tbuckley/cabot-search huggingface dataset:
Pathophysiological Characteristics Underlying Different Glucose Response Curves: A Latent Class Trajectory Analysis From the Prospective EGIR-RISC Study
Authors: Adam Hulman, Daniel R. Witte, Dorte Vistisen, Beverley Balkau, Jacqueline M. Dekker, Christian Herder, Mensud Hatunic, Thomas Konrad, Kristine Færch, Melania Manco
Journal: Diabetes Care (2018)

OBJECTIVE Glucose measurements during an oral glucose tolerance test (OGTT) are useful in predicting diabetes and its complications. However, knowledge of the pathophysiology underlying differences in glucose curve shapes is sparse. We examined the pathophysiological characteristics that create different glucose curve patterns and studied their stability and reproducibility over 3 years of follow-up. RESEARCH DESIGN AND METHODS We analyzed data from participants without diabetes from the observational cohort from the European Group for the Study of Insulin Resistance: Relationship between Insulin Sensitivity and Cardiovascular Disease study; participants had a five–time point OGTT at baseline (n = 1,443) and after 3 years (n = 1,045). Measures of insulin sensitivity and secretion were assessed at baseline with a euglycemic-hyperinsulinemic clamp and intravenous glucose tolerance test. Heterogeneous glucose response patterns during the OGTT were identified using latent class trajectory analysis at baseline and at follow-up. Transitions between classes were analyzed with multinomial logistic regression models. RESULTS We identified four different glucose response patterns, which differed with regard to insulin sensitivity and acute insulin response, obesity, and plasma levels of lipids and inflammatory markers. Some of these associations were confirmed prospectively. Time to glucose peak was driven mainly by insulin sensitivity, whereas glucose peak size was related to both insulin sensitivity and secretion. The glucose patterns identified at follow-up were similar to those at baseline, suggesting that the latent class method is robust. We integrated our classification model into an easy-to-use online application that facilitates the assessment of glucose curve patterns for other studies. CONCLUSIONS The latent class analysis approach is a pathophysiologically insightful way to classify individuals without diabetes based on their response to glucose during an OGTT.
Effect of treatment center volume on outcomes in gastroenteropancreatic neuroendocrine tumor patients.
Authors: Kiwoon Joshua Baeg, Cynthia Harris, Mi Ri Lee, Jacob Andrew Martin, Sheila Rustgi, Grace Mhango, Juan P. Wisnivesky, Michelle Kang Kim
Journal: Journal of Clinical Oncology (2018)

502 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively rare tumors, where patients seek care at medical centers with varying levels of expertise. While treatment center volume is associated with better survival in multiple cancers, it remains unknown whether the same applies to GEP-NETs. The objective of this study was to assess the impact of center volume on GEP-NET treatment outcomes. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) registry linked to Medicare claims data in this study. We included patients diagnosed between 1995-2010 who had no HMO coverage, participated in Medicare parts A and B, were older than 65 at diagnosis, had full tumor grade information, and had no secondary cancer. We used Medicare claims to identify the medical centers at which patients received GEP-NET treatment (surgery, chemotherapy, somatostatin analogues, or radiation therapy). Center volume was divided into tiers – low, medium, and high – based on the number of unique GEP-NET patients treated by a medical center over two years. Kaplan-Meier curves and Cox regression were used to assess the association between volume and disease-specific survival (DSS). Results: We identified 1025 GEP-NET patients, of whom 65%, 28%, and 7% received treatment at low, medium, and high volume centers, respectively. Surgery was the most common first treatment (84-90%). Comorbidity and tumor stage distribution were similar across tiers, but the distribution of patients with poorly-differentiated tumors differed significantly (p &lt; 0.001). Median DSS for patients at low and medium centers were 3.7 years and 6.6 years, respectively, but was not reached for patients at high volume centers. After adjusting for confounders, patients treated at high volume centers had better survival than those treated in low volume centers (HR: 0.55, 95% CI: 0.30-0.99). However, no difference in survival was noted at medium volume centers (HR: 0.98, 95% CI: 0.78-1.22). Conclusions: Our results suggest that centers with expertise in GEP-NET treatment have better patient outcomes. Thus, centralization of care, particularly of more difficult cases, may lead to improved patient outcomes.
Tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils): a systematic review and meta-analysis
Authors: Helen L Petsky, Chris J Cates, Kayleigh M Kew, Anne B Chang
Journal: Thorax (2018)

