tbuckley/cabot-search huggingface dataset:
Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival
Authors: Thomas A. Werfel, Shan Wang, Meredith A. Jackson, Taylor E. Kavanaugh, Meghan Morrison Joly, Linus H. Lee, Donna J. Hicks, Violeta Sanchez, Paula Gonzalez Ericsson, Kameron V. Kilchrist, Somtochukwu C. Dimobi, Samantha M. Sarett, Dana M. Brantley-Sieders, Rebecca S. Cook, Craig L. Duvall
Journal: Cancer Research (2018)

Small-molecule inhibitors of the mTORC2 kinase (torkinibs) have shown efficacy in early clinical trials. However, the torkinibs under study also inhibit the other mTOR-containing complex mTORC1. While mTORC1/mTORC2 combined inhibition may be beneficial in cancer cells, recent reports describe compensatory cell survival upon mTORC1 inhibition due to loss of negative feedback on PI3K, increased autophagy, and increased macropinocytosis. Genetic models suggest that selective mTORC2 inhibition would be effective in breast cancers, but the lack of selective small-molecule inhibitors of mTORC2 have precluded testing of this hypothesis to date. Here we report the engineering of a nanoparticle-based RNAi therapeutic that can effectively silence the mTORC2 obligate cofactor Rictor. Nanoparticle-based Rictor ablation in HER2-amplified breast tumors was achieved following intratumoral and intravenous delivery, decreasing Akt phosphorylation and increasing tumor cell killing. Selective mTORC2 inhibition in vivo, combined with the HER2 inhibitor lapatinib, decreased the growth of HER2-amplified breast cancers to a greater extent than either agent alone, suggesting that mTORC2 promotes lapatinib resistance, but is overcome by mTORC2 inhibition. Importantly, selective mTORC2 inhibition was effective in a triple-negative breast cancer (TNBC) model, decreasing Akt phosphorylation and tumor growth, consistent with our findings that RICTOR mRNA correlates with worse outcome in patients with basal-like TNBC. Together, our results offer preclinical validation of a novel RNAi delivery platform for therapeutic gene ablation in breast cancer, and they show that mTORC2-selective targeting is feasible and efficacious in this disease setting.Significance: This study describes a nanomedicine to effectively inhibit the growth regulatory kinase mTORC2 in a preclinical model of breast cancer, targeting an important pathogenic enzyme in that setting that has been undruggable to date. Cancer Res; 78(7); 1845-58. ©2018 AACR.
RELATIONSHIP BETWEEN MYOCARDIAL BRIDGING AND CHRONIC TOTAL OCCLUSIONS OF THE LEFT ANTERIOR DESCENDING CORONARY ARTERY ASSESSED BY COMBINED MULTIDETECTOR COMPUTED TOMOGRAPHY AND INTRAVASCULAR ULTRASOUND IMAGING
Authors: Myong Hwa Yamamoto, Akiko Maehara, Kohei Koyama, Gary Mintz, Masahiko Ochiai
Journal: Journal of the American College of Cardiology (2018)
Treatment-Free Remission After Second-Line Nilotinib Treatment in Patients With Chronic Myeloid Leukemia in Chronic Phase
Authors: François-Xavier Mahon, Carla Boquimpani, Dong-Wook Kim, Noam Benyamini, Nelma Cristina D. Clementino, Vasily Shuvaev, Sikander Ailawadhi, Jeffrey Howard Lipton, Anna G. Turkina, Raquel De Paz, Beatriz Moiraghi, Franck E. Nicolini, Jolanta Dengler, Tomasz Sacha, Naoto Takahashi, Rafik Fellague-Chebra, Sandip Acharya, Stephane Wong, Yu Jin, Timothy P. Hughes
Journal: Annals of Internal Medicine (2018)

