tbuckley/cabot-search huggingface dataset:
The Business Case for Investing in Physician Well-being
Authors: Tait Shanafelt, Joel Goh, Christine Sinsky
Journal: JAMA Internal Medicine (2017)

Widespread burnout among physicians has been recognized for more than 2 decades. Extensive evidence indicates that physician burnout has important personal and professional consequences.A lack of awareness regarding the economic costs of physician burnout and uncertainty regarding what organizations can do to address the problem have been barriers to many organizations taking action. Although there is a strong moral and ethical case for organizations to address physician burnout, financial principles (eg, return on investment) can also be applied to determine the economic cost of burnout and guide appropriate investment to address the problem. The business case to address physician burnout is multifaceted and includes costs associated with turnover, lost revenue associated with decreased productivity, as well as financial risk and threats to the organization's long-term viability due to the relationship between burnout and lower quality of care, decreased patient satisfaction, and problems with patient safety. Nearly all US health care organizations have used similar evidence to justify their investments in safety and quality. Herein, we provide conservative formulas based on readily available organizational characteristics to determine the financial return on organizational investments to reduce physician burnout. A model outlining the steps of the typical organization's journey to address this issue is presented. Critical ingredients to making progress include prioritization by leadership, physician involvement, organizational science/learning, metrics, structured interventions, open communication, and promoting culture change at the work unit, leader, and organization level.Understanding the business case to reduce burnout and promote engagement as well as overcoming the misperception that nothing meaningful can be done are key steps for organizations to begin to take action. Evidence suggests that improvement is possible, investment is justified, and return on investment measurable. Addressing this issue is not only the organization's ethical responsibility, it is also the fiscally responsible one.
Mutational Analysis of Gene Fusions Predicts Novel MHC Class I–Restricted T-Cell Epitopes and Immune Signatures in a Subset of Prostate Cancer
Authors: Jennifer L. Kalina, David S. Neilson, Yen-Yi Lin, Phineas T. Hamilton, Alexandra P. Comber, Emma M.H. Loy, S. Cenk Sahinalp, Colin C. Collins, Faraz Hach, Julian J. Lum
Journal: Clinical Cancer Research (2017)

Purpose: Gene fusions are frequently found in prostate cancer and may result in the formation of unique chimeric amino acid sequences (CASQ) that span the breakpoint of two fused gene products. This study evaluated the potential for fusion-derived CASQs to be a source of tumor neoepitopes, and determined their relationship to patterns of immune signatures in prostate cancer patients.Experimental Design: A computational strategy was used to identify CASQs and their corresponding predicted MHC class I epitopes using RNA-Seq data from The Cancer Genome Atlas of prostate tumors. In vitro peptide-specific T-cell expansion was performed to identify CASQ-reactive T cells. A multivariate analysis was used to relate patterns of in silico-predicted tumor-infiltrating immune cells with prostate tumors harboring these mutational events.Results: Eighty-seven percent of tumors contained gene fusions with a mean of 12 per tumor. In total, 41% of fusion-positive tumors were found to encode CASQs. Within these tumors, 87% gave rise to predicted MHC class I-binding epitopes. This observation was more prominent when patients were stratified into low- and intermediate/high-risk categories. One of the identified CASQ from the recurrent TMPRSS2:ERG type VI fusion contained several high-affinity HLA-restricted epitopes. These peptides bound HLA-A*02:01 in vitro and were recognized by CD8+ T cells. Finally, the presence of fusions and CASQs were associated with expression of immune cell infiltration.Conclusions: Mutanome analysis of gene fusion-derived CASQs can give rise to patient-specific predicted neoepitopes. Moreover, these fusions predicted patterns of immune cell infiltration within a subgroup of prostate cancer patients. Clin Cancer Res; 23(24); 7596-607. ©2017 AACR.
Arterial Stiffness and Incidence of Diabetes: A Population-Based Cohort Study
Authors: Iram Faqir Muhammad, Yan Borné, Gerd Östling, Cecilia Kennbäck, Mikael Gottsäter, Margaretha Persson, Peter M. Nilsson, Gunnar Engström
Journal: Diabetes Care (2017)