Background Asthma guidelines guide health practitioners to adjust treatments to the minimum level required for asthma control. As many people with asthma have an eosinophilic endotype, tailoring asthma medications based on airway eosinophilic levels (sputum eosinophils or exhaled nitric oxide, FeNO) may improve asthma outcomes. Objective To synthesise the evidence from our updated Cochrane systematic reviews, for tailoring asthma medication based on eosinophilic inflammatory markers (sputum analysis and FeNO) for improving asthma-related outcomes in children and adults. Data sources Cochrane reviews with standardised searches up to February 2017. Study selection The Cochrane reviews included randomised controlled comparisons of tailoring asthma medications based on sputum analysis or FeNO compared with controls (primarily clinical symptoms and/or spirometry/peak flow). Results The 16 included studies of FeNO-based management (seven in adults) and 6 of sputum-based management (five in adults) were clinically heterogeneous. On follow-up, participants randomised to the sputum eosinophils strategy (compared with controls) were significantly less likely to have exacerbations (62 vs 82/100 participants with ≥1 exacerbation; OR 0.36, 95% CI 0.21 to 0.62). For the FeNO strategy, the respective numbers were adults OR 0.60 (95% CI 0.43 to 0.84) and children 0.58 (95% CI 0.45 to 0.75). However, there were no significant group differences for either strategy on daily inhaled corticosteroids dose (at end of study), asthma control or lung function. Conclusion Adjusting treatment based on airway eosinophilic markers reduced the likelihood of asthma exacerbations but had no significant impact on asthma control or lung function.
The Advantage of FLASH Radiotherapy Confirmed in Mini-pig and Cat-cancer Patients
Authors: Marie-Catherine Vozenin, Pauline De Fornel, Kristoffer Petersson, Vincent Favaudon, Maud Jaccard, Jean-François Germond, Benoit Petit, Marco Burki, Gisèle Ferrand, David Patin, Hanan Bouchaab, Mahmut Ozsahin, François Bochud, Claude Bailat, Patrick Devauchelle, Jean Bourhis
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals. Experimental Design: Pig skin was used to investigate a potential difference in toxicity between irradiation delivered at an ultrahigh dose rate called “FLASH-RT” and irradiation delivered at a conventional dose rate called “Conv-RT.” A clinical, phase I, single-dose escalation trial (25–41 Gy) was performed in 6 cat patients with locally advanced T2/T3N0M0 squamous cell carcinoma of the nasal planum to determine the maximal tolerated dose and progression-free survival (PFS) of single-dose FLASH-RT. Results: Using, respectively, depilation and fibronecrosis as acute and late endpoints, a protective effect of FLASH-RT was observed (≥20% dose-equivalent difference vs. Conv-RT). Three cats experienced no acute toxicity, whereas 3 exhibited moderate/mild transient mucositis, and all cats had depilation. With a median follow-up of 13.5 months, the PFS at 16 months was 84%. Conclusions: Our results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLASH-RT in human patients. See related commentary by Harrington, p. 3
Abstract 15551: Eosinophils Mediate Alternative Activation of Macrophages via IL-4 in the Infarcted Adult Mouse Heart to Prevent Adverse Cardiac Remodelling
Authors: Iqbal S Toor, Dominik Ruckerl, Adrian Thomson, Jennifer Felton, Adriano Rossi, Judi Allen, Gillian A Gray
Journal: Circulation (2016)

