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Abstract Background We have reported arginine-sensitive regulation of LAT1 amino acid transporter (SLC 7A5) in normal rodent hepatic cells with loss of arginine sensitivity and high level constitutive expression in tumor cells. We hypothesized that liver cell gene expression is highly sensitive to alterations in the amino acid microenvironment and that tumor cells may differ substantially in gene sets sensitive to amino acid availability. To assess the potential number and classes of hepatic genes sensitive to arginine availability at the RNA level and compare these between normal and tumor cells, we used an Affymetrix microarray approach, a paired in vitro model of normal rat hepatic cells and a tumorigenic derivative with triplicate independent replicates. Cells were exposed to arginine-deficient or control conditions for 18 hours in medium formulated to maintain differentiated function. Results Initial two-way analysis with a p-value of 0.05 identified 1419 genes in normal cells versus 2175 in tumor cells whose expression was altered in arginine-deficient conditions relative to controls, representing 9–14% of the rat genome. More stringent bioinformatic analysis with 9-way comparisons and a minimum of 2-fold variation narrowed this set to 56 arginine-responsive genes in normal liver cells and 162 in tumor cells. Approximately half the arginine-responsive genes in normal cells overlap with those in tumor cells. Of these, the majority was increased in expression and included multiple growth, survival, and stress-related genes. GADD45, TA1/LAT1, and caspases 11 and 12 were among this group. Previously known amino acid regulated genes were among the pool in both cell types. Available cDNA probes allowed independent validation of microarray data for multiple genes. Among genes downregulated under arginine-deficient conditions were multiple genes involved in cholesterol and fatty acid metabolism. Expression of low-density lipoprotein receptor was decreased in both normal and tumor cells. Conclusion Arginine-sensitive regulation appears to be an important homeostatic mechanism to coordinate cell response and nutrient availability in hepatic cells. Genes predicted as arginine-responsive in stringent microarray data analysis were confirmed by Northern blot and RT-PCR. Although the profile of arginine-responsive genes is altered and increased, a considerable portion of the "arginome" is maintained upon neoplastic transformation.

Medical education is a lifelong process that demands constant adaptation. New technologies and new techniques often require new skills or fine-tuning of existing skills. (1) A gap always exists between [...], * Context.--Medical education in pathology relies on the accumulation of experience gained through inspection of numerous samples from each entity. Acquiring sufficient teaching material for rare diseases, such as Hirschsprung disease (HSCR), may be difficult, especially in smaller institutes. The current study makes use of a previously developed decision support system using a decision support algorithm meant to aid pathologists in the diagnosis of HSCR. Objective.--To assess the effect of a short training session on algorithm-assisted HSCR diagnosis. Design.--Five pathologists reviewed a data set of 568 image sets (1704 images in total) selected from 50 cases by the decision support algorithm and were tasked with scoring the images for the presence or absence of ganglion cells. The task was repeated a total of 3 times. Each pathologist had to complete a short educational presentation between the second and third iterations. Results.--The training resulted in a significantly increased rate of correct diagnoses (true positive/negative) and a decreased need for referrals for expert consultation. No statistically significant changes in the rate of false positives/negatives were detected. Conclusions.--A very short ( doi: 10.5858/arpa.2021-0481-OA

Abstract Background Angiogenic therapy with vascular endothelial growth factor (VEGF) has been proposed as a treatment paradigm for patients suffering from an insufficiency of collateral vessels. Diabetes is associated with increase in the production of VEGF and therefore additional VEGF may not be beneficial. Accordingly, we sought to determine the efficacy of VEGF therapy to augment collateral formation and tissue perfusion in a diabetic mouse ischemic hindlimb model. Methods Diabetic and non-diabetic mice were studied in parallel for the efficacy of VEGF administration. Diabetes was induced with streptozotocin. Hindlimb ischemia was produced by severing the left iliac artery. An outlet tube from an osmotic infusion pump with placebo/ 500 micrograms of plasmid-DNA encoding VEGF was fenestrated and tunneled into the left quadriceps muscle. Results VEGF induced more rapid and complete restoration of blood flow in normal mice. However, in the setting of diabetes there was no difference between VEGF Vs. placebo in the rate or adequacy of flow restoration. There was a significant increase in smooth muscle actin and Factor-VIII antigen densities in diabetic animals and in animals which received VEGF. Conclusions Angiogenic therapy with VEGF in the setting of diabetes does not appear to have the beneficial effects seen in the absence of diabetes.

