tbuckley/cabot-search huggingface dataset:
Therapeutic outcome of early-phase clinical trials in multiple myeloma: a meta-analysis
Authors: Niels van Nieuwenhuijzen, Rowan Frunt, Anne M. May, Monique C. Minnema
Journal: Blood Cancer Journal (2021)

Great progress in the treatment of patients with multiple myeloma (MM) has been made due to the development of novel drugs. Patients with relapsed/refractory MM (RRMM) can be enrolled in early-phase clinical trials, but their performance across the last decade is unknown. We conducted a meta-analysis on the overall response rate (ORR) and toxicity. PubMed, Embase, and Cochrane Library were systematically searched for phase I and phase II trials investigating an experimental compound as a single agent or in combination with dexamethasone, published from January 1, 2010 to July 1, 2020. Eighty-eight articles were included, describing 61 phase I trials involving 1835 patients and 37 phase II trials involving 2644 patients. There was a high degree of heterogeneity. Using a random-effects model, the 95% CIs of the estimated ORR were 8-17% for phase I trials and 18-28% for phase II trials. There were significant subgroup differences in ORR between the years of publication in phase I trials and between drug classes in both phase I and phase II trials. The ORR in early-phase clinical trials in RRMM is substantial, especially in phase II trials, but due to high heterogeneity a general assessment of clinical benefit before participation is difficult to offer to patients.
Gastrointestinal lipolysis and trans-epithelial transport of SMEDDS via oral route
Authors: Fei Xia, Zhongjian Chen, Quangang Zhu, Jianping Qi, Xiaochun Dong, Weili Zhao, Wei Wu, Yi Lu
Journal: Acta Pharmaceutica Sinica B (2021)

Self-microemulsifying drug delivery systems (SMEDDSs) have recently returned to the limelight of academia and industry due to their enormous potential in oral delivery of biomacromolecules. However, information on gastrointestinal lipolysis and trans-epithelial transport of SMEDDS is rare. Aggregation-caused quenching (ACQ) fluorescent probes are utilized to visualize the in vivo behaviors of SMEDDSs, because the released probes during lipolysis are quenched upon contacting water. Two SMEDDSs composed of medium chain triglyceride and different ratios of Tween-80 and PEG-400 are set as models, meanwhile Neoral® was used as a control. The SMEDDS droplets reside in the digestive tract for as long as 24 h and obey first order kinetic law of lipolysis. The increased chain length of the triglyceride decreases the lipolysis of the SMEDDSs. Ex vivo imaging of main tissues and histological examination confirm the trans-epithelial transportation of the SMEDDS droplets. Approximately 2%–4% of the given SMEDDSs are transported via the lymph route following epithelial uptake, while liver is the main termination. Caco-2 cell lines confirm the cellular uptake and trans-epithelial transport. In conclusion, a fraction of SMEDDSs can survive the lipolysis in the gastrointestinal tract, permeate across the epithelia, translocate via the lymph, and accumulate mainly in the liver.
B cell engagement with HIV-1 founder virus envelope predicts development of broadly neutralizing antibodies
Authors: Samantha M. Townsley, Gina C. Donofrio, Ningbo Jian, David J. Leggat, Vincent Dussupt, Letzibeth Mendez-Rivera, Leigh Anne Eller, Lauryn Cofer, Misook Choe, Philip K. Ehrenberg, Aviva Geretz, Syna Gift, Rebecca Grande, Anna Lee, Caroline Peterson, Mary Bryson Piechowiak, Bonnie M. Slike, Ursula Tran, M. Gordon Joyce, Ivelin S. Georgiev, Morgane Rolland, Rasmi Thomas, Sodsai Tovanabutra, Nicole A. Doria-Rose, Victoria R. Polonis, John R. Mascola, Adrian B. McDermott, Nelson L. Michael, Merlin L. Robb, Shelly J. Krebs
Journal: Cell Host & Microbe (2021)
Cardiovascular disease risk profile and management practices in 45 low-income and middle-income countries: A cross-sectional study of nationally representative individual-level survey data
Authors: David Peiris, Arpita Ghosh, Jennifer Manne-Goehler, Lindsay M. Jaacks, Michaela Theilmann, Maja E. Marcus, Zhaxybay Zhumadilov, Lindiwe Tsabedze, Adil Supiyev, Bahendeka K. Silver, Abla M. Sibai, Bolormaa Norov, Mary T. Mayige, Joao S. Martins, Nuno Lunet, Demetre Labadarios, Jutta M. A. Jorgensen, Corine Houehanou, David Guwatudde, Mongal S. Gurung, Albertino Damasceno, Krishna K. Aryal, Glennis Andall-Brereton, Kokou Agoudavi, Briar McKenzie, Jacqui Webster, Rifat Atun, Till Bärnighausen, Sebastian Vollmer, Justine I. Davies, Pascal Geldsetzer
Journal: PLoS Medicine (2021)

