tbuckley/cabot-search huggingface dataset:
How many people develop anti-drug antibodies to the biologic drug tildrakizumab, and what impact does this have on the effectiveness of their treatment
Authors: A.B. Kimball, T. Kerbusch, F. van Aarle, P. Kulkarni, Q. Li, A. Blauvelt, K.A. Papp, K. Reich, D. Montgomery
Journal: British Journal of Dermatology (2020)

Biologics are powerful drugs used to treat a range of diseases including psoriasis. They can be very effective; however, the body's immune system, which normally fights off infection, can produce ‘anti‐drug antibodies’ (or ADAs) that see biologics as harmful ‘invaders’ and try to deactivate them. These antibodies may result in serious side effects and/or may reduce the effectiveness of the drug. The authors of this study, based in USA, Canada and Germany, evaluated anti‐drug antibodies in patients participating in three clinical trials of a biologic called tildrakizumab. In the three trials, patients were taking either 100mg or 200mg tildrakizumab. 1400 patients were studied from weeks 12 to 16 of the study, and 780 from weeks 52‐64. Three percent of patients on the 100mg dose developed anti‐drug antibodies. This led to an average reduction in clinical response (meaning the drug did not work so well) at week 52. However, the presence of antibodies was not associated with increased incidence of serious adverse effects (unwanted side effects). Results in patients on the 200mg dose were inconclusive. This drug in the 100mg dose has recently been approved for clinical use in Europe and USA. The authors noted that the incidence of antibodies was less than that observed with other types of biologic drugs. This summary relates to the study: Assessment of the effects of immunogenicity on the pharmacokinetics, efficacy and safety of tildrakizumab
Coronary Sinus Neuropeptide Y Levels and Adverse Outcomes in Patients With Stable Chronic Heart Failure
Authors: Olujimi A. Ajijola, Neal A. Chatterjee, Matthew J. Gonzales, Jeffrey Gornbein, Kun Liu, Dan Li, David J Paterson, Kalyanam Shivkumar, Jagmeet P. Singh, Neil Herring
Journal: JAMA Cardiology (2019)

Chronic heart failure (CHF) is associated with increased sympathetic drive and may increase expression of the cotransmitter neuropeptide Y (NPY) within sympathetic neurons.To determine whether myocardial NPY levels are associated with outcomes in patients with stable CHF.Prospective observational cohort study conducted at a single-center, tertiary care hospital. Stable patients with heart failure undergoing elective cardiac resynchronization therapy device implantation between 2013 and 2015.Chronic heart failure hospitalization, death, orthotopic heart transplantation, and ventricular assist device placement.Coronary sinus (CS) blood samples were obtained during cardiac resynchronization therapy (CRT) device implantation in 105 patients (mean [SD] age 68 [12] years; 82 men [78%]; mean [SD] left ventricular ejection fraction [LVEF] 26% [7%]). Clinical, laboratory, and outcome data were collected prospectively. Stellate ganglia (SG) were collected from patients with CHF and control organ donors for molecular analysis. Mean (SD) CS NPY levels were 85.1 (31) pg/mL. On bivariate analyses, CS NPY levels were associated with estimated glomerular filtration rate (eGFR; rs = -0.36, P < .001); N-terminal-pro hormone brain natriuretic peptide (rs = 0.33; P = .004), and LV diastolic dimension (rs = -0.35; P < .001), but not age, LVEF, functional status, or CRT response. Adjusting for GFR, age, and LVEF, the hazard ratio for event-free (death, cardiac transplant, or left ventricular assist device) survival for CS NPY ≥ 130 pg/mL was 9.5 (95% CI, 2.92-30.5; P < .001). Immunohistochemistry demonstrated significantly reduced NPY protein (mean [SD], 13.7 [7.6] in the cardiomyopathy group vs 31.4 [3.7] in the control group; P < .001) in SG neurons from patients with CHF while quantitative polymerase chain reaction demonstrated similar mRNA levels compared with control individuals, suggesting increased release from SG neurons in patients with CHF.The CS levels of NPY may be associated with outcomes in patients with stable CHF undergoing CRT irrespective of CRT response. Increased neuronal traffic and release may be the mechanism for elevated CS NPY levels in patients with CHF. Further studies are warranted to confirm these findings.ClinicalTrials.gov identifier: NCT01949246.
New onset unilateral arm swelling in a child with periorbital oedema
Authors: Yasmine F Z Cherfi, Krisztina B Szanto, Janette Cansick
Journal: BMJ (2020)

