tbuckley/cabot-search huggingface dataset:
Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives as potent HIV-1 NNRTIs
Authors: Dongwei Kang, Da Feng, Tiziana Ginex, Jinmi Zou, Fenju Wei, Tong Zhao, Boshi Huang, Yanying Sun, Samuel Desta, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
Journal: Acta Pharmaceutica Sinica B (2019)

In this report, a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead K-5a2. The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT). Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations. Especially, compound 26 exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC50 ranging from 6.02 to 23.9 nmol/L, which were comparable to those of etravirine (ETR). Moreover, the RT inhibition activity, preliminary structure-activity relationship and molecular docking were also investigated. Furthermore, 26 exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8%. Taken together, the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection.
Randomized Phase II Study of R-CHOP-14 Versus R-CHOP-14 Followed By Chaser As Induction Therapy for High-Dose Chemotherapy (HDT), LEED, and Autologous Stem-Cell Transplantation (ASCT) in Poor-Risk Diffuse Large B-Cell Lymphoma (DLBCL): Japan Clinical Oncology Group (JCOG) Study (JCOG0908)
Authors: Yoshitoyo Kagami, Kazuhito Yamamoto, Taro Shibata, Kensei Tobinai, Yoshitaka Imaizumi, Toshiki Uchida, Kazuyuki Shimada, Koichiro Minauchi, Noriko Fukuhara, Hirofumi Kobayashi, Nobuhiko Yamauchi, Hideki Tsujimura, Akira Hangaishi, Ryo Tominaga, Youko Suehiro, Shinichiro Yoshida, Yoshiko Inoue, Sachiko Suzuki, Michihide Tokuhira, Hirokazu Nagai, Shigeru Kusumoto, Junya Kuroda, Yoshihiro Yakushijin, Yasushi Takamatsu, Yasushi Kubota, Kisato Nosaka, Satoko Morishima, Shigeo Nakamura, Dai Maruyama, Tomomitsu Hotta, Yasuo Morishima, Kunihiro Tsukasaki
Journal: Blood (2017)
Effective chemoimmunotherapy by co-delivery of doxorubicin and immune adjuvants in biodegradable nanoparticles
Authors: Candido G. Da Silva, Marcel G.M. Camps, Tracy M.W.Y. Li, Luana Zerrillo, Clemens W. Löwik, Ferry Ossendorp, Luis J. Cruz
Journal: Theranostics (2019)

Chemoimmunotherapy is an emerging combinatorial modality for the treatment of cancers resistant to common first-line therapies, such as chemotherapy and checkpoint blockade immunotherapy. We used biodegradable nanoparticles as delivery vehicles for local, slow and sustained release of doxorubicin, two immune adjuvants and one chemokine for the treatment of resistant solid tumors. Methods: Bio-compatible poly(lactic-co-glycolic acid)-PEG nanoparticles were synthesized in an oil/water emulsion, using a solvent evaporation-extraction method. The nanoparticles were loaded with a NIR-dye for theranostic purposes, doxorubicin cytostatic agent, poly (I:C) and R848 immune adjuvants and CCL20 chemokine. After physicochemical and in vitro characterization the nanoparticles therapeutic efficacy were carried-out on established, highly aggressive and treatment resistant TC-1 lung carcinoma and MC-38 colon adenocarcinoma models in vivo. Results: The yielded nanoparticles average size was 180 nm and -14 mV surface charge. The combined treatment with all compounds was significantly superior than separate compounds and the compounds nanoparticle encapsulation was required for effective tumor control in vivo. The mechanistic studies confirmed strong induction of circulating cancer specific T cells upon combined treatment in blood. Analysis of the tumor microenvironment revealed a significant increase of infiltrating leukocytes upon treatment. Conclusion: The multi-drug loaded nanoparticles mediated delivery of chemoimmunotherapy exhibited excellent therapeutic efficacy gain on two treatment resistant cancer models and is a potent candidate strategy to improve cancer therapy of solid tumors resistant to first-line therapies.
The efficacy of app‐supported smartphone interventions for mental health problems: a meta‐analysis of randomized controlled trials
Authors: Jake Linardon, Pim Cuijpers, Per Carlbring, Mariel Messer, Matthew Fuller‐Tyszkiewicz
Journal: World Psychiatry (2019)

