tbuckley/cabot-search huggingface dataset:
Novel driver genes and genomic predictors of immune infiltrates in colorectal cancer.
Authors: Marios Giannakis, Jasmine Xinmeng Mu, Sachet Shukla, Zhi Rong Qian, Ofir Cohen, Reiko Nishihara, Yin Cao, Mai Yamauchi, Yasutaka Sukawa, Katsuhiko Nosho, Kimmie Ng, Jeffrey A. Meyerhardt, Michael Lawrence, Stacey B. Gabriel, Eric Lander, Gad Getz, Catherine Wu, Charles S. Fuchs, Shuji Ogino, Levi A. Garraway
Journal: Journal of Clinical Oncology (2016)

557 Background: Despite progress that has been made in the molecular characterization of colorectal cancer (CRC), prior studies have had limited power to detect, as significantly mutated, less-frequently altered CRC genes. In addition, most large-scale sequencing studies have generally lacked clinicopathologic annotations to link genomic features with important CRC characteristics such as immune infiltration. Methods: We performed Whole-Exome Sequencing on 619 archival primary CRCs from two large prospective cohorts, the Nurses’ Health Study and the Health Professionals Follow-Up Study. We identified CRC driver genes using significance-calling algorithms and employed a novel computational pipeline to calculate tumor neoantigens (peptides resulting from somatic mutations and recognized by the immune system as foreign). The neoantigen load and altered genes/pathways were correlated to immunohistochemically determined immune infiltrates and survival data linked to these specimens. Results: We identified 90 significantly mutated genes in non-hypermutated CRC. These include previously underappreciated genes that participate in pathways such as WNT-signaling and RNA processing. Among all samples, the neoantigen load was associated with increased overall lymphocytic infiltration (P = 2.6e-11), tumor-infiltrating lymphocytes (TILs) (P = 2.0e-19), memory T-cells (P = 0.091) and CRC-specific survival (P = 0.025). Neoantigen load was also associated with higher TILs in microsatellite-stable tumors (P = 0.015). We found that HLA and Antigen Processing Machinery (APM) mutations have undergone positive selection in tumors with TILs. Conclusions: In the largest exome-sequencing study of CRC to date, we leveraged the increased number of samples and their associated clinicopathologic annotations to identify new driver genes and genomic predictors of immune infiltrates in this disease. Neoantigen load is prognostic in CRC and predictive of immune infiltration, even among microsatellite-stable tumors. We also find evidence of positive selection for HLA and APM mutations in immune-cell infiltrated tumors. These results have implications for patient selection in CRC immunotherapy trials.
Trends in seasonal influenza vaccine distribution in the European Union: 2003-4 to 2007-8
Authors: M Rodríguez de Azero, Collective the European Vaccine Manufacturers Influenza Working Group
Journal: Eurosurveillance (2008)

Seasonal influenza is widely regarded as a continuing threat to public health, with vaccination remaining the principal measure of prophylaxis. In 2003, the World Health Organization issued targets for influenza vaccine coverage in the elderly of at least 50% by 2006 and 75% by 2010, endorsed by the European Parliament in two resolutions in 2005 and 2006. However, a number of European public health systems lack mechanisms to assess progress in influenza vaccine uptake. The European Vaccine Manufacturers group (EVM) undertook a Europe-wide survey of vaccine distribution over the last five seasons (between 2003 and 2008) to provide baseline data from which vaccination trends may be extrapolated. The survey data showed that the dose distribution level per capita in the 27 EU countries increased from 17% in 2003-4 to 20% in 2006-7; this growth was not maintained in the season 2007-8. Even without information on which age or risk groups received the vaccine, an immunisation rate of approximately 20% of the whole population falls short of the public health goal by more than half: an estimated 49% of the total population fall into risk groups recommended to receive the influenza vaccine in Europe. These data provide the only systematic review of vaccine dose distribution across Europe from a uniform source. Although they represent an important baseline parameter, age- and risk-group related vaccine uptake data with sufficient detail are needed to assist public health policy decision making, immunisation planning and monitoring. In light of this situation, and to support the improvement of immunisation rates across the EU, EVM aims to provide dose distribution data for each influenza season to assist Member States in the implementation of local immunisation policies.
Junior doctor contract will be imposed, says Hunt
Authors: Abi Rimmer
Journal: BMJ (2016)

A new contract for junior doctors in England will be imposed from October this year, the health secretary has said.

