tbuckley/cabot-search huggingface dataset:
Margaret McCartney: Bruce Keogh’s letter to junior doctors: the importance of independence
Authors: Margaret McCartney
Journal: BMJ (2016)

Independence is so vital a quality, so cherished, that wars have been repeatedly fought over it. In medicine, independence is about ethics. Having independence reflects individual autonomy and is an inherent safety device. When we make up our minds independently we reduce bias, particularly “groupthink.” We protect ourselves against acting in others’ interests rather than those of the patient or person we should be focused on. We ensure that whistleblowers can act.

When independence has been threatened, we’re right to be alarmed. Conflicts in medicine are everywhere, and we can’t get rid of them all. Rather, we have to protect ourselves from undue, conflicting influence by remaining as independent as possible.

The Quality and Outcomes Framework created low value box ticking, …
Abstract 4775: Statins Prevent Poor Short and Mid-term Outcome associated with Post Operative Atrial Fibrillation after Coronary Artery Bypass Grafting
Authors: Nicolas Girerd, Philippe Pibarot, Pascal Daleau, Pierre Voisine, Gilles O'Hara, Jean-Pierre Despres, Patrick Mathieu
Journal: Circulation (2008)

Background: Postoperative atrial fibrillation (POAF) is a frequent complication of coronary artery bypass grafting (CABG) surgery. Although it has been associated with higher postoperative morbidit...
Attitudes on terminal sedation, physician assisted suicide and euthanasia in oncology personnel, oncological patients and relatives
Authors: V. Maier, A. Kunitz, P. C. Thuss-Patience
Journal: Journal of Clinical Oncology (2007)

9068 Background: This survey was performed to elucidate and compare the attitudes on end of life management of participants actively affected by/involved in oncology either as a doctor, nurse, patient or a relative. Methods: In this questionnaire based survey performed in Berlin, Germany, approved by the local ethics committee, 4 groups of participants (oncology doctors (D), oncology nurses (N), oncology patients (P) and relatives (R)) were asked about their attitudes on the management of terminally ill oncological patients. Participants were asked to mark their maximal ethically accepted management of a specific case from a series of 10 destinct management options (opt). These options were destilled into 4 groups ranging from sole pain control (SYM)(opt 1) at the bottom of the scale, through to terminal sedation (SED)(opt 2–4), physician assisted suicide (SUI)(opt 5–7) and finally active euthanasia (EUT)(opt 8–10) at the top of the scale. Each participant marked his attitude by putting himself in the role of the treating physician, in the role of the patient described in the case and in the role of a legislative body. Results: 435 questionnaires distributed, 185 returned (42.5%). Participants: D: 58 N: 61 P: 30 R: 36. All participants answering 1) in the role of a treating physician, 2) in the role of a terminally ill patient, 3) in the role of a legislative body. Table shows attitudes of a) all participants and of the 4 subgroups of participants b) doctors, c) nurses, d) relatives, e) patients. Conclusions: Only a minority of participants would themselves perform or assist in active life terminating measurements (SUI+EUT)(23%), more participants would wish for themselves active measurements (SUI+EUT)(30%) and significantly more participants are for legislation to allow active measurements (SUI+EUT)(47%). Medical personnel (doctors equally as nurses) are significantly more reluctant to assist/perform or wish for themselves active measurements (SUI+EUT) than relatives and patients. [Table: see text] No significant financial relationships to disclose.
Treatment of refractory metastatic renal cell carcinoma (RCC) with bevacizumab and RAD001.
Authors: L. C. Harshman, A. McMillan, S. Srinivas
Journal: Journal of Clinical Oncology (2010)

