tbuckley/cabot-search huggingface dataset:
Risk Stratification With the Use of Coronary Computed Tomographic Angiography in Patients With Nonobstructive Coronary Artery Disease
Authors: Jana Taron, Borek Foldyna, Thomas Mayrhofer, Michael T. Osborne, Nandini Meyersohn, Daniel O. Bittner, Stefan B. Puchner, Hamed Emami, Michael T. Lu, Maros Ferencik, Neha J. Pagidipati, Pamela S. Douglas, Udo Hoffmann
Journal: JACC. Cardiovascular imaging (2021)
ZEBRA: A Multicenter Phase II Study of Pembrolizumab in Patients with Advanced Small-Bowel Adenocarcinoma
Authors: Katrina S. Pedersen, Nathan R. Foster, Michael J. Overman, Patrick M. Boland, Sunnie S. Kim, Kathryn A. Arrambide, Brandy L. Jaszewski, Tanios Bekaii-Saab, Rondell P. Graham, Jack Welch, Richard H. Wilson, Robert R. McWilliams
Journal: Clinical Cancer Research (2021)

Small-bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic disease beyond first-line FOLFOX/CAPOX. SBA has higher rates of microsatellite instability (MSI-H) and T-lymphocyte infiltration than other gastrointestinal cancers. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response.Patients with previously treated advanced SBA received pembrolizumab 200 mg i.v. every 3 weeks until disease progression (PD), toxicity, or 35 doses maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary progression-free survival (PFS), overall survival (OS), and toxicity assessment endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level.Forty patients were treated for a median duration of four cycles (range, 1-35). All patients are off study treatment due to PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AEs, 5%). Three confirmed partial responses [PRs; 8%; 95% confidence interval (CI), 2-20] did not meet predefined success criteria of ORR 30%. Median OS (7.1 months; 95% CI, 5.1-17.1) and median PFS (2.8 months; 95% CI, 2.7-4.2) were similar across primary tumor sites. One confirmed PR (3%) was seen in patients with low MSS/MSI tumors and correlated with high tumor mutation burden (TMB). Fifty percent of patients with MSI-H tumors achieved PR and remain alive without progression. Twenty-five patients (63%) had grade ≥3 AEs and 11 patients (28%) had grade 4/5 AEs.In the largest study of SBA to date, pembrolizumab did not induce the hypothesized response rate; however, we did identify responses in key biomarker-selected cohorts.
Finding associations in a heterogeneous setting: statistical test for aberration enrichment
Authors: Aziz M. Mezlini, Sudeshna Das, Anna Goldenberg
Journal: Genome Medicine (2021)

Abstract Most two-group statistical tests find broad patterns such as overall shifts in mean, median, or variance. These tests may not have enough power to detect effects in a small subset of samples, e.g., a drug that works well only on a few patients. We developed a novel statistical test targeting such effects relevant for clinical trials, biomarker discovery, feature selection, etc. We focused on finding meaningful associations in complex genetic diseases in gene expression, miRNA expression, and DNA methylation. Our test outperforms traditional statistical tests in simulated and experimental data and detects potentially disease-relevant genes with heterogeneous effects.
A benchmark for RNA-seq deconvolution analysis under dynamic testing environments
Authors: Haijing Jin, Zhandong Liu
Journal: Genome biology (2021)

Abstract Background Deconvolution analyses have been widely used to track compositional alterations of cell types in gene expression data. Although a large number of novel methods have been developed, due to a lack of understanding of the effects of modeling assumptions and tuning parameters, it is challenging for researchers to select an optimal deconvolution method suitable for the targeted biological conditions. Results To systematically reveal the pitfalls and challenges of deconvolution analyses, we investigate the impact of several technical and biological factors including simulation model, quantification unit, component number, weight matrix, and unknown content by constructing three benchmarking frameworks. These frameworks cover comparative analysis of 11 popular deconvolution methods under 1766 conditions. Conclusions We provide new insights to researchers for future application, standardization, and development of deconvolution tools on RNA-seq data.
Cannabis Use and Suicidal Behavior and Long-term Harms
Authors: Xue-Lei Fu, Hong-Lin Chen
Journal: JAMA Pediatrics (2021)

