tbuckley/cabot-search huggingface dataset:
Brenner and Rector's The Kidney
Authors: Nadine Bazilinski
Journal: JAMA (1997)

<i>Brenner and Rector's The Kidney</i>, edited by Barry Brenner, remains a classic reference in the field of renal diseases. For 20 years, each new edition of this comprehensive text has described all aspects of nephrology from basic science to clinical diagnosis and therapy. The fifth edition has surpassed the others in size and content. Overall, the new two-volume set has more than 2700 pages, 35 000 references (many recent), and more than 12 000 illustrations and tables. Now, there are more than 120 internationally distingushed contributors. The editor has added new chapters, many involving basic research, and has updated and expanded others. All the while, the authors have maintained the clear and well-organized style and format of previous editions. The first volume consists of two sections. Section one covers normal renal anatomy and physiology. There are new chapters on embryology, cellular biology, and biochemistry. Other chapters review current knowledge on
Rescue endoscopic therapy after malfunctioning choledochoduodenostomy in patient with malignant distal biliary obstruction
Authors: Mauro Manno, Sara Vavassori, Simona Deiana, Laura Ottaviani, Tommaso Gabbani, Paola Soriani
Journal: Endoscopy (2019)

Endoscopic ultrasound-guided choledochoduodenostomy (EUS-CD) using a lumen-apposing metal stent (LAMS) has recently been reported as an alternative approach after failure of endoscopic retrograde cholangiopancreatography (ERCP) in patients with malignant obstructive jaundice [1].
Impact of Somatic Mutations on Outcome in Patients &amp;gt; 60 Years Old with Newly Diagnosed AML Treated with Response-Adapted Sequential Azacitidine and Induction Chemotherapy within the DRKS00004519 Trial (RAS-AZIC) of the East German Study Group of Hematology and Oncology (OSHO)
Authors: Nadja Jaekel, Susann Schulze, Udo Siebolts, Anja Haak, Nikolaos Pazaitis, Michael Cross, Dietger Niederwieser, Mathias Hänel, Georg Maschmeyer, Maxi Wass, Lukas Heukamp, Roopika Menon, Miriam Bertrand, Claudia Wickenhauser, Oana Brosteanu, Haifa Kathrin Al-Ali
Journal: Blood (2019)
Micro/nano-structured TiO2 surface with dual-functional antibacterial effects for biomedical applications
Authors: Xiang Ge, Chengzu Ren, Yonghui Ding, Guang Chen, Xiong Lu, Kefeng Wang, Fuzeng Ren, Meng Yang, Zhuochen Wang, Junlan Li, Xinxin An, Bao Qian, Yang Leng
Journal: Bioactive Materials (2019)

Implant-associated infections are generally difficult to cure owing to the bacterial antibiotic resistance which is attributed to the widespread usage of antibiotics. Given the global threat and increasing influence of antibiotic resistance, there is an urgent demand to explore novel antibacterial strategies other than using antibiotics. Recently, using a certain surface topography to provide a more persistent antibacterial solution attracts more and more attention. However, the clinical application of biomimetic nano-pillar array is not satisfactory, mainly because its antibacterial ability against Gram-positive strain is not good enough. Thus, the pillar array should be equipped with other antibacterial agents to fulfill the bacteriostatic and bactericidal requirements of clinical application. Here, we designed a novel model substrate which was a combination of periodic micro/nano-pillar array and TiO2 for basically understanding the topographical bacteriostatic effects of periodic micro/nano-pillar array and the photocatalytic bactericidal activity of TiO2. Such innovation may potentially exert the synergistic effects by integrating the persistent topographical antibacterial activity and the non-invasive X-ray induced photocatalytic antibacterial property of TiO2 to combat against antibiotic-resistant implant-associated infections. First, to separately verify the topographical antibacterial activity of TiO2 periodic micro/nano-pillar array, we systematically investigated its effects on bacterial adhesion, growth, proliferation, and viability in the dark without involving the photocatalysis of TiO2. The pillar array with sub-micron motif size can significantly inhibit the adhesion, growth, and proliferation of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Such antibacterial ability is mainly attributed to a spatial confinement size-effect and limited contact area availability generated by the special topography of pillar array. Moreover, the pillar array is not lethal to S. aureus and E. coli in 24 h. Then, the X-ray induced photocatalytic antibacterial property of TiO2 periodic micro/nano-pillar array in vitro and in vivo will be systematically studied in a future work. This study could shed light on the direction of surface topography design for future medical implants to combat against antibiotic-resistant implant-associated infections without using antibiotics.