TPS236 Background: Targeting mutations and alterations in growth factor pathways central to RCC pathogenesis has resulted in the broad implementation of the so-called targeted therapies. These agents achieve impressive clinical outcomes, most notably in the form of disease stabilization and prolongation of progression-free survival, but durable complete response rates have remained elusive. Combinations of these cytostatic therapies have great potential to improve efficacy and to escape tumoral resistance mechanisms, but enhanced or supraadditive toxicity is a valid concern. We are investigating a combination of bevacizumab, a monoclonal antibody against VEGF-A, and RAD001 (everolimus), an oral mTOR inhibitor. A prior phase II study of patients who had received zero or one prior targeted therapies demonstrated acceptable toxicity and good clinical benefit with this regimen. This study intends to validate the safety and preliminary efficacy of the combination, but expand its use to include more advanced patients who have had two prior targeted therapies and treated brain metastasis. Correlative studies are assessing novel predictive biomarkers of response and efficacy. Methods: This phase II investigator-initiated, single-arm study is evaluating RAD001 and bevacizumab in metastatic RCC patients who have failed one or two prior multityrosine kinase inhibitors. Nine of 30 patients have been accrued at Stanford Cancer Center. Cycles are 28 days. Bevacizumab is administered by intravenous infusion every two weeks at a dose of 10 mg/kg over 30-90 minutes. RAD001 is orally dosed at 10 mg daily. Patients are treated until disease progression by RECIST criteria or unacceptable toxicity. The primary endpoint is progression-free survival. Secondary endpoints include safety, tolerability, response rate, time to treatment failure, and overall survival. Fasting glucose and lipids are being evaluated as potential biomarkers for RAD001 activity. Serum VEGF levels will be correlated with bevacizumab response. A translational study prospectively validating our prior findings of increased hemoglobin and other erythrocytic indices as markers of improved progression-free survival with VEGF inhibitors is also underway. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Novartis
Protein Delivery of an Artificial Transcription Factor Restores Widespread Ube3a Expression in an Angelman Syndrome Mouse Brain
Authors: Barbara J Bailus, Benjamin Pyles, Michelle M McAlister, Henriette O'Geen, Sarah H Lockwood, Alexa N Adams, Jennifer Trang T Nguyen, Abigail Yu, Robert F Berman, David J Segal
Journal: Molecular Therapy (2016)

Angelman syndrome (AS) is a neurological genetic disorder caused by loss of expression of the maternal copy of UBE3A in the brain. Due to brain-specific genetic imprinting at this locus, the paternal UBE3A is silenced by a long antisense transcript. Inhibition of the antisense transcript could lead to unsilencing of paternal UBE3A, thus providing a therapeutic approach for AS. However, widespread delivery of gene regulators to the brain remains challenging. Here, we report an engineered zinc finger-based artificial transcription factor (ATF) that, when injected i.p. or s.c., crossed the blood–brain barrier and increased Ube3a expression in the brain of an adult mouse model of AS. The factor displayed widespread distribution throughout the brain. Immunohistochemistry of both the hippocampus and cerebellum revealed an increase in Ube3a upon treatment. An ATF containing an alternative DNA-binding domain did not activate Ube3a. We believe this to be the first report of an injectable engineered zinc finger protein that can cause widespread activation of an endogenous gene in the brain. These observations have important implications for the study and treatment of AS and other neurological disorders. Angelman syndrome (AS) is a neurological genetic disorder caused by loss of expression of the maternal copy of UBE3A in the brain. Due to brain-specific genetic imprinting at this locus, the paternal UBE3A is silenced by a long antisense transcript. Inhibition of the antisense transcript could lead to unsilencing of paternal UBE3A, thus providing a therapeutic approach for AS. However, widespread delivery of gene regulators to the brain remains challenging. Here, we report an engineered zinc finger-based artificial transcription factor (ATF) that, when injected i.p. or s.c., crossed the blood–brain barrier and increased Ube3a expression in the brain of an adult mouse model of AS. The factor displayed widespread distribution throughout the brain. Immunohistochemistry of both the hippocampus and cerebellum revealed an increase in Ube3a upon treatment. An ATF containing an alternative DNA-binding domain did not activate Ube3a. We believe this to be the first report of an injectable engineered zinc finger protein that can cause widespread activation of an endogenous gene in the brain. These observations have important implications for the study and treatment of AS and other neurological disorders.
Poly-paclitaxel/cyclodextrin-SPION nano-assembly for magnetically guided drug delivery system
Authors: Hyeonjeong Jeon, Jihoon Kim, Yeong Mi Lee, Jinhwan Kim, Hyung Woo Choi, Junseok Lee, Hyeongmok Park, Youngnam Kang, In-San Kim, Byung-Heon Lee, Allan S. Hoffman, Won Jong Kim
Journal: Journal of Controlled Release (2016)
NHS choir’s number one hit puts health service in media spotlight over Christmas
Authors: Zosia Kmietowicz
Journal: BMJ (2016)

“I’m sure more improbable things have happened, but I can’t think of any,” said

Eddie Chaloner, a member of the Lewisham & Greenwich NHS Choir, which hit the top of the UK singles chart this Christmas with the song “A Bridge Over You” (https://www.youtube.com/watch?v=T8qHXlShfUQ).

The song clinched the number one slot from Justin Bieber on Christmas Day, outselling the Canadian singer’s song “Love Yourself” by 30 000 copies (127 000 versus 97 000). In the first chart of 2016 the song had dropped to number 29.