Background: Treatment-free remission (TFR)—that is, stopping tyrosine kinase inhibitor (TKI) therapy without loss of response—is an emerging treatment goal in chronic myeloid leukemia (CML). Objective: To evaluate TFR after discontinuation of second-line nilotinib therapy. Design: Single-group, phase 2, open-label study. (ClinicalTrials.gov: NCT01698905) Setting: 63 centers in 18 countries. Patients: Adults with CML in chronic phase who received TKI therapy for at least 3 years (>4 weeks with imatinib, then ≥2 years with nilotinib) and achieved MR4.5 (BCR-ABL1 ≤0.0032% on the International Scale [BCR-ABL1 IS]) while receiving nilotinib entered a 1-year consolidation phase. Those with sustained MR4.5 during consolidation were eligible to enter TFR. Interventions: Patients received nilotinib during consolidation; those who entered TFR stopped treatment. Patients with loss of major molecular response (MMR) (BCR-ABL1 IS ≤0.1%) or confirmed loss of MR4 (BCR-ABL1 IS ≤0.01%) during TFR reinitiated nilotinib treatment. Measurements: Proportion of patients without loss of MMR, confirmed loss of MR4, or treatment reinitiation within 48 weeks of stopping treatment (primary end point). Results: 163 patients who had switched from imatinib to nilotinib (for reasons including resistance, intolerance, and physician preference) enrolled in the study and entered the consolidation phase. Of these patients, 126 met the criteria for entering the TFR phase, and 73 (58% [95% CI, 49% to 67%]) and 67 (53% [CI, 44% to 62%]) maintained TFR at 48 weeks (primary end point) and 96 weeks, respectively. Of the 56 patients who reinitiated nilotinib therapy, 55 regained MMR or better and 52 regained MR4.5. None had CML progression to accelerated phase or blast crisis. Musculoskeletal pain was more frequent during the first 48 weeks after nilotinib discontinuation. Limitation: The study included a heterogeneous patient population and was not designed to compare outcomes between patients continuing and those stopping treatment. Conclusion: TFR seems achievable in patients with sustained MR4.5 after switching to nilotinib. Primary Funding Source: Novartis Pharmaceuticals Corporation.
Immediate medical management on the field of play
Authors: Stan Baltsezak
Journal: BMJ (2012)

This two day course is run by the Rugby Football League and is for any medical professional who works for rugby league clubs and gives medical care during games. The usual participants are doctors and physiotherapists.

I did the course after I started covering rugby league games for one of the local clubs.

It is a requirement of the Rugby Football League that any doctor or physiotherapist who covers rugby league games should pass this course to be able to enter …
BTKCys481Ser drives ibrutinib resistance via ERK1/2 and protects BTKwild-type MYD88-mutated cells by a paracrine mechanism
Authors: Jiaji G. Chen, Xia Liu, Manit Munshi, Lian Xu, Nicholas Tsakmaklis, Maria G. Demos, Amanda Kofides, Maria Luisa Guerrera, Gloria G. Chan, Christopher J. Patterson, Kirsten Meid, Joshua Gustine, Toni Dubeau, Patricia Severns, Jorge J. Castillo, Zachary R. Hunter, Jinhua Wang, Sara J. Buhrlage, Nathanael S. Gray, Steven P. Treon, Guang Yang
Journal: Blood (2018)
Seven day service risks destruction of general practice, says RCGP chair
Authors: Matthew Limb
Journal: BMJ (2015)

The government’s plan for a seven day GP service risks the destruction of general practice, Maureen Baker, chair of council at the Royal College of General Practitioners, has said.

Baker said that GPs were already under “extraordinary strain” from rising numbers of consultations of increasing complexity, together with workforce shortages, falling resources, and “overburdensome” administration.

“Trying to meet demand for the services we already run is phenomenally difficult,” she said. “At the very point we should be putting general practice at the core of the NHS, taking time to innovate and building its strength, we’re risking the destruction of this hugely valued and valuable public service.”

