%) and cholestasis jaundice (1.5%) with bilirubin elevated to the level on 19.1 mg/dl. This resolved after stoppage of Pazopanib. Conclusions: Pazopanib at low doses in our series was as efficacious and with similar toxicity as previous literature The option of lower dose pazopanib needs to be explored in Asian population who have lower body weight.
Risk Stratification and Survival after Myocardial Infarction
Journal: New England Journal of Medicine (1983)

We assessed the role of physiologic measurements of heart function in predicting mortality after myocardial infarction. Most of the 866 patients enrolled in our multicenter study underwent 24-hour Holter monitoring and determination of the resting radionuclide ventricular ejection fraction before discharge. Univariate analyses showed a progressive increase in cardiac mortality during one year as the ejection fraction fell below 0.40 and as the number of ventricular ectopic depolarizations exceeded one per hour. Only four risk factors among eight prespecified variables were independent predictors of mortality: an ejection fraction below 0.40, ventricular ectopy of 10 or more depolarizations per hour, advanced New York Heart Association functional class before infarction, and rales heard in the upper two thirds of the lung fields while the patient was in the coronary-care unit. Various combinations of these four factors identified five risk subgroups with two-year mortality rates ranging from 3 per cent (no factors) to 60 per cent (all four factors).
Abstract 4608: Colchicine binding site agents as potent tubulin inhibitors suppressing triple negative breast cancer
Authors: Shanshan Deng, Hao Chen, Raisa Krutilina, Najah G. Albadari, Tiffany N. Seagroves, Duane D. Miller, Wei Li
Journal: Cancer Research (2019)

Abstract Triple-negative breast cancer (TNBC) cases account for about 15% of all breast cancers in the United States and have poorer overall prognosis relative to other molecular subtypes, partially due to the rapid development of drug resistance to chemotherapies and the increased risk of visceral metastasis. One of the standard treatment regimens for TNBC is the use of a taxane-based chemotherapy, such as paclitaxel, which stabilizes microtubules. However, drug resistance and neurotoxicities often limit the clinical efficacy of taxanes. Therefore, there are continuous needs to develop more effective therapies that could overcome resistance to taxanes. In this study, a novel series of structurally related pyridine analogs based on our previously reported lead compound ABI-274, was designed and synthesized to identify a molecule with improved antiproliferative potency. Most of these pyridine compounds exhibited potent cytotoxicity when tested in a panel of melanoma and breast cancer cell lines, with IC50 values in the low nanomolar range. Among them, CH-II-77 is the most potent compound with an IC50 value of 1−3 nM against these cancer cell lines, including paclitaxel-resistant sublines. The high-resolution X-ray crystal structure of CH-II-77 in complex with tubulin protein confirmed its direct binding to the colchicine-binding site. It strongly induced apoptosis and produced G2/M phase cell cycle arrest in TNBC cells in a dose-dependent manner in vitro. In vivo, CH-II-77 inhibited tumor growth in A375 melanoma xenografts and MDA-MB-231 TNBC xenografts in a dose-dependent manner. CH-II-77 was able to induce tumor necrosis and apoptosis in vivo. Collectively, these studies strongly suggest that CH-II-77 is a potent inhibitor of the growth of TNBC in vitro and in vivo. Thus, CH-II-77 and optimization of this analog are promising new generation of tubulin inhibitors for the treatment of TNBC and other types of cancers where tubulin inhibitors are currently being used clinically. Citation Format: Shanshan Deng, Hao Chen, Raisa Krutilina, Najah G. Albadari, Tiffany N. Seagroves, Duane D. Miller, Wei Li. Colchicine binding site agents as potent tubulin inhibitors suppressing triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4608.
Noninvasive ventilation during weaning from prolonged mechanical ventilation
Authors: Piero Ceriana, Stefano Nava, Michele Vitacca, Annalisa Carlucci, Mara Paneroni, Annia Schreiber, Lara Pisani, Nicolino Ambrosino
Journal: Pulmonology (2019)

