tbuckley/cabot-search huggingface dataset:
Polymorphisms in α-Defensin–Encoding DEFA1A3 Associate with Urinary Tract Infection Risk in Children with Vesicoureteral Reflux
Authors: Andrew L. Schwaderer, Huanyu Wang, SungHwan Kim, Jennifer M. Kline, Dong Liang, Pat D. Brophy, Kirk M. McHugh, George C. Tseng, Vijay Saxena, Evan Barr-Beare, Keith R. Pierce, Nader Shaikh, J. Robert Manak, Daniel M. Cohen, Brian Becknell, John D. Spencer, Peter B. Baker, Chack-Yung Yu, David S. Hains
Journal: Journal of the American Society of Nephrology (2016)

The contribution of genetic variation to urinary tract infection (UTI) risk in children with vesicoureteral reflux is largely unknown. The innate immune system, which includes antimicrobial peptides, such as the α -defensins, encoded by DEFA1A3 , is important in preventing UTIs but has not been investigated in the vesicoureteral reflux population. We used quantitative real–time PCR to determine DEFA1A3 DNA copy numbers in 298 individuals with confirmed UTIs and vesicoureteral reflux from the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Study and 295 controls, and we correlated copy numbers with outcomes. Outcomes studied included reflux grade, UTIs during the study on placebo or antibiotics, bowel and bladder dysfunction, and renal scarring. Overall, 29% of patients and 16% of controls had less than or equal to five copies of DEFA1A3 (odds ratio, 2.09; 95% confidence interval, 1.40 to 3.11; P &lt;0.001). For each additional copy of DEFA1A3 , the odds of recurrent UTI in patients receiving antibiotic prophylaxis decreased by 47% when adjusting for vesicoureteral reflux grade and bowel and bladder dysfunction. In patients receiving placebo, DEFA1A3 copy number did not associate with risk of recurrent UTI. Notably, we found that DEFA1A3 is expressed in renal epithelium and not restricted to myeloid-derived cells, such as neutrophils. In conclusion, low DEFA1A3 copy number associated with recurrent UTIs in subjects in the RIVUR Study randomized to prophylactic antibiotics, providing evidence that copy number polymorphisms in an antimicrobial peptide associate with UTI risk.
Abstract IA05: Oncogenic signaling pathways and resistance to therapy in T-ALL
Authors: Adolfo Ferrando
Journal: Cancer Research (2016)

Abstract Aberrant NOTCH1 signaling plays a major role in the pathogenesis of over 60% of T-ALLs harboring activating mutations in the NOTCH1 gene. Most notably, oncogenic NOTCH1 has been proposed as a therapeutic target in NOTCH1-mutant leukemias and small molecule γ-secretase inhibitors (GSIs), which effectively block NOTCH activation via inhibition of a critical intramembrane proteolytic cleavage required for NOTCH signaling. However, the clinical development of anti-NOTCH1 therapies in T-ALL has been hampered by the limited and delayed therapeutic response to these drugs, making the identification of highly effective and synergistic drug combinations capable of delivering strong antileukemic responses a top priority in the field. Here we identify glutaminolysis as a critical pathway for leukemia cell growth downstream of NOTCH1 and a key determinant of clinical response to anti-NOTCH1 therapies. Mechanistically, inhibition of NOTCH1 signaling in T-ALL induces a metabolic shutdown with prominent inhibition of glutaminolysis and triggers autophagy as a salvage pathway supporting leukemia cell metabolism. Consequently, both inhibition of glutaminolysis and inhibition of autophagy strongly and synergistically enhance the antileukemic effects of anti-NOTCH1 therapies. Moreover, Pten loss and consequent activation of the PI3K pathway induces increased glycolysis and consequently rescues leukemic cell metabolism abrogating the antileukemic effects of NOTCH1 inhibition. Overall, these results identify glutaminolysis as a major node in cancer metabolism controlled by NOTCH1 and as therapeutic target for the treatment of T-ALL. These results highlight the fundamental importance of NOTCH1 signaling in the control of leukemia cell metabolism, extend our understanding of the prominent role of PTEN and the PI3K pathway in the control of oncogenic cell growth and provide the basis for the design of new therapeutic strategies targeting cell metabolism for the treatment of T-ALL. Citation Format: Adolfo Ferrando. Oncogenic signaling pathways and resistance to therapy in T-ALL. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA05.
Results of the SMARTE-R-CHOP-14 trial of the German high-grade non-Hodgkin lymphoma study group (DSHNHL).
Authors: M. Pfreundschuh, V. Poeschel, S. Zeynalova, A. Viardot, M. Haenel, U. Keller, M. Reiser, N. Murawski, M. Loeffler, J. Schubert
Journal: Journal of Clinical Oncology (2010)