To the Editor In a population-based study, Fontanella et al1 observed that cannabis use disorder is a common comorbidity and risk marker for self-harm, all-cause mortality, and death by unintentional overdose and homicide among youths with mood disorders.1 However, we have 4 major concerns.
Clonal Cytogenetic Abnormalities in Myeloid Neoplasms Arising from Fanconi Anemia — a Single Center Study from India
Authors: Nancy Beryl Janet Arthur, Vivi M Srivastava, Gaurav Joshi, Anu Korula, Anup Joseph Devasia, Nisham Pn, Uday Prakash Kulkarni, Alok Srivastava, Vikram Mathews, Shaji Ramachandran Velayudhan, Biju George
Journal: Blood (2017)
The bone anchored prostheses for amputees – Historical development, current status, and future aspects
Authors: Yan Li, Li Felländer-Tsai
Journal: Biomaterials (2021)

In the past 50 years, bone anchored prostheses have evolved from a concept for experimental treatment to a rapidly developing area in orthopedics and traumatology. Up to date, there are dozens of centers in the world providing osseointegration amputation reconstructions and more than a thousand patients using the bone anchored prostheses. Compared with conventional socket prostheses, the bone anchored prosthesis by osseointegration avoids the debilitating problems related with soft tissues. It also provides physiological weight bearing, improved range of motion, and sensory feedback, all of which contribute to the improvement on quality of life for amputees. The present article briefly reviews the historical development of osseointegration surgery for amputation reconstruction and the current challenges. The implant design characters and surgical techniques of the two types of implants; the screw-type implant (presented by the OPRA system), and the press-fit implants (presented by EEP and OPL systems) are described. The major complications, infections and mechanical failures, are discussed in detail based on the latest evidence. Future aspects and experimental trials aiming to overcome the current challenges are presented.
The Biosynthesis of Collagen
Authors: Michael E. Grant, Darwin J. Prockop
Journal: New England Journal of Medicine (1972)

INTEREST in the biochemistry of collagen derives in part from its abundance, in part from its unusual properties and in part from its likely importance in diseases of connective tissue. Collagen is probably the most abundant protein in the human body, and it is the major constituent of most connective tissues (Table 1). The other major components of these tissues are elastin, a related fibrous protein, and the class of sugar polymers known as mucopolysaccharides or proteoglycans. Soft organs such as liver contain only a small amount of collagen, whereas in tissues such as skin and tendon, collagen accounts for . . .
FDA Approval Summary: Pembrolizumab for the First-line Treatment of Patients with MSI-H/dMMR Advanced Unresectable or Metastatic Colorectal Carcinoma
Authors: Sandra J. Casak, Leigh Marcus, Lola Fashoyin-Aje, Sirisha L. Mushti, Joyce Cheng, Yuan-Li Shen, William F. Pierce, Leah Her, Kirsten B. Goldberg, Marc R. Theoret, Paul G. Kluetz, Richard Pazdur, Steven J. Lemery
Journal: Clinical Cancer Research (2021)

Abstract The FDA approved pembrolizumab on June 29, 2020, for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) colorectal cancer with no prior systemic treatment for advanced disease. The approval was based on data from Study Keynote-177, which randomly allocated patients to receive either pembrolizumab or standard of care (SOC) with chemotherapy. Overall survival (OS) and independently assessed progression-free survival (PFS) were the primary endpoints. At the time of the final PFS analysis and second prespecified interim OS analysis, the estimated median PFS was 16.5 months (95% CI: 5.4–32.4) versus 8.2 months (95% CI: 6.1–10.2) in the pembrolizumab and SOC arms, respectively [HR: 0.60 (95% CI: 0.45–0.80); two-sided P = 0.0004]. FDA assessed unblinded OS data during the review of the application and identified no safety concerns that would preclude approval of this supplement. Adverse reactions occurring in &amp;gt;30% of patients receiving pembrolizumab were diarrhea, fatigue/asthenia, and nausea. Adverse reactions occurring in &amp;gt;30% of patients receiving SOC were diarrhea, nausea, fatigue/asthenia, neutropenia, decreased appetite, peripheral neuropathy (high-level term), vomiting, abdominal pain, constipation, and stomatitis. Duration of treatment in the pembrolizumab arm was almost double (median 11.1 months, range 0–30.6 months) than the duration of treatment in patients receiving SOC (median, 5.7 months). Approval of pembrolizumab is likely to change the treatment paradigm for first-line treatment with MSI-H advanced colorectal cancer given the study results and different safety profile.
Burden of Tracheal, Bronchus, and Lung Cancer and Its Attributable Risk Factors in 204 Countries and Territories, 1990 to 2019
Authors: Saeid Safiri, Mohammad-Reza Sohrabi, Kristin Carson-Chahhoud, Deepti Bettampadi, Ali Taghizadieh, Amir Almasi-Hashiani, Ahad Ashrafi-Asgarabad, Mahdi Sepidarkish, Arielle Eagen, Mohammad-Ali Mansournia, Ali-Asghar Kolahi
Journal: Journal of Thoracic Oncology (2021)
Triple-modality therapy maximizes antitumor immune responses in a mouse model of mesothelioma
Authors: Junichi Murakami, Licun Wu, Mikihiro Kohno, Mei-Lin Chan, Yidan Zhao, Zhihong Yun, B. C. John Cho, Marc de Perrot
Journal: Science Translational Medicine (2021)

