tbuckley/cabot-search huggingface dataset:
Salvage nivolumab plus ipilimumab after prior PD-1/PD-L1 inhibitor treatment in metastatic renal cell carcinoma: A meta-analysis.
Authors: Ming Yin, Sherry Mori-Vogt, Megan Hinkley, Anish B Parikh, Yuanquan Yang, Katharine Collier, Abdul Miah, Mingjia Li
Journal: Journal of Clinical Oncology (2021)

305 Background: Although not officially approved, salvage nivolumab plus ipilimumab (nivo/ipi) treatment after prior PD-1/PD-L1 immune checkpoint inhibition is frequently used in metastatic renal cell carcinoma (mRCC). However, very limited data are available to guide such therapy. Methods: A search in Medline database and conference abstracts published in English before September 1, 2020 yielded 4 studies reporting salvage nivo/ipi outcomes of mRCC patients. We added additional information from 27 mRCC patients who received salvage nivo/ipi at The Ohio State University after prior PD-1 pathway inhibition. Hence, we performed a meta-analysis of five studies to further characterize the safety and efficacy of salvage nivo/ipi treatment. Results: Among 155 patients with measurable treatment response, we found that salvage nivo/ipi had an objective response rate of 19% (95% CI, 0.13-0.25), which was significantly lower than response to prior PD-1/PD-L1 inhibition (odds ratio, 0.35, 95% CI, 0.18-0.67; p &lt; 0.01). Response to prior PD-1/PD-L1 inhibition did not correlate with salvage nivo/ipi response (odds ratio, 1.41, 95% CI, 0.51-3.87; p = 0.51). Additionally, salvage nivo/ipi was associated with 26% (95% CI, 0.19-0.33) grade ≥ 3 adverse events, which was lower than the toxicity in the upfront setting reported in Checkmate-214 trial. Conclusions: It is feasible to have salvage nivo/ipi treatment in mRCC. Salvage nivo/ipi treatment has a lower efficacy and lower toxicity compared with its use in the first-line setting.
Paradigms on Immunotherapy Combinations with Chemotherapy
Authors: Diego Salas-Benito, José L. Pérez-Gracia, Mariano Ponz-Sarvisé, María E. Rodriguez-Ruiz, Iván Martínez-Forero, Eduardo Castañón, José M. López-Picazo, Miguel F. Sanmamed, Ignacio Melero
Journal: Cancer Discovery (2021)

Abstract Checkpoint inhibitors are being added to standard-of-care chemotherapy in multiple clinical trials. Success has been reported in non–small and small cell lung carcinomas and urothelial, head and neck, gastric, and esophageal cancers, and promising results are already available in triple-negative breast and pancreatic malignancies. The potential mechanisms of synergy include immunogenic tumor cell death, antiangiogenesis, selective depletion of myeloid immunosuppressive cells, and lymphopenia, which reduces regulatory T cells and makes room for proliferation of effector T cells. However, chemotherapy regimens have not been optimized for such combinations, perhaps explaining some recent clinical trial disappointments. Approaches to make the most of chemoimmunotherapy include neoadjuvant and adjuvant schemes. Significance: Immunotherapy of cancer based on PD-1/PD-L1 blockade has prompted a revolution in cancer clinical management. Evidence in phase III clinical trials already supports combinations of immunotherapy with standard-of-care chemotherapy for a number of malignant diseases. This review focuses on such evidence and provides an overview of the potential synergistic mechanisms of action and the opportunities to optimize chemoimmunotherapy regimens.
Considerations for treatment duration in responders to immune checkpoint inhibitors
Authors: Thomas U Marron, Aideen E Ryan, Sangeetha M Reddy, Sabina Kaczanowska, Rania H Younis, Dipti Thakkar, Jiajia Zhang, Todd Bartkowiak, Rachel Howard, Kristin G Anderson, Daniel Olson, Abdul Rafeh Naqash, Ravi B Patel, Esha Sachdev, Maria E Rodriguez-Ruiz, Michal Sheffer, Sarah Church, Christopher Fuhrman, Abigail Overacre-Delgoffe, Rosa Nguyen, Vaia Florou, Jessica E Thaxton, David H Aggen, Jennifer L Guerriero
Journal: Journal for ImmunoTherapy of Cancer (2021)

