tbuckley/cabot-search huggingface dataset:
Atypical response with bone pseudoprogression in a patient receiving nivolumab for advanced cutaneous squamous cell carcinoma
Authors: Leandro J. C. Oliveira, Aline B. L. Gongora, Felipe G. Barbosa, Carlos H. dos Anjos, Rodrigo R. Munhoz
Journal: Journal for ImmunoTherapy of Cancer (2018)

Currently, there is no established standard of care for patients with metastatic CSCC. Based on the mechanisms of CSCC carcinogenesis has been postulated that these tumors may be amenable to PD-1/PD-L1 blockade.This case illustrates a patient with CSCC with nodal involvement and pulmonary metastases, refractory to two lines of platinum-based regimens and salvage surgery, for whom treatment with nivolumab was recommended. His clinical course was marked by an atypical pattern of response, with initial reduction of soft tissue/visceral lesions, yet development of new bone findings, followed by overall improvement in subsequent scans and sustained disease control upon treatment continuation.The case of patient with metastatic CSCC, refractory, received immunotherapy and evolved with atypical pattern of response.
Targeting Sirt-1 controls GVHD by inhibiting T-cell allo-response and promoting Treg stability in mice
Authors: Anusara Daenthanasanmak, Supinya Iamsawat, Paramita Chakraborty, Hung D. Nguyen, David Bastian, Chen Liu, Shikhar Mehrotra, Xue-Zhong Yu
Journal: Blood (2018)
Understanding tumor ecosystems by single-cell sequencing: promises and limitations
Authors: Xianwen Ren, Boxi Kang, Zemin Zhang
Journal: Genome biology (2018)

Cellular heterogeneity within and across tumors has been a major obstacle in understanding and treating cancer, and the complex heterogeneity is masked if bulk tumor tissues are used for analysis. The advent of rapidly developing single-cell sequencing technologies, which include methods related to single-cell genome, epigenome, transcriptome, and multi-omics sequencing, have been applied to cancer research and led to exciting new findings in the fields of cancer evolution, metastasis, resistance to therapy, and tumor microenvironment. In this review, we discuss recent advances and limitations of these new technologies and their potential applications in cancer studies.
HELLS Regulates Chromatin Remodeling and Epigenetic Silencing of Multiple Tumor Suppressor Genes in Human Hepatocellular Carcinoma
Authors: Cheuk‐Ting Law, Lai Wei, Felice Ho‐Ching Tsang, Cerise Yuen‐Ki Chan, Iris Ming‐Jing Xu, Robin Kit‐Ho Lai, Daniel Wai‐Hung Ho, Joyce Man‐Fong Lee, Carmen Chak‐Lui Wong, Irene Oi‐Lin Ng, Chun‐Ming Wong
Journal: Hepatology (2018)

Hepatocellular carcinoma (HCC) is the third most lethal cancer worldwide. Increasing evidence shows that epigenetic alterations play an important role in human carcinogenesis. Deregulation of DNA methylation and histone modifications have recently been characterized in HCC, but the significance of chromatin remodeling in liver carcinogenesis remains to be explored. In this study, by systematically analyzing the expression of chromatin remodeling genes in human HCCs, we found that helicase, lymphoid-specific (HELLS), an SWI2/SNF2 chromatin remodeling enzyme, was remarkably overexpressed in HCC. Overexpression of HELLS correlated with more aggressive clinicopathological features and poorer patient prognosis compared to patients with lower HELLS expression. We further showed that up-regulation of HELLS in HCC was conferred by hyperactivation of transcription factor specificity protein 1 (SP1). To investigate the functions of HELLS in HCC, we generated both gain-of-function and loss-of-function models by the CRISPR activation system, lentiviral short hairpin RNA, and the CRISPR/Cas9 genome editing system. We demonstrated that overexpression of HELLS augmented HCC cell proliferation and migration. In contrast, depletion of HELLS reduced HCC growth and metastasis both in vitro and in vivo. Moreover, inactivation of HELLS led to metabolic reprogramming and reversed the Warburg effect in HCC cells. Mechanistically, by integrating analysis of RNA sequencing and micrococcal nuclease sequencing, we revealed that overexpression of HELLS increased nucleosome occupancy, which obstructed the accessibility of enhancers and hindered formation of the nucleosome-free region (NFR) at the transcription start site. Though this mechanism, up-regulation of HELLS mediated epigenetic silencing of multiple tumor suppressor genes including E-cadherin, FBP1, IGFBP3, XAF1 and CREB3L3 in HCC. Conclusion: Our data reveal that HELLS is a key epigenetic driver of HCC; by altering the nucleosome occupancy at the NFR and enhancer, HELLS epigenetically suppresses multiple tumor suppressor genes to promote HCC progression.
Abstract 16418: The Impact of Glucose Control on High-Risk Coronary Plaque Compositions Assessed by Coronary CT Angiography in Patients With Type 2 Diabetes Mellitus
Authors: Takeshi Hatani, Shuichiro Kaji, Yasuhiro Sasaki, Kitae Kim, Takeshi Kitai, Natsuhiko Ehara, Atsushi Kobori, Makoto Kinoshita, Tomoko Tani, Yutaka Furukawa
Journal: Circulation (2013)

