tbuckley/cabot-search huggingface dataset:
Heart Rate Variability and Cardiac Autonomic Dysfunction: Prevalence, Risk Factors, and Relationship to Arterial Stiffness in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study
Authors: Amy S. Shah, Laure El ghormli, Mary Ellen Vajravelu, Fida Bacha, Ryan M. Farrell, Samuel S. Gidding, Lorraine E. Levitt Katz, Jeanie B. Tryggestad, Neil H. White, Elaine M. Urbina
Journal: Diabetes Care (2019)

To determine whether prior type 2 diabetes (T2D) treatment or glycemic control over time are independently associated with heart rate variability (HRV) and whether the presence of cardiac autonomic dysfunction is associated with arterial stiffness in young adults with youth-onset T2D enrolled in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.Heartbeats over 10 min were measured to derive the normal R-Rs (NN intervals). Outcomes included the standard deviation of the NN intervals (SDNN), the root mean square differences of successive NN intervals (RMSSD), percent of NN beats that differ by more than 50 ms (PNN50), and the low-frequency (LF) power domain, high-frequency (HF) power domain, and their ratio (LF:HF). Autonomic dysfunction was defined as ≥3 of 5 abnormal HRV indices compared with obese controls from a separate study.A total of 397 TODAY participants were evaluated 7 years after randomization. TODAY participants had reduced HRV (SDNN 58.1 ± 29.6 ms vs. controls 67.1 ± 25.4 ms; P < 0.0001) with parasympathetic loss (RMSSD 53.2 ± 36.7 ms vs. controls 67.9 ± 35.2 ms; P < 0.0001) with sympathetic overdrive (LF:HF ratio 1.4 ± 1.7 vs. controls 1.0 ± 1.1; P < 0.0001). Cardiac autonomic dysfunction was present in 8% of TODAY participants, and these participants had greater pulse wave velocity compared with those without dysfunction (P = 0.0001). HRV did not differ by randomized treatment, but higher hemoglobin A1c (HbA1c) over time was independently associated with lower SDNN and RMSSD and higher LF:HF ratio after adjustment for age, race-ethnicity, sex, and BMI.Young adults with youth-onset T2D show evidence of cardiac autonomic dysfunction with both parasympathetic and sympathetic impairments that are associated with higher HbA1c.
Automatic Respiratory Gating Hepatic DCEUS-based Dual-phase Multi-parametric Functional Perfusion Imaging using a Derivative Principal Component Analysis
Authors: Diya Wang, Guy Cloutier, Yan Fan, Yanli Hou, Zhe Su, Qiang Su, Mingxi Wan
Journal: Theranostics (2019)

Purpose: Angiogenesis in liver cancers can be characterized by hepatic functional perfusion imaging (FPI) on the basis of dynamic contrast-enhanced ultrasound (DCEUS).However, accuracy is limited by breathing motion which results in out-of-plane image artifacts.Current hepatic FPI studies do not correct for these artifacts and lack the evaluation of correction accuracy.Thus, a hepatic DCEUS-based dual-phase multi-parametric FPI (DM-FPI) scheme using a derivative principal component analysis (PCA) respiratory gating is proposed to overcome these limitations.Materials and Methods: By considering severe 3D out-of-plane respiratory motions, the proposed scheme's accuracy was verified with in vitro DCEUS experiments in a flow model mimicking a hepatic vein.The feasibility was further demonstrated by considering in vivo DCEUS measurements in normal rabbit livers, and hepatic cavernous hemangioma and hepatocellular carcinoma in patients.After respiratory kinetics was extracted through PCA of DCEUS sequences under free-breathing condition, dual-phase respiratory gating microbubble kinetics was identified by using a derivative PCA zero-crossing dual-phase detection, respectively.Six dual-phase hemodynamic parameters were estimated from the dual-phase microbubble kinetics and DM-FPI was then reconstructed via color-coding to quantify 2.5D angiogenic hemodynamic distribution for live tumors.Results: Compared with no respiratory gating, the mean square error of respiratory gating DM-FPI decreased by 1893.9 ± 965.4 (p < 0.05), and mean noise coefficients decreased by 17.5 ± 7.1 (p < 0.05), whereas correlation coefficients improved by 0.4 ± 0.2 (p < 0.01).DM-FPI observably removed severe respiratory motion artifacts on PFI and markedly enhanced the accuracy and robustness both in vitro and in vivo.Conclusions: DM-FPI precisely characterized and distinguished the heterogeneous angiogenic hemodynamics about perfusion volume, blood flow and flow rate within two anatomical sections in the normal liver, and in benign and malignant hepatic tumors.DCEUS-based DM-FPI scheme might be a useful tool to help clinicians diagnose and provide suitable therapies for liver tumors.
Big Data and Artificial Intelligence Modeling for Drug Discovery
Authors: Hao Zhu
Journal: The Annual Review of Pharmacology and Toxicology (2019)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, heterogeneous, and large nature of drug data sets. As a result, recently developed artificial intelligence approaches such as deep learning and relevant modeling studies provide new solutions to efficacy and safety evaluations of drug candidates based on big data modeling and analysis. The resulting models provided deep insights into the continuum from chemical structure to in vitro, in vivo, and clinical outcomes. The relevant novel data mining, curation, and management techniques provided critical support to recent modeling studies. In summary, the new advancement of artificial intelligence in the big data era has paved the road to future rational drug development and optimization, which will have a significant impact on drug discovery procedures and, eventually, public health.
Keeping<i>cultural</i>in cultural evolutionary psychology: Culture shapes indigenous psychologies in specific ecologies
Authors: Rita Anne McNamara, Tia Neha
Journal: Behavioral and Brain Sciences (2019)

