tbuckley/cabot-search huggingface dataset:
Prospective comparison of early bone marrow evaluation on day 5 versus day 14 of the “3 + 7” induction regimen for acute myeloid leukemia
Authors: Yishai Ofran, Ronit Leiba, Chezi Ganzel, Revital Saban, Moshe Gatt, Ron Ram, Ariela Arad, Shlomo Bulvik, Ilana Hellmann, Sharon Gino‐Moor, Tsila Zuckerman, Ron Hoffman, Netanel Horowitz, Noa Lavi, Shimrit Ringelstein, Israel Henig, Michal Hayun, Jacob M. Rowe
Journal: American Journal of Hematology (2015)

Evaluation of early response during induction therapy for acute myeloid leukemia (AML) is used for prognostication and re‐induction strategy, yet the optimal evaluation time point is unknown. Clearance of bone marrow (BM) blasts by day 14 of therapy does not ensure remission; thus, some patients requiring re‐induction are neglected. This study aimed to examine the role of earlier BM evaluation during induction for predicting remission and overall survival. Results of BM testing on the 5th and 14th day of intensive induction were prospectively compared in 127 adult patients with AML. Re‐induction was given, based on Day 14 results, to 25 patients. Reduction of the BM blast count to &lt;5% as early as by the fifth day of induction was more specifically associated with the achievement of remission compared to Day 14 (88.2% vs. 60%, respectively). Rapid responders have a better 3‐year overall survival (OS). Day 5 results are a stronger predictor of OS by multivariate analysis and better segregate long‐term survivors than the Day 14th BM count (66% vs. 30%, P = 0.0001 and 48% vs. 37%, respectively, P = 0.04). The Day 5 evaluation of BM carries significant clinical information. The benefit of prescribing re‐induction based on such early evaluation should be prospectively studied. Am. J. Hematol. 90:1159–1164, 2015. © 2015 Wiley Periodicals, Inc.
Gal3 Binds Gal80 Tighter than Gal1 Indicating Adaptive Protein Changes Following Duplication
Authors: Tali Lavy, Hayato Yanagida, Dan S. Tawfik
Journal: Molecular Biology and Evolution (2015)

Derived from the yeast whole-genome duplication, Saccharomyces cerevisiae GAL1 and GAL3 encode the catabolic enzyme galactokinase (Gal1) and its transcriptional coinducer (Gal3), whereas the ancestral, preduplicated GAL1 gene performed both functions. Previous studies indicated that divergence was primarily driven by changes in upstream promoter elements, and changes in GAL3's coding region are assumed to be the result of drift. We show that replacement of GAL3's open-reading-frame with GAL1's results in an extended lag phase upon switching to growth on galactose with up to 2.5-fold differences in the initial cell masses. Accordingly, the binding affinity of Gal3 to Gal80 was found to be greater than 10-folds higher than that of Gal1, with both a higher association rate (ka) and lower dissociation (kd) rate. Thus, while changes in the noncoding, regulatory regions were the initial driving force for GAL3's subfunctionalization as a coinducer, adaptive changes in the protein sequence seem to have followed.
Contrast Methods in Diagnostic Roentgenology
Authors: B Felson
Journal: Annual Review of Medicine (1955)

The past year has brought forth few new discoveries in the field of diag­ nostic roentgenology. There has been, in general, a consolidation of earlier advances, with emphasis placed on the finer details of roentgen interpreta­ tion. The newer techniques of roentgen examination have been improved and extended so that many of the experimental methods of previous years have now become standard procedures in most x-ray departments. Since the reviewer's own interests have, to a considerable degree, centered about the subject of roentgen diagnosis through the use of contrast media, and because this subject is intimately related to all phases of diagnostic roentgenology, it has been selected as the topic for this review.
Problems with the new junior doctor contract
Authors: Jessamy Bagenal, Tom Moberly, Fiona Godlee
Journal: BMJ (2015)

Why junior doctors need to channel their anger

Junior doctors are angry. In August 2016 the UK government plans to impose a new contract on doctors in England that threatens to extend their standard working hours while cutting their pay by up to 15%.1

Over 54 000 people have already signed an online petition calling on doctors to take strike action to oppose the imposition of the contract.2 Some medical royal colleges have also taken the unusual step of commenting on contractual terms and conditions, an area usually reserved for trade unions. The Royal College of Paediatrics and Child Health, the Royal College of Physicians of Edinburgh, the Royal College of Psychiatrists, the Royal College of Surgeons, the Association of Surgeon in Training, and others have raised concerns about the potential effect of the changes on the safety of patients and on recruitment and retention.