On Tuesday 5 July the BMA announced that 58% of junior doctors had voted to reject the proposals. In a statement made in the House of Commons on 6 July, Jeremy Hunt said that there would be a phased introduction of the contract agreed with the BMA in May.

Hunt said that it would initially be introduced …
P-285 A randomized, double-blind, placebo-controlled Phase III study of ramucirumab versus placebo as second-line treatment in patients with hepatocellular carcinoma and elevated baseline alpha-fetoprotein following first-line sorafenib (REACH-2)
Authors: Zhu Andrew, Galle Peter, Kudo Masatoshi, Finn Richard, Yang Ling, Abada Paolo, Llovet Josep
Journal: Annals of Oncology (2016)
The Abrogated Thrombopoietin (TPO) Signal Transduction In Pediatric Patients Suffering From Thrombocytopenia-Absent Radii Syndrome Is Restored In Adult Patients, Suggesting An Additional, c-Mpl-Jak2-Independent Mechanism for Platelet Biogenesis.
Authors: Janine Fiedler, Gabriele Strauss, Martin Wannack, Silke Fleischhauer, Kerstin Seidel, Eva Klopocki, Stefan Mundlos, Markus Schmugge, Harald Schulze
Journal: Blood (2010)
P-284 NESC Multicenter phase II trial in the Preoperative Treatment of gastric adenocarcinoma consisting of chemotherapy using docetaxel-cisplatin-5FU + lenograstim followed by chemoradiation (RTCT) based 5FU and oxaliplatin and surgery
Authors: L. Mineur, G. Deplanque, F. Desseigne, L. Moureau-Zabotto, O. Boulat, K. Jalali, D. Smith, S. Obled, M. Belkacemi
Journal: Annals of Oncology (2016)
Drawing the Line in Risk-Reducing Gynecologic Surgery in Women With a <i>BRCA</i> Mutation
Authors: Charles A. Leath, Warner K. Huh, Ronald D. Alvarez
Journal: JAMA Oncology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Abstract 5: Novel Tools for Identification and Purification of Cardiomyocytes, Fibroblasts and Endothelial Cells From Neonatal Mouse and Rat Hearts
Authors: Dominik Eckardt, Manuel Kernbach, Vera Czichowski, Christoph Hintzen, Andreas Bosio
Journal: Circulation Research (2015)

Although isolation of vital cardiac cells from neonatal hearts is one of the most used experimental model in cardiac research, the manual dissociation of neonatal hearts is a laborious and difficult-to-standardize procedure. To shorten sample processing time and increase reproducibility, we developed a fully automated dissociation process followed by magnetic purification of cardiomyocytes (CMs), cardiac fibroblasts (CFs) and endothelial cells (ECs). Neonatal hearts were dissociated within 1 h resulting in high yields of single cells with excellent viability. Depending on age and species following cell ratios were recovered after dissociation: 50-70% CMs, 30-40% CFs, 10-20% ECs. In order to purify CMs from dissociated neonatal hearts, we defined antibody cocktails enabling non-myocyte removal. Our depletion strategy allowed for the enrichment of CMs from whole hearts or preparations of heart chambers with purities of up to 98%. To enable simultaneous detection of CMs and subtypes, we developed recombinant antibodies against general CM markers like alpha Actinin, Myosin Heavy Chain or cardiac Troponin T as well as CM subtype-specific antibodies against MLC2a and MLC2v distinguishing between atrial and ventricular CMs respectively. Besides, we developed magnetic enrichment strategies for the purification of CFs and ECs. Current purification strategies that are solely based on antibodies against EC surface markers do not result in sufficiently pure cardiac ECs. Therefore, we established a 2-step enrichment protocol allowing for the complete removal of contaminating fibroblasts and leukocytes. Our data indicate that this protocol significantly improves the purity of primary cardiac ECs. Functionality of ECs before and after enrichment was proven by Dil-Ac-LDL endocytosis. Similarly, our magnetic enrichment protocol for cardiac fibroblasts revealed homogenous expression of fibroblast markers like Vimentin and Prolyl-Hydroxylase, but virtually no contaminations with CMs or ECs. In summary, we established an automated protocol for dissociation of neonatal hearts enabling subsequent purification, characterization and cultivation of CMs, CFs and ECs which can readily be used for cell culture assays or to generate heart muscle models.
Case 30-1975
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Cyrus C. Hopkins, James J. Galdabini
Journal: New England Journal of Medicine (1975)

