tbuckley/cabot-search huggingface dataset:
A new approach for the quantification of mitochondrial DNA damage and repair in prostate cancer cells
Authors: Jinsong Chen, Fred Kadlubar, Armen Aprikian, Junjian Chen
Journal: Cancer Research (2007)

126   As a gold standard for quantification of starting amounts of nucleic acids, real-time PCR is increasingly used in quantitative analysis of mtDNA copy number in medical research. However, the effect of supercoiling on real-time PCR has not been reported. Using supercoiled plasmid DNA and mtDNA modified both  in vitro  and in cancer cells, we demonstrated that conformational changes in supercoiled DNA have profound influence on real-time PCR quantification. We showed that real-time PCR signal is a positive function of the relaxed forms (open circular and/or linear) rather than the supercoiled form of DNA, and that the conformation transitions mediated by DNA strand breaks are the main basis for sensitive detection of the relaxed DNA. This new finding was then used for sensitive detection of structure-mediated mtDNA damage and repair in stressed prostate cancer cells, and for accurate quantification of total mtDNA copy number when all supercoiled DNA is converted into the relaxed forms using a prior heat-denaturation step. The new approach demonstrated a dynamic mtDNA response to oxidative stress in prostate cancer cells, which involves not only early structural damage and repair but also sustained copy number reduction induced by hydrogen peroxide (H 2 O 2 ). Further analysis of two isogenic prostate cancer cell lines with increasing metastatic potential ( i.e.  LNCaP versus C4-2) revealed differential responses to oxidative damage. The C4-2 cell, an androgen-independent and highly metastatic variant, exhibited increased sensitive to H 2 O 2 -induced mtDNA damage than its parental LNCaP cells. The new findings support the notion that invasive prostate cancers are more susceptible to further oxidative injury probably due to a compromised antioxidant defense or an enhanced level of endogenous ROS production, and may offer new strategies for prostate cancer detection and therapy.
Gordon Anthony Wells Sharrard
Authors: Helen Sharrard
Journal: BMJ (2018)

Gordon Anthony Wells Sharrard was from a medical family and spent his preclinical years at Christchurch College, Oxford. His clinical years were at University College London, where he met his future wife, Margaret, who was a midwife. He started his career training in ear, nose, and throat medicine, with posts in Guildford, Nottingham, at the …
Radiologic Pseudoprogression during Anti–PD-1 Therapy for Advanced Non–Small Cell Lung Cancer
Authors: Sharyn I. Katz, Mark Hammer, Stephen J. Bagley, Charu Aggarwal, Joshua M. Bauml, Jeffrey C. Thompson, Arun C. Nachiappan, Charles B. Simone, Corey J. Langer
Journal: Journal of Thoracic Oncology (2018)
Sorafenib (SFB) low dose in octogenarians with advanced or inoperable (a/i) HCC: Toxicity and efficacy evaluation.
Authors: Ignazio Ugo Carreca
Journal: Journal of Clinical Oncology (2013)

e20719 Background: HCC accounts for approximately 90% of all primary liver cancers, and is the fifth most common cancer in the world. So far prognosis of AHCC is very poor, particularly if consider very elderly pts. Treatment with SFB at standard dose may results in untolerable toxicity especially in very old people with HCC Cancer Aim of the study is to investigate if SFB at reduced dose is efficient and tolerable in octogenarian people with HCC. Methods: 30 patients,16 male and 14 female with AHCC histologically proven were enrolled; mean age was 79. Main Inclusion Criteria: Child-Pugh A or B; adequate liver, hematological, and renal function; informed writed consent acquired. Comprehensive Geriatric Assessment (CGA) according to Balducci’s classification and PFS (ECOG) not greater then 1 were considered as well. Serum CgA, VEGF and αFP were evaluated at baseline. Response evaluation were according to RECIST. Results: Pts received SFB 400 mg p.o., daily until intolerable ADRs or progression disease No discontinuation of treatment was needed for all pts; only 6 pts experienced severe ADRs not discontinued treatment withdrawal was needed. Pts with good OS (median value:11mths) showed also lower values of serum CgA and VEGF better than pts with poor prognosis. This outcome is under investigation. Conclusions: SFB could be administered with “not inferiority criteria vs SFP std treatment. Even if increased age is poor prognostic factor for tolerability, the reduction of dose don’t seem to reduce the efficacy of treatment in this group of patients. On the other hand the minimization of ADRs positively affects the quality of life. Further data were needed to assess how the lower values of serum CgA and VEGF levels, could play a role as new prognostic factors in HCC advanced or inoperable in octogenarian people.
Effect of FK866, NAMPT inhibitor, on small cell lung cancer cell lines.
Authors: Danielle Nicole Desautels, Mathieu Bourrier, Cheryl Peltier, Versha Banerji, Shantanu Otto Banerji
Journal: Journal of Clinical Oncology (2015)