An 8 year old girl was referred to the paediatric assessment unit with four weeks of puffy eyes following a suspected viral upper respiratory tract infection. Her facial swelling had exacerbated in the two weeks before this presentation, and her mother had noticed that her trousers no longer fitted because of abdominal and thigh swelling. The child was eating normally with normal bowel movements, and was afebrile.

On examination, generalised oedema was noted, including periorbital and facial swelling, and a distended, non-tender abdomen. On chest auscultation, there were some fine basal crepitations bilaterally. The child’s left forearm was notably more swollen …
CA2: A Highly Connected Intrahippocampal Relay
Authors: Steven J. Middleton, Thomas J. McHugh
Journal: Annual Review of Neuroscience (2019)

Although Lorente de No’ recognized the anatomical distinction of the hippocampal Cornu Ammonis (CA) 2 region, it had, until recently, been assigned no unique function. Its location between the key players of the circuit, CA3 and CA1, which along with the entorhinal cortex and dentate gyrus compose the classic trisynaptic circuit, further distracted research interest. However, the connectivity of CA2 pyramidal cells, together with unique patterns of gene expression, hints at a much larger contribution to hippocampal information processing than has been ascribed. Here we review recent advances that have identified new roles for CA2 in hippocampal centric processing, together with specialized functions in social memory and, potentially, as a broadcaster of novelty. These new data, together with CA2's role in disease, justify a closer look at how this small region exerts its influence and how it might best be exploited to understand and treat disease-related circuit dysfunctions.
circCAMSAP1 Promotes Tumor Growth in Colorectal Cancer via the miR-328-5p/E2F1 Axis
Authors: Chi Zhou, Hua-shan Liu, Feng-wei Wang, Tuo Hu, Zhen-xing Liang, Nan Lan, Xiao-wen He, Xiao-bin Zheng, Xiao-jian Wu, Dan Xie, Xian-rui Wu, Ping Lan
Journal: Molecular Therapy (2019)

Increasing studies indicated that circular RNAs (circRNAs) play important roles in cancer progression. However, the roles of circRNAs in colorectal cancer (CRC) remain largely unknown. In this study, we determined the circRNA expression profile by next-generation RNA sequencing from eight CRC and paired non-cancerous matched tissues. circCAMSAP1 (originating from exon 2 to exon 3 of the CAMSAP1 gene, hsa_circ_0001900) was significantly upregulated in CRC tissues. Increased circCAMSAP1 expression was significantly correlated with advanced tumor/node/metastasis (TNM) stage and shortened overall survival. An elevation of circCAMSAP1 expression was detected via droplet digital PCR in the serum of CRC patients prior to surgery. Functionally, circCAMSAP1 promoted the malignant behavior of CRC. Mechanism study of upstream biogenesis of circCAMSAP1 indicated that circCAMSAP1 cyclization in CRC was mediated by splicing factor epithelial-splicing regulatory protein 1. Moreover, circCAMSAP1 acted as a sponge for miR-328-5p and abrogated its suppression on transcription factor E2F1. Taken together, our data indicated an essential role of the circCAMSAP1/miR-328-5p/E2F1 axis in the progression of CRC, which implied that circCAMSAP1 could serve as a diagnostic and prognostic biomarker as well as a potential therapeutic target for CRC.Graphical abstract
Severe Hypoglycemia and Cognitive Function in Older Adults With Type 1 Diabetes: The Study of Longevity in Diabetes (SOLID)
Authors: Mary E. Lacy, Paola Gilsanz, Chloe Eng, Michal S. Beeri, Andrew J. Karter, Rachel A. Whitmer
Journal: Diabetes Care (2019)

