tbuckley/cabot-search huggingface dataset:
Prostate cancer: Autologous immunotherapy optimized by indoleamine-2,3-dioxygenase (IDO)-inhibitor as immune-tolerance breaker
Authors: E. M. Lasalvia-Prisco, E. Garcia-Giralt, S. Cucchi, J. Larrañaga, D. Wagner
Journal: Journal of Clinical Oncology (2006)

12509 Background: In several peer review publications (Cancer Biol Ther 2003) our team has reported a procedure of cancer immunotherapy using an autologous thermostable hemoderivative vaccine (ATHV) with anti-progressive tumor effect in metastatic malignant disease from different primary tumors including prostate cancer. Last year (ASCO Meeting 2005) we have reported that the tolerance break for tumor associated antigens through the interference with CD4+CD25+ regulatory cells is a component of the mechanism of action of the ATHV antitumoral effect. Therefore, we have intended to optimize this autologous immunotherapy adding to the procedure different steps of immune-tolerance blockage selected due to their proven efficacy in pre-clinical models and their feasibility in the frame of ATHV technology. In this study we report the results in prostate cancer when the adjuvant step added was the translational knowledge the tolerance blockage by IDO-inhibition through 1-Methyl-Tryptophane or 1-MT (Munn DH et al J Exp Med 1999). Methods: Thirty metastasic prostate cancer patients, hormone and chemotherapy resistant, Performance Status ≤ 2 and PSA progressing serum level, were included in this institutional-IRB approved phase I/II trial. The patients were randomized in 3 groups submitted to 3 different treatments: I, only sympthomatic; II, the previously reported ATHV and III, ATHV + simultaneous s.c. 1-MT. Tumor size increase (tumor growth) measured according RECIST was registered in each case. Mean difference in the 3 groups was statistically assessed (Student’s t-test). Tryptophane to Kynurenine conversion was tested to assess IDO inhibition. Results: Tumor growth was significantly slower in Group II and III than in Group I (p&lt;0.01 and p&lt;0.005). Tumor growth was also significantly slower in Group III than in Group II (p&lt;0.02). IDO-inhibition was confirmed only in Group III. No relevant toxicities were detected. Conclusions: These results support that additional tolerance break by IDO-inhibition optimizes the tumor growth inhibition through immunotherapy with an autologous thermostable hemoderivative vaccine. No significant financial relationships to disclose.
Bias? Not so fast
Authors: Joel M Kremer
Journal: Annals of the Rheumatic Diseases (2016)

Duran et al 1 present the results of a literature search performed on a very large number of publications comparing methotrexate (MTX) with a biologic agent.Their literature review eventually yielded 13 published trials for their analysis.The authors were particularly interested in the dose, and route of administration, of MTX.As the efficacy of the new agent
Acyclovir Prophylaxis of Herpes-Simplex-Virus Infections
Authors: Rein Saral, William H. Burns, Oscar L. Laskin, George W. Santos, Paul S. Lietman
Journal: New England Journal of Medicine (1981)

We conducted a double-blind, placebo-controlled study of acyclovir prophylaxis against infection with herpes simplex virus (HSV) in 20 seropositive recipients of bone-marrow transplants. Acyclovir or placebo was administered for 18 days, starting three days before transplantation. Culture-positive HSV lesions developed during the study in seven of the 10 patients who received placebo. In contrast, no such lesions appeared in the 10 patients who received acyclovir (P≃0.003). None of the patients had evidence of drug toxicity. Five of the patients treated with acyclovir had mild culture-positive HSV infections after cessation of the drug, and two additional patients shed virus without having lesions. Acyclovir appears to be a potent inhibitor of HSV replication. Although acyclovir does not appear to eradicate latent infection, it can provide effective prophylaxis against reactivated infections. (N Engl J Med. 1981; 305:63–7.)
LBA3_PR KEYNOTE-010: Phase 2/3 study of pembrolizumab (MK-3475) vs docetaxel for PD-L1–positive NSCLC after platinum-based therapy
Authors: R.S. Herbst, D.-W. Kim, E. Felip, J.L. Perez-Gracia, E.B. Garon, J.-Y. Han, J. Molina, J.-H. Kim, R. Gervais, M.-J. Ahn, M. Majem, M.J. Fidler, G. De Castro, M. Garrido, G.M. Lubiniecki, Y. Shentu, E. Im, P. Baas
Journal: Annals of Oncology (2015)
Effect of Fluoride Treatment on the Fracture Rate in Postmenopausal Women with Osteoporosis
Authors: B L Riggs, S F Hodgson, W M O'Fallon, E Y Chao, H W Wahner, J M Muhs, S L Cedel, L J Melton
Journal: New England Journal of Medicine (1990)

