tbuckley/cabot-search huggingface dataset:
Adjuvant Systemic Therapy and Adjuvant Radiation Therapy for Stage I to IIIA Completely Resected Non–Small-Cell Lung Cancers: American Society of Clinical Oncology/Cancer Care Ontario Clinical Practice Guideline Update
Authors: Mark G. Kris, Laurie E. Gaspar, Jamie E. Chaft, Erin B. Kennedy, Christopher G. Azzoli, Peter M. Ellis, Steven H. Lin, Harvey I. Pass, Rahul Seth, Frances A. Shepherd, David R. Spigel, John R. Strawn, Yee C. Ung, Michael Weyant
Journal: Journal of Clinical Oncology (2017)

Purpose The panel updated the American Society of Clinical Oncology (ASCO) adjuvant therapy guideline for resected non-small-cell lung cancers. Methods ASCO convened an update panel and conducted a systematic review of the literature, investigating adjuvant therapy in resected non-small-cell lung cancers. Results The updated evidence base covered questions related to adjuvant systemic therapy and included a systematic review conducted by Cancer Care Ontario current to January 2016. A recent American Society for Radiation Oncology guideline and systematic review, previously endorsed by ASCO, was used as the basis for recommendations for adjuvant radiation therapy. An update of these systematic reviews and a search for studies related to radiation therapy found no additional randomized controlled trials. Recommendations Adjuvant cisplatin-based chemotherapy is recommended for routine use in patients with stage IIA, IIB, or IIIA disease who have undergone complete surgical resections. For individuals with stage IB, adjuvant cisplatin-based chemotherapy is not recommended for routine use. However, a postoperative multimodality evaluation, including a consultation with a medical oncologist, is recommended to assess benefits and risks of adjuvant chemotherapy for each patient. The guideline provides information on factors other than stage to consider when making a recommendation for adjuvant chemotherapy, including tumor size, histopathologic features, and genetic alterations. Adjuvant chemotherapy is not recommended for patients with stage IA disease. Adjuvant radiation therapy is not recommended for patients with resected stage I or II disease. In patients with stage IIIA N2 disease, adjuvant radiation therapy is not recommended for routine use. However, a postoperative multimodality evaluation, including a consultation with a radiation oncologist, is recommended to assess benefits and risks of adjuvant radiation therapy for each patient with N2 disease. Additional information is available at www.asco.org/lung-cancer-guidelines and www.asco.org/guidelineswiki .
Abstract 155: C-kit+ Cardiac Progenitor Cells Contain a Subpopulation of Slowly Adherent Cells With Higher Cardiomyogenic and Pro-angiogenic Profile
Authors: Shahab Ghafghazi, Rakesh Ponnapureddy, Mitesh Solanki, Sorabh Sharma, Pramod Kayathi, Bhavna Sharma, Roberto Bolli, Marcin Wysoczynski
Journal: Circulation Research (2015)

Background: Isolation of a pure population of cardiomyogenic cardiac stem cells (CPCs) has been the Holy-Grail in cardiac regeneration. C-kit, a cell surface receptor, has been proposed as a marker of CPCs and the result of multiple preclinical studies and a phase I clinical trial has been encouraging. Nonetheless, optimization of isolation methods is desirable given the heterogeneity of c-kit positive CPCs. We hypothesize that isolation of c-kit positive CPCs based on differential adhesion identifies a superior population of cells. Methods: Non-adherent cells from digested murine hearts were transferred to successive flasks at 2, 4, 24, 48 and 72 hours. Hence, 5 fractions of cells were isolated based on their adhesion profile and labeled rapidly-adherent (1 and 2) and slowly-adherent (3 to 5). Cells were then expanded and sorted based on c-kit expression and expanded to seven passages. Cells were analyzed for surface markers and cardiomyogenic and pluripotent expression profile by flow-cytometry and real-time polymerase chain reaction. Differentiation potential of the two fractions was examined and their paracrine profile compared using human umbilical vein endothelial cells and neonatal rat cardiomyocytes. Results: C-kit expression was maintained in the slowly-adherent fraction while precipitously dropping in the rapidly-adherent one. In addition, the former expressed lower levels of mesenchymal/fibroblast (CD90.2) and macrophage (CD11b/CD45) markers and higher levels of pluripotent (Oct-4, Nanog, Dppa-3, Rif) and cardiac markers (Nkx2.5, Gata4, Mybpc3 and cTnI) comparing to the latter. Finally, slowly-adherent CPCs had superior paracrine profile compared to rapidly-adherent one. Conclusion: C-kit positive CPCs cells isolated from murine myocardium are heterogeneous and better isolation methods are required to enrich a purer population of cardiomyogenic stem cells. In that vein, isolation of c-kit positive CPCs based on their adhesion profile identifies a subpopulation of cells capable of maintaining c-kit positivity and superior in terms of cariomyogenic and pro-angiogenic potential.
P03.21 Casp9 germline mutation in a family with multiple brain tumors
Authors: M. W. Ronellenfitsch, J. Oh, K. Satomi, K. Sumi, P. N. Harter, J. P. Steinbach, J. Felsberg, D. Capper, C. Voegele, J. Schittenhelm, M. Mittelbronn, H. Ohgaki
Journal: Neuro-Oncology (2017)

