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Background: HSCR, a colonic neurocristopathy affecting 1/5000 births, is suggested to associate with cardiac septal defects and conotruncal malformations. However, we question subtle cardiac changes maybe more commonly present due to multi-regulations by HSCR candidate genes, in this instance, ETB. To investigate, we compared the cardiac morphology and quantitative measurements of sl/sl rat to those of the control group.Methods: Eleven neonatal rats were generated from heterozygote (ETB+/-) crossbreeding. Age and bodyweight were recorded at time of sacrifice. Diffusion-staining protocols with 1.5% iodine solution was completed prior to micro-CT scanning. All rats were scanned using an in vivo micro-CT scanner, Caliper Quantum FX, followed by two quality-control scans using a custom-built ex vivo micro-CT system. All scans were reviewed for gross cardiac dysmorphology. Micro-CT data were segmented semi-automatically post-NLM filtering for: whole-heart, LV, RV, LA, RA, and aortic arch. Measurements were taken with Drishti. Following image analysis, PCR genotyping of rats was performed: five sl/sl rats, three wildtype, and three heterozygotes. Statistical comparisons on organ volume, growth rate, and organ volume/bodyweight ratios were made between sl/sl and the control group.Results: Cardiac morphology and constituents were preserved. However, significant volumetric reductions were recorded in sl/sl rats with respect to the control: whole heart (38.70%, p value = 0.02); LV (41.22%, p value = 0.01), RV (46.15%, p value = 0.02), LA (44.93%, p value = 0.06), and RA (39.49%, p value = 0.02). Consistent trend was observed in growth rate (~ 20%) and organ-volume/bodyweight ratios (~ 25%). On the contrary, measurements on aortic arch demonstrated no significant difference among the two groups.Conclusion: Despite the presence of normal morphology, significant cardiac growth retardation was detected in sl/sl rat, supporting the likely association of cardiac anomalies with HSCR, at least in ETB-/- subtype. Structural reduction was likely due to a combination of failure to thrive from enteric dysfunction, alterations to CaNCC colonization, and importantly coronary hypoperfusion from elevated ET-1/ETA-mediated hypervasoconstriction. Little correlation was detected between aortic arch development and sl/sl rat, supporting minor ETB role in large vessels. Although further clinical study is warranted, HSCR patients may likely require cardiac assessment in view of potential congenital cardiac defects. [ABSTRACT FROM AUTHOR]

Objective: To explore the diagnostic accuracy of acute appendicitis among different patient groups and evaluate the statistical diagnostic values of common pathology and imaging tests for the diagnosis of acute appendicitis.Main Measures: Proportions of histology-proven appendicitis in different patient groups. Statistical parameters including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (+LR), negative likelihood ratio (-LR) and diagnostic odds ratio (DOR) between the histology-proven appendicitis and abnormal results of U/S, CT, WCC, CRP, bilirubin, pancreatic, and combined test results of WCC and CRP.Results: Our data showed that up to 25.7% of patients underwent appendectomy has normal appendix. Appendicitis is often accurately diagnosed among male patients, up to 90.3% of the time, while misdiagnosis of appendicitis among young females (<40 years old) is significantly high, up to 30.9%. CT has high diagnostic performance index for appendicitis, sensitivity > 90%, and no individual pathology test out of those examined can rival the sensitivity of CT. Nevertheless, by examining the combined results of WCC and CRP, we found that abnormal results in one or both these yields sensitivity similar to CT scans in detecting acute appendicitis, up to 95%.Conclusion: Young female patients have highest risk of being falsely diagnosed with acute appendicitis and hence unnecessary surgery. Bilirubin and lipase exhibit no correlations with acute appendicitis. Combined interpretation of WCC or CRP abnormal results yields competitive sensitivity as CT. Hencewe would suggest that, under the appropriate clinical context, one can use both WCC and CRP as a simple tool to support the diagnosis of appendicitis. If both tests show normal results, we would highly recommend considering alternative diagnosis. [ABSTRACT FROM AUTHOR]

It is unclear how cells counteract the potentially harmful effects of uncoordinated DNA replication in the context of oncogenic stress. Here, we identify the WRAD (WDR5/RBBP5/ASH2L/DPY30) core as a modulator of DNA replication in pancreatic ductal adenocarcinoma (PDAC) models. Molecular analyses demonstrated that the WRAD core interacts with the replisome complex, with disruption of DPY30 resulting in DNA re-replication, DNA damage, and chromosomal instability (CIN) without affecting cancer cell proliferation. Consequently, in immunocompetent models, DPY30 loss induced T cell infiltration and immune-mediated clearance of highly proliferating cancer cells with complex karyotypes, thus improving anti-tumor efficacy upon anti-PD-1 treatment. In PDAC patients, DPY30 expression was associated with high tumor grade, worse prognosis, and limited response to immune checkpoint blockade. Together, our findings indicate that the WRAD core sustains genome stability and suggest that low intratumor DPY30 levels may identify PDAC patients who will benefit from immune checkpoint inhibitors.

The phosphonate group is a key pharmacophore in many antiviral, antimicrobial, and antineoplastic drugs. Due to its high polarity and short retention time, detecting and quantifying such phosphonate-containing drugs with LC/MS-based methods are challenging and require derivatization with hazardous reagents. Given the emerging importance of phosphonate-containing drugs, developing a practical, accessible, and safe method for their quantitation in pharmacokinetics (PK) studies is desirable. NMR-based methods are often employed in drug discovery but are seldom used for compound quantitation in PK studies. Here, we show that proton-phosphorous ( 1 H- 31 P) heteronuclear single quantum correlation (HSQC) NMR allows for the quantitation of the phosphonate-containing enolase inhibitor HEX in plasma and tissues at micromolar concentrations. Although mice were shown to rapidly clear HEX from circulation (over 95% in <1 h), the plasma half-life of HEX was more than 1 h in rats and nonhuman primates. This slower clearance rate affords a significantly higher exposure of HEX in rat models compared to that in mouse models while maintaining a favorable safety profile. Similar results were observed for the phosphonate-containing antibiotic, fosfomycin. Our study demonstrates the applicability of the 1 H- 31 P HSQC method to quantify phosphonate-containing drugs in complex biological samples and illustrates an important limitation of mice as preclinical model species for phosphonate-containing drugs.