Background: Although type 2 diabetes mellitus (DM) is a risk factor for coronary artery disease (CAD), the influence of glycemic control on coronary plaque compositions in type 2 DM patients has not been well investigated in a noninvasive way. Low attenuation plaque, positive remodeling, and spotty calcification assessed by coronary CT angiography (CCTA) have been reported to be related to adverse outcomes. The purpose of this study was to evaluate the impact of glucose control on high-risk coronary plaque compositions assessed by CCTA in patients with type 2 DM. Methods: A total of 217 consecutive patients with type 2 DM (142 males, 65±10 years) underwent 64-slice CCTA and 2820 coronary segments were analyzed. Enrolled patients had an intermediate to high pre-test probability of obstructive CAD in clinical practice. We classified the patients according to HbA1c level; 86 patients with HbA1c value <6.5% (lower group), 131 patients with HbA1c value ≥6.5% (higher group). We evaluated the numbers of coronary...
FLT3 inhibitors in acute myeloid leukemia
Authors: Mei Wu, Chuntuan Li, Xiongpeng Zhu
Journal: Journal of Hematology & Oncology (2018)

FLT3 mutations are one of the most common findings in acute myeloid leukemia (AML). FLT3 inhibitors have been in active clinical development. Midostaurin as the first-in-class FLT3 inhibitor has been approved for treatment of patients with FLT3-mutated AML. In this review, we summarized the preclinical and clinical studies on new FLT3 inhibitors, including sorafenib, lestaurtinib, sunitinib, tandutinib, quizartinib, midostaurin, gilteritinib, crenolanib, cabozantinib, Sel24-B489, G-749, AMG 925, TTT-3002, and FF-10101. New generation FLT3 inhibitors and combination therapies may overcome resistance to first-generation agents.
Risk-Reducing Oophorectomy and Breast Cancer Risk Across the Spectrum of Familial Risk
Authors: Mary Beth Terry, Mary B Daly, Kelly Anne Phillips, Xinran Ma, Nur Zeinomar, Nicole Leoce, Gillian S Dite, Robert J MacInnis, Wendy K Chung, Julia A Knight, Melissa C Southey, Roger L Milne, David Goldgar, Graham G Giles, Prue C Weideman, Gord Glendon, Richard Buchsbaum, Irene L Andrulis, Esther M John, Saundra S Buys, John L Hopper
Journal: JNCI Journal of the National Cancer Institute (2018)

There remains debate about whether risk-reducing salpingo-oophorectomy (RRSO), which reduces ovarian cancer risk, also reduces breast cancer risk. We examined the association between RRSO and breast cancer risk using a prospective cohort of 17 917 women unaffected with breast cancer at baseline (7.2% known carriers of BRCA1 or BRCA2 mutations). During a median follow-up of 10.7 years, 1046 women were diagnosed with incident breast cancer. Modeling RRSO as a time-varying exposure, there was no association with breast cancer risk overall (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.87 to 1.24) or by tertiles of predicted absolute risk based on family history (HR = 0.68, 95% CI = 0.32 to 1.47, HR = 0.94, 95% CI = 0.70 to 1.26, and HR = 1.10, 95% CI = 0.88 to 1.39, for lowest, middle, and highest tertile of risk, respectively) or for BRCA1 and BRCA2 mutation carriers when examined separately. There was also no association after accounting for hormone therapy use after RRSO. These findings suggest that RRSO should not be considered efficacious for reducing breast cancer risk.
Association of Seizure Spread With Surgical Failure in Epilepsy
Authors: John P. Andrews, Abhijeet Gummadavelli, Pue Farooque, Jennifer Bonito, Christopher Arencibia, Hal Blumenfeld, Dennis D. Spencer
Journal: JAMA Neurology (2018)