Diabetes is known to be associated with increased arterial stiffness. However, the temporal association between increased carotid-femoral pulse wave velocity (c-f PWV) and diabetes is unclear. The aim of this study is to explore the relationship between arterial stiffness, as determined by c-f PWV, and incidence of diabetes.The study population included participants from the Malmö Diet and Cancer cardiovascular cohort, using measurements from the 2007-2012 reexamination as baseline. Arterial stiffness was evaluated by measuring c-f PWV (SphygmoCor). After excluding participants with prevalent diabetes (according to measurements of fasting glucose, oral glucose tolerance tests, and physician's diagnoses), the final study population consisted of 2,450 individuals (mean age = 71.9 ± 5.6 years). Incidence of diabetes was followed by linkage to local and national diabetes registers. Cox proportional hazards regression was used to assess the incidence of diabetes in relation to the tertiles of c-f PWV, adjusted for potential confounders.During a mean follow-up of 4.43 ± 1.40 years, 68 (2.8%) participants developed diabetes. Crude incidence of diabetes (per 1,000 person-years) was 3.5, 5.7, and 9.5, respectively, for subjects in the first, second, and third tertiles of c-f PWV. After adjustment for potential confounders, the hazard ratio of diabetes was 1.00 (reference), 1.83 (95% CI 0.88-3.8), and 3.24 (95% CI 1.51-6.97), respectively, for the tertiles of c-f PWV (P for trend = 0.002).Increased c-f PWV is associated with increased incidence of diabetes, independent of other risk factors. These results suggest that increased arterial stiffness is an early risk marker for developing diabetes.
Clinical implication of serine metabolism associated enzymes expression in colorectal cancer.
Authors: Shinkyo Yoon, Byung Wook Kang, Jong Gwang Kim, Ghil Suk Yoon, An Na Seo, Su Yeon Park, Hye Jin Kim, Jun Seok Park, Gyu Seog Choi
Journal: Journal of Clinical Oncology (2015)

e14644 Background: The metabolic characteristic of cancer cell is an increase in glycolysis instead of oxidative respiration. Recently, it was suggested that the metabolic switch in oncogenesis is regulated by enzymes of serine synthetic pathway (SSP). Therefore, we assessed the expression of enzymes of SSP in colorectal tumor tissue (TT) and paired normal tissue (pNT) and investigated their clinical implications as prognostic marker. Methods: This study was conducted for patients with histologically confirmed CRC who underwent curative surgery at Kyungpook National University Hospital. Phosphoglycerate dehydrogenase (PHGDH) and pyruvate dehydrogenase kinase (PDK) 1, PDK2, pyruvate kinase M2 (PKM2), phosphoserine aminotransferase (PSAT) expression was investigated by immunohistochemical staining (IHC) in TT and pNT using tissue microarrays. For measuring IHC intensity, we divided into four groups as follows: 0 (-), 1 (+), 2 (++), and 3 (+++). For measuring the proportion of stained cells, we divided into five groups as follows: 0 (0%), 1 (1-25%), 2 (26-50%), 3 (51-75%) and 4 (76-100%). IHC values for PHGDH, PDK1, PDK2, PKM2, and PSAT were calculated by multiplying IHC intensity to the proportion. The final score was classified as follows: 0-2 as negative and 3-12 as positive. Results: From September 2006 to December 2010, a total of 486 patients with CRC were included in this study. The median age was 66 years (30-90). The pathologic stage according to AJCC 7th edition was as follows: stage I 98/486 (20.2%); stage II 213/486 (43.8%); stage III 175/486 (36.0%). During the median follow-up duration of 55.5 months (37.4-90.6), 78 patients had recurrence. The expression of PHGDH, PDK1, and PSAT was significantly higher in TT than pNT (p < 0.001 for each enzymes). Univariate analysis for relapse-free survival revealed that TT PDK2 positivity was the only positive prognostic factor (p = 0.047). However, expression of TT PDK2 could not have prognostic value in multivariate analysis. In addition, p53 overexpression using IHC did not correlate with any enzymes of SSP. Conclusions: PHGDH, PDK1, and PSAT were increased in colorectal TT compared to pNT. The prognostic implication of these enzymes needs to be further investigated.
Genetically Confirmed Familial Hypercholesterolemia in Patients With Acute Coronary Syndrome
Authors: Almudena Amor-Salamanca, Sergio Castillo, Emiliano Gonzalez-Vioque, Fernando Dominguez, Lucía Quintana, Carla Lluís-Ganella, Juan Manuel Escudier, Javier Ortega, Enrique Lara-Pezzi, Luis Alonso-Pulpon, Pablo Garcia-Pavia
Journal: Journal of the American College of Cardiology (2017)
Performance of the myelofibrosis secondary to PV and ET-prognostic model (MYSEC-PM) in a series of 262 patients from the Spanish registry of myelofibrosis
Authors: J-C Hernández-Boluda, A Pereira, J-G Correa, A Alvarez-Larrán, F Ferrer-Marín, J-M Raya, J Martínez-López, M Pérez-Encinas, N Estrada, P Velez, M-L Fox, V García-Gutiérrez, A Payer, A Kerguelen, B Cuevas, M-A Durán, M-J Ramírez, M-T Gómez-Casares, M-I Mata-Vázquez, E Mora, C Martínez-Valverde, M Gómez, F Cervantes
Journal: Leukemia (2017)
Protein kinase D inhibitor CRT0066101 suppresses bladder cancer growth in vitro and in vivo through induction of cell cycle arrest at the G2-M phase.
Authors: Qingdi Quentin Li, Iawen Hsu, Thomas Sanford, Reema S. Railkar, Piyush K. Agarwal
Journal: Journal of Clinical Oncology (2017)