Although many details about the proposed changes are missing, they may look fairly harmless at first sight. Changes are based on recommendations of the independent Review Body on Doctors’ and Dentists’ Remuneration. Among other suggestions, they include contractual safeguards to ensure that hours and rest periods are maintained; a separate hourly payment …
Gaps in antenatal care are found in most stillbirths
Authors: Z. Kmietowicz
Journal: BMJ (2015)

Many opportunities to monitor or screen pregnant women who went on to have stillbirths were missed by the NHS, a review of cases has found.1

For two thirds of women and babies, improvements in care could have made a difference to the outcome, investigations showed. Concerns included identifying risk factors and screening for gestational diabetes, identifying fetal growth restriction, and responding to reduced fetal movements.

“Whilst actions in the three key areas may not prevent all term antepartum stillbirths, if we get this right a substantial proportion may be prevented in the future,” said David Richmond, president …
Gq/11α and Gsα mediate distinct physiological responses to central melanocortins
Authors: Yong-Qi Li, Yogendra Shrestha, Mritunjay Pandey, Min Chen, Ahmed Kablan, Oksana Gavrilova, Stefan Offermanns, Lee S. Weinstein
Journal: Journal of Clinical Investigation (2015)

Activation of brain melanocortin 4 receptors (MC4Rs) leads to reduced food intake, increased energy expenditure, increased insulin sensitivity, and reduced linear growth. MC4R effects on energy expenditure and glucose metabolism are primarily mediated by the G protein Gsα in brain regions outside of the paraventricular nucleus of the hypothalamus (PVN). However, the G protein(s) that is involved in MC4R-mediated suppression of food intake and linear growth, which are believed to be regulated primarily though action in the PVN, is unknown. Here, we show that PVN-specific loss of Gqα and G11α, which stimulate PLC, leads to severe hyperphagic obesity, increased linear growth, and inactivation of the hypothalamic-pituitary-adrenal axis, without affecting energy expenditure or glucose metabolism. Moreover, we demonstrate that the ability of an MC4R agonist delivered to PVN to inhibit food intake is lost in mice lacking Gq/11α in the PVN but not in animals deficient for Gsα. The blood pressure response to the same MC4R agonist was only lost in animals lacking Gsα specifically in the PVN. Together, our results exemplify how different physiological effects of GPCRs may be mediated by different G proteins and identify a pathway for appetite regulation that could be selectively targeted by Gq/11α-biased MC4R agonists as a potential treatment for obesity.
The Missing Men: HIV Treatment Scale-Up and Life Expectancy in Sub-Saharan Africa
Authors: Alexander C. Tsai, Mark J. Siedner
Journal: PLoS Medicine (2015)

