tbuckley/cabot-search huggingface dataset:
Systemic inflammation after critical illness: relationship with physical recovery and exploration of potential mechanisms
Authors: David M Griffith, Steff Lewis, Adriano G Rossi, Jillian Rennie, Lisa Salisbury, Judith L Merriweather, Kate Templeton, Timothy S Walsh
Journal: Thorax (2016)

<h3>Background</h3> Physical recovery following critical illness is slow, often incomplete and is resistant to rehabilitation interventions. We aimed to explore the contribution of persisting inflammation to recovery, and investigated the potential role of human cytomegalovirus (HCMV) infection in its pathogenesis. <h3>Methods</h3> In an a priori nested inflammatory biomarker study in a post-intensive care unit (ICU) rehabilitation trial (RECOVER; ISRCTN09412438), surviving adult ICU patients ventilated &gt;48 h were enrolled at ICU discharge and blood sampled at ICU discharge (n=184) and 3 month follow-up (N=123). C-reactive protein (CRP), human neutrophil elastase (HNE), interleukin (IL)-1β, IL-6, IL-8, transforming growth factor β1 (TGFβ1) and secretory leucocyte protease inhibitor (SLPI) were measured. HCMV IgG status was determined (previous exposure), and DNA PCR measured among seropositive patients (lytic infection). Physical outcome measures including the Rivermead Mobility Index (RMI) were measured at 3 months. <h3>Results</h3> Many patients had persisting inflammation at 3 months (CRP &gt;3 mg/L in 59%; &gt;10 mg/L in 28%), with proinflammatory phenotype (elevated HNE, IL-6, IL-8, SLPI; low TGFβ1). Poorer mobility (RMI) was associated with higher CRP (β=0.13; p&lt;0.01) and HNE (β=0.32; p=0.03), even after adjustment for severity of acute illness and pre-existing co-morbidity (CRP β=0.14; p&lt;0.01; HNE β=0.30; p=0.04). Patients seropositive for HCMV at ICU discharge (63%) had a more proinflammatory phenotype at 3 months than seronegative patients, despite undetectable HMCV by PCR testing. <h3>Conclusions</h3> Inflammation is prevalent after critical illness and is associated with poor physical recovery during the first 3 months post-ICU discharge. Previous HCMV exposure is associated with a proinflammatory phenotype despite the absence of detectable systemic viraemia. <h3>Trial registration number</h3> ISRCTN09412438, post results.
Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment
Authors: Stacy Ellen Hatcher, Emmanuelle Waubant, Bardia Nourbakhsh, Elizabeth Crabtree-Hartman, Jennifer S. Graves
Journal: JAMA Neurology (2016)

The appropriate sequencing of agents with strong immune system effects has become increasingly important. Transitions require careful balance between safety and protection against relapse. The cases presented herein highlight that rebound events after ceasing fingolimod treatment may happen even with short washout periods (4 weeks) and may perpetuate despite steroid treatment or the immediate use of fast-acting immune therapies, such as rituximab.To describe rebound syndrome in patients with multiple sclerosis (MS) after cessation of fingolimod treatment.Clinical and demographic data were extracted from electronic medical records from the University of California, San Francisco, Multiple Sclerosis Center from January 2014 to December 2015. Magnetic resonance images were reviewed by MS neurologists (J.S.G., E.W., B.N., and E.C.H.). Rebound syndrome was defined as new severe neurological symptoms after ceasing fingolimod treatment, with the development of multiple new or enhancing lesions exceeding baseline activity. We reviewed the PubMed database from January 2010 to December 2015 for similar cases of severe disease reactivation after ceasing fingolimod treatment using search terms fingolimod and either rebound or reactivation. Participants were included if they stopped receiving fingolimod between January 2014 and December 2015. Five patients were identified who experienced rebound after ceasing fingolimod treatment.Each patient received treatment with oral fingolimod for various durations.Occurrence of rebound after ceasing fingolimod treatment.The mean (SD) age of the 5 female patients presented in this case series was 35.2 (6.4) years. Of the 46 patients that stopped fingolimod treatment within the 2-year period, 5 (10.9%) experienced severe relapse 4 to 16 weeks after ceasing fingolimod treatment. Despite varying prior severity of relapsing-remitting course, all participants experienced unexpectedly severe clinical relapses accompanied by drastic increases in new or enhancing lesions seen on magnetic resonance imaging evidenced by a median (range) increase of 9 (0->30) new gadolinium-enhancing lesions and a median (range) of 9 (0->30) new T2 lesions. New lesion development persisted for 3 to 6 months despite treatment with corticosteroids (n = 3) and initiation of B-cell depleting therapy (n = 2). In addition, 11 patients were identified through literature review reported as having severe relapses consistent with a rebound syndrome and similar features to our 5 cases.These cases provide evidence for a fingolimod rebound syndrome at a clinically relevant frequency, highlighting the need to determine the best methods for sequencing or discontinuing MS therapies. A large prospective registry or population-based study would be helpful to confirm this rebound phenomenon and to determine contributing factors, including immune biomarkers, that increase risk for this syndrome.
The dicoumarin. 3, 3-methylene-bis-(4-hydroxycoumarin). Its pharmacologic and therapeutic action in man.
Authors: I. S. Wright, A. Prandoni
Journal: Journal of Clinical Investigation (1942)