e18562 Background: Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme in the primary salvage pathway for nicotinamide adenine dinucleotide (NAD) synthesis. FK866 is a potent and specific small molecule inhibitor of NAMPT. The objective of this study was to validate the effect of NAD depletion on proliferation, and elucidate mechanism of cell death in small cell lung cancer (SCLC) cell lines. Methods: SCLC chemotherapy-sensitive lines (NCI-H209, NCI-H69, NCI-H446, & DMS79) and a resistant cell line (H69AR) were treated with increasing concentrations of FK866. CellTiter-Glo Luminescent Assay was used to measure ATP to assess cell viability, and the lethal dose 50 (LD50) was determined. A non-SCLC cell line (A549) was treated as a comparator. Treated cell lines were assessed for expression of NAMPT, Bcl-2, PARP and caspase-3 cleavage using Western blot. Chemo-sensitization potential by FK866 to doxorubicin and cisplatin was also evaluated. Results: Cell death measured at 72 hours occurred at very low FK866 concentrations (LD50 range = 0.38-7.2 nM) in both chemotherapy-sensitive and -resistant SCLC cell lines compared to the non-SCLC line (LD50= 100 nM). FK866 did not demonstrate synergy with doxorubicin or cisplatin in SCLC. At 24 hours, evidence of increased apoptosis was not observed as measured by Bcl-2 expression and caspase-3 cleavage, suggesting an alternate mechanism of cell death. Further work to establish mechanism is ongoing. Conclusions: This study confirms that SCLC cell lines are very sensitive to NAMPT inhibition by FK866 in vitro. Phase I clinical trials with FK866 suggest this is a well-tolerated drug. FK866 and related compounds may represent a novel treatment approach for SCLC, especially chemotherapy-resistant disease where active agents are desperately needed.
Efficacy of the hypoxia‐activated prodrug evofosfamide (TH‐302) in nasopharyngeal carcinoma in vitro and in vivo
Authors: Yan Huang, Ying Tian, Yuanyuan Zhao, Cong Xue, Jianhua Zhan, Lin Liu, Xiaobo He, Li Zhang
Journal: Cancer Communications (2018)

Abstract Background Tumor hypoxia is considered an important factor in metastasis and disease relapse. Evofosfamide is a hypoxia‐activated prodrug that selectively targets the hypoxic regions of solid tumors. As hypoxia‐inducible factor‐1α (HIF‐1α) is overexpressed in nasopharyngeal carcinoma (NPC) tissues, we performed the present study to evaluate the efficacy profile of evofosfamide in NPC. Methods We evaluated the efficacy of evofosfamide as a single agent or combined with cisplatin (DDP) in the NPC cell lines CNE‐2, HONE‐1 and HNE‐1, and in nude mouse xenograft tumor models. Results Evofosfamide exhibited hypoxia‐selective cytotoxicity in NPC cell lines, with 50% inhibition concentration (IC 50 ) values of 8.33 ± 0.75, 7.62 ± 0.67, and 0.31 ± 0.07 μmol/L under hypoxia in CNE‐2, HONE‐1 and HNE‐1 cells, respectively. The sensitization ranged from ninefold to greater than 300‐fold under hypoxia compared with normoxia controls. The combination of evofosfamide with DDP had a synergistic effect on cytotoxicity in the NPC cell lines by combination index values assessment. Cell cycle G2 phase was arrested after treated with 0.05 μmol/L evofosfamide under hypoxia. Histone H2AX phosphorylation (γH2AX) (a marker of DNA damage) expression increased while HIF‐1α expression suppressed after evofosfamide treatment under hypoxic conditions. In the HNE‐1 NPC xenograft models, evofosfamide exhibited antitumor activity both as a single agent and combined with DDP. Hypoxic regions in xenograft tissue were reduced after both evofosfamide monotherapy and combined therapy with DDP. Conclusions Our results present preclinical evidence for targeting the selective hypoxic portion of NPC by evofosfamide as a single agent and combined with DDP and provide rationale for the potential clinical application of evofosfamide for the treatment of nasopharyngeal carcinoma.
Correction to: Imipenem–Relebactam and Meropenem–Vaborbactam: Two Novel Carbapenem-β-Lactamase Inhibitor Combinations
Authors: George G. Zhanel, Courtney K. Lawrence, Heather Adam, Frank Schweizer, Sheryl Zelenitsky, Michael Zhanel, Philippe R. S. Lagacé-Wiens, Andrew Walkty, Andrew Denisuik, Alyssa Golden, Alfred S. Gin, Daryl J. Hoban, Joseph P. Lynch, James A. Karlowsky
Journal: Drugs (2018)
Alexander Leslie Florence
Authors: Gill Rutherford
Journal: BMJ (2018)