Introduction: Alternative activation of macrophages by IL-4 promotes tissue repair. We have observed that peripheral blood eosinophil count declines in patients following the onset of myocardial in...
T-cell Responses to <i>TP53</i> “Hotspot” Mutations and Unique Neoantigens Expressed by Human Ovarian Cancers
Authors: Drew C. Deniger, Anna Pasetto, Paul F. Robbins, Jared J. Gartner, Todd D. Prickett, Biman C. Paria, Parisa Malekzadeh, Li Jia, Rami Yossef, Michelle M. Langhan, John R. Wunderlich, David N. Danforth, Robert P.T. Somerville, Steven A. Rosenberg
Journal: Clinical Cancer Research (2018)

Abstract Purpose: This was a study prospectively evaluating intratumoral T-cell responses to autologous somatic mutated neoepitopes expressed by human metastatic ovarian cancers. Patients and Methods: Tumor-infiltrating lymphocytes (TIL) were expanded from resected ovarian cancer metastases, which were analyzed by whole-exome and transcriptome sequencing to identify autologous somatic mutations. All mutated neoepitopes, independent of prediction algorithms, were expressed in autologous antigen-presenting cells and then cocultured with TIL fragment cultures. Secretion of IFNγ or upregulation of 41BB indicated a T-cell response. Results: Seven women with metastatic ovarian cancer were evaluated, and 5 patients had clear, dominant T-cell responses to mutated neoantigens, which were corroborated by comparison with the wild-type sequence, identification of the minimal epitope, human leukocyte antigen (HLA) restriction element(s), and neoantigen-specific T-cell receptor(s). Mutated neoantigens were restricted by HLA-B, -C, -DP, -DQ, and/or -DR alleles and appeared to principally arise from random, somatic mutations unique to each patient. We established that TP53 “hotspot” mutations (c.659A&amp;gt;G; p.Y220C and c.733G&amp;gt;A; p.G245S) expressed by two different patients' tumors were both immunogenic in the context of HLA-DRB3*02:02. Conclusions: Mutation-reactive T cells infiltrated ovarian cancer metastases at sufficient frequencies to warrant their investigation as adoptive cell therapy. In addition, transfer of TP53 “hotspot” mutation-reactive T-cell receptors into peripheral blood T cells could be evaluated as a gene therapy for a diverse range of tumor histologies. Clin Cancer Res; 24(22); 5562–73. ©2018 AACR. See related commentary by McNeish, p. 5493
Pannexin-1 channels contribute to seizure generation in human epileptic brain tissue and in a mouse model of epilepsy
Authors: Elena Dossi, Thomas Blauwblomme, Julien Moulard, Oana Chever, Flora Vasile, Eleonore Guinard, Marc Le Bert, Isabelle Couillin, Johan Pallud, Laurent Capelle, Gilles Huberfeld, Nathalie Rouach
Journal: Science Translational Medicine (2018)

Pannexin-1 channel inhibition blocks seizure activity in brain slices from epileptic patients and reduces spontaneous seizures in a mouse model of pharmacoresistant epilepsy.
Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) <i>v</i> FULV in patients (pts) with estrogen receptor (ER)-positive, <i>PIK3CA</i>-mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER.
Authors: Jose Baselga, Susan Faye Dent, Javier Cortés, Young-Hyuck Im, Véronique Diéras, Nadia Harbeck, Ian E. Krop, Sunil Verma, Timothy R. Wilson, Huan Jin, Lijia Wang, Frauke Schimmoller, Jerry Y. Hsu, Jing He, Michelino DeLaurentiis, Pamela Drullinsky, William Jacot
Journal: Journal of Clinical Oncology (2018)