One of the most interesting and challenging developments in the field of the biologic sciences in recent years has been the recognition, isolation and, finally, synthesis of the substance causing hemorrhagic sweet clover disease in cattle, the dicoumarin 3,3′-methylene-bis-(4-hydroxycoumarin). We must give full credit for this contribution to two keen students of veterinary medicine, Schofield 1 and Roderick, 2 and to an outstanding agricultural chemist, Karl Paul Link. Schofield in Canada and Roderick at the North Dakota Agricultural Experimental Station studied and quite accurately analyzed the factors responsible for this phenomenon in cattle and rabbits. They pointed out that, whereas normal sweet clover silage produced no damage, spoiled sweet clover resulted in hemorrhagic tendencies and often in death. In 1934 Prof. Karl Paul Link and his associates at the Wisconsin Agricultural Experimental station of the University of Wisconsin undertook thetask of identifying the hemorrhagic factor in spoiled sweet clover.
<i>JNCCN</i>Going Forward
Authors: Margaret Tempero
Journal: Journal of the National Comprehensive Cancer Network (2014)

Are you surprised to find me here?Well, in a way, I'm surprised to find myself here!My career has been blessed with so many wonderful opportunities that I sometimes thought that I already had my quota.Then along came this opportunity to lead JNCCN-Journal of the National Comprehensive Cancer Network, and it was too good to pass up!This was an assignment that I had never tried before with an important journal serving an organization that I had the privilege to help launch.How much better could that be?Watching NCCN grow and mature has been such a rewarding experience.In 1995, I sat at the table, representing The University of Nebraska Medical Center, and listened to Joe Simone describe a vision for the fledgling NCCN.Although we faltered a bit for a while, our first permanent CEO, Bill McGivney, took us places we never imagined and helped us create a product in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) that has become synonymous with quality care around the globe.I've been privileged to serve as an NCCN Guidelines Panel Chair from the very beginning, so I was delighted when JNCCN was launched to help disseminate and highlight those guidelines.Eventually, I relocated to University of California, San Francisco (UCSF) and continued to sit on the NCCN Board until 2005.Meanwhile, NCCN continued to flourish.As with all great organizations, leadership changes occur, and last year, Robert Carlson, MD, my colleague down the road at Stanford Cancer Institute, took the helm as CEO.When I heard the news, I reflected on Bob's and my early days in the leadership of NCCN.I suspect that he, like me, never imagined then that we'd have these roles today.Bob has a strong vision for NCCN, is committed to evidencebased care, and cares deeply about the success of the journal.It will be a privilege to work with him in this capacity.As this issue goes to press, we are still discussing ways to shape JNCCN going forward.One thing won't change.JNCCN will still broadcast changes in the NCCN Guidelines and feature articles that naturally spring from the guidelines process: controversies, dissemination of information about new treatments, streamlining care, cost benefit, and so on.At the upcoming NCCN 19th Annual Conference, I'll be meeting with our editorial board, many of whom are Guidelines Panel Chairs, to brainstorm about new features that can bring new readers and additional interest to the journal.In closing, I am deeply grateful to the NCCN Board of Directors for giving me this chance.I am grateful for their confidence in me, for Hal Burstein's exemplary leadership and example as the previous editor-in-chief, and for another opportunity for me to learn new skills.Life is good!
Pulmonary nodules in a man with a history of bone marrow transplantation
Authors: Neil Mendoza, Paritosh Prasad
Journal: BMJ (2016)

