Primary thromboprophylaxis to prevent thrombotic events in pediatric oncology patients with a malignant mediastinal mass.

Children with malignant mediastinal masses have increased thrombotic events (TE). Eligible subjects with malignant mediastinal masses between January 2000 and December 2017 were evaluated for TE, with 19 among 76 subjects receiving enoxaparin thromboprophylaxis. There were 13 TEs among 76 subjects for an incidence of 17.1%. Mediastinal compression directly led to TE in 9.2% of subjects who also had statistically significant superior vena cava compression at diagnosis. Primary thromboprophylaxis did not significantly affect TE occurrence; however, larger studies are warranted to consider strategic thromboprophylaxis guided by radiological monitoring of dynamic vascular compression to improve TE outcomes.

Vagus nerve stimulation primes platelets and reduces bleeding in hemophilia A male mice.

Deficiency of coagulation factor VIII in hemophilia A disrupts clotting and prolongs bleeding. While the current mainstay of therapy is infusion of factor VIII concentrates, inhibitor antibodies often render these ineffective. Because preclinical evidence shows electrical vagus nerve stimulation accelerates clotting to reduce hemorrhage without precipitating systemic thrombosis, we reasoned it might reduce bleeding in hemophilia A. Using two different male murine hemorrhage and thrombosis models, we show vagus nerve stimulation bypasses the factor VIII deficiency of hemophilia A to decrease bleeding and accelerate clotting. Vagus nerve stimulation targets acetylcholine-producing T lymphocytes in spleen and α7 nicotinic acetylcholine receptors (α7nAChR) on platelets to increase calcium uptake and enhance alpha granule release. Splenectomy or genetic deletion of T cells or α7nAChR abolishes vagal control of platelet activation, thrombus formation, and bleeding in male mice. Vagus nerve stimulation warrants clinical study as a therapy for coagulation disorders and surgical or traumatic bleeding.

ACE2 abrogates tumor resistance to VEGFR inhibitors suggesting angiotensin-(1-7) as a therapy for clear cell renal cell carcinoma.

Angiotensin converting enzyme 2 (ACE2) is an enzyme that belongs to the renin-angiotensin system (RAS) and antagonizes the classical angiotensin (Ang) II/angiotensin II receptor type 1 (AT1) receptor pathway. Here, we report that higher ACE2 expression correlates with better overall survival in patients with clear cell renal cell carcinoma (ccRCC). Moreover, ACE2 has inhibitory effects on tumor proliferation in ccRCC in vitro and in preclinical animal models of ccRCC. We further show that Ang-(1-7), a heptapeptide generated by ACE2, is the likely mediator of this effect. Vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) treatment of ccRCC xenografts decreased ACE2 expression, and combination treatment with VEGFR-TKI and Ang-(1-7) generated additive suppression of tumor growth and improved survival outcomes. Last, the addition of Ang-(1-7) to programmed death-ligand 1 (PD-L1) pathway inhibitor and VEGFR-TKI showed further growth suppression in an immunocompetent RCC model. Together, these results suggest that targeting the ACE2/Ang-(1-7) axis is a promising therapeutic strategy against ccRCC.

Characterizing the bacterial consortium ASDF capable of catabolic degradation of fluoranthene and other mono- and poly-aromatic hydrocarbons.

In this study, a bacterial consortium ASDF was developed, capable of degrading fluoranthene (a non-alternant poly-aromatic hydrocarbon). It comprised of three bacterial strains: Pseudomonas sp. ASDF1, Burkholderia sp. ASDF2 and Mycobacterium sp. ASDF3 capable of degrading 100 mg/L of fluoranthene under experimentally defined and optimum conditions (37 °C, pH 7.0, 150 rpm) within 7 days. Consortium had metabolized fluoranthene as sole source of carbon and energy with maximum degradation rate of 0.52 mg/L/h and growth rate of 0.054/h. Fluoranthene degradation is an aerobic process, therefore with increasing the gyratory shaking from 50 to 150 rpm, degradation was concurrently enhanced by 7.1-fold. The synthetic surfactants SDS and CTAB had antagonistic effect on fluoranthene degradation (decreased up to 2.8-fold). The proficiency of consortium was assessed for its inherent ability to degrade seven other hydrocarbons both individually as well as in mixture. The degradation profile was studied using HPLC and the detection of two degraded intermediates (salicylic acid and derivatives of phthalic acid) suggested that fluoranthene degradation might have occurred via ortho- and meta-cleavage pathways. The competency of consortium was further validated through simulated microcosm studies, which showed 96% degradation of fluoranthene in soil ecosystem under the ambient conditions. Hence, the study suggested that the consortium ASDF has an inherent potential for its wide applicability in bioremediation of hydrocarbon-contaminated sites.

