tbuckley/cabot-search huggingface dataset:
Medicolegal aspects of working while unwell
Authors: Marika Davies
Journal: BMJ (2015)

Many doctors continue to work when they are not feeling their best and take pride in the fact that in doing so they avoid letting down patients and colleagues. But those who do so when they are seriously unwell can put patients at risk of harm and may further damage their own health and career. A doctor’s ill health can have a negative effect on performance and team functioning. Concentration and decisionmaking ability may be diminished, increasing the risk of adverse incidents. Doctors can often underestimate the anxiety that their illness will cause them or the impact it will have on their relationships with patients and colleagues. The first sign of an underlying health problem might be an increase in complaints or reports of difficulties at work. The GeneralMedical Council says in its guidanceGoodMedical Practice that doctors need to protect their patients and colleagues from any risk posed by their illness. “If you know or suspect that you have a serious condition that you could pass on to patients, or if your judgment or performance could be affected by a condition or its treatment, you must consult a suitably qualified colleague,” the guidance states. “You must follow their advice about any changes to your practice they consider necessary,” it continues. The GMC guidance is clear that doctors must not rely on their own assessment of the risk to patients. It may be tempting for doctors to do so, especially when they regularly advise patients on whether or not they are fit to work, and it may also seem easy to consult a colleague or medical family member or friend. However, the decision about whether or not a doctor with a serious medical condition is fit to work is one that needs independent and objective advice. “You should be registered with a general practitioner outside your family,” the GMC says. Doctors are entitled to have information about them kept in confidence by their treating doctors. But they must be aware that those doctors have their own professional obligation to protect patients and may need to disclose relevant information to an appropriate person if they are concerned that others may be at risk of serious harm. This may arise if, for example, a doctor continues to work despite being advised not to do so. Doctors should also be aware that they must let the GMC know if they have a health condition, or a problem with alcohol or drugs, that may affect their ability to care for their patients. The GMC will need to consider whether any steps need to be taken to protect patients, so doctors in this situation should seek advice from their defence organisation at the earliest opportunity.
Osteopenia and osteoporosis in untreated non-Hodgkin's lymphoma patients: An important and potentially treatable survivorship issue in lymphoma
Authors: M. A. Thompson, A. Huen, B. B. Toth, R. Vassilopoulou-Sellin, A. O. Hoff, W. A. Murphy, H. Sanjoro, B. N. Bekele, R. B. Arbuckle, F. B. Hagemeister
Journal: Journal of Clinical Oncology (2007)

9055 Background: Alkylating agents and steroids can cause premature osteoporosis, increasing the risk of vertebral and hip fracture. The bisphosphonate pamidronate every 3 months can reduce bone loss and the risk of new vertebral fractures in lymphoma patients receiving chemotherapy.(Kim et al., 2004 Am J Med) We are conducting a randomized study of the more potent bisphosphonate zoledronic acid in untreated non-Hodgkin's lymphoma (NHL) patients to study chemotherapy induced bone loss. Methods: During the accrual period, we report the baseline bone mineral density (BMD) characteristics for screened untreated NHL patients. Exclusion criteria included bone fractures, BMD T-scores worse than -2.0, CrCl &lt; 60 mL/min, dental problems, prior bisphosphonate or significant steroid use. Patients accrued to the study were randomized to receive either: 1) oral calcium and vitamin D (Ca+D) or 2) Ca+D and 4 mg zoledronic acid IV at baseline and at 6 months. Results: Patient characteristics: 59 males and 55 females with median age 63 (range: 18–87). Lymphoma types: B-cell n=111, T-cell 3; follicular (FL) 56, diffuse large B-cell (DLBCL) 33, mantle cell 8, and others, totaling 114 patients. Of untreated NHL individuals screened for baseline BMD to date 11/114 (10%) had osteoporosis and 62/114 (54%) had osteopenia or osteoporosis. The lowest BMD was a T-score of -4.4. Other bone, dental, and endocrine abnormalities excluded some patients from treatment randomization. Patients with T scores &lt; -2.0 were considered for off-study treatment with bisphosphonates. Osteopenia and osteoporosis were common across lymphoma subtypes: FL 25/56 (45%), DLBCL 20/33 (61%), mantle cell 6/8 (75%), and marginal zone 5/6 (83%). The low rate of osteopenia/osteoporosis of 25% for Burkitt/Burkitt-like lymphoma may reflect fast lymphoma kinetics without associated increase in bone loss. Conclusions: Baseline testing of BMD revealed osteopenia or osteoporosis in the majority of untreated NHL patients. This widely available and non-invasive test should be considered in untreated NHL patients. Our ongoing clinical trial will address the potential role of zoledronic acid in preserving bone density for survivors of NHL. ClinicalTrials.gov Identifier: NCT00352846 [Table: see text]
Next-generation sequencing of the basal cell carcinoma miRNome and a description of novel microRNA candidates under neoadjuvant vismodegib therapy: an integrative molecular and surgical case study
Authors: M. Sand, F.G. Bechara, T. Gambichler, D. Sand, M.R. Friedländer, M. Bromba, R. Schnabel, S. Hessam
Journal: Annals of Oncology (2015)
Abstract 20359: Long Term Valvular Outcomes With Patients Supported With HVAD and HeatMate II LVADS
Authors: Scott C Silvestry, Angela D Keith, Toshinobu Kazui, Susan M Joseph, Gregory A Ewald, Akinobu Itoh
Journal: Circulation (2014)

