tbuckley/cabot-search huggingface dataset:
Evolution on the Biophysical Fitness Landscape of an RNA Virus
Authors: Assaf Rotem, Adrian W R Serohijos, Connie B Chang, Joshua T Wolfe, Audrey E Fischer, Thomas S Mehoke, Huidan Zhang, Ye Tao, W Lloyd Ung, Jeong-Mo Choi, João V Rodrigues, Abimbola O Kolawole, Stephan A Koehler, Susan Wu, Peter M Thielen, Naiwen Cui, Plamen A Demirev, Nicholas S Giacobbi, Timothy R Julian, Kellogg Schwab, Jeffrey S Lin, Thomas J Smith, James M Pipas, Christiane E Wobus, Andrew B Feldman, David A Weitz, Eugene I Shakhnovich
Journal: Molecular Biology and Evolution (2018)

Viral evolutionary pathways are determined by the fitness landscape, which maps viral genotype to fitness. However, a quantitative description of the landscape and the evolutionary forces on it remain elusive. Here, we apply a biophysical fitness model based on capsid folding stability and antibody binding affinity to predict the evolutionary pathway of norovirus escaping a neutralizing antibody. The model is validated by experimental evolution in bulk culture and in a drop-based microfluidics that propagates millions of independent small viral subpopulations. We demonstrate that along the axis of binding affinity, selection for escape variants and drift due to random mutations have the same direction, an atypical case in evolution. However, along folding stability, selection and drift are opposing forces whose balance is tuned by viral population size. Our results demonstrate that predictable epistatic tradeoffs between molecular traits of viral proteins shape viral evolution.
Medical students need better mental health support from universities, says BMA
Authors: Rebecca Coombes
Journal: BMJ (2018)

BMA members have called for a review of mental health support provided to medical students after hearing personal stories of unmet need at their annual representative meeting in Brighton this week.

The meeting passed a motion calling for research into the types of mental health issues experienced by medical students, basic training for clinical facilitators so they can better support students, and extended opening hours for student health services for those studying medicine, who are often unable to comply with a 9 to 5 timetable.

The motion also called for mental health awareness and promotion of self care …
Functional Parameters Derived from Magnetic Resonance Imaging Reflect Vascular Morphology in Preclinical Tumors and in Human Liver Metastases
Authors: Pavitra Kannan, Warren W. Kretzschmar, Helen Winter, Daniel Warren, Russell Bates, Philip D. Allen, Nigar Syed, Benjamin Irving, Bartlomiej W. Papiez, Jakob Kaeppler, Bosjtan Markelc, Paul Kinchesh, Stuart Gilchrist, Sean Smart, Julia A. Schnabel, Tim Maughan, Adrian L. Harris, Ruth J. Muschel, Mike Partridge, Ricky A. Sharma, Veerle Kersemans
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Tumor vessels influence the growth and response of tumors to therapy. Imaging vascular changes in vivo using dynamic contrast-enhanced MRI (DCE-MRI) has shown potential to guide clinical decision making for treatment. However, quantitative MR imaging biomarkers of vascular function have not been widely adopted, partly because their relationship to structural changes in vessels remains unclear. We aimed to elucidate the relationships between vessel function and morphology in vivo. Experimental Design: Untreated preclinical tumors with different levels of vascularization were imaged sequentially using DCE-MRI and CT. Relationships between functional parameters from MR (iAUC, Ktrans, and BATfrac) and structural parameters from CT (vessel volume, radius, and tortuosity) were assessed using linear models. Tumors treated with anti-VEGFR2 antibody were then imaged to determine whether antiangiogenic therapy altered these relationships. Finally, functional–structural relationships were measured in 10 patients with liver metastases from colorectal cancer. Results: Functional parameters iAUC and Ktrans primarily reflected vessel volume in untreated preclinical tumors. The relationships varied spatially and with tumor vascularity, and were altered by antiangiogenic treatment. In human liver metastases, all three structural parameters were linearly correlated with iAUC and Ktrans. For iAUC, structural parameters also modified each other's effect. Conclusions: Our findings suggest that MR imaging biomarkers of vascular function are linked to structural changes in tumor vessels and that antiangiogenic therapy can affect this link. Our work also demonstrates the feasibility of three-dimensional functional–structural validation of MR biomarkers in vivo to improve their biological interpretation and clinical utility. Clin Cancer Res; 24(19); 4694–704. ©2018 AACR.
Antibiofilm peptides against biofilms on titanium and hydroxyapatite surfaces
Authors: Dan Wang, Markus Haapasalo, Yuan Gao, Jingzhi Ma, Ya Shen
Journal: Bioactive Materials (2018)