In Cognitive Gadgets, Heyes seeks to unite evolutionary psychology with cultural evolutionary theory. Although we applaud this unifying effort, we find it falls short of considering how culture itself evolves to produce indigenous psychologies fitted to particular environments. We focus on mentalizing and autobiographical memory as examples of how socialization practices embedded within culture build cognitive adaptations.
Culture in the world shapes culture in the head (and vice versa)
Authors: Edward Baggs, Vicente Raja, Michael L Anderson
Journal: Behavioral and Brain Sciences (2019)

Abstract We agree with Heyes that an explanation of human uniqueness must appeal to cultural evolution, and not just genes. Her account, though, focuses narrowly on internal cognitive mechanisms. This causes her to mischaracterize human behavior and to overlook the role of material culture. A more powerful account would view cognitive gadgets as spanning organisms and their (shared) environments.
Effect of the specific P53 stabilizer CBS9106 on multiple myeloma (MM)
Authors: H. Ikeda, T. Hideshima, G. Perrone, Y. Okawa, N. Raje, T. Kawabe, K. Sakakibara, N. Saito, P. Richardson, K. Anderson
Journal: Journal of Clinical Oncology (2009)

8601 Background: The mutations of P53 tumor suppressor protein are associated with progressive in Multiple Myeloma (MM), conversely, stabilization of P53 leads to cell cycle arrest and apoptosis. In this study, we examined p53 protein expression and demonstrated the effect of P53 stabilization using a novel specific P53 stabilizer CBS9106 in MM. Method: We examined P53 protein expression using Immunoblot analysis, as well as the growth inhibitory effect of CBS9106 in MM cell lines and primary tumor cells from MM patients. We also defined whether CBS9106 can overcome the growth promoting effect of exogenous cytokines and bone marrow stroma cells (BMSCs) using [3H]-thymidine uptake assay. Results: Expression of P53 protein was observed in 3/3 primary tumor cells from MM patients and 6/6 MM cell lines. CBS9106 at low nM levels triggered cytotoxicity against p53 wild type MM cell lines and primary tumor cells from MM patients, associated with phosphorylation of P53 (serine15 and 20). In contrast, CBS9106 did not affect the survival of normal peripheral blood mononuclear cells from healthy volunteers at concentrations as high as 10 μM. This agent also induced G1 cell cycle arrest, followed by apoptosis associated with cleavage of caspase-3, -8, -9 and PARP. Neither growth stimulating cytokines (IL-6 and IGF-1) nor BMSCs protected against apoptotic effect of CBS9106. Moreover, we demonstrate that combination of CBS9106 with MDM2 inhibitor Nutrin3 or proteasome inhibitor bortezomib induces synergistic anti-MM activity in both P53 wild type MM cell lines and primary tumor cells from MM patients. Conclusions: Stabilizing P53 by CBS9106 represents a novel promising p53-based therapy in MM. These results provide the preclinical framework supporting evaluation of CBS9106 in clinical trials to improve patient outcome in MM. No significant financial relationships to disclose.
Publisher Correction: Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors
Authors: Paloma Cejas, Yotam Drier, Koen M. A. Dreijerink, Lodewijk A. A. Brosens, Vikram Deshpande, Charles B. Epstein, Elfi B. Conemans, Folkert H. M. Morsink, Mindy K. Graham, Gerlof D. Valk, Menno R. Vriens, Carlos Fernandez-del Castillo, Cristina R. Ferrone, Tomer Adar, Michaela Bowden, Holly J. Whitton, Annacarolina Da Silva, Alba Font-Tello, Henry W. Long, Elizabeth Gaskell, Noam Shoresh, Christopher M. Heaphy, Ewa Sicinska, Matthew H. Kulke, Daniel C. Chung, Bradley E. Bernstein, Ramesh A. Shivdasani
Journal: Nature Medicine (2019)
Cancer survival improves in UK but still lags behind other high income countries
Authors: Jacqui Wise
Journal: BMJ (2019)