LBA1006 Background: Taselisib, a potent, selective PI3K inhibitor, has enhanced activity in PIK3CA-MUT BC cell lines and confirmed partial responses in PIK3CA-MUT BC as a single-agent or with FULV. We assessed taselisib + FULV in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. Methods: SANDPIPER (NCT02340221) is a double-blind, placebo (PBO)-controlled, randomized, phase III study. Postmenopausal pts with disease recurrence or progression during or after an aromatase inhibitor were randomized 2:1 to receive taselisib (4 mg oral, qd) or PBO + FULV (500 mg). Stratification factors were: visceral disease, endocrine sensitivity, and geographic region. Pts with PIK3CA-MUT tumors, assessed by central cobas PIK3CA Mutation Test, were randomized separately from non-MUT tumors. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in pts with PIK3CA-MUT tumors. Secondary endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), duration of objective response (DoR), PFS by blinded independent central review (BICR-PFS), and safety. Results: 516 pts were randomized in the PIK3CA-MUT intention-to-treat (ITT) population. Efficacy is shown in the Table. Taselisib + FULV significantly improved INV-PFS (hazard ratio [HR] 0.70) as confirmed by BICR-PFS (HR 0.66). OS is immature. The most common grade ≥3 adverse events (AEs; preferred terms) in the taselisib + FULV arm in safety-evaluable pts who received ≥ 1 dose of treatment were diarrhea (12%), hyperglycemia (10%), colitis (3%), and stomatitis (2%). AEs led to more taselisib discontinuations (17% v 2%) and dose reductions (37% v 2%), v PBO. Conclusions: Taselisib + FULV significantly improved INV-PFS, v PBO + FULV, in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. The safety profile is largely consistent with previous studies. Clinical trial information: NCT02340221. [Table: see text]
Safety of pazopanib and sunitinib in treatment-naive patients with metastatic renal cell carcinoma: Asian versus non-Asian subgroup analysis of the COMPARZ trial
Authors: Jun Guo, Jie Jin, Mototsugu Oya, Hirotsugu Uemura, Shunji Takahashi, Katsunori Tatsugami, Sun Young Rha, Jae-Lyun Lee, Jinsoo Chung, Ho Yeong Lim, Hsi Chin Wu, Yen Hwa Chang, Arun Azad, Ian D. Davis, Marlene J. Carrasco-Alfonso, Bhupinder Nanua, Jackie Han, Qasim Ahmad, Robert Motzer
Journal: Journal of Hematology & Oncology (2018)

The international, phase 3 COMPARZ study demonstrated that pazopanib and sunitinib have comparable efficacy as first-line therapy in patients with advanced renal cell carcinoma, but that safety and quality-of-life profiles favor pazopanib. Our report analyzed pazopanib and sunitinib safety in Asian and non-Asian subpopulations. Patients were randomized 1:1 to receive pazopanib 800 mg once daily (continuous dosing) or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off). Safety population was composed of 363 Asian patients and 703 non-Asian patients. Asian patients had similar duration of exposure to either drug compared with non-Asian patients, although Asian patients had a higher frequency of dose modifications. Overall, hematologic toxicities, cytopenias, increased AST/ALT, and palmar-plantar erythrodysesthesia (PPE) were more prevalent in Asian patients, whereas gastrointestinal toxicities were more prevalent in non-Asian patients. Among Asian patients, hematologic adverse events and most non-hematologic AEs were more common in sunitinib-treated versus pazopanib-treated patients. Among Asian patients, the most common grade 3/4 AEs with pazopanib were hypertension (grade 3, 22%) and alanine aminotransferase increased (grade 3, 12%; grade 4, 1%); the most common grade 3/4 AEs with sunitinib were thrombocytopenia/platelet count decreased (grade 3, 36%; grade 4, 10%), neutropenia/neutrophil count decreased (grade 3, 24%; grade 4, 3%) hypertension (grade 3, 20%), and PPE (grade 3, 15%). A distinct pattern and severity of adverse events was observed in Asians when compared with non-Asians with both pazopanib and sunitinib. However, the two drugs were well tolerated in both subpopulations. ClinicalTrials.gov, NCT00720941 , Registered July 22, 2008 ClinicalTrials.gov, NCT01147822 , Registered June 22, 2010
A systematic review of randomized controlled trials (RCTs) of exercise interventions using digital activity trackers (E-DAT) in cancer patients.
Authors: Kerry Schaffer, Narmadha Panneerselvam, Kah Poh Loh, Rachel Herrmann, Ian Kleckner, Richard Francis Dunne, Po-Ju Lin, Charles E. Heckler, Lauren B. Bruckner, Eugene Storozynsky, Bonnie Ky, Supriya Gupta Mohile, Karen Michelle Mustian, Chunkit Fung
Journal: Journal of Clinical Oncology (2018)

