Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk ALL subtype with high rates of relapse and poor patient outcome. Activating mutations affecting components of ...the JAK-STAT signaling pathway occur in the majority of Ph-like ALL cases. The use of JAK inhibitors represents a potential treatment option for Ph-like ALL, although we and others have shown that CRLF2-rearranged Ph-like ALL responds poorly to single-agent JAK inhibitors in the preclinical setting. Therefore, the aim of this study was to identify effective combination treatments against CRLF2-rearranged Ph-like ALL, and to elucidate the underlying mechanisms of synergy. We carried out a series of high-throughput combination drug screenings and found that ruxolitinib exerted synergy with standard-of-care drugs used in the treatment of ALL. In addition, we investigated the molecular effects of ruxolitinib on Ph-like ALL by combining mass spectrometry phosphoproteomics with gene expression analysis. Based on these findings, we conducted preclinical in vivo drug testing and demonstrated that ruxolitinib enhanced the in vivo efficacy of an induction-type regimen consisting of vincristine, dexamethasone, and L-asparaginase in 2/3 CRLF2-rearranged Ph-like ALL xenografts. Overall, our findings support evaluating the addition of ruxolitinib to conventional induction regimens for the treatment of CRLF2-rearranged Ph-like ALL.
There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 ...diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.
The current standard of practice for the detection of osseous metastatic disease is the conventional bone scan of the entire body using technetium-99m methylene diphosphonate (Tc-99m MDP). Although ...Tc-99m MDP scintigraphy is sensitive for the detection of advanced skeletal metastatic lesions, early involvement may be missed because this technique relies on the identification of the osteoblastic reaction of the involved bone rather than the detection the tumor itself. Positron emission tomography (PET) has proven to be the gold standard in metabolic imaging. Fluorine -18 deoxyglucose (FDG) provides a means of quantitating the glucose metabolism, with the amount of tracer accumulation reflecting the glucose metabolism: high-grade malignancies tend to have higher rates of glycolysis than do low-grade malignancies and benign lesions; therefore, high-grade malignancies have greater uptake of FDG than that of low-grade or benign lesions. Positron emission tomography has been shown to be superior to scintigraphy in the detection of metastases because it detects the presence of tumor directly by metabolic activity, rather than indirectly by showing tumor involvement due to increased bone mineral turnover. This has allowed the detection of metastatic foci earlier with PET than with bone scintigraphy. Although the spectrum of PET applications is unknown, it now is approved for the diagnosis, staging and restaging of many common malignancies and has shown efficacy for the detection of osseous metastasis from several malignancies including lung carcinoma, breast carcinoma, and lymphoma.
To describe patient characteristics and disease spectrum among foreign visitors to Haiti before and after the 2010 earthquake, we used GeoSentinel Global Surveillance Network data and compared 1 year ...post-earthquake versus 3 years pre-earthquake. Post-earthquake travelers were younger, predominantly from the United States, more frequently international assistance workers, and more often medically counseled before their trip than pre-earthquake travelers. Work-related stress and upper respiratory tract infections were more frequent post-earthquake; acute diarrhea, dengue, and Plasmodium falciparum malaria were important contributors of morbidity both pre- and post-earthquake. These data highlight the importance of providing destination- and disaster-specific pre-travel counseling and post-travel evaluation and medical management to persons traveling to or returning from a disaster location, and evaluations should include attention to the psychological wellbeing of these travelers. For travel to Haiti, focus should be on mosquito-borne illnesses (dengue and P. falciparum malaria) and travelers' diarrhea.
Extracellular histones in neutrophil extracellular traps (NETs) or in chromatin from injured tissues are highly pathological, particularly when liberated by DNases. We report the development of small ...polyanions (SPAs) (~0.9-1.4 kDa) that interact electrostatically with histones, neutralizing their pathological effects. In vitro, SPAs inhibited the cytotoxic, platelet-activating and erythrocyte-damaging effects of histones, mechanistic studies revealing that SPAs block disruption of lipid-bilayers by histones. In vivo, SPAs significantly inhibited sepsis, deep-vein thrombosis, and cardiac and tissue-flap models of ischemia-reperfusion injury (IRI), but appeared to differ in their capacity to neutralize NET-bound versus free histones. Analysis of sera from sepsis and cardiac IRI patients supported these differential findings. Further investigations revealed this effect was likely due to the ability of certain SPAs to displace histones from NETs, thus destabilising the structure. Finally, based on our work, a non-toxic SPA that inhibits both NET-bound and free histone mediated pathologies was identified for clinical development.
Public biomedical data repositories often provide web-based interfaces to collect experimental metadata. However, these interfaces typically reflect the ad hoc metadata specification practices of the ...associated repositories, leading to a lack of standardization in the collected metadata. This lack of standardization limits the ability of the source datasets to be broadly discovered, reused, and integrated with other datasets. To increase reuse, discoverability, and reproducibility of the described experiments, datasets should be appropriately annotated by using agreed-upon terms, ideally from ontologies or other controlled term sources.