We report a novel CASP9 germline mutation that may increase susceptibility to the development of brain tumors. We identified this mutation in a family in which four brain tumors had developed within three generations, including two anaplastic astrocytomas occurring in cousins. The cousins were diagnosed at similar ages (29 and 31 years), and their tumors showed similar histological features. Genetic analysis revealed somatic IDH1 and TP53 mutations in both tumors. However, no germline TP53 mutations were detected, despite the fact that this family fulfills the criteria of Li-Fraumeni-like syndrome. Whole exome sequencing revealed a germline stop-gain mutation (R65X) in the CASP9 gene, which encodes caspase-9, a key molecule for the p53-dependent mitochondrial death pathway. This mutation was also detected in DNA extracted from blood samples from the two siblings who were each a parent of one of the affected cousins. Caspase-9 immunohistochemistry demonstrated the absence of caspase-9 immunoreactivity in the anaplastic astrocytomas and normal brain tissues of the cousins. These observations suggest that CASP9 germline mutations may have played a role at least in part to the susceptibility of development of gliomas in this Li-Fraumeni-like family lacking a TP53 germline mutation.
The PINK1 p.I368N mutation affects protein stability and ubiquitin kinase activity
Authors: Maya Ando, Fabienne C. Fiesel, Roman Hudec, Thomas R. Caulfield, Kotaro Ogaki, Paulina Górka-Skoczylas, Dariusz Koziorowski, Andrzej Friedman, Li Chen, Valina L. Dawson, Ted M. Dawson, Guojun Bu, Owen A. Ross, Zbigniew K. Wszolek, Wolfdieter Springer
Journal: Molecular Neurodegeneration (2017)

Mutations in PINK1 and PARKIN are the most common causes of recessive early-onset Parkinson's disease (EOPD). Together, the mitochondrial ubiquitin (Ub) kinase PINK1 and the cytosolic E3 Ub ligase PARKIN direct a complex regulated, sequential mitochondrial quality control. Thereby, damaged mitochondria are identified and targeted to degradation in order to prevent their accumulation and eventually cell death. Homozygous or compound heterozygous loss of either gene function disrupts this protective pathway, though at different steps and by distinct mechanisms. While structure and function of PARKIN variants have been well studied, PINK1 mutations remain poorly characterized, in particular under endogenous conditions. A better understanding of the exact molecular pathogenic mechanisms underlying the pathogenicity is crucial for rational drug design in the future. Here, we characterized the pathogenicity of the PINK1 p.I368N mutation on the clinical and genetic as well as on the structural and functional level in patients' fibroblasts and in cell-based, biochemical assays. Under endogenous conditions, PINK1 p.I368N is expressed, imported, and N-terminally processed in healthy mitochondria similar to PINK1 wild type (WT). Upon mitochondrial damage, however, full-length PINK1 p.I368N is not sufficiently stabilized on the outer mitochondrial membrane (OMM) resulting in loss of mitochondrial quality control. We found that binding of PINK1 p.I368N to the co-chaperone complex HSP90/CDC37 is reduced and stress-induced interaction with TOM40 of the mitochondrial protein import machinery is abolished. Analysis of a structural PINK1 p.I368N model additionally suggested impairments of Ub kinase activity as the ATP-binding pocket was found deformed and the substrate Ub was slightly misaligned within the active site of the kinase. Functional assays confirmed the lack of Ub kinase activity. Here we demonstrated that mutant PINK1 p.I368N can not be stabilized on the OMM upon mitochondrial stress and due to conformational changes in the active site does not exert kinase activity towards Ub. In patients' fibroblasts, biochemical assays and by structural analyses, we unraveled two pathomechanisms that lead to loss of function upon mutation of p.I368N and highlight potential strategies for future drug development.
Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a proof-of-concept study
Authors: L. Cabel, F. Riva, V. Servois, A. Livartowski, C. Daniel, A. Rampanou, O. Lantz, E. Romano, M. Milder, B. Buecher, S. Piperno-Neumann, V. Bernard, S. Baulande, I. Bieche, J.Y. Pierga, C. Proudhon, F.-C. Bidard
Journal: Annals of Oncology (2017)