Purpose:  The natural history of mitral and tricuspid insufficiency at LVAD implantation and the progression of aortic insufficiency (AI) with continuous flow cfLVADs may alter the effectiveness of prolonged VAD support. To date, no study has examined differences in valvular outcomes between different cfLVADs.   Methods:  We retrospectively reviewed echocardiographic assessments from primary HeartMate II (HMII) or HVAD LVAD implants between 1/16/09 and 5/24/13. We estimated the effect of cfLVADs on valvular function by calculating the change in valve dysfunction from the preoperative to the last postoperative assessment. A chi-square test was used for categorical variables and a t-test was used for continuous variables.   Results:  The average follow up in days for HMII patients (n=151) was 307.3 +/- 310.8and 208.1 +/- 235.6 for HVAD patients (n=21) (p=0.102). The average age was 55.5 +/- 13.5 and 59.0 +/- 12.1 for HMII and HVAD respectively (p=0.093). Pulmonary artery systolic pressures (PASP) were not different between the groups at implant. Post implantation, a significantly lower percentage of HVAD patients experienced worsened AI with a total of 20.0% progressing 1 (10.0%) or 2 (10.0%) grades vs a total of 38.8% in the HMII group progressed by 1 (8.3%), 2 (27.1%), and 3 (3.5%) grades (p=0.03). No difference was seen between devices regarding the change in mitral or tricuspid valve function (p=0.38 and p=0.42, respectively). No patient in either group underwent isolated procedures for AI. Post implant, both devices significantly improved PASP (p=0.00001), with HVAD (n=14) further reducing PASP (24.0 +/- 8.6 mmHg) compared to HMII (n=117) mean PASP of 31.2 +/- 10.7 mmHg (p= 0.01).   Conclusions:  Progression of AI was significantly less in HVAD patients compared to HMII patients. Mitral insufficiency did not differ between the groups, but PASP was reduced further in HVAD patients suggesting greater unloading was achieved. The reason for the observed differences is not clear but may be related to mechanistic differences between pumps, differences in outflow graft sizes, or aortic anastomosis induced turbulence in the aortic root.
A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non–Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib
Authors: Ji Yun Lee, Jong-Mu Sun, Sung Hee Lim, Hae Su Kim, Kwai Han Yoo, Ki Sun Jung, Haa-Na Song, Bo Mi Ku, Jiae Koh, Yeon-Hee Bae, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
Journal: Clinical Cancer Research (2015)

Abstract Purpose: In this phase Ib/II study, we aimed to assess the safety and efficacy of afatinib plus nimotuzumab (N) in advanced non–small cell lung cancer (NSCLC) patients with acquired resistance to gefitinib or erlotinib. Experimental Design: In phase Ib stage, patients received afatinib (40 mg or 30 mg once daily) plus nimotuzumab (100 mg or 200 mg once weekly) for 28-day cycles to determine the recommended phase II dose (RPIID). The safety and efficacy of RPIID dose was evaluated in phase II stage. Results: In total, 50 patients were enrolled (13 to phase Ib and 37 to phase II). In the first dose-finding cohort (afatinib 40 mg plus nimotuzumab 100 mg), one patient experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and in the subsequent cohort (afatinib 40 mg plus nimotuzumab 200 mg), two DLTs (grade 3 diarrhea and grade 3 neutropenia) occurred in 2 of 6 patients. Accordingly, RPIID was determined as afatinib 40 mg plus nimotuzumab 100 mg. In 44 patients treated with RPIID, 7 (16%) patients had grade 3 toxicities; skin rash (7%), diarrhea (5%), acne (2%), and fatigue (2%). The overall response rate was 23% and the median duration of response was 4.3 months (range, 0.7–16.2 months). The median progression-free survival and overall survival were 4.0 months [95% confidence interval (CI), 2.3–5.7 months] and 11.7 months (95% CI, 9.4–14.0 months), respectively. Conclusions: Combination treatment of afatinib and nimotuzumab demonstrated an acceptable safety profile and encouraging antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib. Larger phase III trial is warranted to confirm its efficacy and safety. Clin Cancer Res; 22(9); 2139–45. ©2015 AACR.
Myeloproliferative neoplasms: Morphology and clinical practice
Authors: Tiziano Barbui, Jürgen Thiele, Alessandro M. Vannucchi, Ayalew Tefferi
Journal: American Journal of Hematology (2015)