Chaloner, a consultant vascular surgeon at University Hospital Lewisham, said that Bieber was “very helpful” when he tweeted his 72 million followers: “I’m hearing this UK Christmas race is close . . . but the NHS Choir single is for charity.”

The choir, which includes all types of NHS staff, was …
Impact of High-Dose Chemotherapy on Peripheral T-Cell Lymphomas
Authors: Jose Rodriguez, Mark Munsell, Salim Yazji, Fredrick B. Hagemeister, Anas Younes, Borje Andersson, Sergio Giralt, James Gajewski, Marcos de Lima, Daniel Couriel, Jorge Romaguera, Fernando F. Cabanillas, Richard E. Champlin, Issa F. Khouri
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To evaluate the outcome of high-dose chemotherapy (HDCT) and autologous or allogeneic hematopoietic transplantation in patients with peripheral T-cell lymphoma (PTCL) who experienced disease recurrence after prior conventional chemotherapy. PATIENTS AND METHODS: We performed a retrospective analysis of 36 PTCL patients from the University of Texas M.D. Anderson Cancer Center treated between 1989 and 1998 with HDCT and autologous or allogeneic hematopoietic transplantation. RESULTS: A total of 36 patients were studied (29 received autologous transplantation, and seven received allogeneic transplantation). The overall survival rate at 3 years was 36% (95% confidence interval [CI], 23% to 59%), and the progression-free survival (PFS) rate was 28% (95% CI, 16% to 49%). The pretransplant serum lactate dehydrogenase level was the most important prognostic factor for both survival and PFS rates (P &lt; .001). A Pretransplant International Prognostic Index score of ≤ 1 indicated a superior survival rate (P = .036) but not an improved PFS rate. A median follow-up of 43 months (range, 13 to 126 months) showed 13 patients (36%) were still alive with no evidence of disease. CONCLUSION: Our results are comparable to the published data on HDCT in B-cell non-Hodgkin’s lymphoma (NHL) patients despite the fact that patients with PTCL are known to have a worse outcome compared with B-cell NHL patients. Considering the dismal outcome of conventional chemotherapy in PTCL patients, these data suggest the hypothesis that the poor prognostic implication of T-cell phenotyping in NHL might be overcome by frontline HDCT and transplantation.
Microbiota-induced obesity requires farnesoid X receptor
Authors: Ava Parséus, Nina Sommer, Felix Sommer, Robert Caesar, Antonio Molinaro, Marcus Ståhlman, Thomas U Greiner, Rosie Perkins, Fredrik Bäckhed
Journal: Gut (2016)

Objective The gut microbiota has been implicated as an environmental factor that modulates obesity, and recent evidence suggests that microbiota-mediated changes in bile acid profiles and signalling through the bile acid nuclear receptor farnesoid X receptor (FXR) contribute to impaired host metabolism. Here we investigated if the gut microbiota modulates obesity and associated phenotypes through FXR. Design We fed germ-free (GF) and conventionally raised (CONV-R) wild-type and Fxr−/− mice a high-fat diet (HFD) for 10 weeks. We monitored weight gain and glucose metabolism and analysed the gut microbiota and bile acid composition, beta-cell mass, accumulation of macrophages in adipose tissue, liver steatosis, and expression of target genes in adipose tissue and liver. We also transferred the microbiota of wild-type and Fxr -deficient mice to GF wild-type mice. Results The gut microbiota promoted weight gain and hepatic steatosis in an FXR-dependent manner, and the bile acid profiles and composition of faecal microbiota differed between Fxr−/− and wild-type mice. The obese phenotype in colonised wild-type mice was associated with increased beta-cell mass, increased adipose inflammation, increased steatosis and expression of genes involved in lipid uptake. By transferring the caecal microbiota from HFD-fed Fxr−/− and wild-type mice into GF mice, we showed that the obesity phenotype was transferable. Conclusions Our results indicate that the gut microbiota promotes diet-induced obesity and associated phenotypes through FXR, and that FXR may contribute to increased adiposity by altering the microbiota composition.
Phase I trial of neoadjuvant and postoperative paclitaxel (P), carboplatin (C) and erlotinib with concurrent accelerated hyperfractionation radiation (AHFR) followed by erlotinib maintenance therapy in stage III non-small cell lung cancer (NSCLC)
Authors: T. Mekhail, T. Rice, S. Murthy, D. Adelstein, G. Videtic, P. Mazzone, D. Mason, N. Agrawal, C. Giannini, R. Bukowski
Journal: Journal of Clinical Oncology (2005)