Malignant pleural mesothelioma (MPM) is an intractable disease with an extremely poor prognosis. Our clinical protocol for MPM of subablative radiotherapy (RT) followed by radical surgery achieved better survival compared to other multimodal treatments, but local relapse and metastasis remain a problem. This subablative RT elicits an antitumoral immune response that is limited by the immunosuppressive microenvironment generated by regulatory T (Treg) cells. The antitumor effect of immunotherapy to simultaneously modulate the immune activation and the immune suppression after subablative RT has not been investigated in MPM. Herein, we demonstrated a rationale to combine interleukin-15 (IL-15) superagonist (IL-15SA) and glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonist (DTA-1) with subablative RT in mesothelioma. IL-15SA boosted the systemic expansion of specific antitumoral memory CD8+ T cells that were induced by RT in mice. Their effect, however, was limited by the up-regulation and activation of Treg cells in the radiated tumor microenvironment. Hence, selective depletion of intratumoral Treg cells through DTA-1 enhanced the benefit of subablative RT in combination with IL-15SA. The addition of surgical resection of the radiated tumor in combination with IL-15SA and DTA-1 maximized the benefit of RT and was accompanied by a reproducible abscopal response in a concomitant tumor model. These data support the development of clinical trials in MPM to test such treatment options for patients with locally advanced or metastatic tumors.
Abstract 16653: Ventricular Arrhythmias With Ibrutinib Use: A Systematic Review and Meta-Analysis
Authors: Yaser Khallid, Neethi Dasu, Ankit Shah, Michael G Fradley, Kirti Dasu, Adam Levine
Journal: Circulation (2020)