Global cardiovascular disease (CVD) burden is high and rising, especially in low-income and middle-income countries (LMICs). Focussing on 45 LMICs, we aimed to determine (1) the adult population's median 10-year predicted CVD risk, including its variation within countries by socio-demographic characteristics, and (2) the prevalence of self-reported blood pressure (BP) medication use among those with and without an indication for such medication as per World Health Organization (WHO) guidelines.
Children and young people remain at low risk of COVID-19 mortality
Authors: Sunil S Bhopal, Jayshree Bagaria, Bayanne Olabi, Raj Bhopal
Journal: The Lancet Child & Adolescent Health (2021)

Children and young people remain at low risk of COVID-19 mortalitySince early reports from China stated that severe COVID-19 disease was rare in children, 1 we have analysed child COVID-19 mortality in seven countries.To put the deaths into a context that would help the understanding of parents, clinicians, and policy makers, we previously made comparisons of COVID-19 deaths with modelled mortality from all causes and other causes.Our first publication in April, 2020, 2 was followed by a trend analysis up to August, 2020. 3 We also update a data table online.Here, we update this analysis to February, 2021, in light of increases in adult mortality through the 2020-21 winter, and concerns about variant B.1.1.7,first identified in the UK in December, 2020 (probably circulating since September). 4n the USA, UK, Italy, Germany, Spain, France, and South Korea, deaths from COVID-19 in children remained rare up to February, 2021, at 0•17 per 100 000 popu lation, comprising 0•48% of the estimated total mortality from all causes in a normal year (table, appendix p 2).Deaths from COVID-19 were relatively more frequent in older children compared with younger age groups.The differences between countries need careful interpretation because of small numbers, possible differences in case definition and death reporting mechanisms, and the related condition paediatric inflammatory multi system syn drome temporally associated with COVID-19, which might not always be captured in these data.Overall, there was no clear evidence of a trend of increasing mortality through out the period up to February, 2021, but additional deaths have clearly occurred in children and young people during periods of high community transmission (appendix p 3).Although COVID-19 mortality data are contemporary and likely to The sources of these data are provided in the appendix (p 2).*Includes all deaths from approximately March 1, 2020, to Feb 1, 2021.†Includes all COVID-19 deaths reported from the start of the pandemic up to Feb 3, 2021 (USA), Jan 29
COVID-19: cross-border contact tracing in Germany, February to April 2020
Authors: Inessa Markus, Gyde Steffen, Raskit Lachmann, Adine Marquis, Timm Schneider, Sara Tomczyk, Uwe Koppe, Anna M Rohde, Susanne Barbara Schink, Janna Seifried, Teresa Domaszewska, Ute Rexroth, Maria an der Heiden
Journal: Eurosurveillance (2021)