e16024 Background: Protein Kinase D (PKD) is implicated in tumor growth, death, invasion, and progression. CRT0066101 is an inhibitor of PKD and has antitumor activity in several types of carcinomas. However, the effect and mechanism of CRT0066101 in bladder cancer remain unknown. Methods: The MTS assay was used to evaluate the ability of CRT0066101 to inhibit cellular proliferation in bladder cancer cells. Cell cycle was analyzed by flow cytometry. Protein expression and phosphorylation were assessed by western blotting. Results: We showed that CRT0066101 suppressed the proliferation and migration of 4 bladder cancer cell lines in vitro. We also demonstrated that CRT0066101 inhibited tumor growth in an in vivo mouse model of bladder cancer. To verify the role of PKD in bladder tumor, we found that PKD2 was highly expressed in 8 bladder cancer lines and that RNA interference-mediated silencing of the PKD2 gene dramatically reduced bladder cancer growth in vitro and in vivo, suggesting that the effect of the compound in bladder cancer is mediated through inhibition of PKD2. This notion was confirmed by demonstrating that the levels of PKD2 and phospho-PKD2 (Ser-876) were markedly decreased in CRT0066101-treated bladder cancer. In addition, our cell cycle analysis by flow cytometry revealed that CRT0066101 arrested bladder cancer cells at the G2-M phase. We further validated these data by immunoblotting showing that treatment of bladder carcinoma cells with CRT0066101 downregulated the expression of cyclin B1, cdc2 and cdc25C, but elevated the levels of p27 kip1 , gadd45a, chk1/2, and wee1. Finally, CRT0066101 was found to increase the phosphorylation of cdc2 and cdc25C, which lead to reduction in cdc2-cyclin B1 activity. Conclusions: These novel findings suggest that CRT0066101 inhibits bladder cancer growth through modulating the cell cycle G2 checkpoint and inducing cell cycle G2-M arrest, which lead to blockade of cell cycle progression. QQL and IH contributed equally to this work.
Interstrand crosslinking of DNA by C-1311 (Symadex) and other imidazoacridinones
Authors: Jerzy K. Konopa, Marcin Koba, Agnieszka Dyrcz
Journal: Cancer Research (2005)