Delivery of effective HIV antiretroviral therapy (ART) to the more than 6 million persons with HIV in South Africa is well underway, with early data on the impact of this massive public health effort demonstrating a reversal of the previous decade's precipitous decline in population life expectancy [1].Although South Africa's age and sex disparities in HIV acquisition have traditionally been described as disadvantaging young women [2], accumulating evidence now suggests a reverse disparity: although HIV care is available to both men and women and is nominally free of charge, women are more likely to be tested for HIV, engage in pre-treatment care, initiate treatment earlier, stay on treatment, and survive [3][4][5][6].To adopt the classic Eisenberg and Power [7] analogy of health care as current flowing through an electric circuit, the voltage drops along the entire circuit of HIV care, from HIV infection to AIDS-free survival, are larger for men compared with women (Fig 1).There are simply too many missing men.In recent years, studies from South Africa [8], as well as Rwanda [9] and Uganda [10], have begun to demonstrate the cumulative impact of these voltage drops, which, in total, result in an approximately 10-year life expectancy gap between men and women initiating ART at 20 years of age (Fig 2).However, the findings of these studies should be interpreted in light of important limitations.First, they were based solely on data obtained from persons enrolled in HIV treatment programs.Poverty, food insecurity, HIV stigma, and geographic barriers still exert outsize influences on HIV testing, treatment, and retention in these settings [11][12][13][14], so it is unlikely that these enrollees are representative of the entire population of persons with HIV.Second, mortality had to be estimated among those lost to follow up [9,10].Because persons in HIV treatment programs are much more likely to be lost to care than confirmed as dead [15,16], and because the vast majority of HIV-related mortality events go unreported [17], the mortality estimates in these studies are likely to be biased.Third, and perhaps most notably, none of these studies directly observed non-HIV mortality.Thus, while they were able to document trends in mortality among persons with HIV, they were unable to assess the extent to which these changes were related to HIV care or to unrelated secular trends in health and health behavior.In this context, the research article by Jacob Bor and colleagues [18] that appears this week in PLOS Medicine provides new evidence of a widening gender gap in life expectancy, using data obtained from a general population sample in rural South Africa from 2001-2011, covering a period of coincident ART scale-up.By surveilling all persons in the region-whether HIV-negative, HIV-positive in care, or HIV-positive but not in care-and by using verbal autopsies to categorize mortality events that were recorded by the surveillance teams, this
Combination intraventricular chemotherapy for meningeal neoplasia.
Authors: L Giannone, F A Greco, J D Hainsworth
Journal: Journal of Clinical Oncology (1986)

Twenty two patients with meningeal neoplasia were treated with biweekly combination intraventricular chemotherapy using methotrexate, cytosine arabinoside, and thiotepa. Patients with the following malignancies were included: breast cancer, ten patients; lung cancer, seven; non-Hodgkin's lymphoma, two; malignant melanoma, one; transitional cell carcinoma of the bladder, one; and malignant glioma, one. Eight of 22 patients (36%) had a Karnofsky performance status of less than 50%. Eleven of 22 patients received radiotherapy to symptomatic areas, and seven received systemic chemotherapy in addition to combination intraventricular therapy. Patients were evaluated for both toxicity and response to therapy. Myelosuppression was the major toxic condition and occurred in 17 of 22 patients (77%). Ten patients (45%) had a nadir WBC count of less than 1000/microL or a platelet count of less than 25,000/microL. No patient achieved a complete response (CR), although nine patients (41%) had partial responses (PRs) lasting 4 to 24 + weeks. Median survival for the entire group was 10 weeks (range, 6 to 24+ weeks). In this small group of patients, simultaneous triple-drug intraventricular chemotherapy caused unacceptable myelosuppression without increasing the response rate, response duration, or survival when compared with single-agent methotrexate and radiotherapy.
Phase I and II study of high-dose ifosfamide, carboplatin, and etoposide with autologous bone marrow rescue in lymphomas and solid tumors.
Authors: W H Wilson, V Jain, G Bryant, K H Cowan, C Carter, M Cottler-Fox, B Goldspiel, S M Steinberg, D L Longo, R E Wittes
Journal: Journal of Clinical Oncology (1992)

PURPOSE High-dose chemotherapy produces durable disease-free remissions in a minority of patients with resistant lymphomas and solid tumors. In an attempt to improve on the available regimens, ifosfamide, carboplatin, and etoposide (ICE) were selected for a new high-dose regimen because of their favorable spectrum of nonhematopoietic toxicity and evidence of synergy in in vitro systems. PATIENTS AND METHODS Forty-one patients with drug-resistant Hodgkin's and non-Hodgkin's lymphomas, and breast and testicular cancers were entered onto a phase I and II trial of a single course of ICE with autologous bone marrow rescue. Before transplantation, all patients received combination chemotherapy until maximal tumor response was achieved. RESULTS Patients received total doses of ifosfamide from 10 to 18 g/m2, carboplatin from 0.9 to 1.98 g/m2, and etoposide from 0.6 to 1.5 g/m2 administered during a 4-day period, with a maximum-tolerated dose (MTD) of ifosfamide 16 g/m2, carboplatin 1.8 g/m2, and etoposide 1.5 g/m2. The dose-limiting toxicities included irreversible renal, cardiac, and CNS dysfunction. There were three toxic deaths (7%), and all occurred above the MTD. Thirteen patients who were treated at the MTD tolerated the regimen well; reversible renal dysfunction and grade 2 mucositis commonly were observed. Of 23 heavily pretreated patients with persistent disease at the time of transplant, 10 (43%) achieved complete remissions (CRs) and 11 (48%) achieved partial remissions (PRs). Hodgkin's and non-Hodgkin's lymphoma patients who were treated at or below the MTD had a median potential follow-up of 11.9 months, and 12-month progression-free survivals of 62% and 48%, respectively. CONCLUSION High-dose ICE with bone marrow rescue was well tolerated with a high response rate, and should be considered for further testing.
Strong reproductive isolation between closely related tropical sea urchins (genus Echinometra).
Authors: S R Palumbi, E C Metz
Journal: Molecular Biology and Evolution (1991)