IntroductionThe Robert Koch Institute (RKI) managed the exchange of cross-border contact tracing data between public health authorities (PHA) in Germany and abroad during the early COVID-19 pandemic.AimWe describe the extent of cross-border contact tracing and its challenges.MethodsWe analysed cross-border COVID-19 contact tracing events from 3 February to 5 April 2020 using information exchanged through the European Early Warning Response System and communication with International Health Regulation national focal points. We described events by PHA, number of contacts and exposure context.ResultsThe RKI processed 467 events, initiating contact to PHA 1,099 times (median = 1; interquartile range (IQR): 1-2) and sharing data on 5,099 contact persons. Of 327 (70%) events with known exposure context, the most commonly reported exposures were aircraft (n = 64; 20%), cruise ships (n = 24; 7%) and non-transport contexts (n = 210; 64%). Cruise ship and aircraft exposures generated more contacts with authorities (median = 10; IQR: 2-16, median = 4; IQR: 2-11) and more contact persons (median = 60; IQR: 9-269, median = 2; IQR: 1-3) than non-transport exposures (median = 1; IQR: 1-6 and median = 1; IQR: 1-2). The median time spent on contact tracing was highest for cruise ships: 5 days (IQR: 3-9).ConclusionIn the COVID-19 pandemic, cross-border contact tracing is considered a critical component of the outbreak response. While only a minority of international contact tracing activities were related to exposure events in transport, they contributed substantially to the workload. The numerous communications highlight the need for fast and efficient global outbreak communication channels between PHA.
Novel cryoballoon 180° ablation system for treatment of Barrett’s esophagus-related neoplasia: a first-in-human study
Authors: Anouk Overwater, Sanne N. van Munster, Wouter B. Nagengast, Roos E. Pouw, Jacques J. G. H. M. Bergman, Erik J. Schoon, Bas L. A. M. Weusten
Journal: Endoscopy (2021)

Abstract Background The novel 180° cryoballoon (CbAS180) enables semicircumferential treatment over a length of 3 cm per application. This first-in-human study evaluates its feasibility, efficacy, and safety for the treatment of Barrett’s esophagus (BE) neoplasia. Methods This multicenter study consisted of dose-finding and extension phases. Dose-finding started with the lowest dose possible (1.0 mm/s). For each dose, six patients were treated circumferentially over a 3-cm length. The dose was increased until the median BE regression was ≥ 60 % without serious adverse events (SAEs). In the extension phase, the dose was confirmed in 19 new patients. The outcomes were technical success, BE regression after one treatment, and SAEs. Results 25 patients (median Prague C0M3) were included (6 dose-finding/19 extension). In two patients, the CbAS180 could not be applied because of unstable balloon positioning. The technical success rate was 96 % (22 /23). In the six dose-finding patients, the starting dose resulted in median BE regression of 94 % (95 % confidence interval [CI] 60 %–97 %) without SAEs and was thus considered effective. Overall median BE regression was 80 % (95 %CI 60 %–90 %). Conclusion Single-session CbAS180 seems feasible, safe, and effective, and is a promising technique for the treatment of patients with BE neoplasia.
Predicting Disease Recurrence, Early Progression, and Overall Survival Following Surgical Resection for High-risk Localized and Locally Advanced Renal Cell Carcinoma
Authors: Andres F. Correa, Opeyemi A. Jegede, Naomi B. Haas, Keith T. Flaherty, Michael R. Pins, Adebowale Adeniran, Edward M. Messing, Judith Manola, Christopher G. Wood, Christopher J. Kane, Michael A.S. Jewett, Janice P. Dutcher, Robert S. DiPaola, Michael A. Carducci, Robert G. Uzzo
Journal: European Urology (2021)
Mussel-inspired nanozyme catalyzed conductive and self-setting hydrogel for adhesive and antibacterial bioelectronics
Authors: Zhanrong Jia, Xuanhan Lv, Yue Hou, Kefeng Wang, Fuzeng Ren, Dingguo Xu, Qun Wang, Kelong Fan, Chaoming Xie, Xiong Lu
Journal: Bioactive Materials (2021)