The Lymphoma Tumor Microenvironment Influences Toxicity after CD19 CAR T Cell Therapy
Authors: Michael D. Jain, Rawan Faramand, Verena Staedtke, Renyuan Bai, Sae Bom Lee, Hiroshi Kotani, Kayla Reid, Kristen Spitler, Julio Chavez, Bijal Shah, Christina A Bachmeier, Marian Dam, Brigett Brandjes, Ricardo J Gonzalez, John E Mullinax, Xuefeng Wang, Mohammad Hussaini, Frederick L. Locke, Marco L. Davila
Journal: Blood (2019)
Statins and Stroke — It’s Complicated
Authors: Lawrence R. Wechsler
Journal: New England Journal of Medicine (2019)

Elevated levels of cholesterol are a well-known risk factor for cardiovascular disease, including stroke, and efforts to lower cholesterol levels to reduce risk have been ongoing for decades. Because of their dramatic effect on cholesterol, statins have been widely prescribed to prevent cardiovascular events in patients at high risk. Most trials of primary and secondary prevention with statins have shown a decrease in the incidence of vascular events,1 and statins are now the essential component of medical management in patients at risk for cardiovascular disease. Although statins were designed to reduce cholesterol levels, the ideal use of these agents and . . .
DRES-10. TEMOZOLOMIDE-ASSOCIATED HYPERMUTATION DETECTED WITH A GENE PANEL SIGNATURE IMPROVES IMMUNE RESPONSE IN GLIOBLASTOMA
Authors: Paul Daniel, Brian Meehan, Siham Sabri, Jann Sarkaria, Janusz Rak, Bassam Abdulkarim
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma (GBM) is the most common and deadly type of malignant brain cancer in adults. While current standard of care which combines resection, radiation therapy (RT) and Temozolomide (TMZ) effectively eliminates primary disease, recurrence is inevitable, occurs rapidly following treatment and is ultimately lethal due to limited therapeutic opportunities of recurrent GBM. Hypermutation has been reported to occur in a subset of both low and high-grade gliomas and emerges after exposure to TMZ. Mutational inactivation and loss of mismatch repair (MMR) gene expression lead to the accumulation of single nucleotide polymorphisms throughout the genome. To date, the gain of hypermutation and subsequent therapeutic responses are still largely unknown. We hypothesized that hypermutant (HM) and non-hypermutant (NH) tumors represent two recurrent GBM subtypes, which has distinct therapeutic vulnerabilities. In addition, given the lack of concordance between microsatellite instability (MSI) and occurrence of hypermutation in GBM, we sought to derive a limited gene panel which can be used as surrogate biomarker for hypermutation following TMZ to replace whole exome sequencing (WES). Using public datasets, we demonstrated that recurrent GBM can be clustered into two subtypes: HM and NH. We used matched primary and recurrent GBM datasets to derive a gene panel signature, which is uniquely mutated at recurrence in HM GBM and confirmed the specificity of this panel in an independent dataset. Furthermore, we utilized patient derived xenograft (PDX) models to generate pre-clinical models and demonstrated that HM recurrent GBM are more immune responsive while NH recurrent GBM maintained sensitivity to a range of alternate chemotherapies such as cisplatin and RT. Finally, we demonstrated that this signature is represented in exosomes and can be enriched by use of tumor specific antibody capture methods to improve the sensitivity of hypermutation detection in liquid biopsy.