<h3>Importance</h3> Seizures recur in as many as half of patients who undergo surgery for drug-resistant temporal lobe epilepsy (TLE). Understanding why TLE is resistant to surgery in some patients may reveal insights into epileptogenic networks and direct new therapies to improve outcomes. <h3>Objective</h3> To characterize features of surgically refractory TLE. <h3>Design, Setting, and Participants</h3> Medical records from a comprehensive epilepsy center were retrospectively reviewed for 131 patients who received a standard anteromedial temporal resection by a single surgeon from January 1, 2000, to December 31, 2015. Thirteen patients were excluded for having less than 1 year of follow-up. Patients at the highest risk for seizure recurrence were identified. Intracranial electroencephalogram (iEEG) analyses generated 3-dimensional seizure spread representations and quantified rapid seizure spread. The final analyses of seizure outcome and follow-up data were performed in June 2017. <h3>Main Outcomes and Measures</h3> The Engel class seizure outcome following surgery was evaluated for all patients, defining seizure recurrence as Engel class II or greater. Intracranial recordings of neocortical grids/strips and depth electrodes were analyzed visually for seizure spread. Fast β power was projected onto reconstructions of patients’ brain magnetic resonance imaging scans to visualize spread patterns and was quantified to compare power within vs outside resective margins. <h3>Results</h3> Of 118 patients with 1 year of follow-up or more (mean [SD], 6.5 [4.6] years), 66 (55.9%) were women and 52 (44.1%) were men (median age, 39 years [range, 4-66 years]). The cumulative probability of continuous Engel class I seizure freedom since surgery at postoperative year 10 and afterward was 65.6%, with 92% of recurrences in years 1 to 3. Multivariable statistical analyses found that the selection for iEEG study was the most reliable predictor of seizure recurrence, with a mixed-effects model estimating that the Engel score in the iEEG cohort was higher by a mean (SD) of 1.1 (0.33) (<i>P</i> = .001). In patients with iEEG results, rapid seizure spread in less than 10 seconds was associated with recurrence (hazard ratio, 5.99; 95% CI, 1.7-21.1;<i>P</i> &lt; .01). In the first 10 seconds of seizures, fast β power activity outside the resective margins in the lateral temporal cortex was significantly greater in patients whose seizures recurred compared with patients who were seizure-free (mean [SEM], 137.5% [16.8%] vs 93.4% [4.6%];<i>P</i> &lt; .05). <h3>Conclusions and significance</h3> Rapid seizure spread outside anteromedial temporal resection resective margins plays a significant role in the surgical failure of drug-resistant TLE. Seizure control after epilepsy surgery might be improved by investigating areas of early spread as candidates for resection or neuromodulation.
Use of Prolonged Exposure and Sertraline in the Treatment of Posttraumatic Stress Disorder for Veterans
Authors: Debra L. Kaysen, Michele A. Bedard-Gilligan, Andrew J. Saxon
Journal: JAMA Psychiatry (2018)

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Abstract 15822: miR-29 Contributes to Normal Endothelial Function in Healthy Human Resistance Arterioles and Restores Endothelium-Dependent Vasodilation in Type 2 Diabetes
Authors: Michael E Widlansky, David M Jensen, Jingli Wang, Yong Liu, Aron Geurts, Alison Kriegel, Pengyuan Liu, Rong Ying, Guangyuan Zhang, Marc Casati, Chen Chu, Mobin Malik, Amberly Branum, Michael J Tanner, Kristie Usa, Sudhi Tyagi, Venkat Puppala, Mingyu Liang
Journal: Circulation (2017)

Introduction: The role of microRNAs (miRNAs) in regulating vascular endothelial function in human resistance vessels remains largely unexplored. Early data suggest miR-29 is differentially expresse...
Chronic Vasitis After Mesh Herniorrhaphy
Authors: Minjung Seo, Nam Du Ha, Jae-Cheol Jo, Seol Hoon Park
Journal: Clinical Nuclear Medicine (2018)