5873  Imidazoacridinones are a group of antitumor agents, developed in our laboratory, which include C-1311 (Symadex) currently evaluated in phase I of clinical studies. Preliminary data on the ability of C-1311 to induce interstrand DNA crosslinking of DNA in tumor cells after previous metabolic activation have been already presented (Proc. 87th AACR Meeting, abstr. 2800, 1998). Recent investigations showed that C-1311 induces, in a dose dependent manner the formation of interstrand crosslinking in several tumor cells of human origin (colon cancer HT29, HCT-8, breast cancer MCF7 and lung cancer A-549) sensitive to this drug (EC50 0.01-1x10-6M). Detection of formation of DNA crosslink by the modified Parson‘s method (Biochem. Pharmacol. 47, 2279, 1994) was possible only in the case of cells pretreated (for 18 hrs) with aurinotricarboxylic acid (ATA). ATA inhibits topoisomerase II binding to DNA and thereby prevents drug induced DNA strand scission while integrity of DNA is a prerequisite for the detection of DNA crosslinking by Parson‘s method. Imidazoacridinones inhibited activity of topoisomerase II by blocking cleavable complexes of this enzyme with DNA (Mol. Pharmacol. 49, 772, 1996), which as it was explained above, hampers the detection of DNA crosslink formation. The application of this approach revealed that there is only slight correlation between the ability of formation of DNA crosslink and cytotoxic activity of C-1311 in the cells pretreated with ATA. To avoid pretreatment of cells with ATA, which complicates the interpretations of observed effects, we studied crosslinking of DNA in cells exhibiting low levels of topoisomerase II. To such cells the confluent fibroblast NIH3T3 cells belong in which the activity of topoisomerase II α disappears entirely, and remains only the activity of topoisomerase II β (20% of total) (J. Biol. Chem. 271, 16741, 1996). In confluent NIH3T3 cells, we observed the formation of interstrand DNA crosslinks in a dose and time depedent manner by C-1311 and 10 other imidazoacridinones of divergent cytotoxic activity (EC50 0.05-5x10-7M). However, we do not observe correlation between the ability to crosslink DNA and cytotoxic activity of imidazoacridinones studied. These results thus do not allow to reason about the impact of capability of DNA crosslinking on biological activity of imidazoacridinones.
Massive bleeding after plastic stent removal during ERCP: what’s next?
Authors: Marcos Lera, Mauricio Minata, Ralph Duarte, Sergio Matuguma, Paulo Sakai, Wellington Andraus, Eduardo de Moura
Journal: Endoscopy (2017)

Portal biliopathy or portal cavernoma cholangiopathy refers to cholangiographic abnormalities, which occur in patients with portal cavernoma. These include shallow bile duct impressions and indentations causing wall irregularity, smooth strictures with upstream dilatation, and luminal filling defects ([Fig. 1], [Fig. 2]). These changes occur as a result of pressure on bile ducts from bridging tortuous paracholedochal, epicholedochal, and cholecystic veins [1]. Symptoms of portal cavernoma cholangiopathy include longstanding jaundice due to chronic cholestasis, or biliary pain with or without cholangitis due to biliary stones [2].
The immune system in cancer metastasis: friend or foe?
Authors: Louise M.E. Janssen, Emma E. Ramsay, Craig D. Logsdon, Willem W. Overwijk
Journal: Journal for ImmunoTherapy of Cancer (2017)

Metastatic disease is the leading cause of death among cancer patients and involves a complex and inefficient process. Every step of the metastatic process can be rate limiting and is influenced by non-malignant host cells interacting with the tumor cell. Over a century ago, experiments first indicated a link between the immune system and metastasis. This phenomenon, called concomitant immunity, indicates that the primary tumor induces an immune response, which may not be sufficient to destroy the primary tumor, but prevents the growth of a secondary tumor or metastases. Since that time, many different immune cells have been shown to play a role in both inhibiting and promoting metastatic disease. Here we review classic and new observations, describing the links between the immune system and metastasis that inform the development of cancer therapies.
Rare tumor clinic: The UCSD Moores Cancer Center experience with a precision therapy approach.
Authors: Shumei Kato, Kellie Kurasaki, Sadakatsu Ikeda, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2017)

11578 Background: Rare tumors have an incidence of &lt; 15/100,000 per year; utra-rare, prevalence &lt; 2000 in the USA. Patients (pts) may lack approved treatments and clinical trial access. Although each rare tumor is uncommon, cumulatively they account for &gt; 20% of cancers. We recently initiated a Rare Tumor Clinic that emphasized a precision medicine strategy (genomic and proteomic analysis and individualized therapy). We report our preliminary experience. Methods: We investigated outcome among the first 40 pts presenting to the Rare Tumor Clinic at UC San Diego Moores Center for Personalized Cancer Therapy. Whenever possible, next-generation sequencing (NGS) of tissue and plasma-derived circulating tumor DNA (ctDNA) as well as proteomic markers were assessed. Results: Median age was 58 (range, 31 – 78 yo); 70% (28/40) were women; median number of previous systemic therapies, 2 (range, 0-7). The most common diagnoses were sarcoma (N = 7) for solid tumors; Erdheim-Chester disease (N = 5), for hematologic malignancies. Twenty distinct diagnoses were seen. Examples of ultra-rare tumors included ameloblastoma, yolk sac liver tumor, ampullary cancer, Castleman's disease, and desmoid tumor. 82.5% of pts (33/40) had tissue NGS (182 to 405 genes); 7.5% (3/40), inadequate tissue. The median number of characterized tissue alterations was 3 (range, 0 to 24); 32 pts (80%) had ≥1 characterized genomic alteration. 33 pts (82.5%) had ctDNA analysis; 15 pts had ≥1 characterized alteration. Among those 15 pts, median number of characterized alterations was 3 (range, 1 to 14). 92.5% (37/40) of pts had ≥ 1 actionable target based on either genomic (32 pts) or proteomic markers (27 pts) (FDA-approved [mostly off-label] or investigational agent). 52.5% (21/40) received matched therapy; 52.4% (11/21) achieved SD≥6 months (N = 3)/CR (N = 2)/PR (N = 6). Matched therapy resulted in significantly longer PFS compared to last prior unmatched therapy (HR: 0.26, 95% CI: 0.10 – 0.71 [p = 0.008]). Conclusions: Identifying genomic and proteomic markers in pts with rare and ultra-rare tumors was feasible. When therapies were matched, &gt; 50% of pts attained SD≥6 months/CR/PR. Further clinical investigations focusing on rare and ultra-rare tumors are urgently needed.
One in 10 parents with child in neonatal care don’t see consultant in 24 hours, audit finds
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