Although impressive progress has been made toward developing empirically‐supported psychological treatments, the reality remains that a significant proportion of people with mental health problems do not receive these treatments. Finding ways to reduce this treatment gap is crucial. Since app‐supported smartphone interventions are touted as a possible solution, access to up‐to‐date guidance around the evidence base and clinical utility of these interventions is needed. We conducted a meta‐analysis of 66 randomized controlled trials of app‐supported smartphone interventions for mental health problems. Smartphone interventions significantly outperformed control conditions in improving depressive (g=0.28, n=54) and generalized anxiety (g=0.30, n=39) symptoms, stress levels (g=0.35, n=27), quality of life (g=0.35, n=43), general psychiatric distress (g=0.40, n=12), social anxiety symptoms (g=0.58, n=6), and positive affect (g=0.44, n=6), with most effects being robust even after adjusting for various possible biasing factors (type of control condition, risk of bias rating). Smartphone interventions conferred no significant benefit over control conditions on panic symptoms (g=–0.05, n=3), post‐traumatic stress symptoms (g=0.18, n=4), and negative affect (g=–0.08, n=5). Studies that delivered a cognitive behavior therapy (CBT)‐based app and offered professional guidance and reminders to engage produced larger effects on multiple outcomes. Smartphone interventions did not differ significantly from active interventions (face‐to‐face, computerized treatment), although the number of studies was low (n≤13). The efficacy of app‐supported smartphone interventions for common mental health problems was thus confirmed. Although mental health apps are not intended to replace professional clinical services, the present findings highlight the potential of apps to serve as a cost‐effective, easily accessible, and low intensity intervention for those who cannot receive standard psychological treatment.
The REDUCE FMR Trial
Authors: Klaus K. Witte, Janusz Lipiecki, Tomasz Siminiak, Ian T. Meredith, Christopher J. Malkin, Steven L. Goldberg, Matthew A. Stark, Ralph Stephan von Bardeleben, Paul C. Cremer, Wael A. Jaber, David S. Celermajer, David M. Kaye, Horst Sievert
Journal: JACC Heart Failure (2019)

This study sought to evaluate the effects of the Carillon device on mitral regurgitation severity and left ventricular remodeling. Functional mitral regurgitation (FMR) complicates heart failure with reduced ejection fraction and is associated with a poor prognosis. In this blinded, randomized, proof-of-concept, sham-controlled trial, 120 patients receiving optimal heart failure medical therapy were assigned to a coronary sinus-based mitral annular reduction approach for FMR or sham. The pre-specified primary endpoint was change in mitral regurgitant volume at 12 months, measured by quantitative echocardiography according to an intention-to-treat analysis. Patients (69.8 ± 9.5 years of age) were randomized to either the treatment (n = 87) or the sham-controlled (n = 33) arm. There were no significant differences in baseline characteristics between the groups. In the treatment group, 73 of 87 (84%) had the device implanted. The primary endpoint was met, with a statistically significant reduction in mitral regurgitant volume in the treatment group compared to the control group (decrease of 7.1 ml/beat [95% confidence interval [CI]: −11.7 to −2.5] vs. an increase of 3.3 ml/beat [95% CI: −6.0 to 12.6], respectively; p = 0.049). Additionally, there was a significant reduction in left ventricular volumes in patients receiving the device versus those in the control group (left ventricular end-diastolic volume decrease of 10.4 ml [95% CI: −18.5 to −2.4] vs. an increase of 6.5 ml [95% CI: −5.1 to 18.2]; p = 0.03 and left ventricular end-systolic volume decrease of 6.2 ml [95% CI: −12.8 to 0.4] vs. an increase of 6.1 ml [95% CI: −1.42 to 13.6]; p = 0.04). The Carillon device significantly reduced mitral regurgitant volume and left ventricular volumes in symptomatic patients with functional mitral regurgitation receiving optimal medical therapy. (Carillon Mitral Contour System for Reducing Functional Mitral Regurgitation [REDUCE FMR]; NCT02325830)
Noninvasive Detection of Microsatellite Instability and High Tumor Mutation Burden in Cancer Patients Treated with PD-1 Blockade
Authors: Andrew Georgiadis, Jennifer N. Durham, Laurel A. Keefer, Bjarne R. Bartlett, Magdalena Zielonka, Derek Murphy, James R. White, Steve Lu, Ellen L. Verner, Finey Ruan, David Riley, Robert A. Anders, Erika Gedvilaite, Sam Angiuoli, Siân Jones, Victor E. Velculescu, Dung T. Le, Luis A. Diaz, Mark Sausen
Journal: Clinical Cancer Research (2019)