A 32-Year-Old Woman With Miscarriage, Headache, Hepatitis, and Pulmonary Disease.

CASE PRESENTATION: A 32-year-old Nigerian woman, who became pregnant after undergoing in vitro fertilization, was admitted with nausea and abdominal pain. She had a history of two miscarriages and infertility because of tubal blockage treated by salpingectomy. One week prior, she presented to an outside hospital with premature rupture of membranes resulting in stillborn delivery of twins. Endometrial cultures from dilatation and curettage grew Escherichia coli, and she was started on a fluoroquinolone for chorioamnionitis.

Synergistic biodegradation of phenanthrene and fluoranthene by mixed bacterial cultures.

Polycyclic aromatic hydrocarbons (PAHs) are highly recalcitrant compounds and difficult to degrade. Therefore in this work, using a bioremediation approach, mixed bacterial cultures (ASPF) was developed and enriched from polluted marine sediments capable of degrading 400 mg/L of phenanthrene and fluoranthene in Bushnell Hass medium. ASPF consists of 22 bacterial genera dominated by Azoarcus and Chelativorans. The biostimulation effect of three water soluble fertilizers (NPK, urea, and ammonium sulfate) showed that NPK and ammonium sulfate have enhanced the degradation, whereas urea has decreased their degradation. ASPF was also able to degrade phenanthrene and fluoranthene in the presence of petroleum hydrocarbons. But degradation was found to decrease in the presence of pathway intermediates (phthalic acid and catechol) due to enzymatic feedback inhibition. Optimum degradation of both PAHs was observed under room temperature, suggesting the practical applicability of ASPF.

Study of Cathepsin B inhibition in VEGFR TKI treated human renal cell carcinoma xenografts.

Several therapeutic options are available for metastatic RCC, but responses are almost never complete, and resistance to therapy develops in the vast majority of patients. Consequently, novel treatments are needed to combat resistance to current therapies and to improve patient outcomes. We have applied integrated transcriptome and proteome analyses to identify cathepsin B (CTSB), a cysteine proteinase of the papain family, as one of the most highly upregulated gene products in established human RCC xenograft models of resistance to vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI). We used established RCC models to test the significance of CTSB in the progression of renal cancer. Our evaluation of CTSB showed that stable CTSB knockdown suppressed RCC growth in vitro and in vivo. Stable over-overexpression of wild-type CTSB (CTSBwt/hi), but not of an CTSB active site mutant (CTSBN298A), rescued cell growth in CTSB knockdown cells and abolished the efficacy of VEGFR TKI treatment. Genome-wide transcriptome profiling of CTSB knockdown cells demonstrated significant effects on multiple metabolic and stem cell-related pathways, with ALDHA1A (ALDH1) as one of the most significantly downregulated genes. Importantly, survival analysis across 16 major TCGA cancers revealed that CTSB overexpression is associated with low rates of three and five year patient survival rates (P = 2.5e-08, HR = 1.4). These data strongly support a contribution of CTSB activity to RCC cell growth and tumorigenicity. They further highlight the promise of CTSB inhibition in development of novel combination therapies designed to improve efficacy of current TKI treatments of metastatic RCC.

Extending julius seizure, a bang-sensitive gene, as a model for studying epileptogenesis: Cold shock, and a new insertional mutation.

The bang-sensitive (BS) mutants of Drosophila are an important model for studying epilepsy. We recently identified a novel BS locus, julius seizure (jus), encoding a protein containing two transmembrane domains and an extracellular cysteine-rich loop. We also determined that jussda iso7.8, a previously identified BS mutation, is an allele of jus by recombination, deficiency mapping, complementation testing, and genetic rescue. RNAi knockdown revealed that jus expression is important in cholinergic neurons and that the critical stage of jus expression is the mid-pupa. Finally, we found that a functional, GFP-tagged genomic construct of jus is expressed mostly in axons of the neck connectives and of the thoracic abdominal ganglia. In this Extra View article, we show that a MiMiC GFP-tagged Jus is localized to the same nervous system regions as the GFP-tagged genomic construct, but its expression is mostly confined to cell bodies and it causes bang-sensitivity. The MiMiC GFP-tag lies in the extracellular loop while the genomic construct is tagged at the C-terminus. This suggests that the alternate position of the GFP tag may disrupt Jus protein function by altering its subcellular localization and/or stability. We also show that a small subset of jus-expressing neurons are responsible for the BS phenotype. Finally, extending the utility of the BS seizure model, we show that jus mutants exhibit cold-sensitive paralysis and are partially sensitive to strobe-induced seizures.