Adhesive hydrogels have broad applications ranging from tissue engineering to bioelectronics; however, fabricating adhesive hydrogels with multiple functions remains a challenge. In this study, a mussel-inspired tannic acid chelated-Ag (TA-Ag) nanozyme with peroxidase (POD)-like activity was designed by the in situ reduction of ultrasmall Ag nanoparticles (NPs) with TA. The ultrasmall TA-Ag nanozyme exhibited high catalytic activity to induce hydrogel self-setting without external aid. The nanozyme retained abundant phenolic hydroxyl groups and maintained the dynamic redox balance of phenol-quinone, providing the hydrogels with long-term and repeatable adhesiveness, similar to the adhesion of mussels. The phenolic hydroxyl groups also afforded uniform distribution of the nanozyme in the hydrogel network, thereby improving its mechanical properties and conductivity. Furthermore, the nanozyme endowed the hydrogel with antibacterial activity through synergistic effects of the reactive oxygen species generated via POD-like catalytic reactions and the intrinsic bactericidal activity of Ag. Owing to these advantages, the ultrasmall TA-Ag nanozyme-catalyzed hydrogel could be effectively used as an adhesive, antibacterial, and implantable bioelectrode to detect bio-signals, and as a wound dressing to accelerate tissue regeneration while preventing infection. Therefore, this study provides a promising approach for the fabrication of adhesive hydrogel bioelectronics with multiple functions via mussel-inspired nanozyme catalysis.
The ChAT-acetylcholine pathway promotes group 2 innate lymphoid cell responses and anti-helminth immunity
Authors: Coco Chu, Christopher N. Parkhurst, Wen Zhang, Lei Zhou, Hiroshi Yano, Mohammad Arifuzzaman, David Artis
Journal: Science Immunology (2021)

Activated ILC2s use the ChAT-acetylcholine pathway to enhance their cytokine production and promote helminth expulsion.
The Babinski sign in Renaissance paintings: the fallacy of mis-framed observations
Authors: Brian Hurwitz
Journal: BMJ (2021)

In their paper on Renaissance paintings of the infant Christ,1 Sellal and Tatu equate dorsiflexed postures of the child’s great toe with Babinski signs. Joseph Babinski described a cutaneous reflex in adults in response to a nociceptive stimulus which he applied by “pricking” the plantar surface with a pin.23 Today, the stimulus is delivered to babies using a fingernail or other hard implement along the lateral …
Response to “Efficacy of sonidegib in histologic subtypes of advanced basal cell carcinoma: Results from the final analysis of the randomized phase 2 Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT) trial at 42 months”
Authors: Alessia Villani, Gabriella Fabbrocini, Claudia Costa, Massimiliano Scalvenzi
Journal: Journal of the American Academy of Dermatology (2021)
Efficacy of chemohyperthermia (HIVEC) in patients with high-risk nonmuscle invasive bladder cancer (NMIBC) who fail BCG therapy.
Authors: Geraldine Pignot, Laure Doisy, Jochen Walz, Thibault Marquette, Thomas Maubon, Stanislas Rybikowski, Gwenaelle Gravis
Journal: Journal of Clinical Oncology (2021)