Recent clinical results support the use of new immune checkpoint blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is challenging due to tumor immune infiltration. Changes of circulating tumor DNA (ctDNA) levels during therapy could be a promising tool for very accurate monitoring of treatment efficacy, but data are lacking with ICB.This prospective pilot study was conducted in patients with nonsmall cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels were assessed at baseline and after 8 weeks (w8) by bidirectional pyrophosphorolysis-activated polymerization, droplet digital PCR or next-generation sequencing depending on the mutation type. Radiological evaluation of efficacy of treatment was carried out by using immune-related response criteria.ctDNA was detected at baseline in 10 out of 15 patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed between synchronous changes in ctDNA levels and tumor size. Patients in whom ctDNA levels became undetectable at w8 presented a marked and lasting response to therapy. ctDNA detection at w8 was also a significant prognostic factor in terms of progression-free survival (hazard ratio = 10.2; 95% confidence interval 2.5-41, P < 0.001) and overall survival (hazard ratio = 15; 95% confidence interval 2.5-94.9, P = 0.004).This proof-of-principle study is the first to demonstrate that quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs.
878 Surveillance in the service of safety
Authors: Rashid Jooma
Journal: BMJ (2016)

Background  It has been recommended that the newly motorizing countries establish road injury surveillance to define the burden, identify high risk groups, plan intervention and monitor their impact. Despite its stated importance in the literature, very few examples of sustained surveillance systems are reported from low income countries. We present the results of an urban road injury surveillance program that has been running for the past 8 years in the emergency departments of five major hospitals in Karachi, Pakistan.  Methods  We describe the process of establishing the road injury surveillance system incorporating a multi-institution research group including physicians and transportation engineers. Data was collected from 5 hospitals with details of the injury, severity scoring and information of the circumstances of the crash. Crash site visits supplemented this data and the results were disseminated to municipal authorities along with low cost engineering solutions to rectify hazards in the road network. The impact of these interventions were monitored in the surveillance.  Results  In the 8 years between 2007 and 2014, 262,269 road injury victims were registered. Though 76% of the injuries were categorised as “minor”, 20% led to hospital admission and in 3% deaths occurred. The information on location of crashes and site visits led to an extensive catalogue of road network hazards and their rectification led to demonstrated reductions in crash frequency. Data was also used for safety advocacy in groups found to be vulnerable in the surveillance, such as motorcyclists, road sweepers and school going pedestrians.  Conclusions  We demonstrate that a functional road injury surveillance program can be established and effectively managed in a developing country. The data collected and analysed from the victim’s perspective can be a potent tool for effecting safety education and hazard rectification.
A likely urinary tract infection in a pregnant woman
Authors: Catherine L Johnston, Maximilian J Johnston, Alison Corke, Melissa C Davies
Journal: BMJ (2017)

#### What you need to know A 27 year old pregnant woman of 28 weeks’ gestation complains that she is urinating more often and that it is painful. She is worried that she might have an infection. A urine dipstick test indicates the presence of nitrites, leucocytes, and microscopic haematuria. Urinary tract infection (UTI) in pregnancy is the most common non-obstetric indication for antenatal admission.1 UTIs can cause morbidity such as preterm labour, sepsis, and adult respiratory distress syndrome, and can cause mortality if left untreated.23 Lower urinary tract infection occurs in approximately 1-4% of pregnancies, while upper tract infection (pyelonephritis) occurs in 0.5-2% of pregnant women.4 Find out how the woman’s pregnancy is progressing and whether there is anything that she is particularly worried about.
Abstract P244: Transcriptional Regulation of Cardiac Gene Expression by Med13 Alters Global Energy Balance
Authors: Chad E Grueter, Brett A Johnson, Xiaoxia Qi, John McAnally, Rhonda Bassel-Duby, Eric N Olson
Journal: Circulation Research (2011)