Immune checkpoint inhibitors (ICIs) have improved overall survival for cancer patients, however, optimal duration of ICI therapy has yet to be defined. Given ICIs were first used to treat patients with metastatic melanoma, a condition that at the time was incurable, little attention was initially paid to how much therapy would be needed for a durable response. As the early immunotherapy trials have matured past 10 years, a significant per cent of patients have demonstrated durable responses; it is now time to determine whether patients have been overtreated, and if durable remissions can still be achieved with less therapy, limiting the physical and financial toxicity associated with years of treatment. Well-designed trials are needed to identify optimal duration of therapy, and to define biomarkers to predict who would benefit from shorter courses of immunotherapy. Here, we outline key questions related to health, financial and societal toxicities of over treating with ICI and present four unique clinical trials aimed at exposing criteria for early cessation of ICI. Taken together, there is a serious liability to overtreating patients with ICI and future work is warranted to determine when it is safe to stop ICI.
Assessing the quality of mobile applications in chronic disease management: a scoping review
Authors: Payal Agarwal, Dara Gordon, Janessa Griffith, Natasha Kithulegoda, Holly O. Witteman, R. Sacha Bhatia, Andre W. Kushniruk, Elizabeth M. Borycki, Lise Lamothe, Elena Springall, James Shaw
Journal: npj Digital Medicine (2021)

Abstract While there has been a rapid growth of digital health apps to support chronic diseases, clear standards on how to best evaluate the quality of these evolving tools are absent. This scoping review aims to synthesize the emerging field of mobile health app quality assessment by reviewing criteria used by previous studies to assess the quality of mobile apps for chronic disease management. A literature review was conducted in September 2017 for published studies that use a set of quality criteria to directly evaluate two or more patient-facing apps supporting promote chronic disease management. This resulted in 8182 citations which were reviewed by research team members, resulting in 65 articles for inclusion. An inductive coding schema to synthesize the quality criteria utilized by included articles was developed, with 40 unique quality criteria identified. Of the 43 (66%) articles that reported resources used to support criteria selection, 19 (29%) used clinical guidelines, and 10 (15%) used behavior change theory. The most commonly used criteria included the presence of user engagement or behavior change functions (97%, n = 63) and technical features of the app such as customizability (20%, n = 13, while Usability was assessed by 24 studies (36.9%). This study highlights the significant variation in quality criteria employed for the assessment of mobile health apps. Future methods for app evaluation will benefit from approaches that leverage the best evidence regarding the clinical impact and behavior change mechanisms while more directly reflecting patient needs when evaluating the quality of apps.
Identification of rare and common regulatory variants in pluripotent cells using population-scale transcriptomics
Authors: Marc Jan Bonder, Craig Smail, Michael J. Gloudemans, Laure Frésard, David Jakubosky, Matteo D’Antonio, Xin Li, Nicole M. Ferraro, Ivan Carcamo-Orive, Bogdan Mirauta, Daniel D. Seaton, Na Cai, Dara Vakili, Danilo Horta, Chunli Zhao, Diane B. Zastrow, Devon E. Bonner, Marc Jan Bonder, Daniel Seaton, David A. Jakubosky, Christopher D. Brown, YoSon Park, Matthew T. Wheeler, Helena Kilpinen, Joshua W. Knowles, Erin N. Smith, Kelly A. Frazer, Stephen B. Montgomery, Oliver Stegle
Journal: Nature Genetics (2021)
A promising new γ-secretase modulator for Alzheimer’s disease
Authors: Justyna A. Dobrowolska Zakaria, Robert J. Vassar
Journal: The Journal of Experimental Medicine (2021)

Effective and safe treatments for Alzheimer’s disease (AD) have been an elusive target for scientists who have been working tirelessly to gain control over a disease that is affecting millions of people, with continually rising case numbers as the population ages. However, in this issue of JEM, Rynearson et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20202560) present a beacon of hope for this field with a preclinical evaluation of a potent and robust γ-secretase modulator (GSM).
The prognostic impact of bone metastasis in urothelial carcinoma treated with first-line platinum-based chemotherapy.
Authors: Husam Alqaisi, Zachary William Neil Veitch, Carlos Stecca, Jeenan Kaiser, Scott A. North, Sunil Samnani, Nimira S. Alimohamed, Srikala S. Sridhar
Journal: Journal of Clinical Oncology (2021)

