tbuckley/cabot-search huggingface dataset:
Dynamics of the fecal microbiome in patients with recurrent and nonrecurrent Clostridium difficile infection
Authors: Anna Maria Seekatz, Krishna Rao, Kavitha Santhosh, Vincent Bensan Young
Journal: Genome Medicine (2016)

Recurrent Clostridium difficile infection (CDI) remains problematic, with up to 30 % of individuals diagnosed with primary CDI experiencing at least one episode of recurrence. The success of microbial-based therapeutics, such as fecal microbiota transplantation, for the treatment of recurrent CDI underscores the importance of restoring the microbiota. However, few studies have looked at the microbial factors that contribute to the development of recurrent disease. Here we compare microbial changes over time in patients with or without recurrence to identify microbial signatures associated with the development of recurrence. We used 16S rRNA-encoding gene sequence analysis to compare the fecal microbiota of 93 patients with recurrent and nonrecurrent CDI, sampled longitudinally. Cross-group and intra-individual differences in microbial community diversity and similarity were compared prior to the development of recurrent disease and over time. Samples from these patient groups exhibited variable community profiles, clustering into four distinct community groups. Cross-group comparison of the index sample collected from patients that did or did not develop recurrence revealed differences in diversity and community structure (analysis of molecular variance, p < 0.05). Intra-individual comparisons of the microbiota were more informative and samples from recurrent patients were less likely to recover in diversity (Chi-square test, p < 0.005), exhibiting less community similarity overall (Kruskal-Wallis test, p < 0.05). Interestingly, patients with severe disease harbored a significantly less diverse community, a trend that was observed across both nonrecurrent and recurrent patient groups (Wilcoxon test, p < 0.05). To date, this study represents one of the largest studies focused on the relationship between predictive signals from the gut microbiota and the development of recurrent CDI. Our data demonstrate that specific microbiota-derived characteristics associate with disease severity and recurrence and that future studies could incorporate these characteristics into predictive models.
Point/Counterpoint: Early Detection of Prostate Cancer: Do the Benefits Outweigh the Consequences?
Authors: Peter R. Carroll, Andrew J. Vickers
Journal: Journal of the National Comprehensive Cancer Network (2014)

Few clinical issues have polarized the oncology community as much as screening for prostate cancer, with advocates of prostate-specific antigen (PSA) testing vocal on one side and skeptics just as vocal on the other. At the NCCN 19th Annual Conference, Dr. Peter R. Carroll and Dr. Andrew J. Vickers tackled the controversy surrounding early detection of prostate cancer, focusing attention on the randomized trial results at the heart of the matter; over-detection (the Achilles’ heel of screening); and the rationale behind the new, streamlined 2014 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer Early Detection, which emphasize selective early detection and treatment and are tightly aligned with the NCCN Guidelines for Prostate Cancer.
Wide Variability in the Time Required for Immunotoxins to Kill B Lineage Acute Lymphoblastic Leukemia Cells: Implications for Trial Design
Authors: Fabian Müller, Tyler Cunningham, Xiu Fen Liu, Alan S. Wayne, Ira Pastan
Journal: Clinical Cancer Research (2016)

Recombinant immunotoxins (rITs) targeting CD22 are highly active in hairy cell leukemia, but less so in acute lymphoblastic leukemia (ALL). This study aims to understand the variable activity of an rIT against ALL toward improving responses in clinical application.
A randomized phase III study of gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with localized, unresectable pancreatic cancer: E4201
Authors: P. J. Loehrer, M. E. Powell, H. R. Cardenes, L. Wagner, J. M. Brell, R. K. Ramanathan, C. H. Crane, S. R. Alberts, A. B. Benson
Journal: Journal of Clinical Oncology (2008)