OBJECTIVE In children with type 1 diabetes (T1D), severe hypoglycemia (SH) is associated with poorer cognition, but the association of SH with cognitive function in late life is unknown. Given the increasing life expectancy in people with T1D, understanding the role of SH in brain health is crucial. RESEARCH DESIGN AND METHODS We examined the association between SH and cognitive function in 718 older adults with T1D from the Study of Longevity in Diabetes (SOLID). Subjects self-reported recent SH (previous 12 months) and lifetime history of SH resulting in inpatient/emergency department utilization. Global and domain-specific cognition (language, executive function, episodic memory, and simple attention) were assessed. The associations of SH with cognitive function and impaired cognition were evaluated via linear and logistic regression models, respectively. RESULTS Thirty-two percent of participants (mean age 67.2 years) reported recent SH and 50% reported lifetime SH. Compared with those with no SH, subjects with a recent SH history had significantly lower global cognition scores. Domain-specific analyses revealed significantly lower scores on language, executive function, and episodic memory with recent SH exposure and significantly lower executive function with lifetime SH exposure. Recent SH was associated with impaired global cognition (odds ratio [OR] 3.22, 95% CI 1.30, 7.94) and cognitive impairment on the language domain (OR 3.15, 95% CI 1.19, 8.29). CONCLUSIONS Among older adults with T1D, recent SH and lifetime SH were associated with worse cognition. Recent SH was associated with impaired global cognition. These findings suggest a deleterious role of SH on the brain health of older patients with T1D and highlight the importance of SH prevention.
tmap: an integrative framework based on topological data analysis for population-scale microbiome stratification and association studies
Authors: Tianhua Liao, Yuchen Wei, Mingjing Luo, Guo-Ping Zhao, Haokui Zhou
Journal: Genome biology (2019)

Untangling the complex variations of microbiome associated with large-scale host phenotypes or environment types challenges the currently available analytic methods. Here, we present tmap, an integrative framework based on topological data analysis for population-scale microbiome stratification and association studies. The performance of tmap in detecting nonlinear patterns is validated by different scenarios of simulation, which clearly demonstrate its superiority over the most commonly used methods. Application of tmap to several population-scale microbiomes extensively demonstrates its strength in revealing microbiome-associated host or environmental features and in understanding the systematic interrelations among their association patterns. tmap is available at https://github.com/GPZ-Bioinfo/tmap.
Hürthle Cell Thyroid Adenoma Showing Avid Uptake on 18F-PSMA-1007 PET/CT
Authors: Kun Tang, Zhiqiang Wang, Jie Lin, Xiangwu Zheng
Journal: Clinical Nuclear Medicine (2019)

Abstract We report the case of a 74-year-old man with suspected recurrent prostate carcinoma who underwent 18 F-PSMA-1007 PET/CT for restaging the disease. PET/CT imaging presented an incidentaloma with intense 18 F-PSMA-1007 uptake in the right thyroid lobe. Biopsy and genomic sequencing test confirmed the diagnosis of Hürthle cell thyroid adenoma. Therefore, it is important to raise awareness of this benign lesion in the differential diagnosis of incidental thyroid nodules with high 18 F-PSMA-1007 activity.
Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results
Authors: John C. Byrd, William G. Wierda, Anna Schuh, Stephen Devereux, Jorge M. Chaves, Jennifer R. Brown, Peter Hillmen, Peter Martin, Farrukh T. Awan, Deborah M. Stephens, Paolo Ghia, Jacqueline Barrientos, John M. Pagel, Jennifer A. Woyach, Kathleen Burke, Todd Covey, Michael Gulrajani, Ahmed Hamdy, Raquel Izumi, Melanie M. Frigault, Priti Patel, Wayne Rothbaum, Min Hui Wang, Susan O’Brien, Richard R. Furman
Journal: Blood (2019)
Mechanisms Underlying the Neural Computation of Head Direction
Authors: Brad K. Hulse, Vivek Jayaraman
Journal: Annual Review of Neuroscience (2019)