Biofilms are the main challenges in the treatment of common oral diseases such as caries, gingival and endodontic infection and periimplantitis. Oral plaque is the origin of microbes colonizing in the form of biofilms on hydroxyapatite (tooth) and titanium (dental implant) surfaces. In this study, hydroxyapatite (HA) and titanium (Ti) disks were introduced, and their surface morphology was both qualitatively and quantitatively analyzed by a scanning electron microscope (SEM) and atomic force microscope (AFM). The average roughness of Ti disks (77.6 ± 18.3 nm) was less than that of HA (146.1 ± 38.5 nm) (p < 0.05). Oral multispecies biofilms which were cultured on Ti and HA disks for 6 h and three weeks were visualized by SEM. We investigated the ability of two new antibiofilm peptides, DJK-5 and 1018, to induce killing of bacteria in oral multispecies biofilms on Ti and HA disks. A 6-h treatment by DJK-5 and 1018 (2 or 10 μg/mL) significantly reduced biomass of the multispecies biofilms on both Ti and HA disks. DJK-5 was able to kill more bacteria (40.4–75.9%) than 1018 (30.4–67.0%) on both surfaces (p < 0.05). DJK-5 also led to a more effective killing of microbes after a 3-min treatment of 3-day-old and 3-week-old biofilms on Ti and HA surfaces, compared to peptide 1018 and chlorhexidine (p < 0.05). No significant difference was found in the amount of biofilm killing between Ti and HA surfaces. Both peptide DJK-5 and 1018 may potentially be used as effective antibiofilm agents in clinical dentistry.
Abstract 1638: Is short interval colonoscopy at the discretion of the gastroenterologist
Authors: Hassan Brim, Abhimanyu Tushir, Shashidhar Manchegowda, Negin Farsi, Edward L. Lee, Laiyemo O. Adeyinka, Seyed M. Nouraie, Hassan Ashktorab
Journal: Cancer Research (2018)

Abstract BACKGROUND: Gastroenterologists do not always follow guidelines for performing colonoscopies. Short interval colonoscopies are recommended at the discretion of gastroenterologists depending on various factors. We here evaluated such factors in an African American patient population. AIM: To assess factors contributing to short interval (within 3 months) colonoscopies. METHODS: Data was retrieved retrospectively from Howard University Hospital database (Jan. 2010 to Dec. 2016). African American patients who had repeated colonoscopies within a period of 3 months were selected for this study. We analyzed patients' demographics, family history, polyp characteristics, and reasons for repeat colonoscopy along with latest follow-up findings. RESULTS: There were 36 patients who underwent two colonoscopies within 3 months, 13 females and 23 males with mean age of 61 years. Out of these, 7 patients (19.4%) had poor bowel preparation. For the remaining 29 patients, the reason for second colonoscopy were partial removal and suspicion of partial removal (61.1%), difficult access (16.7%), and follow-up for Crohn's disease (2.8%). Follow-up of these 36 patients after their last colonoscopy revealed that 8 patients (22.2%) had colon cancer/resection, 4 other patients (11.1%) had cancer of other organs. Of the remaining, 6 (16.6%) had future colon polyp resection, 3 (8.3%) had normal screening colonoscopy and 4 (11.1%) visited the hospital for reasons unrelated to gastroenterology while 11 patients (30.6%) had no follow up. CONCLUSION: Even though there are no recommendations to repeat colonoscopy within 3 months, endoscopists perform such colonoscopies at their own discretion based on factors like high risk individuals, poor bowel preparation, multiple lesions, type of lesions and resection clearance. Of interest, a significant number of patients in our study had colon cancer/resection on eventual follow-ups. Citation Format: Hassan Brim, Abhimanyu Tushir, Shashidhar Manchegowda, Negin Farsi, Edward L. Lee, Laiyemo O. Adeyinka, Seyed M. Nouraie, Hassan Ashktorab. Is short interval colonoscopy at the discretion of the gastroenterologist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1638.
The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis in patients with decompensated liver cirrhosis: results of a randomized controlled clinical trial
Authors: S. Piano, F. Salinas, F. Morando, M. Cavallin, A. Romano, S. Rosi, M. Stanco, S. Fasolato, A. Sticca, M. Senzolo, P. Burra, E. Gringeri, U. Cillo, A. Gatta, P. Angeli
Journal: Hepatology (2014)
Abstract 556: Oncogenic properties and response to HDAC inhibitor treatment of H1299 cells expressing GOF p53 mutants
Authors: Brianna Flores, Elizabeth E. Hull
Journal: Cancer Research (2018)