We report two cases of supra-scrotal vasitis incidentally detected in patients who had undergone mesh herniorrhaphy. PET/CT in patients undergoing lymphoma work-up and health check-up revealed hypermetabolic dilatation of vas deferens in the external iliac area. There were no symptoms, and blood test results did not indicate acute inflammation. Interestingly, both had undergone herniorrhaphy for inguinal hernia. Herniorrhaphy is reported to cause vasal complications such as obstruction or inflammation, although most are asymptomatic and probably under-reported. Chronic vasitis after herniorrhaphy may be a potential cause for false positive findings on F-FDG PET/CT in patients undergoing work-up for various oncological indications.
Integrated proteotranscriptomics of breast cancer reveals globally increased protein-mRNA concordance associated with subtypes and survival
Authors: Wei Tang, Ming Zhou, Tiffany H. Dorsey, DaRue A. Prieto, Xin W. Wang, Eytan Ruppin, Timothy D. Veenstra, Stefan Ambs
Journal: Genome Medicine (2018)

Transcriptome analysis of breast cancer discovered distinct disease subtypes of clinical significance. However, it remains a challenge to define disease biology solely based on gene expression because tumor biology is often the result of protein function. Here, we measured global proteome and transcriptome expression in human breast tumors and adjacent non-cancerous tissue and performed an integrated proteotranscriptomic analysis.We applied a quantitative liquid chromatography/mass spectrometry-based proteome analysis using an untargeted approach and analyzed protein extracts from 65 breast tumors and 53 adjacent non-cancerous tissues. Additional gene expression data from Affymetrix Gene Chip Human Gene ST Arrays were available for 59 tumors and 38 non-cancerous tissues in our study. We then applied an integrated analysis of the proteomic and transcriptomic data to examine relationships between them, disease characteristics, and patient survival. Findings were validated in a second dataset using proteome and transcriptome data from "The Cancer Genome Atlas" and the Clinical Proteomic Tumor Analysis Consortium.We found that the proteome describes differences between cancerous and non-cancerous tissues that are not revealed by the transcriptome. The proteome, but not the transcriptome, revealed an activation of infection-related signal pathways in basal-like and triple-negative tumors. We also observed that proteins rather than mRNAs are increased in tumors and show that this observation could be related to shortening of the 3' untranslated region of mRNAs in tumors. The integrated analysis of the two technologies further revealed a global increase in protein-mRNA concordance in tumors. Highly correlated protein-gene pairs were enriched in protein processing and disease metabolic pathways. The increased concordance between transcript and protein levels was additionally associated with aggressive disease, including basal-like/triple-negative tumors, and decreased patient survival. We also uncovered a strong positive association between protein-mRNA concordance and proliferation of tumors. Finally, we observed that protein expression profiles co-segregate with a Myc activation signature and separate breast tumors into two subgroups with different survival outcomes.Our study provides new insights into the relationship between protein and mRNA expression in breast cancer and shows that an integrated analysis of the proteome and transcriptome has the potential of uncovering novel disease characteristics.
Novel susceptibility variants at the ERG locus for childhood acute lymphoblastic leukemia in Hispanics
Authors: Maoxiang Qian, Heng Xu, Virginia Perez-Andreu, Kathryn G. Roberts, Hui Zhang, Wenjian Yang, Shouyue Zhang, Xujie Zhao, Colton Smith, Meenakshi Devidas, Julie M. Gastier-Foster, Elizabeth Raetz, Eric Larsen, Esteban G. Burchard, Naomi Winick, W. Paul Bowman, Paul L. Martin, Michael Borowitz, Brent Wood, Federico Antillon-Klussmann, Ching-Hon Pui, Charles G. Mullighan, William E. Evans, Stephen P. Hunger, Mary V. Relling, Mignon L. Loh, Jun J. Yang
Journal: Blood (2018)
Medical students consider abandoning degree because of financial pressures, survey finds
Authors: Laura Nunez-Mulder
Journal: BMJ (2018)

Four in 10 UK medical students say that they or someone they know has considered quitting medical school because of financial pressures, according to a survey by the Royal Medical Benevolent Fund.1

The survey of a representative sample of 100 students found that almost two thirds (60%) had experienced financial pressure. In a follow up survey of 525 students online, two thirds (65%) of those who had experienced financial pressure said that this had affected their mental health and wellbeing.