Many animals use an internal sense of direction to guide their movements through the world. Neurons selective to head direction are thought to support this directional sense and have been found in a diverse range of species, from insects to primates, highlighting their evolutionary importance. Across species, most head-direction networks share four key properties: a unique representation of direction at all times, persistent activity in the absence of movement, integration of angular velocity to update the representation, and the use of directional cues to correct drift. The dynamics of theorized network structures called ring attractors elegantly account for these properties, but their relationship to brain circuits is unclear. Here, we review experiments in rodents and flies that offer insights into potential neural implementations of ring attractor networks. We suggest that a theory-guided search across model systems for biological mechanisms that enable such dynamics would uncover general principles underlying head-direction circuit function.
Efficacy of capecitabine in secondary prevention of skin cancer in solid organ-transplanted recipients (OTR)
Authors: T. Jirakulaporn, J. Mathew, B. R. Lindgren, A. Z. Dudek
Journal: Journal of Clinical Oncology (2009)

1519 Background: Skin cancers are the most common malignancies in OTR. Topical 5% 5-FU has been used to successfully treat squamous cell carcinoma (SCC) in situ and actinic keratosis (AK). Capecitabine, an orally-administered prodrug of 5-FU, in combination with interferon was shown to be effective in the treatment of advanced SCC of the skin. This study was to determine the efficacy of low-dose capecitabine in secondary prevention of the skin cancers in OTR. Methods: OTR who developed recurrent skin cancers, SCC, and/or basal cell carcinoma (BCC), were given low-dose capecitabine 1g/m2 divided in two daily doses, day 1–14 of 21-day treatment cycle. Skin surveillances were performed by dermatologists every 1 to 3 months. Cumulative incidence rates of SCC, BCC, and AK before and after treatment were scored and statistically compared for each patient with a non-parametric Wilcoxon signed-rank test. Age and number of transplants were assessed with the Spearman non-parametric correlation analysis for their impact on the outcome. Results: 14 patients (12 males and 2 females) were enrolled with median age of 55 (range 40–73). 11 patients received kidney, two lung and one liver, one heart and one pancreas transplant. Two patients received double organ transplants. Mean incidence rates of SCC, BCC, and AK before treatment were 0.45, 0.05, and 4.99 lesions per month, respectively. Mean incidence rates of SCC, BCC, and AK after treatment were 0.22, 0.04, and 2.80 lesions per month, respectively. The differences in incidence rates of SCC, BCC, and AK before and after treatment were 0.24, 0.02, and 2.08 lesions per month with p value of 0.048, 0.844, and 0.151, respectively. Age and the number of transplants were not significantly related to the change in incidence rates for all skin lesion types. Six of the total of 14 patients experienced grade 3/4 toxicities, including mucositis (2), hand-foot syndrome (3), fatigue (2), nausea (1), diarrhea (2), hyperuricemia (1), and anemia (1), and all six needed capecitabine dose reduction or stopping therapy. Conclusions: Oral capecitabine significantly decreases the incidence rates of recurrent SCC in OTR and has manageable toxicity. No significant financial relationships to disclose.
Investigating New Mechanisms of Acquired Resistance to Targeted Therapies: If You Hit Them Harder, Do They Get Up Differently?
Authors: Konstantinos V. Floros, Aaron N. Hata, Anthony C. Faber
Journal: Cancer Research (2020)