456 Background: To evaluate Hyperthermic Intra-Vesical Chemotherapy (HIVEC) efficacy regarding 1-year disease-free survival (DFS) rate and bladder preservation rate in patients with high-risk Non-Muscle Invasive Bladder Cancer (NMIBC) who fail BCG therapy or are contraindicated to BCG. Methods: Between June 2016 and October 2019, patients treated with HIVEC for high-risk NMIBC who failed BCG (Fail-BCG) or BCG-naive if BCG contraindicated (N-BCG) have been included in our study. These patients had a theoretical indication for cystectomy but were ineligible for surgery or refused it. Results: Fifty-three patients, median age 72 [39-93] years, were included (n = 29 Fail-BCG and n = 24 N-BCG). The median follow-up was 18 months. The bladder preservation rate was 92.4%. The RFS rate at 12 months was 60.5%. The RFS rate at 12 months for N-BCG and Fail-BCG groups was respectively 70% and 52.2%. Three patients progressed to muscle-invasive disease, all in the Fail-BCG group and all in the very high-risk EORTC group. Two of them experienced metastatic progression and died from bladder cancer. Conclusions: Chemohyperthermia using HIVEC device achieved a RFS rate of 60% at 1 year and enabled a bladder preservation rate of 92%. Given the low risk of progression in the N-BCG group, HIVEC could be a good alternative. Conversely, for patients with very high-risk tumors that fail BCG, cystectomy should remain the standard of care and HIVEC may be discussed cautiously for patients who are not eligible for surgery and well informed of the risk of progression to muscle-invasive disease.
Abstract PO047: Sensory nerves enhance breast cancer migration through PlexinB3 signaling
Authors: Thanh T. Le, Madeleine J. Oudin
Journal: Cancer Research (2021)

Abstract The tumor microenvironment plays an essential role in the process of metastasis. However, the role of the peripheral nervous system, a crucial component of the tumor microenvironment, in cancer progression remains poorly understood. In breast cancer, nerve presence has been correlated with more invasive disease and worse prognosis. Yet, there is still a lack of detailed investigation into the specific types of nerves that are present in breast cancer as well as the mechanism by which nerve-cancer crosstalk contributes to breast cancer metastasis. We identified sensory nerves as more abundant in triple-negative human breast cancer tumors relative to healthy breast by mining gene expression datasets and immunostaining. Interestingly, the sensory nerve bundle structure in normal breast is disrupted in breast tumor, resulting in discrete nerve fibers throughout the tumor. To investigate the role of these sensory nerves in cancer progression, we cocultured primary sensory neurons from dorsal root ganglia of mice and human triple-negative breast cancer cells (MDA-MB-231). We found that cancer cells tend to attach and move along nerve fibers. These cells also have higher migration speed and proliferation rate when compared to both monoculture and conditioned media control. We then set out to investigate whether sensory nerves impact gene expression in tumors using RNA sequencing. By utilizing published algorithms, we were able to separate the transcriptome of human cancer cells and mouse neurons in coculture. Differential analysis shows that cancer cells in coculture upregulate genes related to cell migration, adhesion, and proliferation pathways, which further validates our experimental findings. We identified the Sema5A-PlexinB3 ligand-receptor pair as a potential mechanism of nerve-cancer crosstalk, where neurons provide Sema5A that interacts with upregulated PlexinB3 receptors on cancer cells. Knockdown of Plexin-B3 in tumor cells reduced the effect of sensory nerves on breast cancer cell migration. In vivo experiments injecting sensory nerves and tumor cells into the mammary gland of mice are ongoing. Overall, these studies demonstrate that sensory nerve density is high in TNBC and that sensory nerves promote tumor cell migration and proliferation via direct cell-cell interactions. We also show for the first time that nerves can induce gene expression changes in cancer cells. In the long-term, these findings could lead to novel treatments for metastatic disease that target nerve-cancer crosstalk. Citation Format: Thanh T. Le, Madeleine J. Oudin. Sensory nerves enhance breast cancer migration through PlexinB3 signaling [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO047.
Genomic landscape of variant urinary tumor histologies.
Authors: Sarah Abou Alaiwi, Amin Nassar, Elio Adib, Elie W. Akl, Kent William Mouw, Catherine Curran, Dory Freeman, Praful Ravi, Charlene Mantia, Andres Acosta, Mark A. Preston, Matthew Mossanen, David J. Kwiatkowski, Guru Sonpavde
Journal: Journal of Clinical Oncology (2021)