Presentation of CaseA 59-year-old man was admitted to the hospital because of dyspnea.He was well until 14 years previously, when he was admitted to the hospital because of the Guillain-Barré syndrome. Examination revealed mild hypertension, and an electrocardiogram showed the pattern of left ventricular hypertrophy. He recovered without incident. Three years before admission he returned for examination, which disclosed that the blood pressure was 170/90 mm Hg; a Grade 2 systolic murmur was heard at the base of the heart. Two years later he began to experience exertional dyspnea and occasional chest pain on coughing. Four days before . . .
The Effect of Sitagliptin on Carotid Artery Atherosclerosis in Type 2 Diabetes: The PROLOGUE Randomized Controlled Trial
Authors: Jun-ichi Oyama, Toyoaki Murohara, Masafumi Kitakaze, Tomoko Ishizu, Yasunori Sato, Kazuo Kitagawa, Haruo Kamiya, Masayoshi Ajioka, Masaharu Ishihara, Kazuoki Dai, Mamoru Nanasato, Masataka Sata, Koji Maemura, Hirofumi Tomiyama, Yukihito Higashi, Kohei Kaku, Hirotsugu Yamada, Munehide Matsuhisa, Kentaro Yamashita, Yasuko K. Bando, Naoki Kashihara, Shinichiro Ueda, Teruo Inoue, Atsushi Tanaka, Koichi Node
Journal: PLoS Medicine (2016)

Background Experimental studies have suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors provide cardiovascular protective effects. We performed a randomized study to evaluate the effects of sitagliptin added on to the conventional therapy compared with conventional therapy alone (diet, exercise, and/or drugs, except for incretin-related agents) on the intima-media thickness (IMT) of the carotid artery, a surrogate marker for the evaluation of atherosclerotic cardiovascular disease, in people with type 2 diabetes mellitus (T2DM). Methods and Findings We used a multicenter PROBE (prospective, randomized, open label, blinded endpoint) design. Individuals aged ≥30 y with T2DM (6.2% ≤ HbA1c < 9.4%) were randomly allocated to receive either sitagliptin (25 to 100 mg/d) or conventional therapy. Carotid ultrasound was performed at participating medical centers, and all parameters were measured in a core laboratory. Of the 463 enrolled participants with T2DM, 442 were included in the primary analysis (sitagliptin group, 222; conventional therapy group, 220). Estimated mean (± standard error) common carotid artery IMT at 24 mo of follow-up in the sitagliptin and conventional therapy groups was 0.827 ± 0.007 mm and 0.837 ± 0.007 mm, respectively, with a mean difference of −0.009 mm (97.2% CI −0.028 to 0.011, p = 0.309). HbA1c level at 24 mo was significantly lower with sitagliptin than with conventional therapy (6.56% ± 0.05% versus 6.72% ± 0.05%, p = 0.008; group mean difference −0.159, 95% CI −0.278 to −0.041). Episodes of serious hypoglycemia were recorded only in the conventional therapy group, and the rate of other adverse events was not different between the two groups. As it was not a placebo-controlled trial and carotid IMT was measured as a surrogate marker of atherosclerosis, there were some limitations of interpretation. Conclusions In the PROLOGUE study, there was no evidence that treatment with sitagliptin had an additional effect on the progression of carotid IMT in participants with T2DM beyond that achieved with conventional treatment. Trial Registration University Hospital Medical Information Network Clinical Trials Registry UMIN000004490
Description and Management of Accelerated Phase and Blast Crisis in 21 CML Pediatric Patients
Authors: Deborah Meyran, Arnaud Petit, Joelle Guilhot, Meinolf Suttorp, Eveline S. de Bont, Chi Kong Li, Krzysztof Kalwak, Birgitte Lausen, Srdjana Culic, Marie-Françoise Dresse, Andrea Biondi, Frédéric Millot
Journal: Blood (2015)
Needle Biopsy of the Liver
Authors: Norman Zamcheck, Richard L. Sidman
Journal: New England Journal of Medicine (1953)