4506 Background: The role of radiation therapy (RT) as part of treatment for pancreatic cancer is uncertain in the post-gemcitabine era. The primary endpoint of this trial was to evaluate the impact upon overall survival for the combination of RT plus gemcitabine (G) versus G alone in locally unresectable pancreatic cancer. Methods: Patients (pts) with histologically proven, locally unresectable pancreatic adenocarcinoma, PS <2, without prior chemotherapy or radiation therapy were eligible. Pts were randomized to ARM A: G alone (1,000 mg/m2 weekly x 3 every 4 weeks) for 7 cycles, or ARM B: RT (50.4 GY in 28 fractions) plus G (600 mg/m2 weekly x 6) followed by 5 cycles of G alone (1,000 mg/m2 weekly x 3 every 4 wks). With a planned sample size of 316 eligible pts, the trial was designed to have an 88% power to detect a 50% improvement in median overall survival from 8 to 12 mos (one-sided log-rank test; significance level = 0.025). Pts were stratified by PS (0 vs.1) and weight loss in prior 6 mos (>10% vs. < 10%). Quality of life (using FACT-Hep) was prospectively measured. Results: From April, 2003 to December, 2005, 74 pts were enrolled. The study was closed early because of slow accrual. Three pts were ineligible because of metastatic disease. Five pts not receiving assigned therapy (metastasis noted during RT planning-2; clinical deterioration-2; withdrew consent-1) are included for survival. Grade IV toxicity, principally gastrointestinal and hematologic, was more common in ARM B (5.7% vs 41.2%; p<0.0001). Objective responses were observed in 2.7% (95% CI [0.09%, 14.1%]) and 8.8% (95% CI [1.9%, 23.7%]) in ARM A and ARM B respectively; the corresponding progression free survivals were 6.1 vs. 6.3 mos (p=0.34). All 71eligible pts have now died (early deaths: ARM A-3, ARM B-1). The MST were 9.2 (95% CI [7.8, 11.4]) and 11.0 (95% CI [8.4, 15.5]) mos for the two arms respectively (p=0.044 two sided stratified log-rank test; one-sided p=0.022). Conclusions: Gemcitabine plus radiotherapy has increased, but generally manageable, toxicities compared to chemotherapy alone. Gemcitabine plus involved field RT is associated with an improved overall survival compared to gemcitabine alone for localized, unresectable pancreatic cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Eli Lilly
PD-1 Shapes B Cells as Evildoers in the Tumor Microenvironment
Authors: Zhenhua Ren, Hua Peng, Yang-Xin Fu
Journal: Cancer Discovery (2016)

Abstract Summary: Protumorigenic PD-1hi B cells, induced in hepatocellular carcinoma, suppress tumor-specific T-cell response via IL10-dependent pathways upon PD-1/PD-L1 interaction. Anti–PD-1 or anti–PD-L1 antibodies may function not only through blocking the PD-1 coinhibitory pathway in T cells but also via abolishing the suppressive function of regulatory B cells. Cancer Discov; 6(5); 477–8. ©2016 AACR. See related article by Xiao et al., p. 546.
ALLERGIC IRRITABILITY
Authors: Paul A. Lewis, Dorothy Loomis
Journal: The Journal of Experimental Medicine (1926)

1. The allergic irritability of the guinea pig (capacity of the animal to react to antigenic substances) is increased by infection with Bacillus abortus and a streptococcus, by the dead tubercle bacillus, and by intensive treatment with trypan blue, respectively. The effect of these influences, while definite, is less pronounced than that previously found for infection with the tubercle bacillus. The production of anti-sheep hemolytic amboceptor was used as the test reaction in these cases. 2. The allergic irritability of the guinea pig with reference to anti-typhoid agglutinin is increased by infection with the tubercle bacillus. 3. The allergic irritability of the rabbit with reference to anti-sheep hemolytic amboceptor is increased by an infection of suitable severity with the tubercle bacillus. 4. In the guinea pig the curve of antibody production is complex. Its peculiarities are developed during the production of antityphoid agglutinins as well as that of anti-sheep hemolytic amboceptor. In the latter case injections of antigen subsequent to the first give rise to a curve of production unchanged in form but somewhat affected in the time relations. 5. The effects of infection with Bacillus tuberculosis on allergic irritability with reference to anti-sheep hemolytic amboceptor are operative throughout a course of immunizing treatments. The successive increases due to the cumulative effect of repeated doses of the antigen are developed on a higher level. The end-result is that the animal with increased irritability furnishes more antibody not only in response to the initial injection of antigen as previously described, but an absolute increase over the amount attainable by a comparable number of treatments in series. That portion of the final result contributed by the increase in allergic irritability appears to be no less, and may even in instances be somewhat more than that due to the earlier doses of the specific antigen.
Psychiatric Factors in Essential Hypertension
Authors: Walter I. Tucker
Journal: New England Journal of Medicine (1950)