Baker was speaking at a seminar on the future of seven day services in primary and secondary care settings, held by the Westminster Health Forum on 10 September. “We need 5000 more GPs promised in the new deal just to stop the …
Targeting Tumor Hypoxia Using Nanoparticle-engineered CXCR4-overexpressing Adipose-derived Stem Cells
Authors: Xinyi Jiang, Christine Wang, Sergio Fitch, Fan Yang
Journal: Theranostics (2018)

Hypoxia, a hallmark of malignant tumors, often correlates with increasing tumor aggressiveness and poor treatment outcomes.Due to a lack of vasculature, effective drug delivery to hypoxic tumor regions remains challenging.Signaling through the chemokine SDF-1α and its receptor CXCR4 plays a critical role in the homing of stem cells to ischemia for potential use as drug-delivery vehicles.To harness this mechanism for targeting tumor hypoxia, we developed polymeric nanoparticle-induced CXCR4-overexpressing human adipose-derived stem cells (hADSCs).Using glioblastoma multiforme (GBM) as a model tumor, we evaluated the ability of CXCR4-overexpressing hADSCs to target tumor hypoxia in vitro using a 2D migration assay and a 3D collagen hydrogel model.Compared to untransfected hADSCs, CXCR4-overexpressing hADSCs showed enhanced migration in response to hypoxia and penetrated the hypoxic core within tumor spheres.When injected in the contralateral brain in a mouse intracranial GBM xenograft, CXCR4-overexpressing hADSCs exhibited long-range migration toward GBM and preferentially penetrated the hypoxic tumor core.Intravenous injection also led to effective targeting of tumor hypoxia in a subcutaneous tumor model.Together, these results validate polymeric nanoparticle-induced CXCR4-overexpressing hADSCs as a potent cellular vehicle for targeting tumor hypoxia, which may be broadly useful for enhancing drug delivery to various cancer types.
CARDIOVASCULAR RISK ASSESSMENT SCORES FOR HISPANICS LIVING IN UNITED STATES: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Carlos Godoy, Haris Riaz, Eduardo Venegas, Samuel A. Urrutia, Eleazar A. Montalván, Laura Young, Marian Simonson, Haitham Ahmed
Journal: Journal of the American College of Cardiology (2018)
Revalidation isn’t centred on patients, claims report
Authors: Caroline White
Journal: BMJ (2012)

There is little evidence that the focus of revalidation is on patient care or that it will have a direct effect on the doctor-patient relationship, argues an independent report into the progress and process of the policy.1

The report, from the Peninsula College of Medicine and Dentistry at Plymouth University, comes just weeks before revalidation is expected to be given the green light by the government, for an official start date in December this year.

The new report draws on a review of …
The New HPV Vaccination Policy in France
Authors: Hervé Lefèvre, M Rose Moro, Jonathan Lachal
Journal: New England Journal of Medicine (2018)

Low Rates of HPV Vaccination in France Although 11 vaccines are mandatory in France, human papillomavirus vaccination is recommended but not required. Because of a high level of skepticism about vaccine efficacy in France, only 19% of 16-year-old girls were vaccinated against HPV in 2016.
HER-2 overexpression in gastroesophageal junction (EGJ) adenocarcinoma as a predictor of prognosis in patients treated with perioperative chemotherapy.
Authors: Tiago Felismino, Audrey Oliveira, Ana Caroline Alves, Victor Hugo Fonseca Jesus, Wilson L. Costa, Felipe José Fernandez Coimbra, Milton Jose De Barros E. Silva, Rachel Pimenta Riechelmann, Maria Dirlei Begnami, Newton Augusto Ferreira Rodrigues, Celso Lopes Mello
Journal: Journal of Clinical Oncology (2018)