THE increasing use of needle biopsy of the liver clearly indicates its wide acceptance as a clinical and investigative tool. More than 20,000 biopsies have been reviewed, and it is now possible to reassess the usefulness and limitations of the procedure.A few conclusions appear to be warranted. Needle biopsy is not necessary for correct diagnosis of most cases of liver disease. It is indispensable, however, in a small but important group. It is also helpful in treatment and prognosis by defining the stage of known disease. Judicious use, based on a broad understanding of liver disease, is accompanied by . . .
PTEN Is a Key Regulator of Collagen-Induced Platelet Activation and Is Involved in αIIbβ3 -Mediated Outside-in Signaling,
Authors: Haixia Niu, Ding Li, Zhen Weng, Yanhua Wang, Lin Zhang, Wang Kemin, Yueping Sun, Guo-Qiang Chen, Weiran Chai, Xinping Luo, T. Kent Gartner, Junling Liu
Journal: Blood (2011)
Spatial distribution of syndesmophytes along the vertebral rim in ankylosing spondylitis: preferential involvement of the posterolateral rim
Authors: Sovira Tan, Abhijit Dasgupta, Jianhua Yao, John A Flynn, Lawrence Yao, Michael M Ward
Journal: Annals of the Rheumatic Diseases (2016)

Syndesmophytes in ankylosing spondylitis (AS) can occur anywhere along the vertebral rim, but little is known about how and where they develop, and particularly if they first form in certain locations along the rim. This information might provide clues to their aetiology. We examined the spatial distribution of syndesmophytes in the thoracolumbar spine in patients with AS using CT.We performed lumbar spine CT scans in 50 patients and used a validated computer algorithm to measure syndesmophyte heights in six intervertebral disc spaces. We measured heights every five radial degrees around the rim of each superior and inferior vertebral endplate.Syndesmophytes were observed in 208 of 296 intervertebral disc spaces. Both ascending and descending syndesmophytes were non-randomly distributed along the vertebral rim (p<0.0001 for deviation from uniform distribution). Syndesmophytes occurred most often at the posterolateral vertebral rim, and least commonly at the posterior rim and anterior rim. In disc spaces with only small isolated syndesmophytes, these were also most likely to occur at the posterolateral rim. Syndesmophyte distribution varied with the vertebral level. Localisation at the posterolateral rim was most pronounced at T10-T11, T12-T12 and T12-L1, while L2-L3 and L3-L4 exhibited little localisation.Syndesmophytes are not randomly distributed around the vertebral rim, as might be expected if they develop solely in response to inflammation. Rather, they preferentially occur, and likely develop first, at the posterolateral rim. Studying factors that can lead to this pattern may help elucidate how syndesmophytes develop.
A treatment planning comparison of proton therapy and intensity-modulated radiotherapy (IMRT) for prostate cancer using the normal tissue complication probability (NTCP).
Authors: Benjamin Walker Fischer-Valuck, Lindsey Olsen, Thomas Mazur, Michael Altman, Beth Bottani, Hiram Alberto Gay, Jeff M. Michalski
Journal: Journal of Clinical Oncology (2016)

153 Background: The volume of rectum receiving high-dose (i.e. &gt; or = 60 Gy) is consistently associated with the risk of Grade &gt; or = 2 rectal toxicity or rectal bleeding based on common terminology criteria for adverse events (CTCAE). Our goal was to compare intensity-modulated photon radiotherapy (IMRT) with proton radiotherapy in regard to the rectal dose using the normal tissue complication probability (NTCP). Methods: Between July 2014 and September 2015 the first 10 consecutive low or intermediate risk prostate cancer patients were treated with proton therapy at our institution. All 10 patients were planned with three-dimensional conformal proton therapy (3D-CPT) using two parallel opposed fields as well as comparison IMRT plans. A rectal balloon filled with water was used in all patients treated. Prescribed dose to the prostate was 79.2 Gy or cobalt Gy equivalent (CBE) for protons. Dose-volume histograms were compared. The Lyman-Kutcher-Burman model (n = 0.09, m = 0.13, and TD 50 = 76.9 Gy) was used to generate NTCP estimates for both IMRT and proton plans. Results: At least 95% of the planning target volume received the prescription dose for both proton and IMRT plans. Dose constraints placed on the rectum included volume receiving 65 Gy (V 65 ) less than 17% and V 40 less than 35%. The mean dose to the rectum was 24.5 Gy (range, 19.5-30.1 Gy) and 31.7 Gy (range, 23.7-39.4 Gy) for the proton and IMRT plans, respectively. The V 65 constraint was unachievable in 3 of the proton plans and 3 of the IMRT plans. The mean V 70 and V 75 for proton plans was 8.4% and 5.4% compared to 7.5% and 4.8% for the IMRT plans. The mean NTCP for proton treatment plans was 7.72% (range, 2.7-11.7%) and 7.92% (range, 1.7-15.3%) for IMRT (P = 0.45). After median follow-up of 6 months, no grade 2 or higher toxicity has been reported. Conclusions: Utilizing NTCP estimations, proton therapy and IMRT have similar predicted rates of rectal toxicity. Currently, a Phase III randomized clinical trial is underway comparing proton therapy and IMRT with regards to rectal toxicity and quality of life.
A phase II study of isoflavone, gemcitabine, and erlotinib in locally advanced (LA) or metastatic pancreatic cancer
Authors: N. Hammad, P. A. Philip, A. F. Shields, F. H. Sarkar, J. L. Abruzzese, A. O. Kaseb, M. M. Javle, G. R. Varadhachary, R. A. Wolff, B. F. El-Rayes
Journal: Journal of Clinical Oncology (2008)