More people are surviving cancer for longer, but the UK has made slower progress than other high income countries, a large international study has found. The International Cancer Benchmarking Partnership analysed data on 3.9 million people with cancer from 1995 to 2014 in seven countries: Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the UK. The study, published in Lancet Oncology ,1 looked at changes in survival, alongside incidence and mortality, in people with cancers of the oesophagus, stomach, colon, rectum, pancreas, lung, and ovary. In the UK, one and five year survival improved in all seven cancers analysed over the 20 year period:
Monitoring Oxygenation Levels Deep in the Tumor Core: Noninvasive Imaging of Hypoxia, Now in Real-Time 3D
Authors: Alexander L. Klibanov, Song Hu
Journal: Cancer Research (2019)

Abstract Understanding the way hypoxia influences tumor biology is important; to study tumor hypoxia, simple and robust quantification of tissue oxygenation levels in vivo is necessary. Real-time noninvasive imaging without the use of expensive large equipment (PET or MRI) is most desirable. Photoacoustic imaging, in the form of volumetric multispectral optoacoustic tomography, as described in this issue of Cancer Research, paves the way for tumor hypoxia studies using an intrinsic optical contrast agent (hemoglobin), up to cm depth and 0.1-mm spatial resolution, in real-time 3D. This approach may find use in the clinic to assess tumor status and therapeutic efficacy. See related article by Ron et al., p. 4767
Long-Term Survival Analysis of Adjuvant Chemotherapy with or without Trastuzumab in Patients with T1, Node-Negative HER2-Positive Breast Cancer
Authors: Xuexin He, Jiali Ji, Mei Tian, Francisco J. Esteva, Gabriel N. Hortobagyi, Sai-Ching Jim Yeung
Journal: Clinical Cancer Research (2019)

Adjuvant therapy for small, node-negative HER2-positive breast cancer (HER2+ BC) is controversial. We aimed to identify the subgroup that would benefit most from adjuvant chemotherapy and trastuzumab.We reviewed records of patients with pT1N0M0 HER2+ BC treated at our institution from January 1, 1998, through October 31, 2009. We compared three groups: A, no adjuvant chemotherapy; B, adjuvant chemotherapy only; and C, adjuvant chemotherapy with trastuzumab. We evaluated disease-free survival (DFS), overall survival (OS), distant recurrence-free survival (DRFS), and breast cancer-specific survival (BCSS) in each group.We reviewed 587 consecutive patients with a median follow-up of 123.0 months. The 10-year DFS rate was 81.0%, 65.4%, and 97.3% in groups A, B, and C, respectively (P < 0.001). The restricted mean survival time ratio did not differ between groups A and B [ratio = 0.982; 95% confidence interval (CI), 0.930-1.036; P = 0.498). Cox regression showed that adjuvant chemotherapy with trastuzumab was associated with better DFS compared with no adjuvant chemotherapy [hazard ratio (HR), 0.071; 95% CI, 0.025-0.204; P < 0.001). Larger tumor size was associated with short DFS (HR, 2.384; 95% CI, 1.549-3.056; P < 0.001); improvements in DFS, OS, DRFS, and BCSS were observed with adjuvant chemotherapy plus trastuzumab in patients with tumors ≥0.8-cm diameter. Receiving adjuvant chemotherapy with trastuzumab was not associated with improved DFS, OS, or DRFS for tumors <0.8 cm.Adjuvant chemotherapy plus trastuzumab should be recommended for patients with pT1N0M0 HER2+ BC ≥0.8 cm in diameter; adjuvant therapy may not be necessary for tumors <0.8 cm.
The test of time
Authors: Elizabeth Loder
Journal: BMJ (2019)