2091 Background: Erlotinib (E), a potent reversible Her1/EGFR tyrosine kinase inhibitor is a radiosensitizer in preclinical studies. Our study was conducted to determine the recommended dose of E when given with P, C and AHFR before/after surgery in patients (pts) with potentially resectable stage III NSCLC. Methods: Pts had biopsy-proven Stage III NSCLC, and ECOG performance status of 0/1. Treatment Plan was: 1) Induction AHFR (30 Gy/1.5 Gy BID), with concurrent P [50 mg/m2] C (AUC 2), weekly x 3, and E at 3 dose levels (DL); I: 50, II: 100, and III: 150 mg, orally once daily (qd) for 4 weeks (wks); 2) Surgery after 4 wks; 3) a second identical course of chemoradiotherapy (CRT) 4–6 wks postoperatively; 4) 2-year maintenance of a fixed dose of E (150 mg qd). 3 to 6 pts were treated at each DL of E. A dose level was deemed intolerable if greater than or equal to 2 of 6 pts develop a dose-limiting toxicity (DLT). Results: Between 8/03 and 11/04, 6 male and 3 female pts were enrolled, 4 at DL I, 3 at DL II, 2 at DL III. Median age was: 61(range 33–68) years. All pts completed induction treatment. 7 pts had surgery (3 lobectomy; 4 pneumonectomy). One patient (pt) progressed; 1 pt was deemed unresectable. 6 of 9 pts received postoperative CRT + E. No DLT was observed at DL I or DL II. One pt at DL 3 had prolonged postoperative recovery from respiratory failure (grade IV toxicity). Common grade I-II toxicities were, rash (6 pts), diarrhea (3 pts), and esophagitis (3 pts). One pt at DL I had reversible posterior leucoencephalopathy, thought to be unrelated to treatment. There were no unexpected surgical complications, and no treatment-related mortality. 4 pts were downstaged at surgery; to stage I: 1 pt, stage II: 2, and 1 pt had complete pathologic response. Maintenance E was started in 6 pts. 7 of 9 pts are progression free at a mean follow-up of 9.1 months (range: 5–15). Additional pts are being treated at DL III to further characterize toxicity. Conclusion: Erlotinib in combination with concurrent weekly P/C/AHFR is well tolerated. The recommended dose of E has not yet been determined. A phase II study is planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis, Genentech, Lilly Oncology, Pfizer, Bayer, Antigenics Amgen, Pfizer, Eyetech, Genentech, Genentech Genentech, Pfizer, Celgene, Antigenics, Amgen, Wyeth
Ubiquitin phosphorylation in Parkinson’s disease: Implications for pathogenesis and treatment
Authors: Lih-Shen Chin, Lian Li
Journal: Translational Neurodegeneration (2016)

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized primarily by the loss of dopaminergic neurons in substantia nigra. The pathogenic mechanisms of PD remain unclear, and no effective therapy currently exists to stop neurodegeneration in this debilitating disease. The identification of mutations in mitochondrial serine/threonine kinase PINK1 or E3 ubiquitin-protein ligase parkin as the cause of autosomal recessive PD opens up new avenues for uncovering neuroprotective pathways and PD pathogenic mechanisms. Recent studies reveal that PINK1 translocates to the outer mitochondrial membrane in response to mitochondrial depolarization and phosphorylates ubiquitin at the residue Ser65. The phosphorylated ubiquitin serves as a signal for activating parkin and recruiting autophagy receptors to promote clearance of damaged mitochondria via mitophagy. Emerging evidence has begun to indicate a link between impaired ubiquitin phosphorylation-dependent mitophagy and PD pathogenesis and supports the potential of Ser65-phosphorylated ubiquitin as a biomarker for PD. The new mechanistic insights and phenotypic screens have identified multiple potential therapeutic targets for PD drug discovery. This review highlights recent advances in understanding ubiquitin phosphorylation in mitochondrial quality control and PD pathogenesis and discusses how these findings can be translated into novel approaches for PD diagnostic and therapeutic development.
Bleeding and Quality of Life∗
Authors: Andrzej Budaj
Journal: Journal of the American College of Cardiology (2016)

It is well-recognized that bleeding during hospitalization for acute coronary syndrome (ACS) or following percutaneous coronary intervention is associated with an increased risk of subsequent adverse outcomes, including death, myocardial infarction (MI), stroke, and stent thrombosis [(1–3)][1].
Triplet chemotherapy (TC) with FOLFIRINOX regimen in metastatic colorectal cancer (mCRC): Experience of two French centres.
Authors: Emmanuelle Samalin, Christelle De La Fouchardiere, Simon Thézenas, Matthieu Sarabi, Eric Assenat, Fabienne Portales, Sebastien Carrere, Michel Rivoire, Philippe Rouanet, Jean-Pierre Bleuse, François Quenet, Marc Ychou
Journal: Journal of Clinical Oncology (2015)