Alexander Leslie Florence was born in Aberdeenshire, Scotland. He was the first in his family to attend university, graduating from the University of Aberdeen in 1950. He served as a general practitioner in Turriff, Scotland until 1966, after which he and his family moved to Tawa, New Zealand, where he practised until he retired in 1998.

He was known and respected by patients as “Dr Florence—such a good GP,” and his thoroughness and acumen were evident in a letter published in The …
Abstract 20592: Allogeneic c-kit+ Cardiac Progenitor Cells are Hypoimmunogenic and Improve Cardiac Function
Authors: Srinivasa Raju Datla, Yin Guo, Rachana Mishra, Ling Chan, Grace Bigham, Godly Jack, Alfredo Garzino-Demo, Sunjay Kaushal
Journal: Circulation (2016)

Background:  Autologous c-kit +  cardiac progenitor cells (c-kit +  CPCs) and cardio-sphere derived cells (CDCs) were reported to be effective in reducing scar size in myocardial infarction patients. We have recently identified that c-kit +  CPCs have superior cardiac regenerative potentials over CDCs, independent of patient specific characteristics. However, c-kit +  CPCs allogeneic potentials were not been investigated. In this study we compared c-kit +  CPCs  in vitro  and  in vivo  immunological tolerance and  in vivo  cardiac recovery potentials using divergent rat strains.   Methods and Results:  We isolated human c-kit +  CPCs (hc-kit +  CPCs), hCDCs from adult coronary artery bypass graft patients and compared with human mesenchymal stem cells (hMSCs). Human c-kit +  CPCs, CDCs and MSCs expressed major histocompatibility complex (MHC) I but not MHC II and co-stimulatory molecules (CD80 and CD86). In mixed lymphocyte reaction (MLR) assay, co-culture of human peripheral blood monocytes with allogeneic hc-kit +  CPCs, hCDCs and hMSCs elicit negligible T-cell proliferation. To further understand the allogeneic potentials of c-kit +  CPCs, Wistar Kyoto (WKY) rat c-kit +  CPCs (rc-kit +  CPSs) and MSCs (rMSCs) were isolated and evaluated their alloantigen expression, which shows similar pattern as human c-kit +  CPCs and MSCs. Co-culture of rc-kit +  CPCs and rMSCs with Brown Norway (BN) rat lymphocytes failed to induce proliferation of T-cells, which is similar to syngeneic rc-kit +  CPCs and allogeneic rMSCs.  In vivo , intra-myocardial transplantation of allogeneic c-kit +  CPCs recover the cardiac function of myocardial infarction rats. In addition, allogeneic and syngeneic c-kit +  CPCs elicit minimal local, systemic and humoral immune responses compared to xenogeneic c-kit +  CPCs.   Conclusion:  Human and rat allogeneic c-kit +  CPCs are immune tolerant and produce minimal immunological response while maintaining their cardiac recovery potentials in immunologically divergent species. Our observations warrant the development of an allogeneic c-kit +  CPC strategy for clinical trail application.
Phase 1/2 trial of GCLAM with dose-escalated mitoxantrone for newly diagnosed AML or other high-grade myeloid neoplasms
Authors: Anna B. Halpern, Megan Othus, Emily M. Huebner, Bart L. Scott, Pamela S. Becker, Mary-Elizabeth M. Percival, Paul C. Hendrie, Kelda M. Gardner, Tara L. Chen, Sarah A. Buckley, Kaysey F. Orlowski, Asma Anwar, Frederick R. Appelbaum, Harry P. Erba, Elihu H. Estey, Roland B. Walter
Journal: Leukemia (2018)
Novel Richter Syndrome Xenograft Models to Study Genetic Architecture, Biology, and Therapy Responses
Authors: Tiziana Vaisitti, Esteban Braggio, John N. Allan, Francesca Arruga, Sara Serra, Alberto Zamò, Wayne Tam, Amy Chadburn, Richard R. Furman, Silvia Deaglio
Journal: Cancer Research (2018)