IN A previous paper the findings of a psychiatric evaluation of 100 patients with essential hypertension were presented.1 These patients were seen because emotional factors seemed important in the illness, or for opinion concerning the advisability of sympathectomy. The series is therefore weighted in favor of those with significant nervous factors. All the patients were under fifty-five years of age; a few were under thirty, but most were between thirty and fifty years. All the patients had a thorough workup in the medical department, and all but a few were free of any significant evidence of cardiac, renal or cerebral . . .
Nondegenerative Evolution in Ancient Heritable Bacterial Endosymbionts of Fungi
Authors: Stephen J. Mondo, Alessandra Salvioli, Paola Bonfante, Joseph B. Morton, Teresa E. Pawlowska
Journal: Molecular Biology and Evolution (2016)

Bacterial endosymbionts are critical to the existence of many eukaryotes. Among them, vertically transmitted endobacteria are uniquely typified by reduced genomes and molecular evolution rate acceleration relative to free-living taxa. These patterns are attributable to genetic drift-dominated degenerative processes associated with reproductive dependence on the host. The degenerative evolution scenario is well supported in endobacteria with strict vertical transmission, such as essential mutualists of insects. In contrast, heritable endosymbionts that are nonessential to their hosts and engage occasionally in horizontal transmission are expected to display deviations from the degenerative evolution model. To explore evolution patterns in such nonessential endobacteria, we focused on Candidatus Glomeribacter gigasporarum ancient heritable mutualists of fungi. Using a collection of genomes, we estimated in Glomeribacter mutation rate at 2.03 × 10−9 substitutions per site per year and effective population size at 1.44 × 108. Both fall within the range of values observed in free-living bacteria. To assess the ability of Glomeribacter to purge slightly deleterious mutations, we examined genome-wide dN/dS values and distribution patterns. We found that these dN/dS profiles cluster Glomeribacter with free-living bacteria as well as with other nonessential endosymbionts, while distinguishing it from essential heritable mutualists of insects. Finally, our evolutionary simulations revealed that the molecular evolution rate acceleration in Glomeribacter is caused by limited recombination in a largely clonal population rather than by increased fixation of slightly deleterious mutations. Based on these patterns, we propose that genome evolution in Glomeribacter is nondegenerative and exemplifies a departure from the model of degenerative evolution in heritable endosymbionts.
The association between anti-carbamylated protein (anti-CarP) antibodies and radiographic progression in early rheumatoid arthritis: a study exploring replication and the added value to ACPA and rheumatoid factor
Authors: S Ajeganova, H W van Steenbergen, M K Verheul, K Forslind, I Hafström, R E M Toes, T W J Huizinga, B Svensson, L A Trouw, A H M van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2016)

Anti-carbamylated protein (anti-CarP) antibodies are reported to associate with more radiographic progression within the total rheumatoid arthritis (RA) population and anti-citrullinated peptide antibody (ACPA)-negative subgroup. We explored the association of anti-CarP with radiographic progression in RA and aimed to replicate the association and evaluate the added value of anti-CarP antibodies in relation to ACPA and rheumatoid factor (RF).576 Swedish and 628 Dutch patients with RA (2394 and 3247 sets of radiographs, respectively) were longitudinally studied. Replication was restricted to the Swedish patients. In both cohorts, the association of anti-CarP with radiographic progression was determined in strata of patients with similar ACPA and RF status; results of both cohorts were combined in fixed-effect meta-analyses. The net percentage of patients for whom the radiographic progression in 5 years was additionally correctly classified when adding anti-CarP to a model including ACPA and RF was evaluated.Anti-CarP associated with radiographic progression in the total Swedish RA population (beta=1.11 per year, p=8.75×10-13) and in the ACPA-negative subgroup (beta=1.14 per year, p=0.034). Anti-CarP associated with more radiographic progression in the strata of ACPA-positive/RF-negative, ACPA-negative/RF-positive and ACPA-positive/RF-positive patients with RA (respective p values 0.014, 0.019 and 0.0056). A model including ACPA and RF correctly classified 54% and 57% of the patients; adding anti-CarP to this model did not increase these percentages (54% and 56% were correctly classified).Anti-CarP antibodies associated with more severe radiographic progression in the total and ACPA-negative RA population. Anti-CarP-positivity had a statistically significant additive value to ACPA and RF, but did not improve correct classification of patients.
Role of Radiotherapy in the Management of Merkel Cell Carcinoma of the Skin
Authors: Roy H. Decker, Lynn D. Wilson
Journal: Journal of the National Comprehensive Cancer Network (2006)

