tbuckley/cabot-search huggingface dataset:
Generation of a safe and efficacious llama single-domain antibody fragment (vHH) targeting the membrane-proximal region of 4-1BB for engineering therapeutic bispecific antibodies for cancer
Authors: Tianhang Zhai, Chao Wang, Yifeng Xu, Weifeng Huang, Zhijun Yuan, Tao Wang, Shuang Dai, Shaogang Peng, Tuling Pang, Wenchao Jiang, Yuhua Huang, Yuefeng Zou, Yingda Xu, Joanne Sun, Xinjiang Gong, Jinping Zhang, Andy Tsun, Bin Li, Xiaoniu Miao
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background The discovery of checkpoint inhibitors towards cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has been revolutionary for the treatment of cancers. These therapies have only offered an average of 20%–30% response rates across the tumor spectrum and the combination of agonists towards the tumor-necrosis superfamily members, such as 4-1BB and CD40, has shown potent efficacy in preclinical studies; however, these agonists have exhibited high degrees of toxicity with limited efficacy in human trials. In this study, we have generated a single-domain antibody towards a unique epitope of 4-1BB that limits its potential on-target toxicity while maintaining sufficient potency. This 4-1BB binder is ideal for use in the engineering of multispecific antibodies to localize 4-1BB activation within the tumor microenvironment, as shown here by a anti-PD-L1/4-1BB bispecific candidate (PM1003). Methods To determine the functional activity of the 4-1BB- and PD-L1-binding elements of PM1003, in vitro luciferase reporter and primary cell assays were used to test the potency of programmed cell death 1 ligand 1 (PD-L1) blockade and PD-L1-mediated 4-1BB activation via cross-bridging. X-ray crystallography was conducted to resolve the binding epitopes of the respective binding arms, and accurate binding kinetics were determined using standard affinity measurement techniques. Human 4-1BB and/or PD-L1 knock-in mice were used in cancer models for testing the in vivo antitumor efficacy of PM1003, and safety was evaluated further. Results PM1003 shows potent activation of 4-1BB and blockade of PD-L1 in cell-based assays. 4-1BB activation was exerted through the bridging of PD-L1 on target cells and 4-1BB on effector cells. No PD-L1-independent activation of 4-1BB was observed. Through X-ray crystallography, a unique binding epitope in the cysteine-rich domain 4 (CRD4) region was resolved that provides high potency and potentially low on-target toxicity as determined by primary immune cell assays and toxicity evaluation in vivo . Conclusions A unique single-domain antibody was discovered that binds to the CRD4 domain of 4-1BB. When incorporated into a 4-1BB/PD-L1 bispecific (PM1003), we have shown the potent inhibition of PD-L1 activity with 4-1BB agonism upon cross-bridging with PD-L1 in vitro . Antitumor activity with minimal toxicity was found in vivo . Thus, PM1003 is a uniquely differentiating and next generation therapeutic agent for cancer therapy.
Baseline Assessment of Patients with Newly-Diagnosed Acquired Bone Marrow Failure Enrolled in a Prospective Observational Study, “Search for Unidentified Links between PNH Clone Size and the Related Clinical Manifestations By High Precision Flow Cytometry (SUPREMACY)”
Authors: Yuji Yonemura, Tatsuya Kawaguchi, Ken Ishiyama, Chiharu Sugimori, Kohei Hosokawa, Naoshi Obara, Hideyoshi Noji, Yukari Shirasugi, Yasutaka Ueda, Hiroyuki Takamori, Tsutomu Shichishima, Shigeru Chiba, Haruhiko Ninomiya, Kiyoshi Ando, Jun-Ichi Nishimura, Yuzuru Kanakura, Masanori Takahashi, Shinji Nakao
Journal: Blood (2017)
Evolutionary linguistics can help refine (and test) hypotheses about how music might have evolved
Authors: Antonio Benítez-Burraco
Journal: Behavioral and Brain Sciences (2021)

Abstract Both the music and social bonding (MSB) hypothesis and the music as a credible signal hypothesis emerge as solid views of how human music and human musicality might have evolved. Nonetheless, both views could be improved (and tested in better ways) with the consideration of the way in which human language(s) might have evolved under the effects of our self-domestication.