Sequence of Second Generation Tyrosine Kinase Inhibitors (TKIs) in the Treatment of Patients with Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukaemia - Real World Experience in the UK
Authors: Jenny Byrne, Joanne Ewing, Adam J. Mead, Heather Oakervee, Gavin Campbell, Ian Amott, Andrew Goringe, Earnest Heartin, Evangelia Dimitriadou, Ian Pamphlett, Siamak Arami, Pratap Neelakantan, Rebecca Frewin, Srinivas Pillai, Hugues De Lavallade, Nicholas C.P. Cross, Michael Thompson
Journal: Blood (2019)
ACTR-61. A RANDOMIZED PHASE 2 TRIAL OF CEDIRANIB IN COMBINATION WITH OLAPARIB VERSUS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Isabel Arrillaga-Romany, Solmaz Sahebjam, David Picconi, Jian Campian, Pierre Giglio, Jan Drappatz, Robert Aiken, John Villano, Eudocia Lee, Mary Welch, Benjamin Ellingson, Douglas Ney, Kevin Becker, Alona Muzikansky, Biswajit Das, Elizabeth Swisher, Andrew Nixon, Chris Karlovich, P Mickey Williams, S Percy Ivy, Tracy Batchelor, Elizabeth Gerstner
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Like most proliferating tumors, GBM relies heavily on accurate DNA repair for maintenance of genome stability. Dysfunction in repair of both single and double strand DNA breaks by PARP inhibition and impairment of homologous recombination, respectively, would be synthetically lethal. In this study we combined the PARP inhibitor olaparib with cediranib, a pan VEGF receptor inhibitor. Cediranib may mediate disruption in the homologous recombination pathway through its antiangiogenic properties. METHODS Through the Experimental Therapeutics Clinical Trials Network, we performed an open-label randomized phase II study of bevacizumab (BEV)- naive adult patients with first or second recurrence of glioblastoma after radiation and temozolomide. Patients were randomized 1:1 to receive either olaparib 200 mg by mouth twice daily with cediranib 30 mg by mouth daily or BEV 10 mg/kg IV every 2 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints included safety and overall survival. Exploratory objectives included blood, tissue and imaging-based biomarkers of response to treatment. RESULTS Seventy patients were enrolled. Median age was 60.5 years (range: 19–79), 39% females, median KPS was 90 (range: 60–100). Baseline characteristics were well balanced. With a data cut-off of 5/2/2019, PFS6 was 14% [95% CI 4–30%] in the cediranib/olaparib arm vs 30.9% [95% CI 12.7–51.2%] in the BEV arm. Median OS was 247 days in the cediranib/olaparib arm vs 201 days in the BEV arm, HR 0.816, 95% CI (0.431, 1.546). Related grade 3, 4 or 5 toxicity was experienced in 29% vs 12% of patients for the cediranib/olaparib vs BEV arm. CONCLUSION Treatment with cediranib/olaparib failed to increase PFS and OS in patients with recurrent GBM. Blood, tissue and imaging correlates will be presented to help understand why this treatment combination was unsuccessful.
Peripheral Blood Absolute Lymphocyte Count at Diagnosis As a New Prognostic Factor in Acute Myeloid Leukemia with t(8;21) Patients
Authors: Jieun Jang, Yu Ri Kim, Hyunsoo Cho, Haerim Chung, Soo-Jeong Kim, Jin Seok Kim, June-Won Cheong, Yoo Hong Min
Journal: Blood (2019)
Androgen Receptor Targeting with Enzalutamide for Mantle Cell Lymphoma: Safety and Efficacy
Authors: Victor A. Chow, Paul S. Martin, Stephen D. Smith, Brian G. Till, Solomon A. Graf, Kerstin L. Edlefsen, Lindsay M. Hannan, Elahe A. Mostaghel, Ajay K. Gopal
Journal: Blood (2019)
Autophagy is induced in prostate cancer by 2-deoxyglucose and is beclin-1 dependent
Authors: Robert DiPaola, Dmitri Dvorzhinski, Michael May, Brian Beaudoin, Eileen White
Journal: Cancer Research (2007)

2767  Meeting the metabolic demands of a tumor cell is challenging due to increased energy utilization and reliance on aerobic glycolysis, making the targeting of metabolism an attractive therapeutic approach for investigation. Autophagy, a regulated cellular process of self digestion, may function to sustain cell survival under conditions of nutrient limitation, or, alternatively, if allowed to continue, result in cell death. We hypothesized that understanding the role of autophagy during treatment of inhibitors of metabolism such as 2-deoxyglucose (2DG), which we are currently studying in an ongoing clinical trial, will be critical to develop future approaches to induce metabolic catastrophe in tumor cells. We found that 2DG induced cytotoxicity in PC-3 and LNCaP cells in a dose dependent fashion. Using a transfected pEGFP-LC3 autophagy reporter construct, we found that 2DG induced LC3 membrane translocation, characteristic of autophagy. Furthermore, knockdown of beclin-1, an essential regulator of autophagy, abrogated the 2DG induced induction of autophagy. Using Western analysis for LC3 protein, we also found increased LC3 expression, again consistent with autophagy. Using immortalized rat prostate cells expressing constituitively active Akt, which activates mTOR and thereby inhibits autophagy, we also demonstrated that the cytotoxic effect of 2DG increased with increased expression of Akt. In an effort to develop markers of autophagy for assessment in clinical trials, we stained human prostate tumors (n=13) and normal tissue (n=35) for Beclin-1 by IHC. Beclin-1 staining was noted in tumor cells, as well as normal epithelial cells, but was increased in tumor tissue compared to normal tissue (p=.003). These data support the potential importance of autophagy as modulating the response of tumor cells to metabolic stress and for the use of metabolic therapeutic approaches; Beclin-1 is an easily measurable marker that requires further study to determine if expression will predict response to studies with agents such as 2DG, which we have ongoing.