415 Background: Metastatic urothelial carcinoma (mUC) is an aggressive disease with a median overall survival (OS) of ≈ 15 months. In the first-line setting, key prognostic factors include ECOG performance status, white blood cell count, and response to treatment per the Galsky nomogram. Bone metastases (BM) in mUC are associated with morbidity and mortality but are grouped with visceral disease; hence, their impact on prognosis is not well established. We aimed to assess the survival impact of BM in mUC patients treated with first-line platinum-based chemotherapy (PBC). Methods: A retrospective collection of patient and tumor characteristics, with clinical response to treatment (complete response [CR], partial response [PR]; stable disease [SD] or progressive disease [PD]) for patients treated at Princess Margaret Cancer Centre, Tom Baker Cancer Centre, and Cross Cancer Institute from 2005-2018 was performed. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method. Univariate (UVA) followed by multivariate analysis (MVA) of patient variables [Cox] using PFS and OS was performed. Results: Overall 376 mUC patients were included; 222 (59%) had soft-tissue metastases (STM) only, 70 (19%) had bone-only metastases, and 84 (22%) had both STM and BM. Overall, 35% had PR or CR, 19% had SD, and 39% had PD (7%: unknown response). The median PFS and OS for the whole cohort were 5.6 months (95%CI: 4.8-6.4) and 9.7 months (95% CI: 8.8-10.8) respectively. Select UVA by metastatic site showed inferior PFS for bone-only (p=0.03) and combination STM and BM (p=0.017). Only combination STM and BM were significant on UVA for OS (p=0.002). MVA showed that bone-only metastases (p=0.03) and ECOG 3-4 (p&lt;0.0001) were associated with worse PFS (Table). Predictors of worse OS were the combination of STM and BM (p=0.02), ECOG 3-4 (p=0.001), and WBCs ≥ULN (p=0.02), (Table). Conclusions: BM are a significant predictor of worse outcomes for mUC patients treated with first-line PBC. Consideration as a treatment stratification factor for future studies is suggested. Strategies for the treatment of mUC patients with BM (ie: bone targeted agents) in the first-line setting should be addressed in future trials. [Table: see text]
Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer to identify targetable BRCA alterations and AR resistance mechanisms.
Authors: Hanna Tukachinsky, Russell Madison, Jon Chung, Lucas Dennis, Bernard Fendler, Samantha Morley, Lei Zhong, Ryon Graf, Jeffrey S. Ross, Brian M Alexander, Wassim Abida, Simon Chowdhury, Charles J. Ryan, Karim Fizazi, Anthony A. Golsorkhi, Simon Paul Watkins, Andrew Simmons, Andrea Loehr, Jeffrey Venstrom, Geoffrey R. Oxnard
Journal: Journal of Clinical Oncology (2021)

25 Background: Comprehensive genomic profiling (CGP) by next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) from plasma provides a minimally invasive method to identify targetable genomic alterations (GAs) and resistance mechanisms in patients with metastatic castration-resistant prostate cancer (mCRPC). The circulating tumor fraction in patients with mCRPC and the clinical validity of GAs detected in plasma remain unknown. We evaluated the landscape of GAs using ctDNA-based CGP and assessed concordance with tissue-based CGP. Methods: Plasma from 3,334 patients with advanced prostate cancer (including 1,674 mCRPC screening samples from the TRITON2/3 trials and 1,660 samples from routine clinical CGP) was analyzed using hybrid-capture-based gene panel NGS assays. Results were compared with CGP of 2,006 metastatic prostate cancer tissue biopsies. Concordance was evaluated in 837 patients with both tissue (archival or contemporaneous) and plasma NGS results. Results: 3,127 patients [94%] had detectable ctDNA. BRCA1/2 were mutated in 295 patients [8.8%]. In concordance analysis, 72/837 [8.6%] patients had BRCA1/2 mutations detected in tissue, 67 [93%] of whom were also identified by ctDNA, and 20 patients were identified using ctDNA but not tissue [23% of all patients identified using ctDNA]. ctDNA detected subclonal BRCA1/2 reversions in 10 of 1,660 [0.6%] routine clinical CGP samples. AR alterations, including amplifications and hotspot mutations, which were detected in 940/2,213 patients [42%]. Rare AR compound mutations, rearrangements, and novel in-frame deletions were identified. Altered pathways included PI3K/AKT/mTOR [14%], WNT/β-catenin [17%], and RAS/RAF/MEK [5%]. Microsatellite instability was detected in 31/2,213 patients [1.4%]. Conclusions: In the largest study of mCRPC plasma samples conducted to date, CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 alterations. It also identified patients who may have gained somatic BRCA1/2 alterations since archival tissue was collected. ctDNA detected more acquired resistance GAs than tissue, including novel AR-activating variants. The large percentage of patients with rich genomic signal from ctDNA, and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.
A single-blinded, multicenter, randomized controlled trial to evaluate NeuroSAFE robotic-assisted radical prostatectomy (RARP) versus standard robotic-assisted radical prostatectomy (RARP) in men with localized prostate cancer: NeuroSAFE PROOF—Trial in progress.
Authors: Eoin Dinneen, Jack Grierson, Aiman Haider, Alex Freeman, Jonathan Aning, Rajendra Persad, Neil Oakley, Imran Ahmad, Lorenzo Dutto, Greg Shaw
Journal: Journal of Clinical Oncology (2021)