Our patient was diagnosed as having Philadelphia chromosome positive pre-B acute lymphoblastic leukaemia with lymphoid blast crisis (blast crisis of chronic myeloid leukaemia) in 2011. Treatment with two cycles of hyper-CVAD (alternating cyclophosphamide+vincristine+doxorubicin+dexamethasone with methotrexate+cytarabine) plus dasatinib resulted in a negative bone marrow biopsy (remission). He had an allogeneic peripheral blood stem cell transplant from a 10/10 HLA matched unrelated donor in 2013. Conditioning was with cyclophosphamide and 1200 cGy total body irradiation. Graft versus host disease prophylaxis was with tacrolimus and methotrexate. Dasatinib was continued after his transplant. In late 2013 he developed relapsed acute lymphoblastic leukaemia. He was treated with fludarabine, cytarabine, and granulocyte colony stimulating factor. Bone marrow biopsy after chemotherapy showed persistent acute lymphoblastic leukaemia, even after he was switched to ponatinib and dexamethasone. Daunorubicin and vincristine were added for one cycle but were discontinued when he was admitted to hospital for cellulitis. Bone marrow biopsy was negative but one three months later showed recurrent acute B lymphoblastic leukaemia. Remission occurred after re-induction with clofarabine in the autumn of 2014; this was followed by 6-mercaptopurine, methotrexate, vincristine, and prednisone maintenance therapy.

He had no history of graft versus host disease and was not taking additional immunosuppressants. After his transplant, both Aspergillus versicolor and A fumigatus were isolated from his sputum, but he had no other evidence of invasive fungal infection. Pneumocystis jirovecii nucleic acid was isolated from his sputum but was thought to represent colonisation rather than infection. He had no evidence of tuberculosis at any time. His prophylactic antimicrobial regimen did not include an antifungal drug (voriconazole was discontinued in 2015 owing to raised liver transaminases) but did include dapsone and aciclovir. About three weeks before admission, pus was noted around his peripherally inserted central catheter (PICC). There was no cellulitis and his PICC was …
Progressive loss of EGFR in a subpopulation of breast cancers: Implications in target-directed therapeutics
Authors: Lee Yee Choong, Simin Lim, Marie Chiew-Shia Loh, Xiaohui Man, Yunhao Chen, Weiyi Toy, Mengfei Pan, Chien-Shing Chen, Anuradha Poonepalli, M Prakash Hande, Puay Hoon Tan, Manuel Salto-Tellez, Chow-Yin Wong, Nilesh Shah, Brian J Druker, Yoon-Pin Lim
Journal: Clinical Cancer Research (2007)

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

B33 

Understanding the molecular etiology and heterogeneity of disease has a direct impact on cancer therapeutics. To identify novel molecular changes associated with breast cancer progression, we conducted phosphoproteomics of the MCF10AT model comprising isogenic, ErbB2- and ErbB3-positive, xenograft-derived cell lines that mimic different stages of breast cancer. Using in vitro , animal model and clinical breast samples, our study revealed marked reduction of EGFR expression with breast cancer progression. Such diminution of EGFR expression was associated with increased resistance to Gefitinib/Iressa in vitro . Fluorescence in situ hybridization demonstrated that loss of EGFR gene copy number was one of the key mechanisms behind the low/null expression of EGFR in clinical breast tumors. Statistical analysis on the immunohistochemistry data of EGFR expression on 93 matched normal and breast tumor samples showed that i) diminished EGFR expression could be detected as early as in the pre neoplastic lesion (ductal carcinoma in situ ) and this culminated in invasive carcinomas; ii) EGFR expression levels could distinguish between normal tissue versus carcinoma in situ and invasive carcinoma with high statistical significance (p<0.001, n=81). However, no significant correlation of EGFR expression with disease free survival and overall survival was observed. This is the first time EGFR expression has been tracked meaningfully and developmentally from normal condition through disease progression using in vitro , xenograft, matched normal and tumor samples. Thus, our study provides a new insight into the role of EGFR in breast cancer development. Although no value of EGFR expression in prognosis was found, our findings are likely to have implications in the design of clinical trials targeting EGFR family of proteins in breast cancer. (IRESSA is a trademark of the AstraZeneca group of companies).
Hiatus hernia in healthy volunteers is associated with intrasphincteric reflux and cardiac mucosal lengthening without traditional reflux
Authors: Elaine V Robertson, Mohammad H Derakhshan, Angela A Wirz, David R Mitchell, James J Going, Andrew W Kelman, Stuart A Ballantyne, Kenneth E L McColl
Journal: Gut (2016)