467 Background: The genetics of urothelial carcinoma (UC), the most common histology of urinary tract (UT) tumors, is well characterized; much less is known about the genomic features of rare histologic variants of UT tumors. We aim to compare the genomic alterations (GA) of UT tumors with adenocarcinoma (AD), small cell (SC), squamous cell (SQ), or plasmacytoid (PC) histologies, to UC tumors. Methods: We identified patients with pure variant (AD, SC, SQ, PC) or UC histology with genetic characterization through the GENIE registry. Patient tumor genomic data were captured by Memorial Sloan Kettering Cancer Center (MSK)-IMPACT and Dana-Farber Cancer Institute (DFCI)-Oncopanel NGS initiatives. Tumors with mixed histology were excluded. We limited our analysis to genes tested &gt;1000 times (N=211). Mutation frequencies and copy number variants (CNVs), collectively called GAs, were determined for AD, SC, SQ, PC, and UC, and were compared using the Fisher’s Exact test and Kruskall Wallis test. Nominal p values were obtained, and FDR correction was employed (q &lt; 0.1). Results: We identified 1199 patients with available genomic data who met the inclusion criteria. Histologic distribution was: 32 AD, 13 SC, 15 SQ, 11 PC, and 1128 UC tumors. The median age was 68 years and 77% of patients were male. Statistically significant differences in genetic alterations by subtype are shown in the table below. ARID1A and KDM6A GAs were higher in UC; PC and SC; CDH1 GAs higher in PC; RB1 and TP53 GAs higher in SC; SMAD4 GAs higher in AD; and NFE2L2 GAs higher in SQ. Conclusions: Variant UT histologies exhibit a distinct pattern of alterations compared to UC, consistent with their divergent clinical behavior. This suggests different biological origins for these variant histologies and possibly different therapeutic vulnerabilities. Exploring the GAs of these UT tumors in larger datasets is warranted. [Table: see text]
Widefield Swept-Source OCT Angiography Metrics Associated with the Development of Diabetic Vitreous Hemorrhage
Authors: Ying Cui, Ying Zhu, Edward S. Lu, Rongrong Le, Inês Laíns, Raviv Katz, Jay C. Wang, Itika Garg, Yifan Lu, Rebecca Zeng, Dean Eliott, Demetrios G. Vavvas, Deeba Husain, Joan W. Miller, Leo A. Kim, David M. Wu, John B. Miller
Journal: Ophthalmology (2021)
Relapsed multiple myeloma demonstrates distinct patterns of immune microenvironment and malignant cell-mediated immunosuppression
Authors: Alissa Visram, Surendra Dasari, Emilie Anderson, Shaji Kumar, Taxiarchis V. Kourelis
Journal: Blood Cancer Journal (2021)

Abstract Immunotherapy has shown efficacy in relapsed multiple myeloma (MM). However, these therapies may depend on a functional tumor immune microenvironment (iTME) for their efficacy. Characterizing the evolution of the iTME over the disease course is necessary to optimize the timing of immunotherapies. We performed mass cytometry, cytokine analysis, and RNA sequencing on bone marrow samples from 39 (13 newly diagnosed [NDMM], 11 relapsed pre-daratumumab exposure [RMM], and 13 triple-refractory [TRMM]) MM patients. Three distinct cellular iTME clusters were identified; cluster 1 comprised mainly of NDMM and RMM patients; and clusters 2 and 3 comprised primarily of TRMM patients. We showed that naive T cells were decreased in clusters 2 and 3, cluster 2 was characterized by increased senescent T cells, and cluster 3 by decreased early memory T cells. Plasma cells in clusters 2 and 3 upregulated E2F transcription factors and MYC proliferation pathways, and downregulated interferon, TGF-beta, interleuking-6, and TNF-αlpha signaling pathways compared to cluster 1. This study suggests that the MM iTME becomes increasingly dysfunctional with therapy whereas the MM clone may be less dependent on inflammation-mediated growth pathways and less sensitive to IFN-mediated immunosurveillance. Our findings may explain the decreased sensitivity of TRMM patients to novel immunotherapies.