Morphological, mitochondrial DNA, and single-copy nuclear DNA differences show that the tropical sea urchin Echinometra mathaei is composed of at least four independent gene pools. Evolutionary distance between species measured with restriction-site changes (for mitochondrial DNA) and thermal renaturation (for single-copy nuclear DNA) is 1%-3% nucleotide divergence. Thus these are the most closely related sea urchin species known. Despite this genetic similarity, strong blocks to interspecific fertilization exist in this genus. Between two Hawaiian species, few eggs are fertilized in hybrid crosses, even in the presence of excess sperm. Microscopic examination of such crosses shows that sperm attachment to heterologous eggs is inhibited. Measures of genetic distance between species can help reveal the tempo of speciation and allow comparisons of morphological, biochemical, and ecological characteristics to be made in an evolutionary framework. Our results show that strong reproductive isolation can evolve by changes in egg-sperm recognition without extensive genetic divergence between species. Such mechanisms are most easily studied in free-spawning animals such as sea urchins but as well may represent an important aspect of speciation in species with internal fertilization.
Interventions requested for psychological reasons should be studied
Authors: M. Somerville, G. Radford, N. Hews
Journal: BMJ (1996)

responders and responders, the statistical power of this analysis was low, and the authors' main conclusion is based on the responses of only 54 patients.We wonder how many of the 31 non-responders would have had to be unsatisfied with the operation to reverse the results of the statistical analysis.We suspect that it would not be many.
Transformative tools for tackling tuberculosis
Authors: Jennifer L. Gardiner, Christopher L. Karp
Journal: The Journal of Experimental Medicine (2015)

The world is in need of more effective approaches to controlling tuberculosis. The development of improved control strategies has been hampered by deficiencies in the tools available for detecting Mycobacterium tuberculosis and defining the dynamic consequences of the interaction of M. tuberculosis with its human host. Key needs include a highly sensitive, specific nonsputum diagnostic; biomarkers predictive of responses to therapy; correlates of risk for disease development; and host response-independent markers of M. tuberculosis infection. Tools able to sensitively detect and quantify total body M. tuberculosis burden might well be transformative across many needed use cases. Here, we review the current state of the field, paying particular attention to needed changes in experimental paradigms that would facilitate the discovery, validation, and development of such tools.
Elucidation of molecular mechanisms of Thrombospondin (TSP-1)-induced cell growth inhibition in childhood acute lymphoblastic leukemia
Authors: Kitty Ng, Suk Hang Cheng, Chi Keung Cheng, Kin Mang Lau, Chi Kong Li, Margaret Ng
Journal: Cancer Research (2008)