Microsatellite instability (MSI) and high tumor mutation burden (TMB-High) are promising pan-tumor biomarkers used to select patients for treatment with immune checkpoint blockade; however, real-time sequencing of unresectable or metastatic solid tumors is often challenging. We report a noninvasive approach for detection of MSI and TMB-High in the circulation of patients.We developed an approach that utilized a hybrid-capture-based 98-kb pan-cancer gene panel, including targeted microsatellite regions. A multifactorial error correction method and a novel peak-finding algorithm were established to identify rare MSI frameshift alleles in cell-free DNA (cfDNA).Through analysis of cfDNA derived from a combination of healthy donors and patients with metastatic cancer, the error correction and peak-finding approaches produced a specificity of >99% (n = 163) and sensitivities of 78% (n = 23) and 67% (n = 15), respectively, for MSI and TMB-High. For patients treated with PD-1 blockade, we demonstrated that MSI and TMB-High in pretreatment plasma predicted progression-free survival (hazard ratios: 0.21 and 0.23, P = 0.001 and 0.003, respectively). In addition, we analyzed cfDNA from longitudinally collected plasma samples obtained during therapy to identify patients who achieved durable response to PD-1 blockade.These analyses demonstrate the feasibility of noninvasive pan-cancer screening and monitoring of patients who exhibit MSI or TMB-High and have a high likelihood of responding to immune checkpoint blockade.See related commentary by Wang and Ajani, p. 6887.
<i>Dermatologic Reactions to Cancer Therapies</i> (Series in Dermatological Treatment), 1st edn. GabriellaFabbrocini, MarioLacouture, AntonellaTosti, eds. Boca Raton, FL: CRC Press, 2019; 173 pp. ISBN: 978‐1‐138‐03553‐9. Price: £74.99.
Authors: T.N. Basu
Journal: British Journal of Dermatology (2019)
Prognostic outcome of gastric cancer patients with cancer stem cell SNPs in Asian versus western countries.
Authors: Melissa Janae Labonte, Takeru Wakatsuki, Wu Zhang, Dongyun Yang, Mizutomo Azuma, Armin Gerger, Michael Stotz, Yan Ning, Nico Benjamin Volz, Sebastian Stintzing, Joseph Ethan Li, Rita Elie El-Khoueiry, Peter M. D. Wilson, Wasaburo Koizumi, Masahiko Watanabe, Martin K. H. Maus, Afsaneh Barzi, Syma Iqbal, Anthony B. El-Khoueiry, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2013)

4110 Background: The clinical significance of cancer stem cells (CSC) has been well established; however, its prognostic role remains controversial. CD44 is recognized as a CSC marker in gastric cancer (GC) and, recently, the clinical impact of CD166 in GC was reported. Our group previously reported SNPs of CD44 and CD166 are associated with outcome in US patients (pts) with adjuvant GC and colorectal cancer, respectively. Since GC has regional differences in epidemiology and clinicopathology, we hypothesized that ethnicity and regional differences in GC could influence the prognostic role of CD44 and CD166. Methods: A total of 369 pts with histopathologically-confirmed localized (stage Ib to IV; AJCC-6 th ) GC were enrolled from Japan (n=169), the US (n=137), and Austria (n=63) between 2002 and 2010. CD44 rs187116 G&gt;A and CD166 rs1157 G&gt;A were analyzed. Genomic DNA was extracted from blood or tissue, and all samples were analyzed by PCR-based direct DNA-sequencing. Results: Pts homozygous for A/A CD44rs187116 (n=20) showed a median OS of 2.0 yrs vs not reached for patients harboring at least one-G allele (n=144) (HR: 2.87 [95%CI: 1.61-5.13], p&lt;0.001) in Japanese cohort, while pts homozygous A/A (n=30) showed a median OS of 7.3 yrs vs 4.1 yrs for pts harboring at least one-G allele (n=94) (HR: 2.0 [95%CI: 0.90-4.55], p=0.079) in the US cohort. There were no significant differences in Austrian cohort alone or in combination with US cohort. In CD166 rs1157, pts harboring at least one-A allele (n=27) showed a median OS of 3.9 yrs vs not reached for pts homozygous G/G (n=142) (HR: 1.81 [95%CI: 1.05-3.12], p=0.033) in Japanese cohort., Although there were no significant differences in the US or Austrian cohort when analyzed separately, combining cohorts demonstrated that pts homozygous A/A (n=12) showed a median OS of not reached yrs vs 4.7 yrs for pts harboring at least one-G allele (n=179) (HR: 5.00 [95%CI: 0.70-35.95], p=0.073). Conclusions: SNP profiles in CSC markers predicted opposite prognostic outcomes in patients with GC among Asian and Western countries. This is the first report suggesting that the prognostic role of CSC markers in GC may differ based on ethnic groups or etiology differences.
VSTM2A suppresses colorectal cancer and antagonizes Wnt signaling receptor LRP6
Authors: Yujuan Dong, Yanquan Zhang, Wei Kang, Guoping Wang, Huarong Chen, Akira Higashimori, Geicho Nakatsu, Minnie Go, Joanna Hm Tong, Shu Zheng, Ka Fai To, Joseph Jy Sung, Xiaoyong Yang, Simon Sm Ng, Jun Yu
Journal: Theranostics (2019)