776 Background: TC is a treatment option for mCRC to improve the tumour response rate in selected patients (pts) and the conversion rate of initially nonresectable liver metastases. The aim of this study was to evaluate the impact and feasibility of FOLFIRINOX regimen in mCRC pts. Methods: We selected all mCRC pts from the ICM and CLB French centres with unresectable disease treated from October 2000 to May 2012 with FOLFIRINOX alone or combined with bevacizumab or cetuximab. Clinical data were collected in a mCRC-specific data base and analysed. Results: 159 pts (52% of men), median age 58 yrs (range: 24-76) were treated with FOLFIRINOX (D1 oxaliplatin 85 mg/m² IV over 2H, then irinotecan 180 mg/m² IV over 90 min and elvorin 200 mg/m², then 5-fluorouracile 200 mg/m² and 2,400 mg/m² IV over 46H, D1=D15) alone (68%) or combined with cetuximab (24%) or bevacizumab (8%) as first–line treatment (88%). Primary tumour was located in colon (77%) or rectum (23%), and 134 pts (84%) presented with synchronous metastases: liver (96%), lung (46%), peritoneum (11%) and nodes (20%). Median number of courses was 8 (range: 1-26). There was 1 toxic death. Grade 3-4 toxicities were as follows: diarrhoea (23%), neuropathy (24%), cutaneous (9%), neutropenia (21%), febrile neutropenia (1%), thrombopenia (4%). Objective response rate according to RECIST V1.0 was 72% [95% CI: 65-79] including 12 pts with complete response. The primary tumour was resected in 127 pts (79%) and 19% had KRAS mutated tumour. Among the 105 pts (66%) with initially non-resectable liver-limited disease (LLD), 59 pts (56%) were eligible for secondary resection and a R0 resection rate was achieved for 44 pts. Median overall survival was 49 months [95% CI: 37-62] and 72 months [95% CI: 48-84] in resected LLD population. Conclusions: These results confirm the feasibility of FOLFIRINOX regimen with or without targeted therapies and its efficacy in LLD selected mCRC population.
Standard cisplatin and etoposide (PE)-based chemotherapy in young adult patients with pineal germinomas.
Authors: O. Feher, N. Formiga, Alessandro Leal, Rodrigo Santa Cruz Guindalini, Vinicius Carrera de Souza, Erlon Gil, Jose Augusto Rinck, Paulo M. Hoff
Journal: Journal of Clinical Oncology (2010)

e12547 Background: Pineal germ cell tumors are very rare, accounting for less than 1% of all intracranial tumors. The peak incidence occurs in the second decade of life. The mainstay of therapy is radiation, especially for germinomas that are very radiosensitive. Leptomeningeal dissemination and histology seem to confer a higher risk for recurrence after radiation. These tumors are also very sensitive to chemotherapy. Attempts to decrease the dose and field of radiation or even to avoid radiotherapy at all have been published. However, the experience with the adult population is very limited. We review retrospectively our experience in adult patients with PGCT that received cisplatin and etoposide-based (PE) chemotherapy in two Brazilian instituition in the last five years. Methods: Consecutive review of patient charts of the last five years of two Brazilian instituitions (Instituto do Cancer de São Paulo and Hospital A. C. Camargo). Results: In the last 5 years we identified 6 young adult patients bearing a PGCT that received PE-based chemotherapy. Median age 21 years (range 17 – 31); all male; all had germinomatous histology; all presented with intracranial hypertension. All patients recieved 45 Gy radiotherapy to the main tumor volume and three recieved 36 Gy spinal irradiation. Four patients received chemotherapy upfront and two patients at relapse after radiotherapy. The main reason for adding chemotherapy to the primary therapy was leptomeningeal involvement in three patients and delay in definitive diagnosis in another one (this patient was erroneously diagnosed initially as a menigioma). Chemotherapy regimens were PEB (cisplatin, etoposide and bleomycin) in four patients and PE in two. Five patients received 4 cycles and one received 3 cycles. Survival data is as follows: of the six patients, five are alive and free of relapse at 9+, 15+, 32+, 52+, 60+ months. One patient died of recurrent systemic disease. Conclusions: Standard PE-based chemotherapy seems to be highly effective when combined to low-dose craniospinal radiotherapy in pineal germinomas in young adult patients. It could be considered as a backbone for future protocols aiming to decrease dose and/or field of radiotherapy in these tumors. No significant financial relationships to disclose.