Abstract Targeted therapies have revolutionized treatment of several different types of cancers. However, in almost an invariable fashion, cancers eventually regrow in the presence of the targeted therapy, a phenomenon referred to as acquired resistance. In this issue of Cancer Research, Finn and colleagues demonstrate that modeling acquired resistance to MET tyrosine kinase inhibition in a MET-amplified gastric cancer cell line by a single, high exposure of the targeted therapy reveals clinically relevant acquired resistant mechanisms, which may be more faithful and comprehensive than the ones revealed through traditional ramp-up approaches. See related article by Finn et al., p. 79
Chronic oral toxicity studies of the angiogenesis inhibitor, ammonium tetrathiomolybdate
Authors: William D. Johnson, David L. McCormick, Robert L. Morrissey, Elizabeth R. Glaze, Joseph E. Tomaszewski
Journal: Cancer Research (2004)

4097  Chronic (6-month and 9-month) oral toxicity studies were conducted in rats and dogs to characterize the toxicity of ammonium tetrathiomolybdate (ATTM), an angiogenesis inhibitor being developed as a cancer therapeutic. In addition to toxicology, clinical pathology, and histopathology endpoints, study designs assessed the utility of copper supplementation in the prevention of ATTM toxicity, and evaluated plasma ceruloplasmin as a possible biomarker of ATTM action. In rats, chronic gavage administration of ATTM at doses of 0.25, 1.0, or 4.0 mg/kg/day did not induce mortality, alterations in body weight, or gross toxicity. No evidence of drug-related ocular toxicity, neurotoxicity, or immunotoxicity was identified in any study animal, and micronucleus evaluations were negative. Effects on hematology, clinical chemistry, and tissue morphology were seen only in rats receiving the high dose of ATTM, and included minimal to mild anemia, modest alterations in several clinical pathology parameters, hepatomegaly, and microscopic alterations in the tibia and epididymis. Anemia, hepatomegaly, most clinical pathology alterations, and most microscopic changes were partially or completely prevented by co-administration of copper; all effects other than sperm granulomas in the epididymis were reversed upon discontinuation of ATTM exposure. In dogs, administration of ATTM at doses of 0.3, 1.0, or 3.0 mg/kg/day for 9 months induced no effects on any toxicologic parameter examined except for microscopic alterations in the liver (1.0 and 3.0 mg/kg/day doses only). Microscopic alterations in dogs treated with ATTM were not reduced by co-administration of copper, and were not reversed upon discontinuation of exposure. In rats, plasma ceruloplasmin was reduced in dose-related fashion by ATTM; this reduction was ameliorated by copper supplementation, suggesting that ceruloplasmin is a useful biomarker of ATTM action in rats. By contrast, baseline levels of ceruloplasmin in dogs were very low, and were not reproducibly altered by ATTM. The No Observed Adverse Effect Level for chronic administration of ATTM was 1.0 mg/kg/day (6 mg/m2/day) in rats and 0.3 mg/kg/day (6 mg/m2/day) in dogs. (N01-CM-85102 from the NCI.)
Germline DNA Sequencing Reveals Novel Mutations Predictive of Overall Survival in a Cohort of Patients with Pancreatic Cancer
Authors: Jennifer B. Goldstein, Li Zhao, Xuemei Wang, Yael Ghelman, Michael J. Overman, Milind M. Javle, Rachna T. Shroff, Gauri R. Varadhachary, Robert A. Wolff, Florencia McAllister, Andrew Futreal, David R. Fogelman
Journal: Clinical Cancer Research (2019)