Abstract 286: Cerebral Microstructure Disruptions are Associated With Poor Neurologic Outcomes in Comatose Cardiac Arrest Patients
Authors: Ona Wu, Eric S Rosenthal, Gaston Cudeumus-Deseda, Brittany Mills, Brian Edlow, W. Taylor Kimberly, Ming Ming Ning, Edilberto Amorim De Cerqueira Filho, M B Westover, Brandon L Hancock, William A Copen, Pamela Schaefer, Joseph T Giacino, David M Greer
Journal: Circulation (2019)

Background: For cardiac arrest survivors who are initially comatose after restoration of spontaneous circulation, the extent of brain injury and expected recovery are crucial for management decisions. Advanced diffusion imaging approaches may provide additional insight into microstructural integrity and potential for arousal recovery (AR). Methods: Multi-shell diffusion imaging was acquired in a prospective study. Neurite orientation dispersion (OD), intracellular volume fraction (ICVF), free water fraction (ISO), mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) and fractional anisotropy (FA) were calculated (see Figure). Median whole-brain values in patients with AR by discharge were compared with those with no AR and to controls (ANOVA, post-hoc 2-tailed Wilcoxon test). Multivariable backward stepwise logistic regression was performed to predict AR. Results: 19 patients (mean ±SD 48±23 y, 42% men) and 5 controls (37±19 y, 40% men) were analyzed (10 patients with AR, 9 without). Median [IQR] time-to-MRI was 5 [4-8] days. Patients with no AR had higher AK (P=0.037), and RK (P=.045) than those with AR. Controls exhibited higher FA than either AR (P=.009) or no AR (P=.02), lower MK than no AR (P=.02), lower AK than no AR (P=.02), lower RK than no AR (P=0.02), lower OD than no AR (P=.008), and lower ICVF than no AR (P=.046). AK (P=.049) and ICVF (P=.01) were found in multivariable regression to be significant predictors of AR with 81% area under the receiver operating curve (AUC). Discussion: Advanced diffusion imaging metrics, AK and ICVF, were able to predict which patients were likely to regain consciousness, with 81% AUC. Despite the small sample size, we note statistically significant differences using more sensitive measures of microstructural injury compared to more commonly used diffusivity metrics. Further investigation of advanced diffusion imaging methods is warranted.
Phase <scp>III</scp>/<scp>IV</scp>, Randomized, <scp>Fifty‐Two</scp>–Week Study of the Efficacy and Safety of Belimumab in Patients of Black African Ancestry With Systemic Lupus Erythematosus
Authors: Ellen Ginzler, Luiz Sergio Guedes Barbosa, David D'Cruz, Richard Furie, Kathleen Maksimowicz‐McKinnon, James Oates, Mittermayer Barreto Santiago, Amit Saxena, Saira Sheikh, Damon L. Bass, Susan W. Burriss, Jennifer A. Gilbride, James G. Groark, Michelle Miller, Amy Pierce, David A. Roth, Beulah Ji
Journal: Arthritis & Rheumatology (2021)

Objective Enrollment of patients of Black African ancestry with systemic lupus erythematosus (SLE) in phase II and phase III of the belimumab trials was not reflective of the racial distribution observed in the lupus population. This study was undertaken to assess the efficacy and safety of intravenous (IV) belimumab plus standard therapy in patients of self‐identified Black race. Methods EMBRACE (GSK Study BEL115471; ClinicalTrials.gov identifier: NCT01632241) was a 52‐week multicenter, double‐blind, placebo‐controlled trial in adults of self‐identified Black race with active SLE who received monthly belimumab 10 mg/kg IV, or placebo, plus standard therapy. The optional 26‐week open‐label extension phase included patients who completed the double‐blind phase. The primary end point of the study was SLE Responder Index (SRI) response rate at week 52 with modified proteinuria scoring adapted from the SLE Disease Activity Index 2000 (SLEDAI‐2K) (SRI–SLEDAI‐2K). Key secondary end points included SRI response rate at week 52, time to first severe SLE flare, and reductions in prednisone dose. Results The modified intent‐to‐treat population comprised 448 patients, of whom 96.9% were women and the mean ± SD age was 38.8 ± 11.42 years. The primary end point (improvement in the SRI–SLEDAI‐2K response rate at week 52) was not achieved (belimumab 48.7%, placebo 41.6%; odds ratio 1.40 [95% confidence interval 0.93, 2.11], P = 0.1068); however, numerical improvements favoring belimumab were observed, in which the SRI–SLEDAI‐2K response rates were higher in those who received belimumab compared with those who received placebo, especially in patients with SLE who had high disease activity or renal manifestations at baseline. The safety profile of belimumab was generally consistent with that observed in previous SLE trials. Adverse events were the primary reasons for double‐blind phase withdrawals (belimumab 5.4%, placebo 6.7%). Conclusion The primary end point of this study was not achieved, but improvement with belimumab versus placebo was observed, suggesting that belimumab remains a suitable treatment option for SLE management in patients of Black African ancestry.