The fund is a UK charity that provides financial support and advice to doctors and medical students. Student applications to the charity have doubled in the past two years. In …
Fine needle aspirates comprehensively sample intrahepatic immunity
Authors: Upkar S Gill, Laura J Pallett, Niclas Thomas, Alice R Burton, Amit A Patel, Simon Yona, Patrick T F Kennedy, Mala K Maini
Journal: Gut (2018)

Objective In order to refine new therapeutic strategies in the pipeline for HBV cure, evaluation of virological and immunological changes compartmentalised at the site of infection will be required. We therefore investigated if liver fine needle aspirates (FNAs) could comprehensively sample the local immune landscape in parallel with viable hepatocytes. Design Matched blood, liver biopsy and FNAs from 28 patients with HBV and 15 without viral infection were analysed using 16-colour multiparameter flow cytometry. Results The proportion of CD4 T, CD8 T, Mucosal Associated Invariant T cell (MAIT), Natural Killer (NK) and B cells identified by FNA correlated with that in liver biopsies from the same donors. Populations of Programmed Death-1 (PD-1) hi CD39 hi tissue-resident memory CD8 T cells (CD69 + CD103 + ) and liver-resident NK cells (CXCR6 + T-bet lo Eomes hi ), were identified by both FNA and liver biopsy, and not seen in the blood. Crucially, HBV-specific T cells could be identified by FNAs at similar frequencies to biopsies and enriched compared with blood. FNAs could simultaneously identify populations of myeloid cells and live hepatocytes expressing albumin, Scavenger Receptor class B type 1 (SR-B1), Programmed Death-Ligand 1 (PD-L1), whereas hepatocytes were poorly viable after the processing required for liver biopsies. Conclusion We demonstrate for the first time that FNAs identify a range of intrahepatic immune cells including locally resident sentinel HBV-specific T cells and NK cells, together with PD-L1-expressing hepatocytes. In addition, we provide a scoring tool to estimate the extent to which an individual FNA has reliably sampled intrahepatic populations rather than contaminating blood. The broad profiling achieved by this less invasive, rapid technique makes it suitable for longitudinal monitoring of the liver to optimise new therapies for HBV.
Acute enlargement of a vascular plaque and gait changes in a young girl
Authors: Kathleen T Tedesco, Jay Sarthy, Navin Pinto, Markus D Boos
Journal: BMJ (2018)

A 15 month old girl presented to the emergency department with a one week history of unsteady gait and approximately three to four unexplained falls each day. She had been walking independently and without difficulty since she was 12 months old. At birth, she had a broad pink patch on the right medial buttock, which had been diagnosed on clinical examination as a congenital haemangioma. The site had grown proportionally with the patient until these symptoms started, when this vascular stain became acutely indurated, and a contiguous, erythematous plaque appeared superiorly, overlying the sacrum. On examination, a swollen, violaceous, warm, subcutaneous plaque with superimposed telangiectases was noted overlaying the sacrum. This extended to the right buttock, where an accompanying pink-purple stain was present (fig 1). No thrills or pulsations were noted. Neurological examination showed no paralysis. Relevant laboratory findings are shown in table 1.



Fig 1 
A swollen, violaceous, subcutaneous plaque overlaying the sacrum with subtle overlaying telangiectases (arrow), extending contiguously to the right buttock with a more prominent vascular stain (arrowhead)



View this table:

Table 1 
Relevant investigation findings



1.  What are the differential diagnoses of lumbosacral swelling in children?

2.  What is the most likely diagnosis?

3.  How would you manage this patient?

### 1. What are the differential diagnoses of lumbosacral swelling in children?

The differential diagnoses for paediatric lumbosacral swelling include congenital haemangioma, deep infantile haemangioma, kaposiform haemangioendothelioma (KHE), sacral meningocele, lipoma, dermatofibrosarcoma protuberans, sacrococcygeal teratoma (SCT), rectal abscess, and cellulitis. KHE and non-accidental trauma should also be considered when a child …
Abstract 18348: Lack of Protective Exosomes to Remove AMZ1 Archaeal Collagenase is Associated With Heart Failure in Chagas' Disease
Authors: Maria de Lourdes Higuchi, Joyce T Kawakami, Marilia H Santos, Renata N Ikegami, Marcia M Reis, Barbara Ianni, Paula Buck, Edimar Bocchi
Journal: Circulation (2017)

Introduction: Cardiomyocytes increase secretion of exosomes (exos), microvesicles lower than 100nm diameter, in pathological conditions such as hypoxia, inflammation or injury, being cardioprotecti...