Abstract The tumor suppressor p53 protein is mutated in over 50% of cancers. The most frequent mutations in p53, termed “hotspot” mutations, occur in the DNA binding domain of the p53 protein. These mutations not only remove normal p53 function but also convey additional oncogenic properties greater than loss of tumor suppressor activities associated with loss of wild-type (WT) p53 activities. With newly acquired oncogenic properties, mutations in the DNA binding domain of p53 are classified as gain of function (GOF) mutations. GOF p53 mutants can be subdivided into conformational mutations (e.g. R175H, H193Y) involving residues necessary for maintenance of structure and contact mutations (e.g. R248Q, R273H) involving resides necessary for DNA interaction. Cancer cells bearing a GOF p53 mutation increase metastasis with application of histone deacetylase inhibitors (HDACi). This uncharacterized pro-oncogenic GOF p53 property is of clinical relevance as HDACi are FDA approved for hematological cancers but have failed in clinical trials for solid tumors. To explore this hypothesis, metastatic capacity and proliferation rates of common GOF p53 mutations were assessed with and without HDACi treatment and in the presence or absence of specific inhibitors of target GOF p53. The p53-null, H1299 non-small cell lung carcinoma line was transfected with GOF p53 mutants and WT p53 using a tetracycline inducible expression system. Inducible expression of stable subclones was varified by immunofluorescence and western blot. Proliferation rate was measured by incorporation of EdU and metastatic capacity was assessed by measuring MMP activity and migration assays with and without HDACi treatment. Specific GOF p53 mutations possess a subset of the oncogenic properties of the entire GOF p53 class. Data suggest that the GOF p53 mutants display differing rates of proliferation with the R175H mutation exhibiting the highest rate. Application of NSC319726 significantly decreases the proliferation rate and appears to successfully refold the R175H mutant to a WT conformation. The R248Q mutation exhibited morphological change suggestive of the epithelial to mesenchymal transition associated with increased metastatic capacity. Preliminary data suggest that HDACi affect among these cell lines in conjunction with NSC 319726 and SCH 529074 treatment. In conclusion, HDACi treatment may be contraindicated while treatment with HDACi may have great benefit in tumors which are WT or null for p53 protein expression. Citation Format: Brianna Flores, Elizabeth E. Hull. Oncogenic properties and response to HDAC inhibitor treatment of H1299 cells expressing GOF p53 mutants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 556.
Mast Cell Activation and KSHV Infection in Kaposi Sarcoma
Authors: Leona W. Ayers, Arturo Barbachano-Guerrero, Shane C. McAllister, Julie A. Ritchie, Elizabeth Asiago-Reddy, Linda C. Bartlett, Ethel Cesarman, Dongliang Wang, Rosemary Rochford, Jeffrey N. Martin, Christine A. King
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Kaposi sarcoma (KS) is a vascular tumor initiated by infection of endothelial cells (ECs) with KS–associated herpesvirus (KSHV). KS is dependent on sustained proinflammatory signals provided by intralesional leukocytes and continued infection of new ECs. However, the sources of these cytokines and infectious virus within lesions are not fully understood. Here, mast cells (MCs) are identified as proinflammatory cells within KS lesions that are permissive for, and activated by, infection with KSHV. Experimental Design: Three validated MC lines were used to assess permissivity of MCs to infection with KSHV and to evaluate MCs activation following infection. Biopsies from 31 AIDS-KS cases and 11 AIDS controls were evaluated by IHC for the presence of MCs in KS lesions and assessment of MC activation state and infection with KSHV. Plasma samples from 26 AIDS-KS, 13 classic KS, and 13 healthy adults were evaluated for levels of MC granule contents tryptase and histamine. Results: In culture, MCs supported latent and lytic KSHV infection, and infection-induced MC degranulation. Within KS lesions, MCs were closely associated with spindle cells. Furthermore, MC activation was extensive within patients with KS, reflected by elevated circulating levels of tryptase and a histamine metabolite. One patient with clinical signs of extensive MC activation was treated with antagonists of MC proinflammatory mediators, which resulted in a rapid and durable regression of AIDS-KS lesions. Conclusions: Using complimentary in vitro and in vivo studies we identify MCs as a potential long-lived reservoir for KSHV and a source of proinflammatory mediators within the KS lesional microenvironment. In addition, we identify MC antagonists as a promising novel therapeutic approach for KS. Clin Cancer Res; 24(20); 5085–97. ©2018 AACR.
Combined Blockade of IL6 and PD-1/PD-L1 Signaling Abrogates Mutual Regulation of Their Immunosuppressive Effects in the Tumor Microenvironment
Authors: Hirotake Tsukamoto, Koji Fujieda, Azusa Miyashita, Satoshi Fukushima, Tokunori Ikeda, Yosuke Kubo, Satoru Senju, Hironobu Ihn, Yasuharu Nishimura, Hiroyuki Oshiumi
Journal: Cancer Research (2018)