Aberrant cardiac metabolism is associated with obesity, type 2 diabetes and heart failure. The heart requires highly efficient metabolism to maintain the levels of ATP needed for contractility and pump function, however little is known about the role of the heart as a metabolic organ. Nuclear hormone receptors, such as thyroid hormone receptor play an important role in cardiovascular disease by significantly altering expression of genes involved in maintaining metabolic activity. The Mediator, a large multiprotein complex functions as a hub to control gene expression through association with transcriptional activators and repressors. We tested the hypothesis that Med13, a component of the Mediator complex, regulates cardiac function in a gain-of-function mouse model. Trangsenic mice overexpressing Med13 in the heart are lean, have increased energy expenditure, are resistant to high fat diet-induced obesity and have enhanced cardiac contractility. Microarray analysis and biochemical assays show that in vivo and in vitro Med13 selectively inhibits nuclear hormone receptor target genes of energy metabolism. These results implicate the Mediator complex regulates energy balance and cardiac contractility and suggests that the heart may function as a key component of mammalian energy homeostasis.
P12.24 The presence of atypia and positivity of the progesterone receptor as predictive factors of recurrence in grade I (WHO) meningiomas
Authors: L. Santos Cardoso, R. Malcata Nogueira
Journal: Neuro-Oncology (2017)

OBJECTIVE: Regarding to World Health Organization (WHO), grade I meningioma have an indolent behavior and reduced rate of recurrence. However, they may be more aggressive in the presence of atypical features. It is intended to determine the predictive factors of recurrence in grade I (WHO) meningiomas and reinforcing surveillance in patients at risk of recurrence / disease progression. METHOD: Review of clinical trials from 2007 to 2014, including. Information regarding age, gender, tumor location, degree of resection (Simpson), histology, immunohistochemistry, follow-up with objectivation of cases of recurrence and treatment time until relapse were obtained. Cases and not cases were related to the parameters measured in the first surgery. Results: Were operated 579 patients with histological diagnosis of grade I meningioma, 428 of whom were female. Mean follow-up was 45.2 months, with 101 cases of recurrence. Of these, only 9 had undergone Simpson I resection. Of the 579 patients operated on, 196 had histological atypia, with a recurrence rate of 29.1%, compared with 11.5% who did not present atypia. In those who had progesterone positive receptors there was a recurrence of 23% and, 13.8% in those who did not present this positive. There was no relation between relapse and Ki67 values> 3.2%. CONCLUSION: Simpson I resection is the most effective measure in the control of the disease. In Simpson II-V resections, it will be useful to consider the presence of progesterone receptor positivity and atypia, in order to promote regular follow-up and increase patients survival and quality of life.
Clinical practice guidelines on the evidence‐based use of integrative therapies during and after breast cancer treatment
Authors: Heather Greenlee, Melissa J. DuPont‐Reyes, Lynda G. Balneaves, Linda E. Carlson, Misha R. Cohen, Gary Deng, Jillian A. Johnson, Matthew Mumber, Dugald Seely, Suzanna M. Zick, Lindsay M. Boyce, Debu Tripathy
Journal: CA A Cancer Journal for Clinicians (2017)

Abstract Answer questions and earn CME/CNE Patients with breast cancer commonly use complementary and integrative therapies as supportive care during cancer treatment and to manage treatment‐related side effects. However, evidence supporting the use of such therapies in the oncology setting is limited. This report provides updated clinical practice guidelines from the Society for Integrative Oncology on the use of integrative therapies for specific clinical indications during and after breast cancer treatment, including anxiety/stress, depression/mood disorders, fatigue, quality of life/physical functioning, chemotherapy‐induced nausea and vomiting, lymphedema, chemotherapy‐induced peripheral neuropathy, pain, and sleep disturbance. Clinical practice guidelines are based on a systematic literature review from 1990 through 2015. Music therapy, meditation, stress management, and yoga are recommended for anxiety/stress reduction. Meditation, relaxation, yoga, massage, and music therapy are recommended for depression/mood disorders. Meditation and yoga are recommended to improve quality of life. Acupressure and acupuncture are recommended for reducing chemotherapy‐induced nausea and vomiting. Acetyl‐L‐carnitine is not recommended to prevent chemotherapy‐induced peripheral neuropathy due to a possibility of harm. No strong evidence supports the use of ingested dietary supplements to manage breast cancer treatment‐related side effects. In summary, there is a growing body of evidence supporting the use of integrative therapies, especially mind‐body therapies, as effective supportive care strategies during breast cancer treatment. Many integrative practices, however, remain understudied, with insufficient evidence to be definitively recommended or avoided. CA Cancer J Clin 2017;67:194–232 . © 2017 American Cancer Society .
High-Grade Diffuse Large B-Cell Lymphoma in Elderly Patients: Russian Multicenter Trial Results in R-EPOCH/R-HMA Protocol
Authors: Olga A. Gavrilina, Eugene E. Zvonkov, Elena N. Parovichnikova, Nelly G. Gabeeva, Vera V. Troitskaya, Inessa Yu. Toropova, Andrey V. Gubkin, Vitalii S. Kanin, Valery A. Lapin, Valery G Savchenko
Journal: Blood (2016)
Outbreak of Occupational Dermatitis Associated With <i>Pyemotes ventricosus</i>
Authors: Martyna Tomczyk-Socha, Katarzyna Jedrzejewska-Jurga, Joanna Limburska, Jaroslaw Tomczyk
Journal: JAMA Dermatology (2017)