8064 Background: In a previous pharmacokinetic study we had shown that the concomitant application of R-CHOP-14 does not achieve a plateau of R serum levels until cycle 5 (Reiser. Blood. 2006;108:778a). In order to achieve a high area under the curve and high R levels early, in the SMARTE-R-CHOP-14 study we shifted the first 3 applications of R towards the early treatment phase and tried to maintain serum levels for a prolonged period by administering the last 3 cycles after the completion of chemotherapy. Methods: 100 elderly pts. with aggressive CD20+ B-cell lymphoma received 6 cycles of biweekly CHOP-14 combined with 8 × R (375 mg/m2) on days -4, -1, 10, 29, 57, 99, 155, and 239. Prophylaxis with levofloxacin, acyclovir and cotrimoxazol was mandatory. The primary endpoint was event-free survival (EFS). 306 pts. treated within the RICOVER-60 trial (Pfreundschuh et al. Blood. 2006;64a.) with 6xR-CHOP-14 + 2 R served as control. Results: 99/100 pts. are evaluable. Despite the worse prognostic profile of the SMARTE-R-CHOP-14 population, grade 3/4 infections decreased from 6.6% to 3.5% (p=0.009), and therapy-associated deaths from 5.6% to 3.0% (p=0.428) with intensified infection prophylaxis. Despite a less favorable study population SMARTE-R-CHOP-14 resulted in a higher CR/CRu (84% vs. 78%; p=0.196) and a lower progression rate (5% vs. 7%) rate. However, after a median time of observation of 20 months, EFS and OS in the SMARTER trial are not different compared to 8 biweekly applications of R in the RICOVER trial. Conclusions: Early densification of R resulted in higher CR/CRu rates in the SMARTE-R-CHOP-14 study compared to the RICOVER-60 trial. However, longer follow-up is needed to determine whether the higher CR/CRu rate will eventually translate into better EFS, PFS and OS rates. The outcome of patients in the SMARTE-R and RICOVER-60 trial will be discussed in light of the different R pharmacokinetics in the two studies. Supported by Dt. Krebshilfe and Roche. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Lilly, Roche
How big a problem is heart failure with a normal ejection fraction?
Authors: Frans H Rutten, Andrew L Clark, Arno W Hoes
Journal: BMJ (2016)

Debate about cut-off levels for natriuretic peptides suggestive of heart failureUK guidelines recommend that the diagnosis of heart failure is ruled out in patients in primary care with B-type natriuretic peptide (BNP) levels below 100 ng/L or N-terminal BNP (NTproBNP) below 400 ng/L. 2 Although, NTproBNP below
STEM-09MicroRNA-128 IS A MASTER SWITCH BETWEEN PRONEURAL AND MESENCHYMAL SUBTYPE IN GLIOBLASTOMA STEM CELLS
Authors: Arun Rooj, Pierpaolo Peruzzi, Agnieszka Bronisz, E. Antonio Chiocca, Jakub Godlewski
Journal: Neuro-Oncology (2015)

Genome-wide analysis of glioblastoma multiforme (GBM) transcriptome revealed that it can be classified into at least four clinically relevant subtypes: proneural (PN), neural, classical, and mesenchymal (MES). The gene expression patterns that are distinct in these individual GBM subtypes, may account for the GBM heterogeneity and differential response to therapy. Based on our published and preliminary data, we demonstrate that microRNA-128 (miR-128), plays a crucial role in gliomagenesis, GBM stem cells (GSCs) self-renewal and radio-sensitivity. We identified miR-128 as a GBM suppressor, and its expression is especially low in MES subtype. MiR-128 exerts its tumor suppressor role by inhibiting the expression of two components of pro-oncogenic Polycomb Repressor Complexes 1 and 2 - Bmi1 and Suz12, respectively, which are highly expressed in MES GSCs. Stable knockdown of miR-128 in PN GSCs up-regulated MES-specific gene signature while its up-regulation in MES GSCs resulted in de-repression of PN-specific signature. We argue that alterations of miR-128 levels are sufficient to cause the shift between GSC subtypes, likely through changing the activity/level of PRCs, and have significant consequence for the tumorigenicity of GSCs in vivo.
Clinical Syndrome of Variant Angina with Normal Coronary Arteriogram
Authors: Arthur Selzer, Manly Langston, Charles Ruggeroli, Keith Cohn
Journal: New England Journal of Medicine (1976)