Although fluoride increases bone mass, the newly formed bone may have reduced strength. To assess the effect of fluoride treatment on the fracture rate in osteoporosis, we conducted a four-year prospective clinical trial in 202 postmenopausal women with osteoporosis and vertebral fractures who were randomly assigned to receive sodium fluoride (75 mg per day) or placebo. All received a calcium supplement (1500 mg per day). Sixty-six women in the fluoride group and 69 women in the placebo group completed the trial. As compared with the placebo group, the treatment group had increases in median bone mineral density of 35 percent (P less than 0.0001) in the lumbar spine (predominantly cancellous bone), 12 percent (P less than 0.0001) in the femoral neck, and 10 percent (P less than 0.0001) in the femoral trochanter (sites of mixed cortical and cancellous bone), but the bone mineral density decreased by 4 percent (P less than 0.02) in the shaft of the radius (predominantly cortical bone). The number of new vertebral fractures was similar in the treatment and placebo groups (163 and 136, respectively; P not significant), but the number of nonvertebral fractures was higher in the treatment group (72 vs. 24; P less than 0.01). Fifty-four women in the fluoride group and 24 in the placebo group had side effects sufficiently severe to warrant dose reduction; the major side effects were gastrointestinal symptoms and lower-extremity pain. We conclude that fluoride therapy increases cancellous but decreases cortical bone mineral density and increases skeletal fragility. Thus, under the conditions of this study, the fluoride-calcium regimen was not effective treatment for postmenopausal osteoporosis.
The End of Barium Enemas?
Authors: Robert H. Fletcher
Journal: New England Journal of Medicine (2000)

For many years, barium enema was the only way to obtain a complete structural examination of the colon, short of surgery. Development of the double-contrast barium enema improved the ability of the method to detect subtle lesions, and this is the only kind of barium enema that is appropriate for detecting polyps and potentially curable cancers. With the advent of fiberoptic technology and the widespread use of colonoscopy in the 1970s, the role of barium enema came into question. As evidence of the effectiveness of screening for colorectal cancer accumulated, followed by consensus on the value of screening programs, skepticism . . .
Occurrence of Painless Myocardial Infarction in Psychotic Patients
Authors: Walter E. Marghand
Journal: New England Journal of Medicine (1955)

THAT infarction of the myocardium can occur without pain is a well established fact. To date there is no wholly satisfactory explanation for such occurrences, although several hypotheses merit consideration.1 2 3 There are also differences of opinion concerning the frequency of painless myocardial infarction. In recent years clinical studies of both small and large series of cases with myocardial infarction have given the prevalence of painless cases as from less than 1 per cent4 to a high of 38 per cent.5 Most reports, however, cite a rate somewhere near 10 per cent.The reason for such a large discrepancy primarily concerns . . .
Risk of meningitis is higher in people treated with antimicrobials in previous year, study shows
Authors: Susan Mayor
Journal: BMJ (2016)

People who had an antimicrobial prescribed in the previous year showed an increased risk of meningitis in a case control study analysing data from a UK primary care clinical database.1

The development of meningitis is thought to involve micro-organisms in the nasopharynx crossing mucosal surfaces into the bloodstream and moving into the subarachnoid space. But it is …
IMCT-01PEMBROLIZUMAB: FIRST EXPERIENCE WITH RECURRENT PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Deborah T. Blumenthal, Michal Yalon, Felix Bokstein
Journal: Neuro-Oncology (2015)

Patients with progressive primary brain tumors (PBT) are attracted to promising new treatments, even prior to convincing data. Anti-PD1 immunotherapies have been in the spotlight since publication of groundbreaking results for metastatic melanoma with pembrolizumab (PBL). Our objective was to report on the response and toxicity of PBL in patients with advanced PBT. We retrospectively reviewed the charts of 22 patients (17 adults and 5 children) with recurrent central nervous system tumors treated with PBL. We analyzed prior antineoplastic therapies, steroid usage, and outcomes. Patients received a median of two neoplastic therapies prior to PBL, and a median of three infusions of PBL in adults and four in children. Twelve patients (9 adults and 3 children) started PBL on steroids (median dose in adults 4 mg; range 2–8, and in children 1.5 mg, range 0.5–4) and five patients received steroids later during PBL treatment. Twelve patients (10 adults and 2 children) received concomitant bevacizumab with PBL. Side effects were minimal. All patients showed progressive tumor growth during therapy. Median OS from the start of PBL was 2.6 months in adults and 3.2 months in children. Two GB patients underwent tumor resection following treatment with PBL. Tumor-lymphocytic response in these cases was unremarkable, and PD-L1 immuno-staining was negative. In this series of 22 patients with recurrent primary brain tumors, PBL showed no clinical or histologic efficacy. We do not recommend further use of PBL for recurrent PBT unless convincing prospective clinical trial data are published.
THE BIRTH OF MODERN SURGERY
Authors: Nils Brage Nordlander
Journal: BMJ (1909)