Respiratory findings in children post-COVID-19 infection
Authors: Leftin Dobkin
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

The COVID-19 disease pandemic has resulted in millions of patients infected globally. Data have emerged that some patients continue to experience long-term adverse outcomes related to COVID-19 after the acute phase of infection;and chronic symptoms following other coronaviruses, specifically Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), have been well documented. There is currently scarce literature describing post-acute symptoms in pediatric patients with COVID-19. Here we describe respiratory findings following acute COVID-19 infection in a cohort of pediatric patients aged 10-to 20-years-old (average age 14-years-old) presenting for pulmonary evaluation. Data were evaluated by retrospective chart review. The majority of patients had pre-existing lung disease (86%). The most common comorbidity was asthma (71%) followed by allergies (29%) and obesity (14%). Most asthmatic patients had mild intermittent asthma (80%) followed by moderate persistent asthma (20%). All patients engaged in regular physical activity prior to COVID-19 infection. Patients were assessed a mean 92 days after SARS-CoV-2 positive PCR. Most common acute COVID-19 symptoms were fever (71%), cough (57%), fatigue (42%), dyspnea (29%) and anosmia (29%). None of the patients required hospitalization, supplemental oxygen, or noninvasive or invasive ventilation. All of the patients experienced dyspnea for at least two months at the time of this abstract following acute COVID-19 infection. The other most common reported chronic symptoms were decreased exercise tolerance (71%), cough (43%) and chest pain (43%). No patients had fevers at time of follow up, and all patients had normal oxyhemoglobin saturations. All patients had normal chest radiographs at the time of follow up. Pulmonary function testing was normal in the majority of cases and average percent predicted spirometry results included FEV1 104.5%, FVC 110%, FEV1/FVC 84% and FEF25-75% 84%. Reduced FEF25-75% was observed in a small number of patients (29%). Exercise intolerance on a six-minute walk test was observed in one patient, with significant tachycardia for age and baseline fitness level, after two minutes. The burden of caring for COVID-19 survivors is expected to be tremendous, and future medical and social interventions must consider the late sequelae of SARS-CoV-2 infection. There is currently limited information about the chronic adverse outcomes of COVID-19 particularly in children, and it is important for healthcare providers and policy makers to understand the long-term impact of COVID-19 on survivors. This information will likely have important implications for public health surveillance, health resource allocation, clinical research, and future treatments.
Newly established patient-derived organoid model of intracranial meningioma
Authors: Shintaro Yamazaki, Fumiharu Ohka, Masaki Hirano, Yukihiro Shiraki, Kazuya Motomura, Kuniaki Tanahashi, Takashi Tsujiuchi, Ayako Motomura, Kosuke Aoki, Keiko Shinjo, Yoshiteru Murofushi, Yotaro Kitano, Sachi Maeda, Akira Kato, Hiroyuki Shimizu, Junya Yamaguchi, Alimu Adilijiang, Toshihiko Wakabayashi, Ryuta Saito, Atsushi Enomoto, Yutaka Kondo, Atsushi Natsume
Journal: Neuro-Oncology (2021)

Abstract Background Recent comprehensive studies have revealed several molecular alterations that are frequently found in meningiomas. However, effective treatment reagents targeting specific molecular alterations have not yet been identified because of the limited number of representative research models of meningiomas. Methods We performed organoid cultures using meningioma cells and meningioma tumor tissues. Using immunohistochemistry and molecular analyses consisting of whole-exome sequencing, RNA-seq, and DNA methylation analyses, we compared the histological findings and molecular profiling of organoid models with those of parental tumors. Further, using these organoid models together with a public database of meningiomas, we explored molecular alterations, which are a potent treatment target for meningioma. Results We established 18 organoid models comprising of two malignant meningioma cells (HKBMM and IOMM-Lee), 10 benign meningiomas, four malignant meningiomas, and two solitary fibrous tumors (SFTs). The organoids exhibited consistent histological features and molecular profiles with those of the parental tumors. Using a public database, we identified that upregulated forkhead box M1 (FOXM1) was correlated with increased tumor proliferation. Overexpression of FOXM1 in benign meningioma organoids increased organoid proliferation; depletion of FOXM1 in malignant organoids decreased proliferation. Additionally, thiostrepton, a FOXM1 inhibitor combined with radiation therapy, significantly inhibited the proliferation of malignant meningioma organoid models. Conclusions An organoid model for meningioma enabled us to elucidate the tumor biology of meningioma along with potent treatment targets for meningioma.