Background: Patients with locally advanced rectal cancer (LARC) treated by neoadjuvant chemoradiotherapy (nCRT) may experience pathological complete response (pCR). Tools that can identify pCR are required to define candidates suitable for the watch and wait (WW) strategy. Automated image analysis is used for predicting clinical aspects of diseases. Texture analysis of magnetic resonance imaging (MRI) wavelets algorithms provides a novel way to identify pCR. We aimed to evaluate wavelets-based image analysis of MRI for predicting pCR. Methods: MRI images of rectal cancer from 22 patients who underwent nCRT were captured at best representative views of the tumor. The MRI images were digitized and their texture was analyzed using different mother wavelets. Each mother wavelet was used to scan the image repeatedly at different frequencies. Based on these analyses, coefficients of similarity were calculated providing a variety of textural variables that were subsequently correlated with histopathology in each case. This allowed for proper identification of the best mother wavelets able to predict pCR. The predictive formula of complete response was computed using the independent statistical variables that were singled out by the multivariate regression model. Results: The statistical model used four wavelet variables to predict pCR with an accuracy of 100%, sensitivity of 100%, specificity of 100%, and PPV and NPV of 100%. Conclusions: Wavelet-transformed texture analysis of radiomic MRI can predict pCR in patients with LARC. It may provide a potential accurate surrogate method for the prediction of clinical outcomes of nCRT, resulting in an effective selection of patients amenable to WW. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is prevalent, but the mechanisms underlying disease development remain elusive. We identify a role for the E3 ubiquitin ligase RNF5 in IBD. Intestinal epithelial cells (IECs) express a high level of RNF5, while the colon of Rnf5-/- mice exhibits activated dendritic cells and intrinsic inflammation. Rnf5-/- mice exhibit severe acute colitis following dextran sodium sulfate (DSS) treatment. S100A8 is identified as an RNF5 substrate, resulting in S100A8 ubiquitination and proteasomal-dependent degradation that is attenuated upon inflammatory stimuli. Loss of RNF5 from IECs leads to enhanced S100A8 secretion, which induces mucosal CD4+ T cells, resulting in Th1 pro-inflammatory responses. Administration of S100A8-neutralizing antibodies to DSS-treated Rnf5-/- mice attenuates acute colitis development and increases survival. An inverse correlation between RNF5 and S100A8 protein expression in IECs of IBD patients coincides with disease severity. Collectively, RNF5-mediated regulation of S100A8 stability in IECs is required for the maintenance of intestinal homeostasis.