Recently emerging cancer immunotherapies combine the applications of therapeutics to disrupt the immunosuppressive conditions in tumor-bearing hosts. In this study, we found that targeting the proinflammatory cytokine IL6 enhances tumor-specific Th1 responses and subsequent antitumor effects in tumor-bearing mice. IL6 blockade upregulated expression of the immune checkpoint molecule programmed death-ligand 1 (PD-L1) on melanoma cells. This PD-L1 induction was canceled in IFNγ-deficient mice or CD4+ T cell-depleted mice, suggesting that CD4+ T cell-derived IFNγ is important for PD-L1 induction in tumor-bearing hosts. In some patients with melanoma, however, treatment with the anti-PD-1 antibody nivolumab increased systemic levels of IL6, which was associated with poor clinical responses. This PD-L1 blockade-evoked induction of IL6 was reproducible in melanoma-bearing mice. We found that PD-1/PD-L1 blockade prompted PD-1+ macrophages to produce IL6 in the tumor microenvironment. Depletion of macrophages in melanoma-bearing mice reduced the levels of IL6 during PD-L1 blockade, suggesting macrophages are responsible for the IL6-mediated defective CD4+ Th1 response. Combined blockade of the mutually regulated immunosuppressive activities of IL6 and PD-1/PD-L1 signals enhanced expression of T cell-attracting chemokines and promoted infiltration of IFNγ-producing CD4+ T cells in tumor tissues, exerting a synergistic antitumor effect, whereas PD-L1 blockade alone did not promote Th1 response. Collectively, these findings suggest that IL6 is a rational immunosuppressive target for overcoming the narrow therapeutic window of anti-PD-1/PD-L1 therapy.Significance: These findings advance our understanding of IL6-PD1/PD-L1 cross-talk in the tumor microenvironment and provide clues for targeted interventional therapy that may prove more effective against cancer. Cancer Res; 78(17); 5011-22. ©2018 AACR.
Overdiagnosis and overtreatment in rheumatology: a little caution is in order
Authors: Robert B M Landewé
Journal: Annals of the Rheumatic Diseases (2018)

Overdiagnosis is a term coined by experts in cancer screening to point to indolent cancers detected by screening that would have never led to manifest health problems. Overdiagnosis leads to unnecessary medical care (overtreatment), anxiety and cost. In rheumatology overdiagnosis and overtreatment are hardly discussed but likely present. This viewpoint examines how our prevailing views on the management of inflammatory rheumatic diseases may relate to overdiagnosis and overtreatment. Six paradigms of modern rheumatology will be discussed: early diagnosis, intensive treatment, remission, prognosis and risk stratification, evidence-based rheumatology, and precision medicine. It is concluded that, in spite of the enormous progress that they have brought, all paradigms bear the intrinsic dangers of overdiagnosis and overtreatment. So a little caution is in order.
Trimethoprim–sulfamethoxazole prophylaxis prevents severe/life-threatening infections following rituximab in antineutrophil cytoplasm antibody-associated vasculitis
Authors: Andreas Kronbichler, Julia Kerschbaum, Seerapani Gopaluni, Joanna Tieu, Federico Alberici, Rachel Bronwen Jones, Rona M Smith, David R W Jayne
Journal: Annals of the Rheumatic Diseases (2018)