The care delivered in 2016 to around 95 000 babies admitted to UK neonatal units was better than in 2015, but continuing variation in practice meant that babies in some parts of the country were much less likely to get the care they needed, an audit has found.1

Results of the National Neonatal Audit Programme, published by the Royal College of Paediatrics and Child Health, showed that among preterm babies 94% (8597) had timely screening for retinopathy of prematurity in England, Scotland, and Wales in 2016. In the Shropshire, Staffordshire, and Black Country neonatal network this outcome improved from 87% in 2015 to 98% in 2016. …
Lenalidomide Up-Regulates SPARC and Inhibits In Vitro Growth of the Malignant Clone in Myelodysplastic Syndrome Patients with 5q Deletion.
Authors: Andrea Pellagatti, Martin Jädersten, Ann-Mari Forsblom, Helen Cattan, Birger Christensson, Emma K. Emanuelsson, Mats Merup, Lars Nilsson, Jan Samuelsson, Birgitta Sander, James S. Wainscoat, Jacqueline Boultwood, Eva Hellström-Lindberg
Journal: Blood (2006)
Foot orthoses for plantar heel pain: a systematic review and meta-analysis
Authors: Glen A Whittaker, Shannon E Munteanu, Hylton B Menz, Jade M Tan, Chantel L Rabusin, Karl B Landorf
Journal: British Journal of Sports Medicine (2017)

Objective To investigate the effectiveness of foot orthoses for pain and function in adults with plantar heel pain. Design Systematic review and meta-analysis. The primary outcome was pain or function categorised by duration of follow-up as short (0 to 6 weeks), medium (7 to 12 weeks) or longer term (13 to 52 weeks). Data sources Medline, CINAHL, SPORTDiscus, Embase and the Cochrane Library from inception to June 2017. Eligibility criteria for selecting studies Studies must have used a randomised parallel-group design and evaluated foot orthoses for plantar heel pain. At least one outcome measure for pain or function must have been reported. Results A total of 19 trials (1660 participants) were included. In the short term , there was very low-quality evidence that foot orthoses do not reduce pain or improve function. In the medium term , there was moderate-quality evidence that foot orthoses were more effective than sham foot orthoses at reducing pain (standardised mean difference −0.27 (−0.48 to −0.06)). There was no improvement in function in the medium term. In the longer term , there was very low-quality evidence that foot orthoses do not reduce pain or improve function. A comparison of customised and prefabricated foot orthoses showed no difference at any time point. Conclusion There is moderate-quality evidence that foot orthoses are effective at reducing pain in the medium term, however it is uncertain whether this is a clinically important change.
Figures show big increase in outstanding general practice premises fees
Authors: Gareth Iacobucci
Journal: BMJ (2017)

General practices in England owe more than £90m (€103m; $120m) to NHS Property Services in outstanding premises fees, official figures have shown.

The figures were disclosed in parliament by the health minister Philip Dunne in response to a request from Labour’s shadow health minister Justin Madders.1 They show that the total costs charged to GP tenants of NHS Property Services that remain outstanding were £9m in 2014-15, £28m in 2015-16, and £55m in 2016-17.

The disclosure came as talks continued between the BMA and the NHS Property Services in a bid to resolve the ongoing dispute over substantial increases that the agency had applied to GPs’ rent and service charges.

NHS Property Services is a limited company owned by the Department of …