15540 Background: Preclinical and clinical data suggest that the EGFR/Akt/NF-κB signaling pathways are frequently deregulated in pancreatic cancer and contribute to cell growth, invasion, angiogenesis, metastasis and chemoresistance. Akt and NF-κB can be activated independent of EGFR and may be major determinants of treatment failure with other EGFR inhibitors or cytotoxic drugs. Isoflavone demonstrated direct inactivation of Akt and NF-κB and enhancement of the anti-tumor activity of erlotinib and gemcitabine. This phase II study was undertaken to determine the effects of adding isoflavone to a regimen of gemcitabine and erlotinib. Methods: The primary endpoint was survival at 6 months. Eligibility included patients with metastatic or LA pancreatic adenocarcinoma who were previously untreated. Patients must have a performance status (PS) of 0–2. Patients received gemcitabine 1,000 mg/m2 on days 1, 8, and 15, and eroltinib 150 mg once daily on day 1 to day 28. Isoflavone (Novasoy containing the isoflavones genistein, diazdein and glycitein) was administered at a dose of 177 mg twice daily starting day -7 until day 28. Cycle was repeated every 28 days. Results: A total of 20 patients (median age 59 years, males 60%, metastatic disease 85%) were enrolled on the study. Median PS was 1. 12 patients are still on treatment. No treatment related deaths were observed. The most commonly observed grade 3/4 toxicities were neutropenia (3), nausea/vomiting (3) and diarrhea (2). Grade 2 rash was seen in 4 patients. Conclusion: Isoflavone can be safely administered in combination with gemcitabine and erlotinib. Preliminary data is encouraging. Mature survival data are expected in the next three months. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology
Transmission of α-synucleinopathy from olfactory structures deep into the temporal lobe
Authors: Daniel M. Mason, Negin Nouraei, Deepti B. Pant, Kristin M. Miner, Daniel F. Hutchison, Kelvin C. Luk, John F. Stolz, Rehana K. Leak
Journal: Molecular Neurodegeneration (2016)

α-synucleinopathy emerges quite early in olfactory structures such as the olfactory bulb and anterior olfactory nucleus (OB/AON) in Parkinson's disease. This may contribute to smell impairments years before the commencement of motor symptoms. We tested whether α-synucleinopathy can spread from the OB/AON to regions of the limbic telencephalon that harbor connections with olfactory structures. α-synuclein fibrils were infused into the OB/AON. Inclusions containing pathologically phosphorylated α-synuclein (pSer129) were observed three months later in the piriform and entorhinal cortices, amygdala, and hippocampal formation. The retrograde tract-tracer FluoroGold confirmed the existence of first-order afferents at these sites. Some sites harbored FluoroGold+ neurons but no inclusions, suggestive of selective vulnerabilities. Multiple areas close to the injection site but not connected with the OB/AON remained free of inclusions, suggesting a lack of widespread uptake of fibrils from interstitial diffusion. Two independent pSer129 antibodies revealed the same labeling patterns and preadsorption control experiments confirmed a loss of pSer129 staining. Dense total α-synuclein (but not pSer129) staining was apparent in the OB/AON 1.5 h following fibril infusions, suggesting that pSer129+ staining did not reflect exogenously infused material. Waterbath sonication of fibrils for 1 h improved α-synucleinopathy transmission relative to 1 min-long probe sonication. Electron microscopy revealed that longer sonication durations reduced fibril size. The Thioflavin stain labeled cells at the infusion site and some, but not all inclusions contained ubiquitin. Three-dimensional confocal analyses revealed that many inclusions ensconced NeuN+ neuronal nuclei. Young and aged mice exhibited similar topographical spread of α-synucleinopathy. 1) α-synucleinopathy in this model is transmitted through some, but not all neuroanatomical connections, 2) pathology is largely confined to first-order afferent sites at three months and this is most parsimoniously explained by retrograde transport, and 3) transmission in aged animals is largely similar to that in young control animals at three months post-infusion.