In myeloproliferative neoplasms (MPNs), controversy persists regarding the usefulness and reproducibility of bone marrow (BM) features. Disagreements concerning the WHO classification are mainly focused on the discrimination between essential thrombocythemia (ET) and prefibrotic/early primary myelofibrosis (prePMF) and prodromal polycythemia vera (PV). Criticism mostly refers to lack of standardization of distinctive BM features precluding correct morphological pattern recognition. The distinction between WHO-defined ET and prePMF is not trivial because outcome is significantly worse in prePMF. Morphology was generally considered to be non-specific for the diagnosis of PV. Recent studies have revealed under-diagnosis of morphologically and biologically consistent PV.
Derivation of genetic biomarkers for cancer risk stratification in Barrett’s oesophagus: a prospective cohort study
Authors: Margriet R Timmer, Pierre Martinez, Chiu T Lau, Wytske M Westra, Silvia Calpe, Agnieszka M Rygiel, Wilda D Rosmolen, Sybren L Meijer, Fiebo J W ten Kate, Marcel G W Dijkgraaf, Rosalie C Mallant-Hent, Anton H J Naber, Arnoud H A M van Oijen, Lubbertus C Baak, Pieter Scholten, Clarisse J M Böhmer, Paul Fockens, Carlo C Maley, Trevor A Graham, Jacques J G H M Bergman, Kausilia K Krishnadath
Journal: Gut (2015)

<h3>Objective</h3> The risk of developing adenocarcinoma in non-dysplastic Barrett9s oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. <h3>Methods</h3> In a prospective cohort of patients with non-dysplastic Barrett9s oesophagus, we evaluated six molecular markers: <i>p16</i>, <i>p53</i>, <i>Her-2/neu</i>, <i>20q</i>, <i>MYC</i> and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis. <h3>Results</h3> A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barrett9s length, and the markers, <i>p16</i> loss, <i>MYC</i> gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an 'Abnormal Marker Count' that counted abnormalities in <i>p16, MYC</i> and aneusomy, which significantly improved risk prediction beyond using just age and Barrett9s length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95% CI 0.66 to 0.86). <h3>Conclusions</h3> A prediction model based on age, Barrett9s length and the markers <i>p16, MYC</i> and aneusomy determines progression risk in non-dysplastic Barrett9s oesophagus.
A comprehensive haplotype analysis of IGF-1 and breast cancer risk: the multiethnic cohort
Authors: V. Wendy Setiawan, Iona Cheng, Daniel Stram, Kathryn Penney, Loic Le Marchand, David Altshuler, Joel Hirschhorn, Brian Henderson, Matthew Freedman
Journal: Cancer Research (2005)