Introduction: Ibrutinib is a widely used treatment option for patients with chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia. There is limited investigation on the relationship between ibrutinib and the development of ventricular arrhythmias. Hypothesis: We hypothesized that the incidence of ventricular arrhythmias in patients taking ibrutinib compared to the patients on other treatment regimens would be higher. Methods: We performed an aggregate data meta-analysis on nine studies to examine the incidence of ventricular arrhythmias. We further assessed a meta-regression analysis to evaluate the effect of duration of therapy on incidence of ventricular arrhythmias. Relative risk (RR) and 95% confidence intervals (CI) were estimated using a random-effects model. Results: Of 3809 patients being treated with ibrutinib, the incidence of ventricular arrhythmias was almost 8-fold higher in patients being treated with ibrutinib compared to other tyrosine kinase inhibitors (TKIs), other chemotherapies, or immunotherapy. (RR 8.13, 95% CI 4.37-15.10, p &lt;0.0001). On meta-regression analysis, the incidence increased further with longer duration of treatment (coefficient = 0.0206, p=0.049); patient populations greater than 60 years have a higher incidence of ventricular arrhythmias (coefficient = 0.0237, p=0.044). Over 50% of patients diagnosed with ventricular arrhythmias on ibrutinib died of sudden death. Conclusions: For patients treated with ibrutinib, there was a markedly higher rate of ventricular arrhythmias and an increased incidence with longer duration of treatment. These data highlight the need for guidelines on surveillance and management for ventricular arrhythmias for patients taking ibrutinib.
The Effect of Tolvaptan on BP in Polycystic Kidney Disease: A Post Hoc Analysis of the TEMPO 3:4 Trial
Authors: Judith E. Heida, Ron T. Gansevoort, Vicente E. Torres, Olivier Devuyst, Ronald D. Perrone, Jennifer Lee, Hui Li, John Ouyang, Arlene B. Chapman
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement Patients with autosomal dominant polycystic kidney disease are treated with tolvaptan, a V2 receptor antagonist, to slow progression toward ESKD. In theory, tolvaptan could have both BP-increasing and BP-decreasing effects. To investigate the magnitude and time course of the effect of tolvaptan use on BP, the authors conducted a post hoc analysis of data from the TEMPO 3:4 trial, which randomized 1445 patients with autosomal dominant polycystic kidney disease to tolvaptan or placebo. Their analysis shows that directly after start of tolvaptan therapy, BP does not change, but in the long term, BP gradually becomes lower in patients with tolvaptan compared with placebo. This observation might be attributed to the beneficial effect of tolvaptan on disease progression, a sustained natriuretic effect, or both. Background The V2 receptor antagonist tolvaptan is prescribed to patients with autosomal dominant polycystic kidney disease to slow disease progression. Tolvaptan may alter BP via various acute and chronic effects. Methods To investigate the magnitude and time course of the effect of tolvaptan use on BP, we conducted a post hoc study of the TEMPO 3:4 trial, which included 1445 patients with autosomal dominant polycystic kidney disease randomized 2:1 to tolvaptan or placebo for 3 years. We evaluated systolic and diastolic BP, mean arterial pressure, hypertension status, and use and dosing of antihypertensive drugs over the course of the trial. Results At baseline, BP did not differ between study arms. After 3 weeks of tolvaptan use, mean body weight had decreased from 79.7 to 78.8 kg, and mean plasma sodium increased from 140.4 to 142.6 mmol/L (both P &lt;0.001), suggesting a decrease in circulating volume. We observed none of these changes in the placebo arm. Nonetheless, BP remained similar in the study arms. After 3 years of treatment, however, mean systolic BP was significantly lower in participants receiving tolvaptan versus placebo (126 versus 129 mm Hg, respectively; P =0.002), as was mean diastolic BP (81.2 versus 82.6 mm Hg, respectively; P =0.01). These differences leveled off at follow-up 3 weeks after discontinuation of the study medication. Use of antihypertensive drugs remained similar in both study arms during the entire study. Conclusions Long-term treatment with tolvaptan gradually lowered BP compared with placebo, which may be attributed to a beneficial effect on disease progression, a continued natriuretic effect, or both. Clinical Trial registry name and registration number: TEMPO 3:4, NCT00428948
Abstract 16634: Treatment Patterns &amp; Clinical Outcomes Among Asian Americans With Atrial Fibrillation: An Analysis From the NCRD® PINNACLE Registry
Authors: Dhruv Mahtta, Kevin Gu, Amar Kaneria, Parija Sharedalal, Brittany Dennis, Yang Song, Wei Xin, Mirza Khalid, Paul Hess, Sung-Hae Cho, Salim S Virani
Journal: Circulation (2020)

Introduction: Although treatment modalities for Atrial Fibrillation (AF) continue to evolve, there is paucity of data on AF management and associated clinical outcomes among Asian Americans (AA). We investigated risk factor profiles, racial disparities in clinical management and associated adverse clinical outcomes among AA compared to Whites. Hypothesis: Racial disparities exist between White and AA with regards to AF management and related adverse clinical outcomes. Methods: Using the National Cardiovascular Data Registry (NCDR®) Practice Innovation and Clinical Excellence (PINNACLE) registry and linked Centers of Medicare and Medicaid Services data to identify AA and White patients with AF between 1/1/13-6/30/18, we characterized risk factors, management strategies (rate vs. rhythm control), anticoagulation use and rates of adverse events across racial groups. The two race groups were compared using hierarchical multivariable adjusted regression models to account for site and potential confounders. Results: Our analysis included 1359827 patients with AF (18793 AA; 1341034 Whites). Compared to Whites, AA were more likely to be treated with rate control strategy (OR:1.20, 95% CI:1.15-1.25) in adjusted analyses. AA had lower odds of use of rhythm control strategy (atrial ablations, cardioversions, or use of antiarrhythmic drugs) (OR:0.83, 95% CI:0.80-0.87). Overall use of oral anticoagulants (OAC) and direct oral anticoagulants were similar across both racial groups. There were no significant race-based differences in likelihood of adverse clinical events including all-cause mortality, strokes, and bleeding. Analyses performed using propensity score matching were consistent with the main results. Conclusions: AA with AF have a lower likelihood of being managed with rhythm control strategies. Overall use of OAC and AF related adverse events remain similar between the two racial groups.
FDG PET/CT Showing a Primary Lymphoma of the Sternoclavicular Joint
Authors: Rang Wang, Pan Tang, Rong Tian
Journal: Clinical Nuclear Medicine (2021)