Background and aims Hiatus hernia (HH) is a key mediator of gastro-oesophageal reflux disease but little is known about its significance in the general population. We studied the structure and function of the gastro-oesophageal junction in healthy volunteers with and without HH. Methods We compared 15 volunteers with HH, detected by endoscopy or MRI scan, but without gastro-oesophageal reflux disease with 15 controls matched for age, gender and body weight. Jumbo biopsies were taken across the squamocolumnar junction (SCJ). High-resolution pH metry (12 sensors) and manometry (36 sensors) were performed upright and supine, before and after a meal. The SCJ was marked with an endoscopically placed clip and visualised fluoroscopically. Results Cardiac mucosa was longer in volunteers with HH (3.5 vs 2.5 mm, p=0.01). There was no excessive acid reflux 5 cm above the upper border of the lower oesophageal sphincter (LOS) in either group but those with HH had short segment reflux 11 mm above the pH transition point after the meal when supine (pH&lt;4 for 5.5% vs 0.3% of time, p=0.01). The SCJ and pH transition point were proximally displaced within the gastro-oesophageal junction in those with HH versus controls (p&lt;0.05). The pH transition point was proximal to the peak LOS pressure point in HH subjects but distal to it in controls after the meal (p&lt;0.05). When supine, the postprandial pH transition point crossed the SCJ in those with HH (p=0.03). Conclusions Healthy volunteers with HH have increased intrasphincteric reflux and lengthening of cardiac mucosa in the absence of traditional transsphincteric reflux.
Cholesterol metabolism and prostate cancer-specific mortality.
Authors: Konrad Hermann Stopsack, Jennifer A. Sinnott, James Robert Cerhan, Lorelei A. Mucci, Jennifer R. Rider
Journal: Journal of Clinical Oncology (2015)

12 Background: Cholesterol is needed in prostate cancer cells for cell proliferation and for androgen biosynthesis. Cholesterol-lowering statin drug use is associated with a lower risk of total and advanced prostate cancer and lower prostate cancer-specific mortality (PCSM). We hypothesized that tumor expression of cholesterol synthesis enzymes, transporters and regulators is associated with PCSM. Methods: We studied mRNA expression of 43 cholesterol metabolism genes in surgical specimens from 249 participants in the Health Professionals' Follow-up Study diagnosed with prostate cancer between 1986 and 2004. We included 81 cases of lethal prostate cancer and 168 indolent cases who survived &gt;8 years without metastases. After multivariate dimensionality reduction for the synthesis, transport and regulator pathways using principal components analysis, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. We adjusted for age, year of diagnosis, body mass index, smoking status, family history, multivitamin use, high serum cholesterol and cholesterol-lowering drug use. Results: Reflecting the impact of the synthesis pathway and of the regulator pathway, respectively, the expression of squalene epoxidase (SQLE) and low-density lipoprotein receptor (LDLR) were significantly associated with lethal cancer in opposing directions. Compared to men with the mean level of SQLE expression, men with SQLE expression &gt;1 standard deviation (SD) above the mean were 15.4 times more likely to have lethal cancer (95% CI: 3.31–71.53). For LDLR, expression &gt;1 SD above the mean was associated with 96% lower odds of lethal cancer (95% CI: 0.01–0.70). Higher SQLE expression and lower LDLR expression were associated with higher Gleason grades (Fisher's test, p &lt; 0.001 and p = 0.036, respectively) and were also predictive of PCSM independently from grade and tumor stage. Conclusions: These results suggest that the local cholesterol metabolism of the prostate tumor is tightly linked with mortality. Lethal cancers have higher activity of the second rate-controlling enzyme of cholesterol synthesis and are less dependent on cholesterol uptake.
TCTAP C-203 Successful Percutaneous Renal Artery Angioplasty of Branch Occlusion Caused by Spontaneous Renal Artery Dissection
Authors: Minato Hayashi, Hiroaki Yamamoto, Hideo Miura, Chieko Itamoto, Tsunesuke Kohno
Journal: Journal of the American College of Cardiology (2016)
PWE-164 Neutrophil-lymphocyte ratio predicts survival following neoadjuvant chemotherapy in oesophageal adenocarcinoma: Abstract PWE-164 Table 1
Authors: J Young, B Stewart, M Forshaw, P Glen
Journal: Gut (2015)