Follicular T helper cells shape the HCV-specific CD4+ T cell repertoire after virus elimination
Authors: Maike Smits, Katharina Zoldan, Naveed Ishaque, Zuguang Gu, Katharina Jechow, Dominik Wieland, Christian Conrad, Roland Eils, Catherine Fauvelle, Thomas F. Baumert, Florian Emmerich, Bertram Bengsch, Christoph Neumann-Haefelin, Maike Hofmann, Robert Thimme, Tobias Boettler
Journal: Journal of Clinical Investigation (2019)

BACKGROUNDChronic hepatitis C virus (HCV) infection is characterized by a severe impairment of HCV-specific CD4+ T cell help that is driven by chronic antigen stimulation. We aimed to study the fate of HCV-specific CD4+ T cells after virus elimination.METHODSHCV-specific CD4+ T cell responses were longitudinally analyzed using MHC class II tetramer technology, multicolor flow cytometry, and RNA sequencing in a cohort of patients chronically infected with HCV undergoing therapy with direct-acting antivirals. In addition, HCV-specific neutralizing antibodies and CXCL13 levels were analyzed.RESULTSWe observed that the frequency of HCV-specific CD4+ T cells increased within 2 weeks after initiating direct-acting antiviral therapy. Multicolor flow cytometry revealed a downregulation of exhaustion and activation markers and an upregulation of memory-associated markers. Although cells with a Th1 phenotype were the predominant subset at baseline, cells with phenotypic and transcriptional characteristics of follicular T helper cells increasingly shaped the circulating HCV-specific CD4+ T cell repertoire, suggesting antigen-independent survival of this subset. These changes were accompanied by a decline of HCV-specific neutralizing antibodies and the germinal center activity.CONCLUSIONWe identified a population of HCV-specific CD4+ T cells with a follicular T helper cell signature that is maintained after therapy-induced elimination of persistent infection and may constitute an important target population for vaccination efforts to prevent reinfection and immunotherapeutic approaches for persistent viral infections.FUNDINGDeutsche Forschungsgemeinschaft (DFG, German Research Foundation), the National Institute of Allergy and Infectious Diseases (NIAID), the European Union, the Berta-Ottenstein-Programme for Advanced Clinician Scientists, and the ANRS.
Targeting interleukin-17 in chronic inflammatory disease: A clinical perspective
Authors: Pascale Zwicky, Susanne Unger, Burkhard Becher
Journal: The Journal of Experimental Medicine (2019)

Chronic inflammatory diseases like psoriasis, Crohn’s disease (CD), multiple sclerosis (MS), rheumatoid arthritis (RA), and others are increasingly recognized as disease entities, where dysregulated cytokines contribute substantially to tissue-specific inflammation. A dysregulation in the IL-23/IL-17 axis can lead to inflammation of barrier tissues, whereas its role in internal organ inflammation remains less clear. Here we discuss the most recent developments in targeting IL-17 for the treatment of chronic inflammation in preclinical models and in patients afflicted with chronic inflammatory diseases.
Organoids Reveal That Inherent Radiosensitivity of Small and Large Intestinal Stem Cells Determines Organ Sensitivity
Authors: Maria Laura Martin, Mohammad Adileh, Kuo-Shun Hsu, Guoqiang Hua, Sang Gyu Lee, Christy Li, John D. Fuller, Jimmy A. Rotolo, Sahra Bodo, Stefan Klingler, Adriana Haimovitz-Friedman, Joseph O. Deasy, Zvi Fuks, Philip B. Paty, Richard N. Kolesnick
Journal: Cancer Research (2019)

Tissue survival responses to ionizing radiation are nonlinear with dose, rather yielding tissue-specific descending curves that impede straightforward analysis of biologic effects. Apoptotic cell death often occurs at low doses, while at clinically relevant intermediate doses, double-strand break misrepair yields mitotic death that determines outcome. As researchers frequently use a single low dose for experimentation, such strategies may inaccurately depict inherent tissue responses. Cutting edge radiobiology has adopted full dose survival profiling and devised mathematical algorithms to fit curves to observed data to generate highly reproducible numerical data that accurately define clinically relevant inherent radiosensitivities. Here, we established a protocol for irradiating organoids that delivers radiation profiles simulating the organ of origin. This technique yielded highly similar dose-survival curves of small and large intestinal crypts in vivo and their cognate organoids analyzed by the single-hit multi-target (SHMT) algorithm, outcomes reflecting the inherent radiation profile of their respective Lgr5+ stem cell populations. As this technological advance is quantitative, it will be useful for accurate evaluation of intestinal (patho)physiology and drug screening. SIGNIFICANCE: These findings establish standards for irradiating organoids that deliver radiation profiles that phenocopy the organ of origin.See related commentary by Muschel et al., p. 927.