2555  A number of experimental and epidemiologic studies support the role of Insulin-Like Growth Factor-1 (IGF-1) in the etiology of breast cancer. We employed a haplotype-based association approach to examine the contribution of common genetic variation at the IGF-1 locus to breast cancer risk among African-American, Hawaiian, Japanese, Latina and White women in the Multiethnic Cohort Study (MEC). We characterized linkage disequilibrium and haplotype patterns at the IGF-1 locus by genotyping 64 densely spaced single-nucleotide polymorphisms (SNPs) (1 SNP per 2.4 kb) spanning 156 kb in a multiethnic panel (N=69-70 for each ethnic group) (Cheng et al). Four distinct haplotype blocks, ranging from 11 to 60 kb, were identified and within each block, six to ten common haplotypes (i.e. frequency ≥ 5%) were observed. Twenty-nine haplotype-tagging SNPs (htSNPs) were selected to predict the common haplotypes with high probability (average Rh2=0.86) and genotyped in a large breast cancer case-control study of 1,716 cases and 2,505 controls. The frequency of the common haplotypes predicted by the htSNPs in the multiethnic panel were similar to those observed in the larger sample of cases and controls. Odds Ratios (OR) and 95% confidence intervals for each haplotype were estimated using all other haplotypes as the reference group. All analyses were adjusted for age and also for ethnicity in any analysis that combined all five ethnic groups. Global likelihood ratio tests of common haplotype effects in each block were not significant (P > 0.4). Assessment of individual haplotype effect within each block and single SNP analysis also yielded no significant association with breast cancer risk. Analysis of cases with advanced disease only (N=447) did not alter the results. Our findings suggest that common genetic variation in IGF-1 is not a major contributor to breast cancer susceptibility in this multiethnic cohort. We are currently examining the relationship between IGF-1 haplotypes and circulating IGF-1 levels and also between two genes that produce IGF binding proteins, IGFBP-1 and IGFBP-3, with breast cancer risk.
Definition and initial validation of a Lupus Low Disease Activity State (LLDAS)
Authors: Kate Franklyn, Chak Sing Lau, Sandra V Navarra, Worawit Louthrenoo, Aisha Lateef, Laniyati Hamijoyo, C Singgih Wahono, Shun Le Chen, Ou Jin, Susan Morton, Alberta Hoi, Molla Huq, Mandana Nikpour, Eric F Morand
Journal: Annals of the Rheumatic Diseases (2015)

Aims Treating to low disease activity is routine in rheumatoid arthritis, but no comparable goal has been defined for systemic lupus erythematosus (SLE). We sought to define and validate a Lupus Low Disease Activity State (LLDAS). Methods A consensus definition of LLDAS was generated using Delphi and nominal group techniques. Criterion validity was determined by measuring the ability of LLDAS attainment, in a single-centre SLE cohort, to predict non-accrual of irreversible organ damage, measured using the Systemic Lupus International Collaborating Clinics Damage Index (SDI). Results Consensus methodology led to the following definition of LLDAS: (1) SLE Disease Activity Index (SLEDAI)-2K ≤4, with no activity in major organ systems (renal, central nervous system (CNS), cardiopulmonary, vasculitis, fever) and no haemolytic anaemia or gastrointestinal activity; (2) no new lupus disease activity compared with the previous assessment; (3) a Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI physician global assessment (scale 0–3) ≤1; (4) a current prednisolone (or equivalent) dose ≤7.5 mg daily; and (5) well tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents. Achievement of LLDAS was determined in 191 patients followed for a mean of 3.9 years. Patients who spent greater than 50% of their observed time in LLDAS had significantly reduced organ damage accrual compared with patients who spent less than 50% of their time in LLDAS (p=0.0007) and were significantly less likely to have an increase in SDI of ≥1 (relative risk 0.47, 95% CI 0.28 to 0.79, p=0.005). Conclusions A definition of LLDAS has been generated, and preliminary validation demonstrates its attainment to be associated with improved outcomes in SLE.
Author's reply
Authors: C. Butler, N. Stott
Journal: BMJ (1995)

The MHC class II transactivator (CIITA) is a critical regulator of MHC class II genes and other genes involved in the Ag presentation pathway. CIITA-deficient mice lack MHC class II expression on almost all APCs. In this study, we show that these mice also have aberrant Fas ligand expression on both CD4 T cells and B cells. We found that Fas ligand expression was greatly increased on CIITA-deficient CD4 T cells during the Th1 differentiation process. However, both CIITA-deficient and control Th1 effector cells up-regulated Fas ligand to similar levels if cells were reactivated. The introduction of CIITA into primary CD4 T cells via retroviral infection resulted in a reduction in the level of Fas ligand and delay in apoptosis after activation. Interestingly, activated B cells from the CIITA-deficient mice also showed increased levels of Fas ligand that could be to some degree inhibited by the introduction of IL-4.
The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase
Authors: Tatiana Erazo, Mar Lorente, Anna López-Plana, Pau Muñoz-Guardiola, Patricia Fernández-Nogueira, José A. García-Martínez, Paloma Bragado, Gemma Fuster, María Salazar, Jordi Espadaler, Javier Hernández-Losa, Jose Ramon Bayascas, Marc Cortal, Laura Vidal, Pedro Gascón, Mariana Gómez-Ferreria, José Alfón, Guillermo Velasco, Carles Domènech, Jose M. Lizcano
Journal: Clinical Cancer Research (2015)