Family history of BRCA-related tumors may correlate with response to chemotherapy and overall survival (OS) in pancreatic cancer. The frequency of germline mutations has been reported in patients predominantly under the age of 60 or with strong family history. We examine the incidence of deleterious germline mutations and compare the chemotherapy responses and OS in an unselected group of patients with metastatic pancreatic cancer.Patients with metastatic pancreatic cancer, who were seen at a single cancer center between 2010 and 2016, were included. Germline DNA was sequenced using a 263-gene panel to identify novel mutations (N = 133 MD Anderson cohort, N = 127 TCGA cohort). Chemotherapy response and OS were determined by review of medical records.Deleterious germline mutations were identified in 26 of 133 patients (19.5%). Patients with DNA damage repair (DDR) gene mutations (ATM, BRCA1/2, CDKN2A, CHEK2, ERCC4, PALB2, n = 15) had an improved OS as compared with patients without (16.8 vs. 9.1 months, P = 0.03). Conversely, patients with other deleterious mutations had a trend toward worse OS. However, survival in the latter group was longer (P = NS) in those mutants initially treated with gemcitabine/nab-paclitaxel. A family history of multiple breast, ovarian, and pancreatic cancers was associated with DDR gene mutations and better survival.We have identified novel germline mutations that are prognostic for survival in patients with pancreatic cancer. We observe improved survival in patients with DDR gene mutations and worsened survival in patients with deleterious mutations in non-DDR genes.
Genetic Factors, Adherence to Healthy Lifestyle Behavior, and Risk of Invasive Breast Cancer Among Women in the UK Biobank
Authors: Rhonda S Arthur, Tao Wang, Xiaonan Xue, Victor Kamensky, Thomas E Rohan
Journal: JNCI Journal of the National Cancer Institute (2019)

Breast cancer is considered to result from a combination of genetic and lifestyle-related factors, but the degree to which an overall healthy lifestyle may attenuate the impact of multiple genetic variants on invasive breast cancer risk remains equivocal.Using Cox proportional hazards regression models, we examined the association of a modified healthy lifestyle index (HLI) with risk of invasive breast cancer by genetic risk group among 146 326 women from the UK Biobank. We generated an HLI score based on a combination of diet, physical activity, smoking, alcohol consumption and anthropometry, and a polygenic risk score (PRS) using 304 breast cancer-associated genetic loci.Among premenopausal and postmenopausal women, a favorable lifestyle (highest tertile) was associated with 22% and 31% reductions in invasive breast cancer risk, respectively (hazard ratio [HR]high vs low = 0.78, 95% confidence interval [CI] = 0.64 to 0.94; HRhigh vs low = 0.69, 95% CI = 0.63 to 0.77, respectively), whereas a high PRS (highest tertile) was associated with more than a doubling in the risk in both groups. For premenopausal women, the greatest risk reduction in association with the HLI was seen among those with a high PRS (HRhigh vs low = 0.73, 95% CI = 0.75 to 0.95). In postmenopausal women, those with a favorable lifestyle had 30%, 29%, and 32% reductions in risk of invasive breast cancer in the low, intermediate, and high PRS groups, respectively (HRhigh vs low = 0.70, 95% CI = 0.56 to 0.88; HRhigh vs low = 0.71, 95% CI = 0.59 to 0.84; and HRhigh vs low = 0.68, 95% CI = 0.59 to 0.78, respectively). There was an additive but not multiplicative interaction between the HLI score and PRS for postmenopausal and, to a lesser extent, premenopausal women.Our findings support the view that an overall healthy lifestyle may attenuate the impact of genetic factors on invasive breast cancer risk among women of European ancestry.
Non-Pharmacological Therapies in People with Alzheimer Dementia: Comparing Hand Massage and Conversational Approach in the Italian Context
Authors: Belacchi Carmen, Capotosto Emanuela
Journal: Alzheimers Disease & Dementia (2017)

Non-pharmacological therapies have shown to have significant benefits in reducing behavioral psychological symptoms in people with dementia. This is a pilot study to compare the efficacy of two non-pharmacological treatments in people with mild to moderate Alzheimer's Dementia (AD) with behavioral psychological symptoms: hand massage and conversational approach.