Objective We aimed to assess risk factors for the development of severe infection in patients with antineutrophil cytoplasm antibody-associated vasculitis (AAV) receiving rituximab. Methods 192 patients with AAV were identified. Univariate and multivariate analyses were performed to identify risk factors for severe infection following rituximab. Severe infections were classified as grade ≥3 as proposed by the Common Terminology Criteria for Adverse Events V.4.0. Results 95 severe infections were recorded in 49 (25.52%) patients, corresponding to an event rate of 26.06 per 100 person-years. The prophylactic use of trimethoprim–sulfamethoxazole was associated with a lower frequency of severe infections (HR 0.30, 95% CI 0.13 to 0.69), while older age (HR 1.03, 95% CI 1.01 to 1.05), endobronchial involvement (HR 2.21, 95% CI 1.14 to 4.26), presence of chronic obstructive pulmonary disease (HR 6.30, 95% CI 1.08 to 36.75) and previous alemtuzumab use (HR 3.97, 95% CI 1.50 to 10.54) increased the risk. When analysis was restricted to respiratory tract infections (66.3% of all infections), endobronchial involvement (HR 4.27, 95% CI 1.81 to 10.06), severe bronchiectasis (HR 6.14, 95% CI 1.18 to 31.91), higher neutrophil count (HR 1.19, 95% CI 1.06 to 1.33) and major relapse (HR 3.07, 95% CI 1.30 to 7.23) as indication for rituximab use conferred a higher risk, while refractory disease (HR 0.25, 95% CI 0.07 to 0.90) as indication had a lower frequency of severe infections. Conclusions We found severe infections in one quarter of patients with AAV receiving rituximab. Trimethoprim–sulfamethoxazole prophylaxis reduced the risk, while especially bronchiectasis and endobronchial involvement are risk factors for severe respiratory infections.
Current and Emerging Diagnostic Imaging-Based Techniques for Assessment of Osteoporosis and Fracture Risk
Authors: Anu Shaju Areeckal, Michel Kocher, Sumam David S.
Journal: IEEE Reviews in Biomedical Engineering (2018)

Osteoporosis is a metabolic bone disorder characterized by low bone mass, degradation of bone microarchitecture, and susceptibility to fracture. It is a growing major health concern across the world, especially in the elderly population. Osteoporosis can cause hip or spinal fractures that may lead to high morbidity and socio-economic burden. Therefore, there is a need for early diagnosis of osteoporosis and prediction of fragility fracture risk. In this review, state of the art and recent advances in imaging techniques for diagnosis of osteoporosis and fracture risk assessment have been explored. Segmentation methods used to segment the regions of interest and texture analysis methods used for classification of healthy and osteoporotic subjects are also presented. Furthermore, challenges posed by the current diagnostic tools have been studied and feasible solutions to circumvent the limitations are discussed. Early diagnosis of osteoporosis and prediction of fracture risk require the development of highly precise and accurate low-cost diagnostic techniques that would help the elderly population in low economies.
Abstract 662: IMA_Detect: Mass spectrometry guided development and clinical application of a companion diagnostic for adoptive cellular therapy against tumor associated HLA peptides
Authors: Jens Fritsche, Arun Satelli, Helen Hörzer, Barbara Rakitsch, Franziska Hoffgaard, Norbert Hilf, Oliver Schoor, Harpreet Singh-Jasuja, Weinschenk Toni
Journal: Cancer Research (2018)

Abstract Adoptive cellular therapy (ACT) has dramatically changed the landscape of cancer immunotherapy. ACTolog® and ACTengine® are actively personalized ACT approaches employing T-cell receptor products based on a warehouse of human leucocyte antigen (HLA)-bound peptide targets. Selecting the relevant target candidates requires the establishment of biomarkers predictive for HLA peptide presentation and their development into companion diagnostic devices. Here we describe the development of IMA_Detect, a diagnostic test based on gene expression analysis of primary patient tumor material by qPCR which is predictive for presentation of a target peptide by HLA. To establish mRNA expression levels which indicate actual peptide presentation, data of Immatics' XPRESIDENT® target discovery platform was used by integrating quantitative immunopeptidomics data (label-free LC-MS) with paired transcriptomics data (RNA-Seq). The peptide-specific correlation between peptide presentation and expression of the coding exons was verified for each target individually. The resulting RNA-Seq thresholds were mapped to qPCR thresholds using calibration curves followed by validation of the qPCR assay. The IMA_Detect test is performed in a CLIA/CAP approved setting and is currently being applied in the phase I ACT trials IMA101-101 and IMA201-101 to determine whether a patient's tumor expresses any of the tested targets at levels considered sufficient for potential benefit from the administered T-cell therapy. IMA101-101 uses autologous T-cell products (ACTolog®) for patients with solid cancers while IMA201-101 is based on TCR-engineered T Cells (ACTengine®) in NSCLC and HNSCC patients. We will present first results of the patient screening and the personalized target selection. Citation Format: Jens Fritsche, Arun Satelli, Helen Hörzer, Barbara Rakitsch, Franziska Hoffgaard, Norbert Hilf, Oliver Schoor, Harpreet Singh-Jasuja, Weinschenk Toni. IMA_Detect: Mass spectrometry guided development and clinical application of a companion diagnostic for adoptive cellular therapy against tumor associated HLA peptides [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 662.