Background
While children with acute lymphoblastic leukemia (ALL) experience close to a 90% likelihood of cure, the outcome for certain high‐risk pediatric ALL subtypes remains dismal. Spleen ...tyrosine kinase (SYK) is a prominent cytosolic nonreceptor tyrosine kinase in pediatric B‐lineage ALL (B‐ALL). Activating mutations or overexpression of Fms‐related receptor tyrosine kinase 3 (FLT3) are associated with poor outcome in hematological malignancies. TAK‐659 (mivavotinib) is a dual SYK/FLT3 reversible inhibitor, which has been clinically evaluated in several other hematological malignancies. Here, we investigate the in vivo efficacy of TAK‐659 against pediatric ALL patient‐derived xenografts (PDXs).
Methods
SYK and FLT3 mRNA expression was quantified by RNA‐seq. PDX engraftment and drug responses in NSG mice were evaluated by enumerating the proportion of human CD45+ cells (%huCD45+) in the peripheral blood. TAK‐659 was administered per oral at 60 mg/kg daily for 21 days. Events were defined as %huCD45+ ≥ 25%. In addition, mice were humanely killed to assess leukemia infiltration in the spleen and bone marrow (BM). Drug efficacy was assessed by event‐free survival and stringent objective response measures.
Results
FLT3 and SYK mRNA expression was significantly higher in B‐lineage compared with T‐lineage PDXs. TAK‐659 was well tolerated and significantly prolonged the time to event in six out of eight PDXs tested. However, only one PDX achieved an objective response. The minimum mean %huCD45+ was significantly reduced in five out of eight PDXs in TAK‐659‐treated mice compared with vehicle controls.
Conclusions
TAK‐659 exhibited low to moderate single‐agent in vivo activity against pediatric ALL PDXs representative of diverse subtypes.
The exploration of copy-number variation (CNV), notably of somatic cells, is an understudied aspect of genome biology. Any differences in the genetic makeup between twins derived from the same zygote ...represent an irrefutable example of somatic mosaicism. We studied 19 pairs of monozygotic twins with either concordant or discordant phenotype by using two platforms for genome-wide CNV analyses and showed that CNVs exist within pairs in both groups. These findings have an impact on our views of genotypic and phenotypic diversity in monozygotic twins and suggest that CNV analysis in phenotypically discordant monozygotic twins may provide a powerful tool for identifying disease-predisposition loci. Our results also imply that caution should be exercised when interpreting disease causality of de novo CNVs found in patients based on analysis of a single tissue in routine disease-related DNA diagnostics.
Eltrombopag is a small molecule, thrombopoietin receptor agonist approved for the treatment of patients with aplastic anemia and chronic immune thrombocytopenia. It is also a polyvalent cation ...chelator and inhibits leukemia cell proliferation via reduction of intracellular iron. The in vivo efficacy of eltrombopag was tested against a panel of six Pediatric Preclinical Testing Consortium osteosarcoma xenografts at doses of 5 mg/kg/day (moderate dose) and 50 mg/kg/day (high dose). Eltrombopag, at moderate doses, failed to significantly improve event-free survival (EFS) in 6/6 models. At high doses, eltrombopag significantly prolonged EFS in 2/2 models, though the effect size was small. All models tested demonstrated progressive disease. While eltrombopag did not meaningfully inhibit osteosarcoma growth, it also did not stimulate tumor growth, suggesting it may be safely investigated as a supportive care agent to enhance platelet recovery post chemotherapy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
OBJECTIVES:Vulvar squamous cell carcinoma (vSCC) is a gynecologic malignancy diagnosed in nearly 4500 women in the United States each year. Current criteria for treatment planning provide inadequate ...assessment of aggressive vSCC cases, resulting in insufficient use of adjuvant treatments and high rates of vSCC recurrence. Perineural invasion (PNI) is a pathologic feature inconsistently included in the assessment of vSCC, because its relevance to clinical outcomes in these women is not well defined. The purpose of this study was to determine the association between PNI and relevant clinical parameters such as recurrence.
METHODS:A total of 103 cases of vSCC were evaluated for PNI using pathology report review and immunohistochemistry dual-chromogen staining for S100 and AE1/3. Medical records were reviewed for clinical and follow-up data. Data were analyzed using univariate and multivariate logistic regression statistical methods.
RESULTS:Patients with vSCC containing PNI had a greater risk for cancer recurrence than those whose tumors did not contain PNI (odds ratio=2.8, P=0.0290). There was no significant correlation between the presence of PNI and nodal involvement, stage, or lymphovascular invasion. Tumors with PNI had greater depth of invasion (DOI) (P=0.0047); however, DOI was not associated with recurrence (P=0.2220). When analyzed using a multivariable logistic regression model, PNI was an independent predictor of recurrence in vSCC (adjusted odds ratio=2.613, P=0.045).
CONCLUSIONS:PNI is an independent indicator of risk for recurrence in vSCC. The association of PNI with increased risk for recurrence, independent of DOI, nodal involvement, lymphovascular invasion, or stage, should encourage practicing pathologists to thoroughly search for and report the presence of PNI in vSCC.