TPS262 Background: Robot-assisted radical prostatectomy (RARP) offers cure for localised prostate cancer but is associated with considerable toxicity. Potency and urinary continence are improved when the neurovascular bundles (NVBs) are preserved during a nerve-sparing (NS) RARP. The NeuroSAFE (intra-operative frozen section examination of the neurovascular structure adjacent prostate margin) seeks to promote optimal NS to maximise the opportunity for functional recovery without jeopardising oncological safety. The NeuroSAFE technique in RP has never been evaluated against a standard of care in an randomised controlled trial. Methods: This is a pragmatic, multicentre, single-blinded randomised controlled trial (RCT) in which men are allocated in a 1:1 ratio to NeuroSAFE RARP or standard RARP. Men in the NeuroSAFE RARP arm will undergo RARP with NS guided by the NeuroSAFE technique. Men in the standard RARP arm will undergo RARP with NS guided by standard current practice (prostate cancer clinical characteristics, multi-parametric magnetic resonance imaging (mpMRI) recommendations and digital rectal examination (DRE)). Eligible men will have operable localised prostate cancer, will be opting for RARP as primary treatment and will have good baseline erectile function (EF) (as defined by an Internatinoal Index of Erectile Function (IIEF)-5 score &gt;21). The primary outcome is the proportion of men who achieve EF recovery at 12-months according to the IIEF. Oncological safety will be ensured by the independent DMC who will routinely review proportions of men with treatment failure (adjuvant therapy or biochemical recurrence (BCR)) in each arm. A sample size of 404 is estimated required. NeuroSAFE PROOF will continue to follow participant recovery for 5 years following treatment. Key secondary outcomes include patient-reported urinary continence recovery, sexual satisfaction, quality of life, and economic analyses. NeuroSAFE PROOF will be the first RCT of frozen section in radical prostatectomy (RP) in the world. Ethics and dissemination: Ethical approval was obtained from the National Research Ethics Committee North London (17/LO/1978). Results of this study will be disseminated through national and international papers, and to study participants. Clinical trial information: NCT03317990.
Production and Function of Immunoglobulin A
Authors: Timothy W. Hand, Andrea Reboldi
Journal: Annual Review of Immunology (2021)

Among antibodies, IgA is unique because it has evolved to be secreted onto mucosal surfaces. The structure of IgA and the associated secretory component allow IgA to survive the highly proteolytic environment of mucosal surfaces but also substantially limit IgA's ability to activate effector functions on immune cells. Despite these characteristics, IgA is critical for both preventing enteric infections and shaping the local microbiome. IgA's function is determined by a distinct antigen-binding repertoire, composed of antibodies with a variety of specificities, from permissive polyspecificity to cross-reactivity to exquisite specificity to a single epitope, which act together to regulate intestinal bacteria. Development of the unique function and specificities of IgA is shaped by local cues provided by the gut-associated lymphoid tissue, driven by the constantly changing environment of the intestine and microbiota.
Colorectal cancer risk following polypectomy in a multicentre, retrospective, cohort study: an evaluation of the 2020 UK post-polypectomy surveillance guidelines
Authors: Amanda J Cross, Emma C Robbins, Kevin Pack, Iain Stenson, Bhavita Patel, Matthew D Rutter, Andrew M Veitch, Brian P Saunders, Stephen W Duffy, Kate Wooldrage
Journal: Gut (2021)

Colonoscopy surveillance aims to reduce colorectal cancer (CRC) incidence after polypectomy. The 2020 UK guidelines recommend surveillance at 3 years for 'high-risk' patients with ≥2 premalignant polyps (PMPs), of which ≥1 is 'advanced' (serrated polyp (or adenoma) ≥10 mm or with (high-grade) dysplasia); ≥5 PMPs; or ≥1 non-pedunculated polyp ≥20 mm; 'low-risk' patients without these findings are instead encouraged to participate in population-based CRC screening. We examined the appropriateness of these risk classification criteria and recommendations.
One‐Step Formation of Protein‐Based Tubular Structures for Functional Devices and Tissues
Authors: Wuyang Gao, Nima Vaezzadeh, Kelvin Chow, Haotian Chen, Patricia Lavender, Mark D. Jeronimo, Arianna McAllister, Onofrio Laselva, Jia‐Xin Jiang, Blair K. Gage, Shinichiro Ogawa, Arun Ramchandran, Christine E. Bear, Gordon M. Keller, Axel Günther
Journal: Advanced Healthcare Materials (2021)