Non invasive ventilation (NIV) is currently employed for weaning from invasive ventilation (IMV) in the acute setting but its use for weaning from prolonged ventilation is still occasional and not standardized. We wanted to evaluate whether a combined protocol of NIV and decannulation in tracheostomized patients needing prolonged mechanical ventilation was feasible and what would be the one-year outcome.We studied patients still dependent from invasive mechanical ventilation with the following inclusion criteria: a) tolerance of at least 8h of unsupported breathing, b) progressive hypercapnia/acidosis after invasive ventilation discontinuation, c) good adaptation to NIV, d) favorable criteria for decannulation. These patients were switched from IMV to NIV and decannulated; then they were discharged on home NIV and followed-up for one year in order to evaluate survival and complications rate.Data from patients consecutively admitted to a weaning unit were prospectively collected between 2005 and 2018. Out of 587 patients admitted over that period, 341 were liberated from prolonged mechanical ventilation. Fifty-one out of 147 unweaned patients (35%) were eligible for the protocol but only 46 were enrolled. After a mean length of stay of 35 days they were decannulated and discharged on domiciliary NIV. After one year, 38 patients were still alive (survival rate 82%) and 37 were using NIV with good adherence (only one patient was switched again to invasive ventilation).NIV applied to patients with failed weaning from prolonged IMV is feasible and can facilitate the decannulation process. Patients successfully completing this process show good survival rates and few complications.
Neurological Adverse Events Determine Morbidity and Mortality Post Allogeneic Hematopoietic Cell Transplantation
Authors: Ioanna Sakellari, Eleni Gavriilaki, Sotirios Papagiannopoulos, Maria Gavriilaki, Ioannis Batsis, Despina Mallouri, Anna Vardi, Varnavas Constantinou, Michalis Iskas, Marianna Masmanidou, Evangelia Yannaki, Triantafyllos Geroukis, Dimitrios Kazis, Vasilis Kimiskidis, Achilles Anagnostopoulos
Journal: Blood (2018)
Vitamin D Receptor Activation in Liver Macrophages Ameliorates Hepatic Inflammation, Steatosis, and Insulin Resistance in Mice
Authors: Bingning Dong, Ying Zhou, Wei Wang, Jessica Scott, KangHo Kim, Zhen Sun, Qi Guo, Yang Lu, Naomi M. Gonzales, Huaizhu Wu, Sean M. Hartig, Robert Brian York, Feng Yang, David D. Moore
Journal: Hepatology (2019)

Obesity-induced chronic inflammation is a key component in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and insulin resistance. Increased secretion of proinflammatory cytokines by macrophages in metabolic tissues promotes disease progression. In the diet-induced obesity (DIO) mouse model, activation of liver resident macrophages, or Kupffer cells (KCs), drives inflammatory responses, which recruits circulating macrophages and promotes fatty liver development, and ultimately contributes to impaired hepatic insulin sensitivity. Hepatic macrophages express the highest level of vitamin D receptors (VDRs) among nonparenchymal cells, whereas VDR expression is very low in hepatocytes. VDR activation exerts anti-inflammatory effects in immune cells.Here we found that VDR activation exhibits strong anti-inflammatory effects in mouse hepatic macrophages, including those isolated from DIO livers, and mice with genetic loss of Vdr developed spontaneous hepatic inflammation at 6 months of age. Under the chronic inflammation conditions of the DIO model, VDR activation by the vitamin D analog calcipotriol reduced liver inflammation and hepatic steatosis, significantly improving insulin sensitivity. The hyperinsulinemic euglycemic clamp revealed that VDR activation greatly increased the glucose infusion rate, while hepatic glucose production was remarkably decreased. Glucose uptake in muscle and adipose did not show similar effects, suggesting that improved hepatic insulin sensitivity is the primary contributor to the beneficial effects of VDR activation. Finally, specifically ablating liver macrophages by treatment with clodronate liposomes largely abolished the beneficial metabolic effects of calcipotriol, confirming that VDR activation in liver macrophages is required for the antidiabetic effect.Activation of liver macrophage VDRs by vitamin D ligands ameliorates liver inflammation, steatosis and insulin resistance. Our results suggest therapeutic paradigms for treatment of NAFLD and type 2 diabetes mellitus.
The transcription factor Zfp281 sustains CD4+ T lymphocyte activation through directly repressing Ctla-4 transcription
Authors: Jing Guo, Zhonghui Xue, Ruoyu Ma, Weiwei Yi, Zhaoyuan Hui, Yixin Guo, Yuxi Yao, Wenqiang Cao, Jianli Wang, Zhenyu Ju, Linrong Lu, Lie Wang
Journal: Cellular and Molecular Immunology (2019)