Background: Lung cancer is among the most prevalent and serious forms of cancer, characterized by an allogenic phenotype that presents significant therapeutic challenges. Materials and Methods: We analyzed medical records from January 2022 to August 2023, focusing on individuals aged 18 and older diagnosed with resectable NSCLC who received neoadjuvant chemo-immunotherapy prior to surgical intervention. Results: The cohort comprised 56 patients, predominantly smokers (95%) and male (74%), with 80% presenting the disease at stage III. Of the participants, 44 underwent surgery, with 95% receiving lobar resection. Clinical assessments via PET-CT imaging revealed an 86% rate of response or disease stabilization, while pathological evaluations showed complete and major pathological responses in 61% of cases. Conclusions: This real-world data supports the safety and efficacy of incorporating immune checkpoint inhibitors in the neoadjuvant treatment of NSCLC, followed by surgical resection. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is a common gastrointestinal disease with high morbidity and mortality rate. Unfortunately, neither the etiology nor the pathophysiology of AP are fully understood and causal treatment options are not available. Recently we demonstrated that heparanase (Hpa) is adversely involved in the pathogenesis of AP and inhibition of this enzyme ameliorates the manifestation of the disease. Moreover, a pioneer study demonstrated that Aspirin has partial inhibitory effect on Hpa. Another compound, which possesses a mild pancreato‐protective effect against AP, is Trehalose, a common disaccharide. We hypothesized that combination of Aspirin, Trehalose, PG545 (Pixatimod) and SST0001 (Roneparstat), specific inhibitors of Hpa, may exert pancreato‐protective effect better than each drug alone. Thus, the current study examines the pancreato‐protective effects of Aspirin, Trehalose, PG545 and SST0001 in experimental model of AP induced by cerulein in wild‐type (WT) and Hpa over‐expressing (Hpa‐Tg) mice. Cerulein‐induced AP in WT mice was associated with significant rises in the serum levels of lipase (X4) and amylase (X3) with enhancement of pancreatic edema index, inflammatory response, and autophagy. Responses to cerulein were all more profound in Hpa‐Tg mice versus WT mice, evident by X7 and X5 folds increase in lipase and amylase levels, respectively. Treatment with Aspirin or Trehalose alone and even more so in combination with PG545 or SST0001 were highly effective, restoring the serum level of lipase back to the basal level. Importantly, a novel newly synthesized compound termed Aspirlose effectively ameliorated the pathogenesis of AP as a single agent. Collectively, the results strongly indicate that targeting Hpa by using anti‐Hpa drug combinations constitute a novel therapy for this common orphan disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer is the third most common gynecologic cancer and the eighth most common cause of death from cancer in women. Comprehensive genomic profiling (CGP) is a test that checks hundreds of genes. Changes in these genes and may help to suggest which anti-cancer treatment may be the most effective for the tested individual. As the test is expensive, and the treatments aimed at treating specific genes related to cancer are both limited and expensive, CGP is not often used. In this study, we investigated whether women with ovarian cancer who had the CGP test had better outcomes (i.e., had longer times with no advancing of disease or lived longer) than women who did not have this test. Our results suggest that women who had the CGP test lived longer than those who did not, but more studies are needed to confirm this. Comprehensive genomic profiling (CGP) allows for the detection of driver alterations at high resolution, but the limited number of approved targeted therapies and their high costs have contributed to its limited clinical utilization. We retrospectively compared data of 946 women with ovarian cancer (11.4% were referred to CGP, and 88.6% served as control) to examine whether CGP provides a prognosis benefit. Patient baseline parameters were similar between the groups. Cox regression analysis adjusted for age, disease stage at diagnosis, and recurrence status showed statistically significantly longer median overall survival (mOS) in the CGP group versus the control (73.4 versus 54.5 months, p < 0.001). Fifty-four patients (52.9%) had actionable mutations with potential treatments; twenty-six (48.2%) were treated with matched targeted therapy, showing a trend for longer mOS than the eighty-six women in the CGP group who were not given a suggested treatment (105.5 versus 63.6 months, p = 0.066). None of the genomic alterations predicted metastasis location. CCNE1 amplification and KRAS mutations were associated with shorter mOS. Patients with tumor mutation burden ≥4 mutations/megabase had longer mOS. High loss of heterozygosity was associated with longer mOS (99.0 versus 48.2 months, p = 0.004). CGP testing may provide both prognostic and predictive insights for treatment of patients with ovarian cancer. Prospective studies of larger cohorts are warranted. [ABSTRACT FROM AUTHOR]

The potential use of avocado as a fiber source was evaluated. The total dietary fiber content of fresh avocado fruit of the Ettinger variety was 5.2 g/100 g. Approximately 75% was insoluble, and 25% soluble. The water-holding capacity of dry defatted avocado pulp was similar to that of cellulose, and trypsin inhibitors were not detected. The dietary and metabolic consequences of the avocado pulp were studied in male rats fed normal and hypercholesterolemic diets. Rats consumed semipurified diets containing either avocado pulp as the dietary fiber source or cellulose (control) with or without 10 g/kg cholesterol and 5 g/kg cholic acid. Food consumption and body weight gain were lower in rats fed avocado compared with those fed cellulose. Relative cecum weight was higher in avocado-fed rats. Plasma and hepatic cholesterol levels did not differ in rats fed diets without cholesterol, but plasma cholesterol was greater in avocado-fed than in cellulose-fed rats that consumed cholesterol. Regardless of dietary cholesterol, hepatic total fat levels, as evaluated histologically, but not directly, were lower in avocado-fed rats. These data suggest the presence of an appetite depressant in avocado and that avocado pulp interferes with hepatic fat metabolism. J. Nutr. 132: 2015-2018, 2002. KEY WORDS: * avocado * dietary fiber * weight gain * cholesterol * hepatic fat