In ancient India and Persia surgeons were highly respected and their operating skill with nose plastic and catatact couching is documented. In mediaeval Europe surgery was classified as a handicraft profession and belonged to the barbers guild with the soapcup as symbol, much inferior to the academic trained medical doctors. In war surgery leg amputation after shotwounds demanded great rapidity, since no anestetic but alcohol was available. In the 18th century surgeons becamea accepted as medical doctors e.g. John Hunter in London and OlofAcrel in Stockholm. A great step in the development of surgery was Mortons introduction of eter narcosis 1846. Now surgeons could work carefully without hurry. The next step took Joseph Lister. Born in 1827 he studied medicine in London and then qualified as surgeon at the famous James Syme's clinic in Edinburgh- In 1860 he became professor of surgery in Glasgow. His clinic like all others was afflicted with suppuration, septicemia, erysipelas and gangrene. He happened to read a thesis by Louis Pasteur, who proved that fermentation and putrefaction in wine production were caused by bacteria. Lister saw the similarity with wound suppuration. Carbolic acid was used in wood industri to prevent putrefaction and Lister now introduced this as a mean to cure or prevent suppuration and septicemia. He washed the wound and soaked the bandage with carbolic acid, which he also sprayed in the air of the operation theatre to prevent air carried infection. In 1867 he published his experiences in the Lancet: Out of 11 complicated fractures (where the bone-ends penetrated the skin) 9 healed without complications. Earlier such fractures ended with dead or amputation. The wards were now free from infected wounds. Abroad Listers findings were received with entusiasm, Ernst von Bergmann i Berlin modified the antiseptic method into a aseptic one and sterilized the room, the instruments and clothes and could so avoid the carbolic acid spray, which was irritating for the surgeons breath. Lister applied the aseptic method from 1887. Abdominal and thoracic surgery now became possible and developed rapidly. In England his ideas were accepted with some delay. In 1877 he was appointed professor in London, was made a peer and president of the Royal Society nad was celebrated all over the world. He died 1912, 85 years old.
Frequency of Osteosarcoma Among First-Degree Relatives of St. Bernard Dogs2
Authors: Steen Bech-Nielsen, Mark E. Haskins, John S. Reif, Robert S. Brodey, Donald F. Patterson, Richard Spielman
Journal: JNCI Journal of the National Cancer Institute (1978)

Journal Article Frequency of Osteosarcoma Among First-Degree Relatives of St. Bernard Dogs Get access Steen Bech-Nielsen, D.V.M., M.Sc., Steen Bech-Nielsen, D.V.M., M.Sc. Search for other works by this author on: Oxford Academic PubMed Google Scholar Mark E. Haskins, V.M.D., M.S.,, Mark E. Haskins, V.M.D., M.S., 5 5Address reprint requests to Dr. Haskins, Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pa. 19104. Search for other works by this author on: Oxford Academic PubMed Google Scholar John S. Reif, D.V.M., M.Sc., John S. Reif, D.V.M., M.Sc. Search for other works by this author on: Oxford Academic PubMed Google Scholar Robert S. Brodey, D.V.M., M.Sc., Robert S. Brodey, D.V.M., M.Sc. Search for other works by this author on: Oxford Academic PubMed Google Scholar Donald F. Patterson, D.V.M., D.Sc., Donald F. Patterson, D.V.M., D.Sc. Search for other works by this author on: Oxford Academic PubMed Google Scholar Richard Spielman, Ph.D Richard Spielman, Ph.D Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 60, Issue 2, February 1978, Pages 349–353, https://doi.org/10.1093/jnci/60.2.349 Published: 01 February 1978 Article history Received: 12 April 1977 Accepted: 22 September 1977 Published: 01 February 1978
Abstract 1210: Biopterin metabolism drives tumor progression
Authors: Christopher Rabender, Asim Alam, Mike Waters, Ross Mikkelsen
Journal: Cancer Research (2015)