Which of today's headline breakthroughs will still be judged important years from now?Many treatments don't stand the test of time: they are effective in the short run but fail to produce lasting health benefits.It can be difficult to evaluate the long term effects of medical interventions, especially when outcomes of interest may not occur for decades.Such is the case with antibiotic treatment for Helicobacter pylori infection.For this reason, research reported this week by Jing-Yu Zhang and colleagues deserves our attention (doi:10.1136/bmj.l5016).The authors report on over two decades of follow-up of a randomised, placebo controlled trial of brief antibiotic treatment for H pylori (in trial participants who tested positive for it) and longer term vitamin and garlic supplementation.Treatment of H pylori infection and vitamin supplementation were both associated with meaningful reductions in the development of gastric cancer, and all three interventions were associated with a reduced risk of death related to cancer.The study took place in China, where the risk of gastric cancer is high and vitamin deficiencies are common.It remains uncertain whether the results can be generalised to better nourished populations or those with a lower baseline risk of gastric cancer.
US Food and Drug Administration Approvals of Drugs and Devices Based on Nonrandomized Clinical Trials
Authors: Marianne Razavi, Paul Glasziou, Farina A. Klocksieben, John P. A. Ioannidis, Iain Chalmers, Benjamin Djulbegovic
Journal: JAMA Network Open (2019)

The size of estimated treatment effects on the basis of which the US Food and Drug Administration (FDA) has approved drugs and devices with data from nonrandomized clinical trials (non-RCTs) remains unknown.To determine how often the FDA has authorized novel interventions based on non-RCTs and to assess whether there is an association of the magnitude of treatment effects with FDA requirements for additional testing in randomized clinical trials (RCTs).Overall, 606 drug applications for the Breakthrough Therapy designation from its inception in January 2012 were downloaded from the FDA website in January 2017 and August 2018, and 71 medical device applications for the Humanitarian Device Exemption from its inception in June 1996 were downloaded in August 2017.Approved applications based on non-RCTs were included; RCTs, studies with insufficient information, duplicates, and safety data were excluded.Data were extracted by 2 independent investigators. A statistical association of the magnitude of estimated effect (expressed as an odds ratio) with FDA requests for RCTs was assessed. The data were also meta-analyzed to evaluate the differences in odds ratios between applications that required further testing and those that did not. The results are reported according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.Disease, laboratory, and patient-related outcomes, including disease response or patient survival, were considered.Among 677 drug and medical device applications, 68 (10.0%) were approved by the FDA based on non-RCTs. Estimates of effects were larger when no further RCTs were required (mean natural logarithm of the odds ratios, 2.18 vs 1.12; odds ratios, 8.85 vs 3.06; P = .03). The meta-analysis results confirmed these findings: estimated effects were approximately 2.5-fold higher for treatments or devices that were approved based on non-RCTs than for treatments or devices for which further testing in RCTs was required (6.30 [95% CI, 4.38-9.06] vs 2.46 [95% CI, 1.70-3.56]; P < .001). Overall, 9 of 677 total applications (1.3%) that were approved on the basis of non-RCTs had relative risks of 10 or greater and 12 (1.7%) had relative risks of 5 or greater. No clear threshold above which the FDA approved interventions based on the magnitude of estimated effect alone was detected.In this study, estimated magnitudes of effect were larger among studies for which the FDA did not require RCTs compared with studies for which it did. There was no clear threshold of treatment effect above which no RCTs were requested.
Response to Anti-EGFR Therapy in Patients with BRAF non-V600–Mutant Metastatic Colorectal Cancer
Authors: Rona Yaeger, Daisuke Kotani, Sebastián Mondaca, Aparna R. Parikh, Hideaki Bando, Emily E. Van Seventer, Hiroya Taniguchi, HuiYong Zhao, Claire N. Thant, Elisa de Stanchina, Neal Rosen, Ryan B. Corcoran, Takayuki Yoshino, Zhan Yao, Hiromichi Ebi
Journal: Clinical Cancer Research (2019)