Abstract Tubular biological structures consisting of extracellular matrix (ECM) proteins and cells are basic functional units of all organs in animals and humans. ECM protein solutions at low concentrations (5–10 milligrams per milliliter) are abundantly used in 3D cell culture. However, their poor “printability” and minute‐long gelation time have made the direct extrusion of tubular structures in bioprinting applications challenging. Here, this limitation is overcome and the continuous, template‐free conversion of low‐concentration collagen, elastin, and fibrinogen solutions into tubular structures of tailored size and radial, circumferential and axial organization is demonstrated. The approach is enabled by a microfabricated printhead for the consistent circumferential distribution of ECM protein solutions and lends itself to scalable manufacture. The attached confinement accommodates minute‐long residence times for pH, temperature, light, ionic and enzymatic gelation. Chip hosted ECM tubular structures are amenable to perfusion with aqueous solutions and air, and cyclic stretching. Predictive collapse and reopening in a crossed‐tube configuration promote all‐ECM valves and pumps. Tissue level function is demonstrated by factors secreted from cells embedded within the tube wall, as well as endothelial or epithelial barriers lining the lumen. The described approaches are anticipated to find applications in ECM‐based organ‐on‐chip and biohybrid structures, hydraulic actuators, and soft machines.
A transient developmental increase in prefrontal activity alters network maturation and causes cognitive dysfunction in adult mice
Authors: Sebastian H. Bitzenhofer, Jastyn A. Pöpplau, Mattia Chini, Annette Marquardt, Ileana L. Hanganu-Opatz
Journal: Neuron (2021)

Disturbed neuronal activity in neuropsychiatric pathologies emerges during development and might cause multifold neuronal dysfunction by interfering with apoptosis, dendritic growth, and synapse formation. However, how altered electrical activity early in life affects neuronal function and behavior in adults is unknown. Here, we address this question by transiently increasing the coordinated activity of layer 2/3 pyramidal neurons in the medial prefrontal cortex of neonatal mice and monitoring long-term functional and behavioral consequences. We show that increased activity during early development causes premature maturation of pyramidal neurons and affects interneuronal density. Consequently, altered inhibitory feedback by fast-spiking interneurons and excitation/inhibition imbalance in prefrontal circuits of young adults result in weaker evoked synchronization of gamma frequency. These structural and functional changes ultimately lead to poorer mnemonic and social abilities. Thus, prefrontal activity during early development actively controls the cognitive performance of adults and might be critical for cognitive symptoms in neuropsychiatric diseases.
Viral G Protein–Coupled Receptors: Attractive Targets for Herpesvirus-Associated Diseases
Authors: Timo W. M. De Groof, Elizabeth G. Elder, Marco Siderius, Raimond Heukers, John H. Sinclair, Martine J. Smit
Journal: Pharmacological Reviews (2021)

Herpesviruses are ubiquitous pathogens that establish lifelong, latent infections in their host. Spontaneous reactivation of herpesviruses is often asymptomatic or clinically manageable in healthy individuals, but reactivation events in immunocompromised or immunosuppressed individuals can lead to severe morbidity and mortality. Moreover, herpesvirus infections have been associated with multiple proliferative cardiovascular and post-transplant diseases. Herpesviruses encode viral G protein–coupled receptors (vGPCRs) that alter the host cell by hijacking cellular pathways and play important roles in the viral life cycle and these different disease settings. In this review, we discuss the pharmacological and signaling properties of these vGPCRs, their role in the viral life cycle, and their contribution in different diseases. Because of their prominent role, vGPCRs have emerged as promising drug targets, and the potential of vGPCR-targeting therapeutics is being explored. Overall, these vGPCRs can be considered as attractive targets moving forward in the development of antiviral, cancer, and/or cardiovascular disease treatments. <h3>Significance Statement</h3> In the last decade, herpesvirus-encoded G protein–coupled receptors (GPCRs) have emerged as interesting drug targets with the growing understanding of their critical role in the viral life cycle and in different disease settings. This review presents the pharmacological properties of these viral receptors, their role in the viral life cycle and different diseases, and the emergence of therapeutics targeting viral GPCRs.