Comparison of Reduced-Intensity Conditioning (RIC) Regimens for Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Classical Hodgkin Lymphoma (cHL):a Center for International Blood &amp; Marrow Transplant Research (CIBMTR) Analysis
Authors: Sairah Ahmed, Nilanjan Ghosh, Manoj Khanal, Kwang Woo Ahn, Carlos Litovich, Timothy S. Fenske, Mohamed A Kharfan-Dabaja, Anna Sureda, Mehdi Hamadani
Journal: Blood (2019)
Sex-Related Differences in Heart Failure After ST-Segment Elevation Myocardial Infarction
Authors: Edina Cenko, Mihaela van der Schaar, Jinsung Yoon, Olivia Manfrini, Zorana Vasiljevic, Marija Vavlukis, Sasko Kedev, Davor Miličić, Lina Badimon, Raffaele Bugiardini
Journal: Journal of the American College of Cardiology (2019)
Using a Novel Diagnostic Nomogram to Differentiate Malignant from Benign Parathyroid Neoplasms
Authors: Angelica M. Silva-Figueroa, Roland Bassett, Ioannis Christakis, Pablo Moreno, Callisia N. Clarke, Naifa L. Busaidy, Elizabeth G. Grubbs, Jeffrey E. Lee, Nancy D. Perrier, Michelle D. Williams
Journal: Endocrine Pathology (2019)
Chronic TCR-MHC (self)-interactions limit the functional potential of TCR affinity-increased CD8 T lymphocytes
Authors: Minh Ngoc Duong, Efe Erdes, Michael Hebeisen, Nathalie Rufer
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Affinity-optimized T cell receptor (TCR)-engineered lymphocytes targeting tumor antigens can mediate potent antitumor responses in cancer patients, but also bear substantial risks for off-target toxicities. Most preclinical studies have focused on T cell responses to antigen-specific stimulation. In contrast, little is known on the regulation of T cell responsiveness through continuous TCR triggering and consequent tonic signaling. Here, we addressed the question whether increasing the TCR affinity can lead to chronic interactions occurring directly between TCRs and MHC-(self) molecules, which may modulate the overall functional potency of tumor-redirected CD8 T cells. For this purpose, we developed two complementary human CD8 T cell models (i.e. HLA-A2 knock-in and knock-out) engineered with incremental-affinity TCRs to the HLA-A2/NY-ESO-1 tumor antigen. <h3>Methods</h3> The impact of HLA-A2 recognition, depending on TCR affinity, was assessed at the levels of the TCR/CD3 complex, regulatory receptors, and signaling, under steady-state conditions and in kinetic studies. The quality of CD8 T cell responses was further evaluated by gene expression and multiplex cytokine profiling, as well as real-time quantitative cell killing, combined with co-culture assays. <h3>Results</h3> We found that HLA-A2 per se (in absence of cognate peptide) can trigger chronic activation followed by a tolerance-like state of tumor-redirected CD8 T cells with increased-affinity TCRs. HLA-A2<sup>pos</sup> but not HLA-A2<sup>neg</sup> T cells displayed an activation phenotype, associated with enhanced upregulation of c-CBL and multiple inhibitory receptors. T cell activation preceded TCR/CD3 downmodulation, impaired TCR signaling and functional hyporesponsiveness. This stepwise activation-to-hyporesponsive state was dependent on TCR affinity and already detectable at the upper end of the physiological affinity range (K<sub>D</sub> ≤ 1 μM). Similar findings were made when affinity-increased HLA-A2<sup>neg</sup> CD8 T cells were chronically exposed to HLA-A2<sup>pos</sup>-expressing target cells. <h3>Conclusions</h3> Our observations indicate that sustained interactions between affinity-increased TCR and self-MHC can directly adjust the functional potential of T cells, even in the absence of antigen-specific stimulation. The observed tolerance-like state depends on TCR affinity and has therefore potential implications for the design of affinity-improved TCRs for adoptive T cell therapy, as several engineered TCRs currently used in clinical trials share similar affinity properties.