108 Background: Exercise ameliorates cancer and treatment-related toxicities but adherence to exercise is a barrier. Few studies in the general population suggest that E-DAT may improve exercise adherence. We conducted a systematic review to examine the effects of E-DAT on physical function, health-related quality of life (HRQOL), and serum inflammatory markers during and after cancer treatment. Methods: We used PubMed, Embase, and the Cochrane Library to identify RCTs of E-DAT in cancer patients aged ≥18 years published in English between 1/1/2008 and 7/27/2017. Two authors independently reviewed the titles of articles from the search (n = 160), removed duplicates (n = 49), and reviewed the remaining 111 articles for eligibility and substantive results. We excluded RCTs that used digital activity trackers solely for data collection. Results: Twelve RCTs met eligibility criteria, including 1,450 patients (mean age: 50-70 years) with the following cancers: breast (n = 5 RCTs), colon or breast (n = 2), prostate (n = 1), acute leukemia (n = 1) and various type (n = 3). Duration of E-DAT ranged from 4-24 weeks. Follow-up period was 4-24 weeks with retention of 54-95%. Half of the RCTs had E-DAT with in-person exercise training and the rest had self-directed training. The technology component of E-DAT included pedometers (n = 8); pedometers with smart phone application (n = 1), Wii-Fit (n = 1), or heart rate monitor (n = 1); and a wireless sensor with accelerometer, gyroscope, and magnetometer (n = 1). Adherence to E-DAT was &gt; 70% in 5 of 7 RCTs. Compared to controls (exercise interventions without digital activity trackers or standard of care), E-DAT significantly improved the step count in 60% of 5 RCTs, activity level in 56% of 9 RCTs, and HRQOL in 56% of 9 RCTs (all p &lt; 0.05), with no significant changes of inflammatory markers (i.e. TNF, CRP, c-peptide) in 2 RCTs. No significant correlations were found between duration of E-DAT with adherence (Spearman’s r = 0.16; p = 0.75) or study retention (Spearman’s r = -0.42; p = 0.17). Conclusions: This systematic review shows that E-DAT is feasible to implement in cancer patients. Future research should examine the optimal type, dose and schedule of E-DAT.
Effect of carboplatin on pathologic complete remission rate and hematotoxicity incidence in neoadjuvant treatment of triple-negative breast cancer: A meta-analysis.
Authors: Hong-Fei Gao, Ci-Qiu Yang, Teng Zhu, Liu-Lu Zhang, Kun Wang
Journal: Journal of Clinical Oncology (2018)