While mutations in BRAF in metastatic colorectal cancer (mCRC) most commonly occur at the V600 amino acid, with the advent of next-generation sequencing, non-V600 BRAF mutations are increasingly identified in clinical practice. It is unclear whether these mutants, like BRAF V600E, confer resistance to anti-EGFR therapy.We conducted a multicenter pooled analysis of consecutive patients with non-V600 BRAF-mutated mCRCs identified between 2010 and 2017. Non-V600 BRAF mutations were divided into functional classes based on signaling mechanism and kinase activity: activating and RAS-independent (class 2) or kinase-impaired and RAS-dependent (class 3).Forty patients with oncogenic non-V600 BRAF-mutant mCRC received anti-EGFR antibody treatment [n = 12 (30%) class 2 and n = 28 (70%) class 3]. No significant differences in clinical characteristics were observed by mutation class. In contrast, while only 1 of 12 patients with class 2 BRAF mCRC responded, 14 of 28 patients with class 3 BRAF responded to anti-EGFR therapy (response rate, 8% and 50%, respectively, P = 0.02). Specifically, in first- or second-line, 1 of 6 (17%) patients with class 2 and 7 of 9 (78%) patients with class 3 BRAF mutants responded (P = 0.04). In third- or later-line, none of 6 patients with class 2 and 7 of 19 (37%) patients with class 3 BRAF mutants responded (P = 0.14).Response to EGFR antibody treatment in mCRCs with class 2 BRAF mutants is rare, while a large portion of CRCs with class 3 BRAF mutants respond. Patients with colorectal cancer with class 3 BRAF mutations should be considered for anti-EGFR antibody treatment.See related commentary by Fontana and Valeri, p. 6896.
CAV1 - GLUT3 signaling is important for cellular energy and can be targeted by Atorvastatin in Non-Small Cell Lung Cancer
Authors: Azhar Ali, Elena Levantini, Chee Wai Fhu, Jun Ting Teo, John G. Clohessy, Julian L. Goggi, Chan-shuo Wu, Leilei Chen, Tan Min Chin, Daniel G Tenen
Journal: Theranostics (2019)

Background: The development of molecular targeted therapies, such as EGFR-TKIs, has positively impacted the management of EGFR mutated NSCLC. However, patients with innate and acquired resistance to EGFR-TKIs still face limited effective therapeutic options. Statins are the most frequently prescribed anti-cholesterol agents and have been reported to inhibit the progression of various malignancies, including in lung. However, the mechanism by which statin exerts its anti-cancer effects is unclear. This study is designed to investigate the anti-proliferative effects and identify the mechanism-of-action of statins in NSCLC. Methods: In this study, the anti-tumoral properties of Atorvastatin were investigated in NSCLC utilizing cell culture system and in vivo models. Results: We demonstrate a link between elevated cellular cholesterol and TKI-resistance in NSCLC, which is independent of EGFR mutation status. Atorvastatin suppresses growth by inhibiting Cav1 expression in tumors in cell culture system and in in vivo models. Subsequent interrogations demonstrate an oncogenic physical interaction between Cav1 and GLUT3, and glucose uptake found distinctly in TKI-resistant NSCLC and this may be due to changes in the physical properties of Cav1 favoring GLUT3 binding in which significantly stronger Cav1 and GLUT3 physical interactions were observed in TKI-resistant than in TKI-sensitive NSCLC cells. Further, the differential effects of atorvastatin observed between EGFR-TKI resistant and sensitive cells suggest that EGFR mutation status may influence its actions. Conclusions: This study reveals the inhibition of oncogenic role of Cav1 in GLUT3-mediated glucose uptake by statins and highlights its potential impact to overcome NSCLC with EGFR-TKI resistance.
Eyebrow involvement in frontal fibrosing alopecia: A clinicopathologic cohort study for the reversibility of hair loss
Authors: Alexander C. Katoulis, Vasileia Damaskou, Konstantina Diamanti, Abraham Pouliakis, Despina Mortaki, Andriani Zacharatou, Evangelia Bozi, Dimitrios Sgouros, Ioannis G. Panayiotides
Journal: Journal of the American Academy of Dermatology (2019)