Hyperactivation of Wnt/β-catenin signaling pathway is a critical step in colorectal tumorigenesis. In this study, we identified that V-set and transmembrane domain containing 2A (VSTM2A) was a top-downregulated secreted protein that negatively regulated Wnt singling pathways in colorectal cancer (CRC). We investigated the functional mechanisms and clinical implication of VSTM2A in CRC. Methods: Function of VSTM2A was investigated in vitro and in vivo. VSTM2A binding partner was identified by mass spectrometry, immunoprecipitation and Western blot. The clinical impact of VSTM2A was assessed in 355 CRC patients and TCGA cohort. Results: VSTM2A protein was prominently silenced in CRC tumor tissues and cell lines mediated by its promoter hypermethylation. VSTM2A DNA promoter hypermethylation and VSTM2A protein downregulation was associated with poor survival of CRC patients. Ectopic expression of VSTM2A inhibited colon cancer cell lines and organoid growth, induced CRC cells apoptosis, inhibited cell migration and invasion, and suppressed growth of xenograft tumors in nude mice. VSTM2A was released from CRC cells through a canonical secretion pathway. Secreted VSTM2A significantly suppressed Wnt signaling pathway in colon cancer cells. Wnt signaling co-receptor LDL receptor related protein 6 (LRP6) was identified as a cell membrane binding partner of VSTM2A. Using deletion/mutation and immunoprecipitation, we demonstrated that VSTM2A bound to LRP6 E1-4 domain with its IgV domain. VSTM2A suppressed LRP6 phosphorylation in a time and dose dependent manner, and induced LRP6 endocytosis and lysosome-mediated degradation, which collectively contributing to the inactivation of Wnt signaling. Conclusions: VSTM2A is a novel antagonist of canonical Wnt signaling by directly binding to LRP6 and induces LRP6 endocytosis and degradation. VSTM2A is a potential prognostic biomarker for the outcome of CRC patients.
Trends in incidence of total or type 2 diabetes: systematic review
Authors: Dianna J Magliano, Rakibul M Islam, Elizabeth L M Barr, Edward W Gregg, Meda E Pavkov, Jessica L Harding, Maryam Tabesh, Digsu N Koye, Jonathan E Shaw
Journal: BMJ (2019)

Abstract Objective To assess what proportions of studies reported increasing, stable, or declining trends in the incidence of diagnosed diabetes. Design Systematic review of studies reporting trends of diabetes incidence in adults from 1980 to 2017 according to PRISMA guidelines. Data sources Medline, Embase, CINAHL, and reference lists of relevant publications. Eligibility criteria Studies of open population based cohorts, diabetes registries, and administrative and health insurance databases on secular trends in the incidence of total diabetes or type 2 diabetes in adults were included. Poisson regression was used to model data by age group and year. Results Among the 22 833 screened abstracts, 47 studies were included, providing data on 121 separate sex specific or ethnicity specific populations; 42 (89%) of the included studies reported on diagnosed diabetes. In 1960-89, 36% (8/22) of the populations studied had increasing trends in incidence of diabetes, 55% (12/22) had stable trends, and 9% (2/22) had decreasing trends. In 1990-2005, diabetes incidence increased in 66% (33/50) of populations, was stable in 32% (16/50), and decreased in 2% (1/50). In 2006-14, increasing trends were reported in only 33% (11/33) of populations, whereas 30% (10/33) and 36% (12/33) had stable or declining incidence, respectively. Conclusions The incidence of clinically diagnosed diabetes has continued to rise in only a minority of populations studied since 2006, with over a third of populations having a fall in incidence in this time period. Preventive strategies could have contributed to the fall in diabetes incidence in recent years. Data are limited in low and middle income countries, where trends in diabetes incidence could be different. Systematic review registration Prospero CRD42018092287.
Don’t charge migrants for maternity care, say midwives
Authors: Jacqui Wise
Journal: BMJ (2019)

Midwives have called on the government to end the policy of charging some migrants for maternity care, saying it undermines trust and creates a climate of fear among vulnerable pregnant women.

A report by Maternity Action, backed by the Royal College of Midwives, says some women were seeking maternity care late in pregnancy, missing tests and treatments, or completely avoiding antenatal care for fear of charges and Home Office sanctions.1

The report says that the current NHS charging policy is especially damaging for undocumented migrant women, many of whom are economically marginalised and vulnerable. Charges for standard maternity care for overseas pregnant women start at £7000 (€7830; $8655).