Abstract Richter syndrome represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B-cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemoimmunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft (PDX) models of Richter syndrome, RS9737 and RS1316. Richter syndrome xenografts were genetically, morphologically, and phenotypically stable and similar to the corresponding primary tumor. RS9737 was characterized by biallelic inactivation of CDKN2A and TP53, monoallelic deletion of 11q23 (ATM), and mutations of BTK, KRAS, EGR2, and NOTCH1. RS1316 carried trisomy 12 and showed mutations in BTK, KRAS, MED12, and NOTCH2. RNA sequencing confirmed that in both cases &amp;gt;80% of the transcriptome was shared between primary tumor and PDX. In line with the mutational profile, pathway analyses revealed overactivation of the B-cell receptor, NFκB, and NOTCH pathways in both tumors, potentially providing novel tumor targets. In conclusion, these two novel models of Richter syndrome represent useful tools to study biology and response to therapies of this highly aggressive and still incurable tumor. Significance: Two patient-derived xenograft models of Richter syndrome represent the first ex vivo model to study biology of the disease and to test novel therapeutic strategies. Cancer Res; 78(13); 3413–20. ©2018 AACR.
Outcomes of Endoscopic Submucosal Dissection vs Esophagectomy for T1 Esophageal Squamous Cell Carcinoma in a Real-World Cohort
Authors: Yiun Zhang, Han Ding, Tao Chen, Xiaoen Zhang, Wei-Feng Chen, Quanin Li, Liing Yao, Praneet Korrapati, Xue-Juan Jin, Yong-Xing Zhang, Mei-Dong Xu, Ping-Hong Zhou
Journal: Clinical Gastroenterology and Hepatology (2018)
Advances in CD30- and PD-1-targeted therapies for classical Hodgkin lymphoma
Authors: Yucai Wang, Grzegorz S. Nowakowski, Michael L. Wang, Stephen M. Ansell
Journal: Journal of Hematology & Oncology (2018)

CD30 and programmed cell death protein 1 (PD-1) are two ideal therapeutic targets in classical Hodgkin lymphoma (cHL). The CD30 antibody-drug conjugate (ADC) brentuximab vedotin and the PD-1 antibodies nivolumab and pembrolizumab are highly efficacious in treating relapsed and/or refractory cHL. Ongoing studies are evaluating their efficacy in earlier lines of therapy and have demonstrated encouraging results. These agents are expected to further change the landscape of cHL management. Increased cure rates and reduced long-term toxicity from traditional chemotherapy and radiotherapy are likely with the emergence of these novel targeted therapies.
From microscopic to macroscopic sports injuries. Applying the complex dynamic systems approach to sports medicine: a narrative review
Authors: Rafel Pol, Robert Hristovski, Daniel Medina, Natalia Balague
Journal: British Journal of Sports Medicine (2018)

A better understanding of how sports injuries occur in order to improve their prevention is needed for medical, economic, scientific and sports success reasons. This narrative review aims to explain the mechanisms that underlie the occurrence of sports injuries, and an innovative approach for their prevention on the basis of complex dynamic systems approach. First, we explain the multilevel organisation of living systems and how function of the musculoskeletal system may be impaired. Second, we use both, a constraints approach and a connectivity hypothesis to explain why and how the susceptibility to sports injuries may suddenly increase. Constraints acting at multiple levels and timescales replace the static and linear concept of risk factors, and the connectivity hypothesis brings an understanding of how the accumulation of microinjuries creates a macroscopic non-linear effect, that is, how a common motor action may trigger a severe injury. Finally, a recap of practical examples and challenges for the future illustrates how the complex dynamic systems standpoint, changing the way of thinking about sports injuries, offers innovative ideas for improving sports injury prevention.
Incidence, Risk Factors, and Sequelae of Post-kidney Transplant Delirium
Authors: Christine E. Haugen, Alexandra Mountford, Fatima Warsame, Rachel Berkowitz, Sunjae Bae, Alvin G. Thomas, Charles H. Brown, Daniel C. Brennan, Karin J. Neufeld, Michelle C. Carlson, Dorry L. Segev, Mara McAdams-DeMarco
Journal: Journal of the American Society of Nephrology (2018)