e12638 Background: To evaluate the efficacy and safety of carboplatin-based neoadjuvant chemotherapy in triple-negative breast cancer patients (TNBC). Methods: PubMed, EMBASE, the Web of Science, the Cochrane Library, major clinical trial registries, and abstract collections from major international meetings were systematically searched for relevant randomized controlled trials. Endpoints included rates of pathologic complete response (pCR) and hematotoxicity. Relative risk (RR) was calculated for each endpoint using a fixed- or random-effect model depending on the heterogeneity among included studies. Results: A total of 6 randomized controlled trials involving 1007 patients were included in the meta-analysis. Carboplatin-based chemotherapy was associated with a pooled pCR rate of 53.3%, which was significantly higher than the rate associated with non-carboplatin therapy (37.8%, RR: 1.43, 95%CI: 1.24-1.64, p < 0.00001). Carboplatin-based chemotherapy was associated with higher incidence of grade 3 or 4 anemia (RR = 16.67, 95% CI 7.65-50.56, p < 0.00001), neutropenia(RR = 2.40, 95% CI 1.42-4.06, p = 0.001), and thrombocytopenia (RR = 11.15, 95% CI 5.89-21.10, p < 0.00001) than non-carboplatin therapy. Conclusions: The available evidence suggests that carboplatin-based neoadjuvant chemotherapy is associated with significantly better pCR and higher hematotoxicity rates than non-carboplatin-based therapy in TNBC patients.
Inactivating hepatic follistatin alleviates hyperglycemia
Authors: Rongya Tao, Caixia Wang, Oliver Stöhr, Wei Qiu, Yue Hu, Ji Miao, X. Charlie Dong, Sining Leng, Margaret Stefater, Nicholas Stylopoulos, Lin Lin, Kyle D. Copps, Morris F. White
Journal: Nature Medicine (2018)
Diversification and independent domestication of Asian and European pears
Authors: Jun Wu, Yingtao Wang, Jiabao Xu, Schuyler S. Korban, Zhangjun Fei, Shutian Tao, Ray Ming, Shuaishuai Tai, Awais M. Khan, Joseph D. Postman, Chao Gu, Hao Yin, Danman Zheng, Kaijie Qi, Yong Li, Runze Wang, Cecilia H. Deng, Satish Kumar, David Chagné, Xiaolong Li, Juyou Wu, Xiaosan Huang, Huping Zhang, Zhihua Xie, Xiao Li, Mingyue Zhang, Yanhong Li, Zhen Yue, Xiaodong Fang, Jiaming Li, Leiting Li, Cong Jin, Mengfan Qin, Jiaying Zhang, Xiao Wu, Yaqi Ke, Jian Wang, Huanmimg Yang, Shaoling Zhang
Journal: Genome biology (2018)

Pear (Pyrus) is a globally grown fruit, with thousands of cultivars in five domesticated species and dozens of wild species. However, little is known about the evolutionary history of these pear species and what has contributed to the distinct phenotypic traits between Asian pears and European pears.
BCL-2 as therapeutic target for hematological malignancies
Authors: Guilherme Fleury Perini, Glaciano Nogueira Ribeiro, Jorge Vaz Pinto Neto, Laura Tojeiro Campos, Nelson Hamerschlak
Journal: Journal of Hematology & Oncology (2018)

Disruption of the physiologic balance between cell proliferation and cell death is an important step of cancer development. Increased resistance to apoptosis is a key oncogenic mechanism in several hematological malignancies and, in many cases, especially in lymphoid neoplasias, has been attributed to the upregulation of BCL-2. The BCL-2 protein is the founding member of the BCL-2 family of apoptosis regulators and was the first apoptosis modulator to be associated with cancer. The recognition of the important role played by BCL-2 for cancer development and resistance to treatment made it a relevant target for therapy for many diseases, including solid tumors and hematological neoplasias. Among the different strategies that have been developed to inhibit BCL-2, BH3-mimetics have emerged as a novel class of compounds with favorable results in different clinical settings, including chronic lymphocytic leukemia (CLL). In April 2016, the first inhibitor of BCL-2, venetoclax, was approved by the US Food and Drug Administration for the treatment of patients with CLL who have 17p deletion and had received at least one prior therapy. This review focuses on the relevance of BCL-2 for apoptosis modulation at the mitochondrial level, its potential as therapeutic target for hematological malignancies, and the results obtained with selective inhibitors belonging to the BH3-mimetics, especially venetoclax used in monotherapy or in combination with other agents.