We compared patients with variant angina (ST-segment elevation during pain) who had normal or near normal coronary arteriograms (Group 1) with 20 in whom variant angina occurred in the presence of obstructive coronary lesions (Group 2). A long history of nonexertional angina without angina of effort or previous infarction was the rule in Group 1, whereas recent-onset unstable angina preceded by effort angina and infarction predominated in Group 2 (P<0.001). Normal electrocardiograms at rest, with ischemic ST-segment elevation in the inferior leads, and ischemia-induced heart block and bradycardia, characterized Group 1, whereas abnormal electrocardiograms, ischemic involvement of anterolateral leads and ventricular tachycardia or fibrillation were more common in Group 2 (P<0.001). Variant angina with normal coronary arteriogram generally has a benign course and is probably unrelated to atherosclerosis. (N Engl J Med 295:1343–1347, 1976)
Individual Patient Data Of Conditional Survival Analysis In a Large Cohort Of 816 Multiple Myeloma (MM) Patients Constitutes a Different Way To Identify Patients With Extended Life Expectancy
Authors: Martina Kleber, Stefanie Hieke, Milena Pantic, Bernd Koch, Gabriele Ihorst, Ralph Waesch, Philippe Moreau, Martin Schumacher, Monika Engelhardt
Journal: Blood (2013)
IgE Anti-Haemophilus Influenzae Type b (Hib) Antibodies Detected in Serum of Hib Vaccinated Asthmatic and Non-Asthmatic Pediatric Patients
Authors: Tehila A. Saadia, Stephan Kohlhoff, Natalie Banniettis, Yitzchok M. Norowitz, Rauno Joks, Helen G. Durkin, Tamar A. Smith-Norowitz
Journal: Journal of Allergy and Clinical Immunology (2016)
Joseph Bell, M.D. — The Real Sherlock Holmes
Authors: Edward E. Harnagel
Journal: New England Journal of Medicine (1958)

JOSEPH Bell was the last of a distinguished family of physicians who for a hundred and forty years occupied positions of prominence in the medical affairs of Edinburgh. After graduation from the University in 1859, he became house physician to Professor James Syme in the Royal Infirmary, and also held an appointment as demonstrator of anatomy at the University. At the age of twenty-six he began to lecture on systematic surgery in Surgeon Square, and in 1878, having reached the post of senior surgeon at the Infirmary, he became eligible to teach the subject of clinical surgery. He was an . . .
Present-Day Management of Pleural Empyema in Infants and Adults
Authors: Gustaf E. Lindskog
Journal: New England Journal of Medicine (1956)

DURING the past fifteen years there has been a dramatic decline in the incidence of empyema. This decrease is related to the early treatment of pneumonia with antibiotics, frequently outside hospitals and often without bacteriologic controls. However, a review of empyema and its treatment is not as outdated and impertinent as one might suppose. Cases of empyema still require hospital admission, although in reduced numbers. The patients tend to be chronically rather than acutely ill, some with complicated problems about whose treatment there is considerable diversity of opinion.In a four-year period ending July, 1943, there were 493 admissions to . . .
Nervous-System Glycoproteins in Mental Disorders
Authors: Samuel Bogoch, Karl T. Dussik, Peter Conran
Journal: New England Journal of Medicine (1961)

IN approaching the relation of mental order and disorder to the structure and activity of the nervous system, one of the requirements appears to be the use of suitable quantitative methods for the longitudinal study of nervous-system structure and activity in parallel with careful clinical study of individual patients. Because of the relative autonomy of Central-nervous-system chemistry as compared with that of other body organs and fluids1 studies on blood and urine bear unusual risks of nonrelevance or secondary relevance to the mind-brain problem. Yet because of the design of the nervous system, and one's attitude to it, direct study . . .
Diagnosis of Pseudoxanthoma Elasticum by Scar Biopsy in Patients without Characteristic Skin Lesions
Authors: Mark Lebwohl, Robert G. Phelps, Lawrence Yannuzzi, Stanley Chang, Ira Schwartz, Wayne Fuchs
Journal: New England Journal of Medicine (1987)