Abstract The expression of coinhibitory receptors, such as CTLA-4, on effector T cells is a key mechanism for the negative regulation of T-cell activation. However, the transcriptional regulation of CTLA-4 is not well understood. Zfp281, a C2H2 zinc finger protein, is a negative regulator of pluripotency maintenance of embryonic stem cells. Nevertheless, the function of Zfp281 in differentiated cells has not been studied. We generated Zfp281 conditional knockout mice in which the function of the Zfp281 gene was conditionally disrupted by the Cd4 Cre transgene to study its impact on T cell function. Zfp281 had no effect on T-cell development, but CD4 + T cell activation and cytokine production were impaired due to diminished T-cell receptor signaling. Furthermore, Zfp281 deficiency inhibited in vivo T cell responses to Listeria monocytogenes infection. Using genome-wide expression profiling assays, we determined that Zfp281 repressed Ctla-4 expression by directly binding to GC-rich sites in its promoter, which inhibited the negative feedback of T cell activation. In line with this result, CTLA-4 blockade and shRNA knockdown partly rescued the reduced cytokine production caused by Zfp281 deficiency. These findings indicate that Zfp281 sustains CD4 + T lymphocyte activation by directly repressing Ctla-4 transcription.
Drug Sensitivity Prediction Models Reveal a Link between DNA Repair Defects and Poor Prognosis in HNSCC
Authors: Paul B.M. Essers, Martijn van der Heijden, Caroline V.M. Verhagen, Emily M. Ploeg, Reinout H. de Roest, C. René Leemans, Ruud H. Brakenhoff, Michiel W.M. van den Brekel, Harry Bartelink, Marcel Verheij, Conchita Vens
Journal: Cancer Research (2019)

Abstract Head and neck squamous cell carcinoma (HNSCC) is characterized by the frequent manifestation of DNA crosslink repair defects. We established novel expression-based DNA repair defect markers to determine the clinical impact of such repair defects. Using hypersensitivity to the DNA crosslinking agents, mitomycin C and olaparib, as proxies for functional DNA repair defects in a panel of 25 HNSCC cell lines, we applied machine learning to define gene expression models that predict repair defects. The expression profiles established predicted hypersensitivity to DNA-damaging agents and were associated with mutations in crosslink repair genes, as well as downregulation of DNA damage response and repair genes, in two independent datasets. The prognostic value of the repair defect prediction profiles was assessed in two retrospective cohorts with a total of 180 patients with advanced HPV-negative HNSCC, who were treated with cisplatin-based chemoradiotherapy. DNA repair defects, as predicted by the profiles, were associated with poor outcome in both patient cohorts. The poor prognosis association was particularly strong in normoxic tumor samples and was linked to an increased risk of distant metastasis. In vitro, only crosslink repair–defective HNSCC cell lines are highly migratory and invasive. This phenotype could also be induced in cells by inhibiting rad51 in repair competent and reduced by DNA-PK inhibition. In conclusion, DNA crosslink repair prediction expression profiles reveal a poor prognosis association in HNSCC. Significance: This study uses innovative machine learning-based approaches to derive models that predict the effect of DNA repair defects on treatment outcome in HNSCC.
68Ga-PSMA PET/CT in Giant Retroperitoneal Liposarcoma
Authors: Sabahat Inanir, Selin Kesim, Rabia Ergelen, İlker Tınay, Hüseyin Kemal Türköz
Journal: Clinical Nuclear Medicine (2019)

Primary retroperitoneal liposarcoma is an extremely rare malignant tumor. Herein, we report a case with an incidentally detected giant retroperitoneal liposarcoma on Ga-PSMA PET/CT during primary staging for prostate cancer.
Biogenesis, functions and clinical significance of circRNAs in gastric cancer
Authors: Chan Shan, Yinfeng Zhang, Xiaodan Hao, Jinning Gao, Xinzhe Chen, Kun Wang
Journal: Molecular Cancer (2019)

Abstract Gastric cancer (GC) is one of the most common malignant tumours in the world and has high morbidity and mortality. Circular RNAs (circRNAs) are a class of non-coding RNAs with covalently linked circular structures. In recent years, plentiful circRNAs have been discovered that participate in many biological processes, including the initiation and development of tumours. Increasing evidences suggest important biological functions of circRNAs, implying that circRNAs may serve as vital new biomarkers and targets for disease diagnosis and prognosis. Among these, circRNAs are tend to aberrantly expressed and are regarded as potential biomarkers in the carcinogenesis and progression of GC. This review systematically summarised the biogenesis, biological properties and functions of circRNAs, with a focus on their relationship with GC, as well as their probable clinical implications on GC. As our cognition of the relation between circRNAs and GC deepens, more molecular mechanisms of GC progression will be discovered, and new therapeutic strategies will be used for the prevention and treatment of GC.
JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms
Authors: Tata Nageswara Rao, Nils Hansen, Julian Hilfiker, Shivam Rai, Julia-Magdalena Majewska, Danijela Leković, Deniz Gezer, Nicola Andina, Serena Galli, Teresa Cassel, Florian Geier, Julien Delezie, Ronny Nienhold, Hui Hao-Shen, Christian Beisel, Serena Di Palma, Sarah Dimeloe, Jonel Trebicka, Dominik Wolf, Max Gassmann, Teresa W.-M. Fan, Andrew N. Lane, Christoph Handschin, Stefan Dirnhofer, Nicolaus Kröger, Christoph Hess, Thomas Radimerski, Steffen Koschmieder, Vladan P. Čokić, Radek C. Skoda
Journal: Blood (2019)