Abstract Previous studies demonstrate that nitric oxide synthases (NOS’s) can become uncoupled during inflammatory disease states. A hallmark of this uncoupling is superoxide production from NOS in lieu of nitric oxide (NO) resulting from a reduced tetrahydrobiopterin:dihydrobiopterin ratio (BH4:BH2 ratio). As BH4 is a necessary cofactor for NO production from NOS, when this ratio is reduced, NOS becomes a peroxynitrite synthase enhancing the pro-inflammatory/pro-survival tumor environment. Our lab demonstrated that NOS is uncoupled in a variety of tumor cells both in vitro and in vivo, as well as in paired human colorectal samples due to a reduced BH4:BH2 ratio and that recoupling NOS in via exogenous BH4 both in vitro and in vivo leads to decreased tumor cell proliferation. To examine the mechanism behind the reduced BH4:BH2 ratio we used the DSS/AOM model of colitis and colon tumorigenesis. Here we demonstrate that BH4:BH2 ratio is reduced in mouse colon tumors vs mouse normal colon tissue, 1.36±0.35 vs 7.1±0.6. We determined that this reduced ratio is due at least in part to direct oxidation of BH4 to BH2, as treatment of colon cells with an NADPH Oxidase inhibitor increased the BH4:BH2 two-fold; however, this is unable to account for the degree of uncoupling associated with tumor cells. Given that inflammation appears to drive NOS uncoupling, we extracted colons from DSS/AOM treated animals and preferentially harvested colonic epithelial cells and colonic tumor cells at different stages of inflammation to assess the molecular and biochemical changes in molecules important in the regulation and production of BH4. The molecules we focused on were: GTP cyclohydrolase-1 (GCH1, rate limiting enzyme in de novo BH4 synthesis), GTP cyclohydrolase 1 feedback regulatory protein (GCHFRP, regulates GCH1 expression), quinoiddihydropteridine reductase (QDPR, necessary for salvage pathway) and sepiapterin reductase (SR, necessary for both de novo synthesis and salvage of BH4). Transcript levels of these molecules in DSS treated epithelial cells showed that GCH1 and SR were upregulated but QDPR was significantly downregulated when compared with untreated cells, potentially leading to an increase in total BH4 but once oxidized to BH2, a decrease in the salvage back to BH4. Our current research investigates the protein levels as well biochemical activity of these molecules in DSS treated epithelial cells, as well as tumor cells compared with normal cells to further understand the molecular component of the decrease in BH4:BH2 ratio in tumors. Note: This abstract was not presented at the meeting. Citation Format: Christopher Rabender, Asim Alam, Mike Waters, Ross Mikkelsen. Biopterin metabolism drives tumor progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1210. doi:10.1158/1538-7445.AM2015-1210
P50 Predicting readmission following exacerbation of COPD using a non-contact sensor – A Proof of Concept Study
Authors: P Minnis, R O’Meara, H Kane, A Zaffaroni, F O’Dea, J Britton, B Caulfield, SC Donnelly
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> Chronic Obstructive Pulmonary Disease (COPD) is the second most common cause of emergency admission to hospital in the UK. Following an exacerbation there is a high risk of recurrence. Early identification and prompt treatment of exacerbations have been shown to reduce risk of hospital admission.<sup>1</sup> Respiratory rate changes during an episode of exacerbation and may serve as the warning signal of developing exacerbation. We aimed to determine whether a non-contact bedside sensor (SleepMinder TM) recording Nocturnal Respiratory Rate (NRR) could detect exacerbations in patients with COPD following hospital discharge. <h3>Methods</h3> Patients were enrolled following a hospital admission for an exacerbation of there underlying COPD. They were followed prospectively for 12 weeks and monitored by SleepMinder TM (Resmed) technology recording NRR. Demographics and clinical details were extracted from medical records. A research nurse contacted each participant weekly and recorded CAT scores and any healthcare contacts. <h3>Results</h3> 15 patients completed the study period and recorded &gt;75% of study data. Of these 8 patients had further exacerbations. Median time post discharge for an exacerbation was 56.5 days (IQR 41–67). There were no differences in baseline demographics between those who had an exacerbation and those that did not however there was a trend towards increased BMI, baseline CAT score and length of stay. Of the 8 patients who had an exacerbation a clear signal in NRR could be identified, by visual inspection, in 5 (62.5%) around the time of recorded health care contact. The average time from a signal to health care contact was 6.6 days indicating a window of opportunity for intervention. The was no significant trend between change of CAT score and change of NRR indicating patients may be unaware of impending exacerbation (p value 0.243). <h3>Conclusions</h3> SleepMinder TM technology assessing nocturnal respiratory rate may have use in a real time clinician led connected health setting to trigger early intervention and prevent readmission following discharge. <h3>Reference</h3> 1 Wilkinson TM, Donaldson GC, Hurst JR, <i>et al</i>. Early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease. <i>Am J Respir Crit Care Med</i>. 2004;<b>169</b>:1298–303
Subtypes of HPV-Positive Head and Neck Cancers Are Associated with HPV Characteristics, Copy Number Alterations, PIK3CA Mutation, and Pathway Signatures
Authors: Yanxiao Zhang, Lada A. Koneva, Shama Virani, Anna E. Arthur, Alisha Virani, Pelle B. Hall, Charles D. Warden, Thomas E. Carey, Douglas B. Chepeha, Mark E. Prince, Jonathan B. McHugh, Gregory T. Wolf, Laura S. Rozek, Maureen A. Sartor
Journal: Clinical Cancer Research (2016)