<h3>Introduction</h3> Neoadjuvant chemotherapy (NAC) before resection is now standard of care in oesophageal adenocarcinoma. Neutrophil-lymphocyte ratio (NLR) is recognised as a prognostic indicator in this disease. There is increasing evidence that staging post neo-adjuvant chemotherapy is more accurate than at time of diagnosis. We wished to assess neutrophil lymphocyte ratio at time of diagnosis and after neo-adjuvant chemotherapy in our cohort of patients. <h3>Method</h3> Consecutive patients who underwent oesophageal resection after NAC for oesophageal adenocarcinoma between 2008–2013, were identified from our prospectively collected database. In these patients systemic inflammation was assessed by modified Glasgow Prognostic Score (mGPS) and NLR and the electronic patient record was accessed to obtain blood results required (albumin, CRP, neutrophils and lymphocytes). These results were obtained at time of diagnosis and immediatly prior to resection. NLR was calculated and stratified as &lt; 2.5, 2.5–5, and &gt;5. Modified Glasgow Prognostic Score was assigned as 0, 1 or 2, CRP &lt;10 scoring 0; CRP &gt;10 and albumin &gt;35 scoring 1; and CRP &gt;10 and albumin &lt;35 scoring 2. Survival analysis was performed by Kaplan Meier and compared by log rank with the aid of SPSS. <h3>Results</h3> 169 patients undergoing neo-adjuvant chemotherapy and resection for oesophageal adenocarcinoma were included in the analysis. As shown in the table below neither mGPS or NLR measured at time of diagnosis, before neo-adjuvant chemotherapy, predicted survival following oesophagectomy. Only 12 of the 98 patients in whom mGPS could be calculated scored either 1 or 2 at this point. Post-NAC again mGPS did not show any significant effect on survival (p = 0.524). When NLR was used to stratify patients at this time, this did significantly predict outcome following resection, with median survival of 38 months in the low NLR group compared to 15 months in the high NLR group (P = 0.003). <h3>Conclusion</h3> Neutrophil lymphocyte ratio post-neo adjuvant chemotherapy is a predictor of survival following oesophageal resection for oesophageal adenocarcinoma. This supports recent findings that suggest staging investigations post-NAC best determine patients’ outcomes for resectional surgery. <h3>Disclosure of interest</h3> None Declared.
Call for preventive care for rheumatic heart disease in refugee children
Authors: Gabriele Rossi, Vivian Sau Wai Lee
Journal: BMJ (2016)

We support Murphy and colleagues’ call for better access to healthcare for Syrian refugees scattered in neighbouring countries.1 In particular, they suggest upgrading and adapting the medical response to the refugees’ needs by considering the specific disease profile of the Syrian population, characterised by the dominance of non-communicable diseases in adults. …
H<sub>2</sub>metabolism is widespread and diverse among human colonic microbes
Authors: Patricia G. Wolf, Ambarish Biswas, Sergio E. Morales, Chris Greening, H. Rex Gaskins
Journal: Gut Microbes (2016)

Microbial molecular hydrogen (H2) cycling is central to metabolic homeostasis and microbial composition in the human gastrointestinal tract. Molecular H2 is produced as an endproduct of carbohydrate fermentation and is reoxidised primarily by sulfate-reduction, acetogenesis, and methanogenesis. However, the enzymatic basis for these processes is incompletely understood and the hydrogenases responsible have not been investigated. In this work, we surveyed the genomic and metagenomic distribution of hydrogenase-encoding genes in the human colon to infer dominant mechanisms of H2 cycling. The data demonstrate that 70% of gastrointestinal microbial species listed in the Human Microbiome Project encode the genetic capacity to metabolise H2. A wide variety of anaerobically-adapted hydrogenases were present, with [FeFe]-hydrogenases predominant. We subsequently analyzed the hydrogenase gene content of stools from 20 healthy human subjects. The hydrogenase gene content of all samples was overwhelmingly dominated by fermentative and electron-bifurcating [FeFe]-hydrogenases emerging from the Bacteroidetes and Firmicutes. This study supports that H2 metabolism in the human gut is driven by fermentative H2 production and interspecies H2 transfer. However, it suggests that electron-bifurcation rather than respiration is the dominant mechanism of H2 reoxidation in the human colon, generating reduced ferredoxin to sustain carbon-fixation (e.g. acetogenesis) and respiration (via the Rnf complex). This work provides the first comprehensive bioinformatic insight into the mechanisms of H2 metabolism in the human colon.