The role of radiotherapy in treating local and regional disease in patients with clinically localized Merkel cell carcinoma remains controversial. Given the lack of randomized evidence and patient and treatment heterogeneity in published retrospective series, sound clinical judgment is required to assess individual patient risk factors. Although many single-institution series have shown that adjuvant radiation to the primary tumor site decreases the risk for local and regional failure, evidence is emerging that there is a cohort of patients at relatively low risk for local recurrence after wide local excision alone. Node dissection, radiotherapy, and combined modality treatment may all play a role in managing occult or clinically evident nodal disease, depending on the anatomic location of draining lymphatics and the extent of microscopic or macroscopic disease. For select patients, primary radiotherapy is a reasonable option with a low risk for local or regional recurrence.
Prognostic significance of endogenous erythropoietin in long‐term outcome of patients with acute decompensated heart failure
Authors: Toshiyuki Nagai, Kunihiro Nishimura, Takehiro Honma, Aya Higashiyama, Yasuo Sugano, Michikazu Nakai, Satoshi Honda, Naotsugu Iwakami, Atsushi Okada, Shoji Kawakami, Tomoaki Kanaya, Yasuhide Asaumi, Takeshi Aiba, Yoko Nishida, Yoshimi Kubota, Daisuke Sugiyama, Tomonori Okamura, Teruo Noguchi, Kengo Kusano, Hisao Ogawa, Satoshi Yasuda, Toshihisa Anzai
Journal: European Journal of Heart Failure (2016)
Soundings: Beauty and the obese
Authors: Liam Farrell
Journal: BMJ (2006)

You really know that you are getting old when a short and balding middle aged man comes up to you and says, “Dr Farrell, you used to be my tutor at medical school.”

So in an attempt to regain my lost youth, when I was virile and strong with flowing raven locks, the body of an Adonis, and a bottom like a peach (at least that's what my Auntie Mamie used to say—we were a close family, perhaps a bit closer than was entirely healthy, but that's rural Ireland for you), I took the family to Orlando, Florida.

And I must say it has been fantastic. Walking down Main Street, USA, towards Cinderella's Castle was like being a child again, the mother ship calling me home. The happiness is unrelenting, the artifice uncompromising, the ingenuity unremitting. The Spider-Man three dimensional simulation ride at the Islands of Adventure theme park combines a roller coaster, special effects, and virtual reality. The killer whales at Sea World are magnificent, and, despite my uneasiness about their captivity, the palpable bond they share with their trainers is surprisingly moving. In the Fantasmic!, a spectacular daily show at Disney-MGM Studios, Mickey Mouse defeats the forces of evil in a blizzard of pyrotechnics.

A fortnight on holiday allows only the most superficial observations on US society, but gosh, so many Americans are really fat, and some of the aetiological factors are obvious. For example, moving walkways are so called because one is meant to walk on them; they're not called “Sit your big fat butt down and block every one behind you”-ways. The restaurant portions are correspondingly enormous.

One menu included an advertisement for a self-referral coronary heart disease screening clinic. The advertisement was directly opposite the dessert section (which was filling even to look at)—no irony there.

I am prejudiced against private medicine; once patients become clients it is tempting to exploit their gullibility and vulnerability. But I have patients at home who have skipped long queues for hip replacements and cardiac bypasses by paying for them themselves, and they do not regret their investment. Having a prejudice confounded is unsettling.

In the land of the free, money can buy anything, and perhaps there's no better way to spend it.
TCTAP A-053 Bioabsorbable Vascular Scaffold Overexpansion Compared to Metallic Platforms: Insights from In-Vitro Experiments
Authors: Nicolas Foin, Daryl R. Lee, Jaryl Ng, Yoshinobu Onuma, Alessio Mattesini, Gianluca Caizzano, Justin E. Davies, Carlo Di Mario, Patrick W. Serruys, Philip Wong, Holger Nef
Journal: Journal of the American College of Cardiology (2016)
Genetic functions of the NAIP family of inflammasome receptors for bacterial ligands in mice
Authors: Yue Zhao, Jianjin Shi, Xuyan Shi, Yupeng Wang, Fengchao Wang, Feng Shao
Journal: The Journal of Experimental Medicine (2016)