Nanoporous titanium implant surface promotes osteogenesis by suppressing osteoclastogenesis via integrin β1/FAKpY397/MAPK pathway
Authors: Yide He, Zhe Li, Xin Ding, Boya Xu, Jinjin Wang, Yi Li, Fanghao Chen, Fanhui Meng, Wen Song, Yumei Zhang
Journal: Bioactive Materials (2021)

Macrophages and osteoclasts are both derived from monocyte/macrophage lineage, which plays as the osteoclastic part of bone metabolism. Although they are regulated by bone implant surface nanoarchitecture and involved in osseointegration, the beneath mechanism has not been simultaneously analyzed in a given surface model and their communication with osteoblasts is also blurring. Here, the effect of implant surface topography on monocyte/macrophage lineage osteoclastogenesis and the subsequent effect on osteogenesis are systematically investigated. The nanoporous surface is fabricated on titanium implant by etching and anodizing to get the nanotubes structure. The early bone formation around implant is significantly accelerated by the nanoporous surface in vivo. Meanwhile, the macrophage recruitment and osteoclast formation are increased and decreased respectively. Mechanistically, the integrin mediated FAK phosphorylation and its downstream MAPK pathway (p-p38) are significantly downregulated by the nanoporous surface, which account for the inhibition of osteoclastogenesis. In addition, the nanoporous surface can alleviate the inhibition of osteoclasts on osteogenesis by changing the secretion of clastokines, and accelerate bone regeneration by macrophage cytokine profiles. In conclusion, these data indicate that physical topography of implant surface is a critical factor modulating monocyte/macrophage lineage commitment, which provides theoretical guidance and mechanism basis for promoting osseointegration by coupling the osteogenesis and osteoclastogenesis.
Weight Loss by Low-Calorie Diet Versus Gastric Bypass Surgery in People With Diabetes Results in Divergent Brain Activation Patterns: A Functional MRI Study
Authors: Victoria Salem, Lysia Demetriou, Preeshila Behary, Kleopatra Alexiadou, Samantha Scholtz, George Tharakan, Alexander D. Miras, Sanjay Purkayastha, Ahmed R. Ahmed, Stephen R. Bloom, Matthew B. Wall, Waljit S. Dhillo, Tricia M.-M. Tan
Journal: Diabetes Care (2021)

Weight loss achieved with very-low-calorie diets (VLCDs) can produce remission of type 2 diabetes (T2D), but weight regain very often occurs with reintroduction of higher calorie intakes. In contrast, bariatric surgery produces clinically significant and durable weight loss, with diabetes remission that translates into reductions in mortality. We hypothesized that in patients living with obesity and prediabetes/T2D, longitudinal changes in brain activity in response to food cues as measured using functional MRI would explain this difference.Sixteen participants underwent gastric bypass surgery, and 19 matched participants undertook a VLCD (meal replacement) for 4 weeks. Brain responses to food cues and resting-state functional connectivity were assessed with functional MRI pre- and postintervention and compared across groups.We show that Roux-en-Y gastric bypass surgery (RYGB) results in three divergent brain responses compared with VLCD-induced weight loss: 1) VLCD resulted in increased brain reward center food cue responsiveness, whereas in RYGB, this was reduced; 2) VLCD resulted in higher neural activation of cognitive control regions in response to food cues associated with exercising increased cognitive restraint over eating, whereas RYGB did not; and 3) a homeostatic appetitive system (centered on the hypothalamus) is better engaged following RYGB-induced weight loss than VLCD.Taken together, these findings point to divergent brain responses to different methods of weight loss in patients with diabetes, which may explain weight regain after a short-term VLCD in contrast to enduring weight loss after RYGB.