There is substantial heterogeneity within human papillomavirus (HPV)-associated head and neck cancer (HNC) tumors that predispose them to different outcomes; however, the molecular heterogeneity in this subgroup is poorly characterized due to various historical reasons.We performed unsupervised gene expression clustering on deeply annotated (transcriptome and genome) HPV(+) HNC samples from two cohorts (84 total primary tumors), including 18 HPV(-) HNC samples, to discover subtypes and characterize the differences between subgroups in terms of their HPV characteristics, pathway activity, whole-genome somatic copy number alterations, and mutation frequencies.We identified two distinct HPV(+) subtypes (namely HPV-KRT and HPV-IMU). HPV-KRT is characterized by elevated expression of genes in keratinocyte differentiation and oxidation-reduction process, whereas HPV-IMU has strong immune response and mesenchymal differentiation. The differences in expression are likely connected to the differences in HPV characteristics and genomic changes. HPV-KRT has more genic viral integration, lower E2/E4/E5 expression levels, and higher ratio of spliced to full-length HPV oncogene E6 than HPV-IMU; the subgroups also show differences in copy number alterations and mutations, in particular the loss of chr16q in HPV-IMU and gain of chr3q and PIK3CA mutation in HPV-KRT.Our characterization of two subtypes of HPV(+) HNC tumors provides valuable molecular level information that point to two main carcinogenic paths. Together, these results shed light on stratifications of the HPV(+) HNCs and will help to guide personalized care for HPV(+) HNC patients. Clin Cancer Res; 22(18); 4735-45. ©2016 AACR.
The neurokinin-2 receptor antagonist ibodutant improves overall symptoms, abdominal pain and stool pattern in female patients in a phase II study of diarrhoea-predominant IBS
Authors: J Tack, K Schumacher, G Tonini, S Scartoni, A Capriati, C A Maggi
Journal: Gut (2016)

<h3>Background</h3> Tachykinins have been implicated in the pathophysiology of IBS with diarrhoea (IBS-D). Our aim was to study the efficacy and safety of ibodutant, a selective neurokinin-2 (NK2) receptor antagonist, in patients with IBS-D. <h3>Methods</h3> This multinational double-blind, placebo-controlled study recruited 559 patients with IBS-D according to Rome III criteria. After a 2-week treatment-free run-in, patients were randomised to ibodutant 1 mg, 3 mg, 10 mg or placebo once daily for eight consecutive weeks. Responders were those with a combined response of satisfactory relief (weekly binary question yes/no) of overall IBS symptoms and abdominal pain/discomfort on ≥75% weeks (primary end point). Secondary end points included abdominal pain and stool pattern. Data were also analysed according to US Food and Drug Administration (FDA)-approved interim end points (improvement of pain and stool consistency). Safety was assessed by monitoring adverse events and laboratory tests. Prespecified statistical analysis involved the whole group as well as gender subgroups. <h3>Results</h3> Demographics and baseline characteristics were comparable for all treatment arms. In the overall population, responsiveness tended to increase with escalating ibodutant doses. In the prespecified analysis by gender, ibodutant 10 mg demonstrated significant superiority over placebo in females (p=0.003), while no significant effect occurred in males. This was confirmed for secondary end points and for the responder analysis according to FDA-approved end points. The tolerability and safety of ibodutant was excellent at all doses. <h3>Conclusions</h3> Ibodutant showed dose-dependent efficacy response in IBS-D, reaching statistical significance at the 10 mg dose in female patients. The safety and tolerability profile of ibodutant was similar to placebo. <h3>Trial registration number</h3> NCT01303224.