151 Background: Approximately 15% of all gastroesophageal adenocarcinomas overexpress HER-2. This is more common in intestinal subtype and proximal tumors. HER-2 status is associated with poor prognosis in non-metastatic patients, but its prognostic impact on the outcomes of pts treated with perioperative chemotherapy (CT) is unclear. Methods: The aim of this study was to retrospectively analyze the influence of HER-2 status on the overall survival (OS) and Relapse Free Survival (RFS) of pts with locally advanced gastroesophageal adenocarcinoma treated with perioperative CT. HER-2 positive tumors were defined by 3+ immunohistochemical staining or fluorescence in situ hybridization positivity. Independent variables used in the Cox model were: Lauren's subtype, clinical staging, and a combination of primary site and HER-2 status. Results: A total of 97 patients were included: median age was 62y, 62 (63.9%) were male; N = 57 (58.8%) had cT3 tumors and 60 (60.1%) had cN+. Lauren’s subtype was intestinal in N = 35 (36.1%), and diffuse in N = 44 (45.4%). CT regimens were mainly FOLFOX (46.4%), EOX (23.7%) or DCF (13.4%). Regarding primary site and HER-2 status: gastric HER-2 negative N = 61, Gastric HER-2 positive N = 8, GEJ HER-2 negative N = 23, GEJ HER-2 positive N = 5. In a Cox multivariate analyses for OS and RFS, EGJ HER-2 positive pts had higher chance of recurrence (HR = 3.57, 1.08 – 11.77, p = 0.03) and death (HR = 6.14, 1.83 – 20.60, p = 0.003). EGJ HER-2+ 3y RFS was zero and 3y OS was 20%. Conclusions: EGJ HER-2+ tumors carried a dismal prognosis and had little benefit from conventional perioperative CT strategies. Although further studies are needed to confirm our data, we believe that a different approach, possible combining anti-HER-2 drugs, should be tested in this scenario.
AMP-activated Protein Kinase Phosphorylation of Angiotensin-Converting Enzyme 2 in Endothelium Mitigates Pulmonary Hypertension
Authors: Jiao Zhang, Jianjie Dong, Marcy Martin, Ming He, Brendan Gongol, Traci L. Marin, Lili Chen, Xinxing Shi, Yanjun Yin, Fenqing Shang, Yan Wu, Hsi-Yuan Huang, Jin Zhang, Yu Zhang, Jian Kang, Esteban A. Moya, Hsien-Da Huang, Frank L. Powell, Zhen Chen, Patricia A. Thistlethwaite, Zu-Yi Yuan, John Y.-J. Shyy
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Endothelial dysfunction plays an integral role in pulmonary hypertension (PH). AMPK (AMP-activated protein kinase) and ACE2 (angiotensin-converting enzyme 2) are crucial in endothelial homeostasis. The mechanism by which AMPK regulates ACE2 in the pulmonary endothelium and its protective role in PH remain elusive.We investigated the role of AMPK phosphorylation of ACE2 Ser680 in ACE2 stability and deciphered the functional consequences of this post-translational modification of ACE2 in endothelial homeostasis and PH.Bioinformatics prediction, kinase assay, and antibody against phospho-ACE2 Ser680 (p-ACE2 S680) were used to investigate AMPK phosphorylation of ACE2 Ser680 in endothelial cells. Using CRISPR-Cas9 genomic editing, we created gain-of-function ACE2 S680D knock-in and loss-of-function ACE2 knockout (ACE2-/-) mouse lines to address the involvement of p-ACE2 S680 and ACE2 in PH. The AMPK-p-ACE2 S680 axis was also validated in lung tissue from humans with idiopathic pulmonary arterial hypertension.Phosphorylation of ACE2 by AMPK enhanced the stability of ACE2, which increased Ang (angiotensin) 1-7 and endothelial nitric oxide synthase-derived NO bioavailability. ACE2 S680D knock-in mice were resistant to PH as compared with wild-type littermates. In contrast, ACE2-knockout mice exacerbated PH, a similar phenotype found in mice with endothelial cell-specific deletion of AMPKα2. Consistently, the concentrations of phosphorylated AMPK, p-ACE2 S680, and ACE2 were decreased in human lungs with idiopathic pulmonary arterial hypertension.Impaired phosphorylation of ACE2 Ser680 by AMPK in pulmonary endothelium leads to a labile ACE2 and hence is associated with the pathogenesis of PH. Thus, AMPK regulation of the vasoprotective ACE2 is a potential target for PH treatment.
Pregnancy Outcomes after ZIKV Infection in French Territories in the Americas
Authors: Bruno Hoen, Bruno Schaub, Anna L. Funk, Vanessa Ardillon, Manon Boullard, André Cabié, Caroline Callier, Gabriel Carles, Sylvie Cassadou, Raymond Césaire, Maylis Douine, Cécile Herrmann-Storck, Philippe Kadhel, Cédric Laouénan, Yoann Madec, Alice Monthieux, Mathieu Nacher, Fatiha Najioullah, Dominique Rousset, Catherine Ryan, Kinda Schepers, Sofia Stegmann-Planchard, Benoît Tressières, Jean-Luc Voluménie, Samson Yassinguezo, Eustase Janky, Arnaud Fontanet
Journal: New England Journal of Medicine (2018)