This work presents "CEDAR OnDemand", a browser extension powered by the NCBO (National Center for Biomedical Ontology) BioPortal that enables users to seamlessly enter ontology-based metadata through existing web forms native to individual repositories. CEDAR OnDemand analyzes the web page contents to identify the text input fields and associate them with relevant ontologies which are recommended automatically based upon input fields' labels (using the NCBO ontology recommender) and a pre-defined list of ontologies. These field-specific ontologies are used for controlling metadata entry. CEDAR OnDemand works for any web form designed in the HTML format. We demonstrate how CEDAR OnDemand works through the NCBI (National Center for Biotechnology Information) BioSample web-based metadata entry.
CEDAR OnDemand helps lower the barrier of incorporating ontologies into standardized metadata entry for public data repositories. CEDAR OnDemand is available freely on the Google Chrome store https://chrome.google.com/webstore/search/CEDAROnDemand.
Clinical Encounters in Sexuality makes an intervention into the fields of clinical psychoanalysis and sexuality studies, in an effort to think about a range of issues relating to sexuality from a ...clinical psychoanalytic perspective. This book concentrates on a number of concepts, namely identity, desire, pleasure, perversion, ethics and discourse. The editors, Noreen Giffney and Eve Watson, have chosen queer theory, a sub-field of sexuality studies, as an interlocutor for the clinical contributors, because it is at the forefront of theoretical considerations of sexuality, as well as being both reliant upon and suspicious of psychoanalysis as a clinical practice and discourse. The book brings together a number of psychoanalytic schools of thought and clinical approaches, which are sometimes at odds with one another and thus tend not to engage in dialogue about divisive theoretical concepts and matters of clinical technique. Traditions represented here include: Freudian, Kleinian, Independent, Lacanian, Jungian, and Relational. The volume also stages, for the first time, a sustained clinical psychoanalytic engagement with queer theory. By virtue of its editorial design, this book aims to foster a self-reflective attitude in clinical readers about sexuality which historically has tended toward reification
Early studies conflict regarding improved patient outcomes with cardiologist-directed care for acute myocardial infarction (AMI). We sought to assess the magnitude and mechanism of the influence of ...physician specialty on inpatient mortality for AMI. Using data from the Pennsylvania Health Care Cost Containment Council and elsewhere, we developed age-stratified logistic regression models of inpatient mortality, utilizing a split sample strategy for model development and validation. Referral bias and physician caseload were explicitly addressed. We analyzed 30,351 admissions for AMI. In patients <65 years old, the adjusted odds ratio (OR) for mortality with cardiologist care was 0.89 (95% confidence interval CI 0.640 to 1.24, p = 0.49) relative to generalist care. In patients ≥65 years of age, the adjusted OR was 0.86 (95% CI 0.72 to 1.03, p = 0.10). Caseload was significantly higher among cardiologists and was inversely related to inpatient mortality. Mortality models with caseload but not physician designation or physician designation without caseload found each predictor statistically significant in the absence of the other (OR for cardiologist care 0.82, 95% CI 0.71 to 0.95, p = 0.007; OR for patients with low volume physicians relative to high volume 1.27, 95% CI 1.05 to 1.51, p = 0.014). Older patients of physicians with higher case loads had a lower risk adjusted inpatient mortality for AMI. This probably explains the trend toward better outcomes among patients of cardiologists rather than noncardiologists.
A new approach to 3-nitro-2-substituted thiophenes has been developed. Exposure of commercially available 1,4-dithane-2,5-diol to nitroalkenes in the presence of 20% triethylamine results in a tandem ...Michael-intramolecular Henry reaction to form the corresponding tetrahydrothiophene. Subsequent microwave irradiation on acidic alumina in the presence of chloranil effects the solvent free dehydration and aromatization to form 3-nitro-2-substituted thiophenes cleanly and rapidly. A simple workup procedure removes the requirement for purification by chromatography in most cases.
Adoptive T cell transfer therapy (ACT) using tumor infiltrating lymphocytes or lymphocytes redirected with antigen receptors (CAR or TCR) has revolutionized the field of cancer immunotherapy. ...Although CAR T cell therapy mediates robust responses in patients with hematological malignancies, this approach has been less effective for treating patients with solid tumors. Additionally, toxicities post T cell infusion highlight the need for safer ACT protocols. Current protocols traditionally expand T lymphocytes isolated from patient tumors or from peripheral blood to large magnitudes in the presence of high dose IL-2 prior to infusion. Unfortunately, this expansion protocol differentiates T cells to a full effector or terminal phenotype
, consequently reducing their long-term survival and antitumor effectiveness
. Post-infusion, T cells face further obstacles limiting their persistence and function within the suppressive tumor microenvironment. Therapeutic manipulation of T cells with common γ chain cytokines, which are critical growth factors for T cells, may be the key to bypass such immunological hurdles. Herein, we discuss the primary functions of the common γ chain cytokines impacting T cell survival and memory and then elaborate on how these distinct cytokines have been used to augment T cell-based cancer immunotherapy.
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