2698   Thrombospondin-1 (TSP-1) is a multifunctional protein which participates in multiple biological processes including angiogenesis and apoptosis. We and others have previously demonstrated that the gene (THBS1) encoding TSP-1 is often downregulated in childhood B-lineage acute lymphoblastic leukemia (B-ALL) and TSP-1 treatment could induce apoptosis independent of CD36, which is lacking in the patient B-ALL cells. Concordantly, we have also first shown that the promoter region was frequently hypermethylated. To further elucidate the molecular mechanisms of TSP-1 induced cell growth inhibition in childhood B-ALL, we assessed the extent of apoptotic induction, the involvements of both caspase dependent and independent pathways and activation of the TGF-β by TSP-1 treatment in the bone marrow mononuclear cells (BMMNC) from 8 children with B-ALL at diagnosis.  Our results showed that 7/8 BMMNC samples treated with TSP-1 has increased apoptotic activities with greater Annexin-V positive cell proportions (6.7±9.1%). Furthermore, TSP-1 treated cells in these samples have increased activated caspase-3 level as revealed by detection of caspase-3 cleavage products. These data thus suggest TSP-1 could induce caspase-dependent apoptosis in B-ALL.  Because TSP-1 is well known to be responsible for the activation of TGF-β in different cell types, we examined the phosphorylated forms of TGF-β activated targets (Smad2/3, p38 and JNK) subsequent to TSP-1 treatment. We found increased levels of p-SMAD2/3 (9.69%), p-p38 (10.82%) and p-JNK (14.67%), when compared to untreated cells. To further confirm the effect of TGF-β activation by TSP-1, we next determined whether blockade of TGF-β would affect TSP-1 induced apoptotic activity. We demonstrated that addition of TGF-β blocking antibody led to a reduction of Annexin-V positive cells in 3/8 TSP-1 treated cells, and no response in 5/8 samples. These variable responses may be attributed to the heterogeneous nature within B-ALL cells and the variable status of promoter methylation of  THBS1 . The expected high endogenous TSP-1 level in THBS1 unmethylated cases (3/8) may render the cells less sensitive to TSP-1 treatment and blockade.  It has also been reported that TSP-1 could induce apoptosis through the binding with its receptor CD47 in CLL cells. Such pathway is characterized by the decrease in mitochondrial transmembrane potential (ΔΨ m ). We examined the effect of TSP-1 on ΔΨ m  of B-ALL, in which 7/8 (87.5%) demonstrated reduced ΔΨ m  after TSP-1 treatment. In line with these findings, we also confirmed the positive expression of CD47 (% positive expression of leukemic blasts: 71.3±21.0%, n=8). These data suggest that TSP-1 could also activate CD47-mediated apoptotic pathway in B-ALL.  Overall, our initial findings support that TSP-1 participates in various pathways and plays a significant role in childhood B-ALL pathogenesis.
ASSESSMENT OF NARCOTIC ANTAGONISTS IN THE TREATMENT OF OPIOID DEPENDENCE
Authors: R. B. Resnick, E. Schuyten-Resnick, A. M. Washton
Journal: The Annual Review of Pharmacology and Toxicology (1980)

After a traumatic childhood in Europe during the Second World War, I found that scientific research in Israel was a pleasure beyond my expectations. Over the last 65 year, I have worked on the chemistry and pharmacology of natural products. During the ...Read More
An Update of Concepts of Essential Amino Acids
Authors: Willard J. Visek
Journal: Annual Review of Nutrition (1984)

INTRODUCTION .... . . ... . . . . . .. . . . ... . . . . ..... ..... . .. . . . . ...... . . . . . . . . . . . . . . . . . . .... . . . . . . . . . . . . .. 137 GENERAL OVERVIEW OF ESSENTIAL AMINO ACIDS . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 Disp ensable Versus Indispensable Amino Acids . . . . . ........ . . . . . . . ... . . . . . . . . ..... ......... 138 Nitrogen and Amino Acid Requirements . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Comparative Study of Metabolism of Nitrogenous Compounds . . . . . . . . . . . . . . . . . ....... . . . 140 RECENT INFORMATIN ON H ISTIDINE REQUIREMENTS . . . . . . . . . .. . . . . . . ...... . . . . . . .. 141 RECENT INFORMATION ON ARGININE .. . . . . . . .....   .....   144 Arginine, Protein Repletion, Insulin, and Glucose Tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 Arginine and R eye's Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Arginine and Recovery from Trauma. . . . . . . . .     148 Arginine and Hereditary Urea Cycle Deficiencies . . . . . . . . . ..... . . . . . . . ,  148 Arginine and Gyrate Atrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 OROTIC ACID EXCRETION . . . . . .. . . . . .. . .. . .. . . . .. . . . . ....... . . . .. . ... .. . . . .... ..... . . . . . . ... . . . 149