Background Frail kidney transplant (KT) recipients may be particularly vulnerable to surgical stressors, resulting in delirium and subsequent adverse outcomes. We sought to identify the incidence, risk factors, and sequelae of post-KT delirium. Methods We studied 125,304 adult KT recipients (1999–2014) to estimate delirium incidence in national registry claims. Additionally, we used a validated chart abstraction algorithm to identify post-KT delirium in 893 adult recipients (2009–2017) from a cohort study of frailty. Delirium sequelae were identified using adjusted logistic regression (length of stay ≥2 weeks and institutional discharge [skilled nursing or rehabilitation facility]) and adjusted Cox regression (death-censored graft loss and mortality). Results Only 0.8% of KT recipients had a delirium claim. In the cohort study, delirium incidence increased with age (18–49 years old: 2.0%; 50–64 years old: 4.6%; 65–75 years old: 9.2%; and ≥75 years old: 13.8%) and frailty (9.0% versus 3.9%); 20.0% of frail recipients aged ≥75 years old experienced delirium. Frailty was independently associated with delirium (odds ratio [OR], 2.05; 95% confidence interval [95% CI], 1.02 to 4.13; P =0.04), but premorbid global cognitive function was not. Recipients with delirium had increased risks of ≥2-week length of stay (OR, 5.42; 95% CI, 2.76 to 10.66; P &lt;0.001), institutional discharge (OR, 22.41; 95% CI, 7.85 to 63.98; P &lt;0.001), graft loss (hazard ratio [HR], 2.73; 95% CI, 1.14 to 6.53; P =0.03), and mortality (HR, 3.12; 95% CI, 1.76 to 5.54; P &lt;0.001). Conclusions Post-KT delirium is a strong risk factor for subsequent adverse outcomes, yet it is a clinical entity that is often missed.
Letter by El-Battrawy et al Regarding Article, “Sex Differences and Similarities in Atrial Fibrillation Epidemiology, Risk Factors, and Mortality in Community Cohorts: Results From the BiomarCaRE Consortium (Biomarker for Cardiovascular Risk Assessment in Europe)”
Authors: Ibrahim El-Battrawy, Martin Borggrefe, Ibrahim Akin
Journal: Circulation (2018)
Depletion of RIPK1 in hepatocytes exacerbates PolyI:C and Murine Hepatitis Virus induced liver damage
Authors: M. Farooq, C. Piquet-Pellorce, S. Dion, M.S. Eugenio, A. Filliol, C. Raguenes-Nicol, M.-T. Dimanche-Boitrel, J.L. Seyec, M. Samson
Journal: Journal of Hepatology (2018)
Responses to Alectinib in ALK-rearranged Papillary Renal Cell Carcinoma
Authors: Sumanta K. Pal, Paulo Bergerot, Nazli Dizman, Cristiane Bergerot, Jacob Adashek, Russell Madison, Jon H. Chung, Siraj M. Ali, Jeremy O. Jones, Ravi Salgia
Journal: European Urology (2018)
Residual Function Effectively Controls Plasma Concentrations of Secreted Solutes in Patients on Twice Weekly Hemodialysis
Authors: Sheldon C. Leong, Justin N. Sao, Abigail Taussig, Natalie S. Plummer, Timothy W. Meyer, Tammy L. Sirich
Journal: Journal of the American Society of Nephrology (2018)

Background Most patients on hemodialysis are treated thrice weekly even if they have residual kidney function, in part because uncertainty remains as to how residual function should be valued and incorporated into the dialysis prescription. Recent guidelines, however, have increased the weight assigned to residual function and thus reduced the treatment time required when it is present. Increasing the weight assigned to residual function may be justified by knowledge that the native kidney performs functions not replicated by dialysis, including solute removal by secretion. This study tested whether plasma concentrations of secreted solutes are as well controlled in patients with residual function on twice weekly hemodialysis as in anuric patients on thrice weekly hemodialysis. Methods We measured the plasma concentration and residual clearance, dialytic clearance, and removal rates for urea and the secreted solutes hippurate, phenylacetylglutamine, indoxyl sulfate, and p -cresol sulfate in nine patients on twice weekly hemodialysis and nine patients on thrice weekly hemodialysis. Results Compared with anuric patients on thrice weekly dialysis with the same standard Kt/V urea , patients on twice weekly hemodialysis had lower hippurate and phenylacetylglutamine concentrations and similar indoxyl sulfate and p -cresol sulfate concentrations. Mathematical modeling revealed that residual secretory function accounted for the observed pattern of solute concentrations. Conclusions Plasma concentrations of secreted solutes can be well controlled by twice weekly hemodialysis in patients with residual kidney function. This result supports further study of residual kidney function value and the inclusion of this function in dialysis adequacy measures.