The risk of congenital neurologic defects related to Zika virus (ZIKV) infection has ranged from 6 to 42% in various reports. The aim of this study was to estimate this risk among pregnant women with symptomatic ZIKV infection in French territories in the Americas.From March 2016 through November 2016, we enrolled in this prospective cohort study pregnant women with symptomatic ZIKV infection that was confirmed by polymerase-chain-reaction (PCR) assay. The analysis included all data collected up to April 27, 2017, the date of the last delivery in the cohort.Among the 555 fetuses and infants in the 546 pregnancies included in the analysis, 28 (5.0%) were not carried to term or were stillborn, and 527 were born alive. Neurologic and ocular defects possibly associated with ZIKV infection were seen in 39 fetuses and infants (7.0%; 95% confidence interval, 5.0 to 9.5); of these, 10 were not carried to term because of termination of pregnancy for medical reasons, 1 was stillborn, and 28 were live-born. Microcephaly (defined as head circumference more than 2 SD below the mean for sex and gestational age) was detected in 32 fetuses and infants (5.8%), of whom 9 (1.6%) had severe microcephaly (more than 3 SD below the mean). Neurologic and ocular defects were more common when ZIKV infection occurred during the first trimester (24 of 189 fetuses and infants [12.7%]) than when it occurred during the second trimester (9 of 252 [3.6%]) or third trimester (6 of 114 [5.3%]) (P=0.001).Among pregnant women with symptomatic, PCR-confirmed ZIKV infection, birth defects possibly associated with ZIKV infection were present in 7% of fetuses and infants. Defects occurred more frequently in fetuses and infants whose mothers had been infected early in pregnancy. Longer-term follow-up of infants is required to assess any manifestations not detected at birth. (Funded by the French Ministry of Health and others; ClinicalTrials.gov number, NCT02916732 .).
Abstract P3-10-13: Bilateral breast cancer in China: A 10-year single-center retrospective study
Authors: H Li, H Jiang, R Zhang, B Shao, Y Yan, R Ran, L Di
Journal: Cancer Research (2018)