Biochemical studies suggest that the NAIP family of NLR proteins are cytosolic innate receptors that directly recognize bacterial ligands and trigger NLRC4 inflammasome activation. In this study, we generated Naip5−/−, Naip1−/−, and Naip2−/− mice and showed that bone marrow macrophages derived from these knockout mice are specifically deficient in detecting bacterial flagellin, the type III secretion system needle, and the rod protein, respectively. Naip1−/−, Naip2−/−, and Naip5−/− mice also resist lethal inflammasome activation by the corresponding ligand. Furthermore, infections performed in the Naip-deficient macrophages have helped to define the major signal in Legionella pneumophila, Salmonella Typhimurium and Shigella flexneri that is detected by the NAIP/NLRC4 inflammasome. Using an engineered S. Typhimurium infection model, we demonstrate the critical role of NAIPs in clearing bacterial infection and protecting mice from bacterial virulence–induced lethality. These results provide definitive genetic evidence for the important physiological function of NAIPs in antibacterial defense and inflammatory damage–induced lethality in mice.
Deacetylase inhibitor (DACI) panobinostat in relapsed small cell lung cancer (SCLC) patients: Results of a multicenter phase II trial.
Authors: F. De Marinis, A. Atmaca, M. Tiseo, L. Ciuffreda, C. Gridelli, V. Gebbia, M. Wolf, L. Dal Zotto, S. Marsoni
Journal: Journal of Clinical Oncology (2010)

e17521 Background: Panobinostat (P) is a pan deacetylase inhibitor hydroxamic acid derivative, currently in the clinic in several solid and haematological malignancies. In vitro P is cytotoxic in several SCLC cell lines with LD50 values < 25 nmol/L, and significantly decreases tumour growth in vivo (Crisanti et al: Mol Cancer Ther 2009; 8(8) 2222-2230). This is the first phase II multicenter trial of P in SCLC. Methods: Twenty-one SCLC patients (pts) who either initially responded to chemotherapy and then relapsed/progressed within 3 mos. (resistant), or initially responded and then relapsed/progressed after 3 mos. (sensitive), entered this 2-step study, and were treated with 20 mg/m2 iv of P on day 1 and 8 q21 until progression or toxicity. A maximum of 2 prior chemotherapy lines was allowed. RECIST-defined tumour response (q6 wks) was the primary endpoint of the study. Toxicity was graded by the NCI CTCAE. Results: Pts characteristics: M/F 12/9, median age 63 yrs (47-75); ECOG PS 0/1 43/57%; extensive/limited disease 12/7; 38% resistant; 33% 2 prior lines of treatment. Pts received a median of 2 cycles (1- 6). P was well tolerated; the most common toxicities were G1-2 GI disorders (nausea 38%, diarrhoea 24%, vomiting 19%), mild thrombocytopenia (G1-2 14.3%, G3 1 pt). One pt experienced hypertension G3. Among 110 ECGs analyzed, there was no QTc > 480 ms increased from baseline. Out of 19 pts evaluable for efficacy we observed: 2 cases of shrinkages > 30% at first assessment (wk 6) no longer qualifying for PR at wk 12 due to appearance of a new lesion in 1 case, and to reduced shrinkage (19% SD) in the second case (time to progression 14 and 21 wks); 3 long-lasting disease stabilizations of 12, 10, 13 wks. Conclusions: To our knowledge this is the first report of a DACi inducing tumour shrinkage and sustained SDs in SCLC. Thus, although the trial was prematurely closed in absence of RECIST-defined PRs, we believe that the antitumor activity observed combined with a favourable safety profile, warrants a further exploration of the potential contribution of P to standard cytotoxic regimens. Two Ph I-II trials combining P with etoposide plus either cisplatin or carboplatin are currently ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration SENDO Foundation Novartis, SENDO Foundation Novartis
Case 15-1966
Authors: Morton N. Swartz, Benjamin Castleman
Journal: New England Journal of Medicine (1966)

Presentation of CaseA fifty-three-year-old man was admitted to the hospital because of a severe burn.Four days previously, in the course of his work in Puerto Rico, he received an accidental electric flash burn involving the face, upper extremities and most of the trunk above the iliac crest, with an estimated involvement of 44 per cent of the body surface by second-degree burn and 17 per cent by third-degree burn; the nasopharynx and oropharynx appeared clear. Nitrofurazone (Furacin) dressings were applied; a cutdown was performed on the right saphenous vein, and he was treated with fluids given intravenously, penicillin . . .