The lack of bacteriophages capable of infecting the Listeria species, Listeria grayi, is academically intriguing and presents an obstacle to the development of bacteriophage-based technologies for ...Listeria. We describe the isolation and engineering of a novel L. grayi bacteriophage, LPJP1, isolated from farm silage. With a genome over 200,000 base pairs, LPJP1 is the first and only reported jumbo bacteriophage infecting the Listeria genus. Similar to other Gram-positive jumbo phages, LPJP1 appeared to contain modified base pairs, which complicated initial attempts to obtain genomic sequence using standard methods. Following successful sequencing with a modified approach, a recombinant of LPJP1 encoding the NanoLuc luciferase was engineered using homologous recombination. This luciferase reporter bacteriophage successfully detected 100 stationary phase colony forming units of both subspecies of L. grayi in four hours. A single log phase colony forming unit was also sufficient for positive detection in the same time period. The recombinant demonstrated complete specificity for this particular Listeria species and did not infect 150 non-L. grayi Listeria strains nor any other bacterial genus. LPJP1 is believed to be the first reported lytic bacteriophage of L. grayi as well as the only jumbo bacteriophage to be successfully engineered into a luciferase reporter.
Background
The objective of this study was to characterize hypernatremia patients at hospital admission into clusters using an unsupervised machine learning approach and to evaluate the mortality ...risk among these distinct clusters.
Methods
We performed consensus cluster analysis based on demographic information, principal diagnoses, comorbidities, and laboratory data among 922 hospitalized adult patients with admission serum sodium of > 145 mEq/L. We calculated the standardized difference of each variable to identify each cluster’s key features. We assessed the association of each hypernatremia cluster with hospital and 1-year mortality.
Results
There were three distinct clusters of patients with hypernatremia on admission: 318 (34%) patients in cluster 1, 339 (37%) patients in cluster 2, and 265 (29%) patients in cluster 3. Cluster 1 consisted of more critically ill patients with more severe hypernatremia and hypokalemic hyperchloremic metabolic acidosis. Cluster 2 consisted of older patients with more comorbidity burden, body mass index, and metabolic alkalosis. Cluster 3 consisted of younger patients with less comorbidity burden, higher baseline eGFR, hemoglobin, and serum albumin. Compared to cluster 3, odds ratios for hospital mortality were 15.74 (95% CI 3.75–66.18) for cluster 1, and 6.51 (95% CI 1.48–28.59) for cluster 2, whereas hazard ratios for 1-year mortality were 6.25 (95% CI 3.69–11.46) for cluster 1 and 4.66 (95% CI 2.73–8.59) for cluster 2.
Conclusion
Our cluster analysis identified three clinically distinct phenotypes with differing mortality risk in patients hospitalized with hypernatremia.
Graphic abstract
Background: The aim of this study was to assess the relationship between admission serum phosphate levels and in-hospital mortality in all hospitalized patients.
Methods: All adult hospitalized ...patients who had admission serum phosphate available between years 2009 and 2013 were enrolled. Admission serum phosphate was categorized based on its distribution into six groups (<2.5, 2.5-3.0, 3.1-3.6, 3.7-4.2, 4.3-4.8 and ≥4.9 mg/dL). The odds ratio (OR) of in-hospital mortality by admission serum phosphate, using the phosphate category of 3.1-3.6 mg/dL as the reference group, was obtained by logistic regression analysis.
Results: 42,336 patients were studied. The lowest incidence of in-hospital mortality was associated with a serum phosphate within 3.1-4.2 mg/dL. A U-shaped curve emerged demonstrating higher in-hospital mortality associated with both serum phosphate <3.1 and >4.2 mg/dL. After adjusting for potential confounders, both serum phosphate <2.5 and >4.2 mg/dL were associated with in-hospital mortality with ORs of 1.60 (95%CI 1.25-2.05), 1.60 (95%CI 1.29-1.97), and 3.89 (95%CI 3.20-4.74) when serum phosphate were <2.5, 4.3-4.8 and ≥4.9 mg/dL, respectively. Among subgroups of patients with chronic kidney disease (CKD) and cardiovascular disease (CVD), the highest mortality was associated with a serum phosphate ≥4.9 mg/dL with ORs of 4.11 (95%CI 3.16-5.39) in CKD patients and 5.11 (95%CI 3.33-7.95) in CVD patients.
Conclusion: Hospitalized patients with admission serum phosphate <2.5 and >4.2 mg/dL are associated with an increased risk of in-hospital mortality. The highest mortality risk is associated with CKD and CVD patients with admission hyperphosphatemia.
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•Chronic TCE decreased IFN-γ production by effector/memory CD4+ T cells.•TCE increased DNA methylation of Ifng promoter in effector/memory CD4+ T cells.•Ifng promoter of ...effector/memory CD4+ T cells susceptible to epigenetic drift.
CD4+ T cells in female MRL+/+ mice exposed to solvent and water pollutant trichloroethylene (TCE) skew toward effector/memory CD4+ T cells, and demonstrate seemingly non-monotonic alterations in IFN-γ production. In the current study we examined the mechanism for this immunotoxicity using effector/memory and naïve CD4+ T cells isolated every 6 weeks during a 40 week exposure to TCE (0.5mg/ml in drinking water). A time-dependent effect of TCE exposure on both Ifng gene expression and IFN-γ protein production was observed in effector/memory CD4+ T cells, with an increase after 22 weeks of exposure and a decrease after 40 weeks of exposure. No such effect of TCE was observed in naïve CD4+ T cells. A cumulative increase in DNA methylation in the CpG sites of the promoter of the Ifng gene was observed in effector/memory, but not naïve, CD4+ T cells over time. Also unique to the Ifng promoter was an increase in methylation variance in effector/memory compared to naïve CD4+ T cells. Taken together, the CpG sites of the Ifng promoter in effector/memory CD4+ T cells were especially sensitive to the effects of TCE exposure, which may help explain the regulatory effect of the chemical on this gene.
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