<h3>Importance</h3> Although<i>Pyemotes</i>species have been known to cause dermatitis, recent reports are rare. During the past 30 years, only 3 outbreaks of dermatitis caused by<i>Pyemotes ventricosus</i>have been reported. <h3>Objective</h3> To analyze the causative agent of skin changes in employees of a company that produced herbal medicines. <h3>Design, Setting, and Participants</h3> This case series includes 18 patients (8 men, 10 women; mean age, 44 years) who contracted unusual dermatitis after an occupational exposure in July and August of 2012 while working for a company that produced herbal medicines. The patients were examined at the Lower Silesia Regional Centre of Occupational Medicine in Wroclaw, Poland. <h3>Exposures</h3> Workers weighed and packed 1 part of the<i>Helichrysum arenarium </i>herb. <h3>Main Outcomes and Measures</h3> We hypothesized the causative agent to be<i>P ventricosus</i>. An examination of the herbal specimens for ectoparasites confirmed the diagnosis. <h3>Results</h3> Initially 16 employees developed pruritic skin changes. Skin lesions with pruritic vesicles on an erythematous base with surrounding swelling and edema were observed. Several employees also developed a flulike illness. After 44 days, 2 new employees presented with the same skin changes. The analysis of working conditions showed that the same part of the<i>H arenarium</i>herb was weighed and packed at that time. <h3>Conclusions and Relevance</h3> We found that changing the time when the herbs were weighed and abandoning gas fumigation containing methyl bromide resulted in the recurrence of an almost forgotten disease.
Phosphorylation by mTORC1 stablizes Skp2 and regulates its oncogenic function in gastric cancer
Authors: Qirong Geng, Jianjun Liu, Zhaohui Gong, Shangxiang Chen, Shuai Chen, Xiaoxing Li, Yue Lu, Xiaofeng Zhu, Hui-kuan Lin, Dazhi Xu
Journal: Molecular Cancer (2017)

Both mTOR and Skp2 play critical roles in gastric cancer (GC) tumorigenesis. However, potential mechanisms for the association between these two proteins remains unidentified. The regulatory role for mTORC1 in Skp2 stability was tested using ubiquitination assay. The functions of p-Skp2 (phosphorylation of Skp2) were studied in vitro and in vivo. Expression of p-Skp2 and p-mTOR (phosphorylation of mTOR) were shown in GC lines and in 169 human primary GC tissues. mTORC1 can directly interact with Skp2 and phosphorylated Skp2 at Ser64, which sequentially protect Skp2 from ubiquitination and degradation. Furthermore, the phospho-deficient p-Skp2 (S64) mutant significantly suppresses GC cell proliferation and tumorigenesis. The expression of p-Skp2 was associated with p-mTOR in GC cell lines and tissues. Interestingly, the combination of p-Skp2 and p-mTOR was a better predictor of survival than either factor alone. The mTORC1 function to regulate Skp2 by Ser64 phosphorylation may represent an oncogenic event in GC tumorigenesis. Moreover, our study also indicates that Skp2 Ser64 expression is a potential indicator in the treatment of GC patients using mTORC1 inhibitor.
Alternative interpretation of data for recommendations on how to manage rheumatoid arthritis
Authors: Laura Pirilä, Tuulikki Sokka, Markku J Kauppi, Vappu M Rantalaiho, Eero Mervaala, Kari Puolakka
Journal: Annals of the Rheumatic Diseases (2017)

This letter is inspired by the ‘EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update’.1

There is no question that we are in full agreement with the overarching principles of the EULAR recommendations. What goes against our principles, however, is the tone of the bullet points. …