Pseudoxanthoma elasticum is a disorder of connective tissue that is associated with numerous systemic complications, including accelerated atherosclerosis, gastrointestinal bleeding, angioid streaks in the ocular fundus, and blindness. Diagnosis of the disease is important because many of its complications can be prevented and genetic counseling can be offered to family members of affected patients. The purpose of this study was to examine the usefulness of scar biopsy in establishing a diagnosis of pseudoxanthoma elasticum in patients with angioid streaks but without characteristic skin lesions. Ten patients with angioid streaks but without cutaneous findings indicative of pseudoxanthoma elasticum were evaluated by biopsy of scars and flexural skin. The biopsy specimens were compared with those from unaffected controls. In 6 of the 10 patients, scar biopsies showed fragmentation and clumping of elastic tissue in the deep dermis. Three patients also had these histologic features of pseudoxanthoma elasticum in biopsy specimens of flexural skin that appeared to be normal. We conclude that biopsies of scars in randomly chosen sites may be useful when pseudoxanthoma elasticum is suspected despite the absence of typical skin lesions.
Phase II study of a TGF-β2 antisense gene modified allogeneic tumor cell vaccine (Lucanix) in advanced NSCLC
Authors: J. J. Nemunaitis, R. O. Dillman, P. Schwarzenberger, N. Senzer, A. Tong, E. Devol, T. Chamberlin, D. Shawler, H. Fakhrai
Journal: Journal of Clinical Oncology (2006)

7018 Background: Lucanix (L) is a non-viral gene based allogeneic tumor cell vaccine which demonstrates enhancement of tumor antigen recognition as a result of Transforming Growth Factor (TGF-β2) inhibition. Methods: We performed a randomized dose variable phase II trial involving stage IIIB/IV non small cell lung cancer (NSCLC). Each patient received one of 3 doses (1.25, 2.5, 5.0x10 7 cells/injection) of L, given intradermally, to a maximum of 16 injections either monthly or every other month. Immune function, safety and anticancer activity were monitored. Results: Sixty-one patients (15 IIIB/ 46 IV; 51/61 (84%) ≥ prior cytotoxic therapy), received a total of 417 vaccinations. No significant (≥ grade 3) adverse events probably or definitely associated with administration of the vaccine were observed. A dose-related survival difference was demonstrated in patients who received ≥ 2.5 × 10 7 cells/injection versus those who received &lt;2.5 × 10 7 cells/injection (p=0.0151). The percent of patients surviving 1 and 2 years was 61% and 52% for the high dose group and 40% and 13% for the low dose group. Fifteen percent of patients achieved a partial response. Cytokine production (IFN-γ, p=0.006; IL-6, p=0.004; IL4, p=0.007) was induced, antibody mediated response to vaccine HLA antigen was observed (p=0.014) and cell mediated response showed a correlation trend (p=0.086) in patients achieving stable disease or partial response (15%) compared to those with progressive disease. Conclusions: In conclusion, L is safe and well tolerated. A survival advantage is suggested in patients who receive ≥ 2.5x10 7 cells/injection thereby supporting the justification for further phase III evaluation. Phase III investigation is recommended. [Table: see text]
Tacrine as a Treatment for Alzheimer's Dementia
Authors: Arnold S. Relman
Journal: New England Journal of Medicine (1991)

IN November 1986 the Journal published an article by Summers and his colleagues1 on the use of oral tetrahydroaminoacridine (tacrine, or THA) in the treatment of 17 patients with moderate-to-severe Alzheimer's  These workers reported encouraging initial results, suggesting that the agent may be at least temporarily useful in the long-term palliative treatment of patients with Alzheimer's disease. They concluded, We stress that further observations will be required before a clear assessment of the role of this agent can be made. The Journal's editors had deliberated long and hard before deciding to publish this work. Reviewers pointed out that . . .
Clinical and Physiologic Studies in a Negro with Sickle-Cell Hemoglobin D Disease
Authors: Paul R. McCurdy, Mona M. Gieschen
Journal: New England Journal of Medicine (1960)

HEMOGLOBIN D was the fifth human hemoglobin to be described after hemoglobin A (normal adult), hemoglobin F (normal fetal), hemoglobin S (sickle) and hemoglobin C. It was found with hemoglobin S in 2 white siblings with hemoglobin S-D disease.1 , 2 Three additional cases of this disorder have been reported, 2 in Caucasians3 , 4 and 1 in a mulatto.5 A survey of a nearby city found the incidence of hemoglobin D trait to be 0.85 per 1000 Negroes.6 It was suggested that hemoglobin S-D disease was being overlooked in the Negro.Hemoglobin D has the same mobility on filter-paper electrophoresis at pH 8.6 . . .
Predictive Role of Neutrophil/Lymphocyte Ratio (Nlr) for Oxaliplatin Efficacy in Metastatic Pancreatic Cancer Patients (Pts)
Authors: V. Formica, C. Morelli, P. Ferroni, A. Nardecchia, M. Tesauro, V. Cereda, F. Guadagni, M. Roselli
Journal: Annals of Oncology (2014)
Zinc in the Management of Diarrhea in Young Children
Authors: Mary E. Penny, Claudio F. Lanata
Journal: New England Journal of Medicine (1995)