We presented a case of primary lymphoma of the sternoclavicular joint. A 67-year-old woman with a history of swelling at the sternoclavicular joint region was considered as osteoarthritis initially. Chest CT found a soft tissue mass around the sternoclavicular joint. Biopsy demonstrated diffuse large B-cell lymphoma. The subsequent FDG PET/CT revealed FDG-avid articular destruction with surrounding soft tissue mass without any other abnormal findings, suggesting a primary extranodal lymphoma of sternoclavicular joint.
Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy
Authors: Chirag Krishna, Renzo G. DiNatale, Fengshen Kuo, Raghvendra M. Srivastava, Lynda Vuong, Diego Chowell, Sounak Gupta, Chad Vanderbilt, Tanaya A. Purohit, Ming Liu, Emily Kansler, Briana G. Nixon, Ying-Bei Chen, Vladimir Makarov, Kyle A. Blum, Kyrollis Attalla, Stanley Weng, Michael L. Salmans, Mahdi Golkaram, Li Liu, Shile Zhang, Raakhee Vijayaraghavan, Traci Pawlowski, Victor Reuter, Maria I. Carlo, Martin H. Voss, Jonathan Coleman, Paul Russo, Robert J. Motzer, Ming O. Li, Christina S. Leslie, Timothy A. Chan, A. Ari Hakimi
Journal: Cancer Cell (2021)
Thrombotic complications of vaccination against SARS-CoV-2: what pharmacovigilance reports tell us – and what they don't
Authors: Stavros V. Konstantinides
Journal: European Respiratory Journal (2021)

In the present issue of the European Respiratory Journal , Smadja et al. [1] present an analysis of global pharmacovigilance reports of thrombotic events following severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) vaccination. More specifically, the authors analysed the data entered into the World Health Organization (WHO) Global Database for Individual Case Safety Reports (VigiBase) between 13 December, 2020 and 16 March, 2021, covering, at that time, a population of almost 362 million vaccinated individuals across the world. The study focuses on three of the coronavirus disease 2019 (COVID-19) vaccines available to date, namely Pfizer-BioNtech (BNT162b2), Moderna (mRNA-1273) and OxfordAstraZeneca (ChAdOx1 nCov-19). The study by Smadja et al. [1] confirms the rarity of possible thrombotic complications in association with COVID-19 vaccination, reporting only 0.21 (95% CI 0.19–0.22) cases of thrombotic events per million person vaccinated-days. However, there were also some unexpected observations which deserve closer attention and cautious interpretation. Thrombotic complications of COVID-19 vaccination are very rare, but awareness is needed https://bit.ly/3n4vaXe
Inhaled nitric oxide improves the hepatopulmonary syndrome: a physiologic analysis
Authors: Samir Gupta, Rosalind Tang, Abdul Al-Hesayen
Journal: Thorax (2021)

The hepatopulmonary syndrome (HPS) is defined by liver dysfunction, intrapulmonary vasodilatation and abnormal oxygenation. Hypoxaemia is progressive and liver transplant is the only effective treatment. Severe hypoxaemia is a life-threatening HPS complication, particularly after transplant. We evaluated gas-exchange and haemodynamic effects of invasive therapies in a consecutive sample of 26 pre-transplant patients. Inhaled nitric oxide significantly improved partial pressure of oxygen (12.4 mm Hg; p=0.001) without deleterious effects on cardiac output. Trendelenburg positioning resulted in a small improvement, and methylene blue did not, though individual responses were variable. Future studies should prospectively evaluate these strategies in severe post-transplant hypoxaemia.
Abstract 14767: Prognostic Impact of Muscle, Fat, and Bone Mass in Patients With Heart Failure
Authors: Masaaki Konishi, Eiichi Akiyama, Yasushi Matsuzawa, Ryosuke Sato, Hidefumi Nakahashi, Shinnnosuke Kikuchi, Nobuhiko Maejima, Noriaki Iwahashi, Kiyoshi Hibi, Masami Kosuge, Kouichi Tamura, Kazuo Kimura
Journal: Circulation (2018)

Introduction: There is a paucity of data regarding muscle, fat, and bone mass in patients with heart failure (HF). Hypothesis: Muscle, fat, and bone mass have different impact on prognosis in HF. M...