<i>Parabacteroides distasonis</i>: intriguing aerotolerant gut anaerobe with emerging antimicrobial resistance and pathogenic and probiotic roles in human health
Authors: Jessica C. Ezeji, Daven K. Sarikonda, Austin Hopperton, Hailey L. Erkkila, Daniel E. Cohen, Sandra P. Martinez, Fabio Cominelli, Tomomi Kuwahara, Armand E. K. Dichosa, Caryn E. Good, Michael R. Jacobs, Mikhail Khoretonenko, Alida Veloo, Alexander Rodriguez-Palacios
Journal: Gut Microbes (2021)

Parabacteroides distasonis is the type strain for the genus Parabacteroides, a group of gram-negative anaerobic bacteria that commonly colonize the gastrointestinal tract of numerous species. First isolated in the 1930s from a clinical specimen as Bacteroides distasonis, the strain was re-classified to form the new genus Parabacteroides in 2006. Currently, the genus consists of 15 species, 10 of which are listed as 'validly named' (P. acidifaciens, P. chartae, P. chinchillae, P. chongii, P. distasonis, P. faecis, P. goldsteinii, P. gordonii, P. johnsonii, and P. merdae) and 5 'not validly named' (P. bouchesdurhonensis, P. massiliensis, P. pacaensis, P. provencensis, and P. timonensis) by the List of Prokaryotic names with Standing in Nomenclature. The Parabacteroides genus has been associated with reports of both beneficial and pathogenic effects in human health. Herein, we review the literature on the history, ecology, diseases, antimicrobial resistance, and genetics of this bacterium, illustrating the effects of P. distasonis on human and animal health.
Circulating HPV DNA as a Marker for Early Detection of Relapse in Patients with Cervical Cancer
Authors: Emmanuelle Jeannot, Aurélien Latouche, Claire Bonneau, Marie-Ange Calméjane, Corine Beaufort, Kirsten Ruigrok-Ritstier, Guillaume Bataillon, Linda Larbi Chérif, Célia Dupain, Charlotte Lecerf, Marina Popovic, Anne de la Rochefordière, Fabrice Lecuru, Virginie Fourchotte, Ekaterina S. Jordanova, Heiko von der Leyen, Carine Tran-Perennou, Marie-Emmanuelle Legrier, Sylvain Dureau, Laurence Raizonville, Diana Bello Roufai, Christophe Le Tourneau, Ivan Bièche, Roman Rouzier, Els M.J.J. Berns, Maud Kamal, Suzy Scholl
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Almost all cervical cancers are caused by human papillomavirus (HPV) and patients with advanced stage are at high risk for relapse. Circulating HPV DNA (HPV ctDNA) may serve as a residual tumor marker at the end of chemoradiation or to predict relapse during the follow-up period. Experimental Design: We analyzed serum samples from 94 HPV16- or HPV18-related CCs from the BioRAIDs prospective cohort. Samples were collected before and after treatment and during an 18-month follow-up period. Using digital droplet PCR (ddPCR), we assessed the relevance of circulating HPV E7 gene as a marker for residual disease compared to HPV integration site and PIK3CA mutations. Finally, the prognostic impact of circulating HPV E7 gene was assessed with its prediction value of relapse. Results: HPV E7 gene was the most sensitive tumor marker, superior to both HPV integration sites and PIK3CA mutations in serum. Circulating HPV DNA (HPV ctDNA) was detected in 63% (59/94) of patients, before treatment. HPV ctDNA detection in serum sample was associated with high FIGO stage (P = 0.02) and para-aortic lymph node involvement (P = 0.01). The level of HPV ctDNA was positively correlated with HPV copy number in the tumor (R = 0.39, P &amp;lt; 0.001). Complete clearance of HPV ctDNA by the end of treatment was significantly associated with a longer PFS (P &amp;lt; 0.0001). Patients with persistent HPV ctDNA in serum relapsed with a median time of 10 months (range, 2–15) from HPV ctDNA detection. Conclusions: HPV ctDNA detection is a useful marker to predict relapse in cervical cancer. See related commentary by Wentzensen and Clarke, p. 5733
Arterial thromboembolism in multiple myeloma in the context of modern anti-myeloma therapy
Authors: Rajshekhar Chakraborty, Lisa Rybicki, Jason Valent, Alex V. Mejia Garcia, Beth M. Faiman, Jack Khouri, Christy J. Samaras, Faiz Anwer, Alok A. Khorana
Journal: Blood Cancer Journal (2021)