“Midwives should not act as gatekeepers to maternity services,” said Gill Walton, chief executive and general secretary of the Royal College of Midwives. “Women affected by these …
Medical Marijuana Miscalculation
Authors: Anita Mudan, Francis DeRoos, Jeanmarie Perrone
Journal: New England Journal of Medicine (2019)

Marijuana MiscalculationTo the Editor: Pennsylvania legalized medical marijuana in 2016, and since then its use has skyrocketed. 1 The doses of the active ingredients of marijuana -tetrahydrocannabinol (THC) and cannabidiol (CBD) -are not standardized, product concentrations are not regulated, and prescribing practices vary.A 52-year-old man with an anaplastic astrocytoma, which was treated with radiation therapy, temozolomide, and bevacizumab, presented to the emergency department with acute delirium.His wife reported progressive restlessness and garbled speech over a period of 2 days.On examination, the blood pressure was 150/80 mm Hg, and the heart rate was 87 beats per minute.He was awake but unable to answer questions, intermittently redirectable, and in a state of hyperactive delirium.The oral mucosa was dry, the pupils were 3 mm in diameter and reactive, and the neurologic examination was nonfocal.Laboratory evaluation revealed normal electrolyte
A mass on the shin
Authors: Stamatis Gregoriou, Anastasia I Petra, George Kontochristopoulos
Journal: BMJ (2019)

A 55 year old white woman presented with a mass on her shin. It had been present for six months and had an exophytic growth pattern. She reported a history of psoriasis for the past 13 years, for which she had received ciclosporin, a T-lymphocyte immunosuppressant, intermittently for the first 12 years (3 mg/kg for six months each year), and secukinumab, a human monoclonal antibody against interleukin 17A (IL-17A) (300 mg every four weeks), for the past 12 months. She did not report increased sun exposure or use of a tanning bed.

Physical examination revealed a 5×4 cm growth, sparsely scattered with micro-haemorrhages and crusts (fig 1). Popliteal and …
EGFRv3 and PTEN as prognostic markers in head and neck squamous cell carcinoma patients treated with cetuximab.
Authors: Alexandre Andre Balieiro Anastacio da Costa, Adriana Regina G. Ribeiro, Andrea Paiva Guimaraes, Ludmilla Thome Chinen, Clovis Pinto, Vladmir C. Lima
Journal: Journal of Clinical Oncology (2013)

e17032 Background: Cetuximab (CTx) is used in treatment of locally advanced (LAD) head and neck squamous cell carcinoma (HNSCC) in combination with radiotherapy (RT) or in metastatic disease (MD). There is no comparison between CTx plus RT and cisplatin plus RT. Patients treated with CTx in daily clinical practice are frequently different from the selected population treated in clinical trials. There are no biomarkers for efficacy of CTx in HNSCC. EGFR variant 3 mutation (EGFRv3), an extracellular domain mutation of EGFR, has been reported in different frequencies in HNSCC in the last years and its association with prognosis and CTx efficacy is still unknown. Methods: Retrospective review of data from patients with HNSCC treated with CTx at a single institution from 2007 to 2010. We evaluated CTx efficacy and expression of EGFRv3, EGFR, PTEN, CD44 and CD44v6 and their impact in objective response rate (ORR), progression free survival (PFS) and overall survival (OS). Biomarkers were analyzed by immunohistochemistry in tissue microarray. Results: For a median follow-up time of 13 months, 61 patients with LAD treated with RT plus CTx had a median OS of 22.7 months, and a median PFS of 8.0 months. Age adjusted Charlson Comorbidity Index (AA-CCI) and ECOG performance status were the most important predictors of poor prognosis in this population. For a median follow-up time of 10.9 months, 44 patients with MD had a median OS of 13.0 months and a median PFS of 7.0 months, for an ORR of 53.7%. EGFRv3 was expressed in 27.1% of tumor samples and was not associated with any clinical outcome. EGFR positivity was associated to higher ORR in LAD and PTEN negativity was associated with shorter OS in the MD setting. Conclusions: In a non selected population with LAD treatment results with CTx in combination with radiotherapy were worse than expected by the phase III study, median OS 22.7 months vs 49.0 months. This difference may be attributed to different population characteristics with higher ECOG and AA-CCI in our study and warrants an adequate proof of efficacy of CTx in this population. EGFRv3 is present in HNSCC but does not impact prognosis. PTEN and EGFR expression emerged as potential biomarkers in HNSCC patients treated with CTx.