Abstract Purpose: ABTL0812 is a novel first-in-class, small molecule which showed antiproliferative effect on tumor cells in phenotypic assays. Here we describe the mechanism of action of this antitumor drug, which is currently in clinical development. Experimental Design: We investigated the effect of ABTL0812 on cancer cell death, proliferation, and modulation of intracellular signaling pathways, using human lung (A549) and pancreatic (MiaPaCa-2) cancer cells and tumor xenografts. To identify cellular targets, we performed in silico high-throughput screening comparing ABTL0812 chemical structure against ChEMBL15 database. Results: ABTL0812 inhibited Akt/mTORC1 axis, resulting in impaired cancer cell proliferation and autophagy-mediated cell death. In silico screening led us to identify PPARs, PPARα and PPARγ as the cellular targets of ABTL0812. We showed that ABTL0812 activates both PPAR receptors, resulting in upregulation of Tribbles-3 pseudokinase (TRIB3) gene expression. Upregulated TRIB3 binds cellular Akt, preventing its activation by upstream kinases, resulting in Akt inhibition and suppression of the Akt/mTORC1 axis. Pharmacologic inhibition of PPARα/γ or TRIB3 silencing prevented ABTL0812-induced cell death. ABTL0812 treatment induced Akt inhibition in cancer cells, tumor xenografts, and peripheral blood mononuclear cells from patients enrolled in phase I/Ib first-in-human clinical trial. Conclusions: ABTL0812 has a unique and novel mechanism of action, that defines a new and drugable cellular route that links PPARs to Akt/mTORC1 axis, where TRIB3 pseudokinase plays a central role. Activation of this route (PPARα/γ-TRIB3-Akt-mTORC1) leads to autophagy-mediated cancer cell death. Given the low toxicity and high tolerability of ABTL0812, our results support further development of ABTL0812 as a promising anticancer therapy. Clin Cancer Res; 22(10); 2508–19. ©2015 AACR.
Transplantation of adipose tissue mesenchymal cells conjugated with VEGF-releasing microcarriers promotes repair in murine myocardial infarction
Authors: Rosalinda Madonna, Lyubomir Petrov, Maria Anna Teberino, Lamberto Manzoli, Jean-Pierre Karam, Francesca Vera Renna, Peter Ferdinandy, Claudia N. Montero-Menei, Seppo Ylä-Herttuala, Raffaele De Caterina
Journal: Cardiovascular Research (2015)

RationaleEngraftment and survival of transplanted stem or stromal cells in the microenvironment of host tissues may be improved by combining such cells with scaffolds to delay apoptosis and enhance regenerative properties. AimsWe examined whether poly(lactic-co-glycolic acid) pharmacologically active microcarriers (PAMs) releasing vascular endothelial growth factor (VEGF) enhance survival, differentiation, and angiogenesis of adipose tissue-mesenchymal stromal cells (AT-MSCs).We analysed the efficacy of transplanted AT-MSCs conjugated with PAMs in a murine model of acute myocardial infarction (AMI). Methods and resultsWe used fibronectin-coated (empty) PAMs or VEGF-releasing PAMs covered with murine AT-MSCs.Twelve-monthold C57 mice underwent coronary artery ligation to induce AMI, and were randomized into five treatment groups: AMI control (saline 20 mL, n ¼ 7), AMI followed by intramyocardial injection with AT-MSCs (2.5 × 10 5 cells/20 mL, n ¼ 5), or concentrated medium (CM) from AT-MSCs (20 mL, n ¼ 8), or AT-MSCs (2.5 × 10 5 cells/20 mL) conjugated with empty PAMs (n ¼ 7), or VEGF-releasing PAMs (n ¼ 8).Sham-operated mice (n ¼ 7) were used as controls.VEGF-releasing PAMs increased proliferation and angiogenic potential of AT-MSCs, but did not impact their osteogenic or adipogenic differentiation.AT-MSCs conjugated with VEGF-releasing PAMs inhibited apoptosis, decreased fibrosis, increased arteriogenesis and the number of cardiac-resident Ki-67 positive cells, and improved myocardial fractional shortening compared with AT-MSCs alone when transplanted into the infarcted hearts of C57 mice.With the exception of fractional shortening, all such effects of AT-MSCs conjugated with VEGF-PAMs were paralleled by the injection of CM. ConclusionsAT-MSCs conjugated with VEGF-releasing PAMs exert paracrine effects that may have therapeutic applications.
Hepatocyte Growth Factor/Scatter Factor Promotes Adhesion of Lymphoma Cells to Extracellular Matrix Molecules Via α4β1 and α5β1 Integrins
Authors: Iris S. Weimar, Daphne de Jong, Egbert J. Muller, Toshikazu Nakamura, Joost M.H.H. van Gorp, Gijsbert C. de Gast, Winald R. Gerritsen
Journal: Blood (1997)