Each year, millions of children die of diarrhea. Many more suffer frequent diarrheal illnesses, which stunt their growth and add to the problems of their often overburdened parents. Nonetheless, there have been substantial reductions in deaths from diarrhea, primarily as a result of the development and use of a standard oral rehydration solution (containing 90 mmol of sodium and 111 mmol of glucose per liter; total osmolality, 311 mOsm per kilogram). Actively promoted by agencies including the World Health Organization (WHO) and the United Nations Children's Fund, this inexpensive but efficacious treatment is now accessible to nearly everyone in practically . . .
Malaria Imported from Somalia
Authors: William D. Bone, James A. Newton, Edward C. Oldfield
Journal: New England Journal of Medicine (1993)

To the Editor: Malaria should be considered in the differential diagnosis of fever in any patient returning from an area where the disease is endemic1. During the Vietnam War, there were more than 14,000 cases of imported malaria among U.S. military personnel2. We are concerned that U.S. troops who served in Somalia in Operation Restore Hope may present with imported malaria after returning home3. A 21-year-old Marine was deployed to Mogadishu, Somalia, on December 15, 1992. The patient received a third-degree burn on December 24. Subsequently, he was evacuated to a U.S. military medical facility in Germany. . . .
An Unusual False-Positive Uptake of Radioiodine in Pericardial Effusion on Posttherapy Scan
Authors: Gaurav Malhotra, Surendra H. Moghe, Rohit Ranade, R. Ramesh V. Asopa
Journal: Clinical Nuclear Medicine (2016)

Posttherapy scan in a 21-year-old woman with papillary carcinoma of thyroid with lymph node metastasis, who received 5.55 GBq of radioiodine (I), revealed halo-like diffuse tracer uptake in the pericardial region. Echocardiography showed no abnormality except pericardial effusion, which subsided after reinstitution of levothyroxine therapy. Although rare, false-positive radioiodine uptake can occur in pericardial effusion secondary to thyroxine withdrawal-related hypothyroidism and needs close monitoring of the patient.
Abstract 1749: Bortezomib and JQ1 hold promise for human and canine osteosarcoma
Authors: Yating Yang, Vilma Yuzbasiyan-Gurkan
Journal: Cancer Research (2015)

Abstract Osteosarcoma (OS) is the most common primary malignant bone tumor of both humans and dogs. Despite advances in treatment of other cancers, the clinical outcome of OS remains poor for the past decades. Therefore, there is a great need to identify novel and effective treatments for osteosarcoma. Several classes of novel small molecules with anti-tumor activities have become available in the last few years. Among these are tyrosine kinase inhibitors (TKIs) which are able to inhibit kinase activity of many receptor tyrosine kinases. Another class of molecules target bromodomains which modify chromatin and block transcription of key factors, another class of molecules target inhibition of the proteasome which induces cell death through various mechanisms. Previous findings from our lab identified two TKIs (sunitinib, sorafenib), a bromodomain inhibitor (JQ1), and a proteasome inhibitor (bortezomib) as having good growth inhibition effects in low concentrations on three canine OS cell lines (D17, Abrams, and Gracie) and two human OS cell lines (SAOS2 and U2OS) in a series of drug screening assay. Among these candidates, we hypothesized that bortezomib and JQ1 would be effective against canine and human OS cell lines. We then determined the exact IC50 values of these two drugs, the concentration capable of inhibiting proliferation by 50%. The IC50 values of bortezomib varied in cells from 0.01 to 0.22 μM and JQ1 from 0.5 μM to 12.5 μM, which all within achievable plasma concentration and tolerable levels. In addition, these two drugs shown to decrease cell migration ability in wound healing assay as well as invasion ability in matrigel assay. With the promising results from in vitro studies, we further exam JQ1 as therapeutic strategy in an orthotopic tumor xenograft mouse model. However, the evaluation of JQ1 efficiency need to be evaluated before human and canine OS clinical trials. Citation Format: Yating Yang, Vilma Yuzbasiyan-Gurkan. Bortezomib and JQ1 hold promise for human and canine osteosarcoma. [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 1749. doi:10.1158/1538-7445.AM2015-1749