Abstract BACKGROUD: Women with unilateral breast cancer are at increased risk for developing contralateral disease. The objective of the single-center retrospective study was to evaluate the incidence of bilateral breast cancer (BBC) and to analyze the clinicopathological characteristics for BBC in China. METHODS: We retrospectively reviewed the electronic medical records of 3924 female patients with breast cancer consecutively treated at the department of Breast Oncology in the Peking University Cancer Hospital between 2006 and 2016. BBC was categorized as synchronous (within 6 months) or metachronous bilateral breast cancer (after 6 months of a first tumor). Patients with BBC were identified according to the criteria described by Chaudary et al. Patients with stage IV first breast cancer, and those who were found to have distant metastases between the first and second primary breast cancer were excluded. Analyses of demographic, clinicopathologic, and treatment characteristics were done between sBBC and mBBC. RESULTS: The incidence of BBC in our population was 3.2% (127 of 3924). Of those, 2.5 % ( 99 of 3924) were metachronous bilateral breast cancer ( mBBC ), and 0.71 % (28 of 3924) were synchronous bilateral breast cancer ( sBBC ). The overall median age of the patients at first diagnosis was 45 years (range, 27-81 years). The age of onset of the first mBBC was significantly younger than that of sBBC ( p = 0.027). In mBBC subgroups, the median time interval between first and second tumors was 68 months (range, 7-342 months), and 80.8% of the second tumor were diagnosed within 10 years of the diagnosis of the first tumor. A positive family history of breast cancer was found in 25% of sBBC and 9.1% of mBBC ( p = 0.025). In ER-negative first tumor of mBBC, 56.1% of the second tumor were ER-positive. Mastectomy was the commonest surgery performed in these patients. CONCLUSIONS: Our results confirmed the necessity of screening contralateral breast at the diagnosis of unilateral breast cancer and following-up for Chinese patients with breast cancer. Citation Format: Li H, Jiang H, Zhang R, Shao B, Yan Y, Ran R, Di L. Bilateral breast cancer in China: A 10-year single-center retrospective study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-13.
BMA agrees Scotland only GP contract
Authors: Helen Jaques
Journal: BMJ (2012)

The BMA’s Scottish General Practitioners Committee and the Scottish government have agreed a country specific general medical services (GMS) contract for 2013-14 that excludes some of the changes proposed by the UK government.

The association and the Scottish government began talks on alternative country specific arrangements last month after the UK government put the brakes on negotiations and sought to impose changes to the …
Clonotypic T-cell responses in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with standard sipuleucel-T (sip-T) compared with patients receiving a booster treatment.
Authors: Li Zhang, Harini Kandadi, Alan T Paciorek, Tao He, Nadeem Anwar Sheikh, Lawrence Fong
Journal: Journal of Clinical Oncology (2018)

107 Background: Sip-T is an FDA-approved autologous cellular immunotherapy for asymptomatic or minimally symptomatic mCRPC. Neoadjuvant sip-T induced activated T-cell infiltration to the prostate tissue (Fong 2014) and broadened the T cell receptor (TCR) repertoire vs control (Sheikh 2016). To test if sip-T induces memory T-cell responses, we compared treatment-induced changes in TCR repertoire of treatment-naïve pts (STRIDE) with those retreated with sip-T (P10-1). Methods: In STRIDE (N=52), pts received sip-T with concurrent or sequential enzalutamide (Petrylak 2015). In P10-1 (N=8), pts previously treated with sip-T in an androgen-dependent setting were retreated with a booster course after a median of 8.6 years (Beer 2013). PBMCs were collected at baseline and during/post–sip-T. Deep sequencing was performed using the ImmunoSEQ assay (Adaptive Biotechnologies). TCR diversity was assessed by Shannon diversity index and clonality. TCR dynamics was evaluated by Morisita’s distance (Zhang 2017). Results: Baseline TCR diversity was similar between the two trials (p=0.590, Shannon diversity index; p=0.700, clonality). Significant decreases in clonality were observed from baseline to wk 4 (p&lt;0.001) and wk 6 (p=0.030) in STRIDE, but not in P10-1, indicating more expansion of T cell clones in STRIDE. Morisita’s distance was significantly higher at wk 2 (p=0.040) and 26 (p=0.013) in STRIDE vs P10-1, indicating a more consistent TCR repertoire in STRIDE across timepoints. The proportion of the clones enriched after sip-T treatment was significantly higher in P10-1 vs STRIDE (wk 6: p=0.007, wk 26: p=0.015, wk 52: p=0.026). The extent of change within the top 100 most abundant TCR sequences (clonal shuffling) was greater and initiated earlier in P10-1 vs STRIDE. Conclusions: Initial sip-T treatment of naïve mCRPC pts programs the TCR repertoire, which is maintained over time. Consistent with immunologic memory, retreatment with sip-T rapidly expands the number of enriched T-cell clones persisting up to 1 year after retreatment, which is characteristic of immunological boosting following successful treatment.