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Abstract
Background and aims: Intestinal adaptation in short bowel syndrome (SBS) includes morphologic processes and functional mechanisms. This study investigated whether digestive enzyme expression in the duodenum and colon is upregulated in SBS patients. Method: Sucrase‐isomaltase (SI), lactase‐phlorizin hydrolase (LPH), and neutral Aminopeptidase N (ApN) were analyzed in duodenal and colonic biopsies from nine SBS patients in a late stage of adaptation as well as healthy and disease controls by immunoelectron microscopy (IEM), Western blots, and enzyme activities. Furthermore, proliferation rates and intestinal microbiota were analyzed in the mucosal specimen. Results: We found significantly increased amounts of SI, LPH, and ApN in colonocytes in most SBS patients with large variation and strongest effect for SI and ApN. Digestive enzyme expression was only partially elevated in duodenal enterocytes due to a low proliferation level measured by Ki‐67 staining. Microbiome analysis revealed high amounts of Lactobacillus resp. low amounts of Proteobacteria in SBS patients with preservation of colon and ileocecal valve. Colonic expression was associated with a better clinical course in single cases. Conclusion: In SBS patients disaccharidases and peptidases can be upregulated in the colon. Stimulation of this colonic intestinalization process by drugs, nutrients, and pre‐ or probiotics might offer better therapeutic approaches.
Background
We investigated the association between low cardiorespiratory fitness and liver fat content (LFC) in the general population.
Materials and Methods
We evaluated data from 2151 adults (51.1% women) from two population-based cohorts of the Study of Health in Pomerania (SHIP-2 and SHIP-TREND-0). We analysed the cross-sectional associations of peak oxygen uptake (VO2peak) with LFC, assessed by magnetic resonance imaging proton density fat fraction, as well as serum gamma-glutamyltransferase (GGT) and aminotransferase concentrations by multivariable regression models.
Results
We observed significant inverse associations of VO2peak with LFC and serum GGT, but not with serum aminotransferase levels. Specifically, a 1 L/min lower VO2peak was associated with a 1.09% (95% confidence interval [CI]: 0.45-1.73; P = .002) higher LFC and a 0.18 μkatal/L (95% CI: 0.09-0.26; P < .001) higher GGT levels. The adjusted odds ratio (OR) for the risk of prevalent hepatic steatosis (HS) by a 1 L/min decrease in VO2peak was 1.61 (95% CI: 1.22-2.13; P = .001). Compared to subjects with high VO2peak, obese and overweight individuals with low VO2peak had 1.78% (95% CI: 0.32-3.25; P = .017) and 0.94% (95% CI: 0.15-1.74; P = .021) higher mean LFC, respectively. Compared to those with high VO2peak, low VO2peak was independently associated with a higher risk of prevalent HS in the obese (adjusted-OR 2.29, 95% CI=1.48-3.56; P < .001) and overweight (adjusted OR 1.57, 95% CI=1.16-2.14; P = .04) groups.
Conclusions
Lower VO2peak was significantly associated with greater LFC and higher serum GGT levels in a population-based cohort of adult individuals. Our results suggest that low VO2peak might be a risk factor for HS.
Simple Summary
Recent clinical trials suggest that combination therapies that include either gemcitabine or 5-fluorouracil (5-FU) both give significant survival benefits for pancreatic cancer patients. The tumor level of the nucleoside transporter hENT1 is prognostic in patients treated with adjuvant gemcitabine but not adjuvant 5-FU. This work shows for the first time that hENT1 is only predictive of benefit from gemcitabine over 5-FU in patients with low levels of CDA transcript. A choice between adjuvant 5-FU based combination therapies (such as FOLFIRINOX) and gemcitabine-based therapy (e.g., GemCap) could be made based on a combination of hENT1 protein and CDA mRNA measured in a resected tumor.
Abstract
Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine; median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm; 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine; 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient.
Abstract
Body weight loss is frequently regarded as negatively related to outcomes in patients with malignancies. This retrospective analysis of the FIRE‐3 study evaluated the evolution of body weight in patients with metastatic colorectal cancer (mCRC). FIRE‐3 evaluated first‐line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab or bevacizumab in mCRC patients with RAS‐WT tumors (ie, wild‐type in KRAS and NRAS exons 2‐4). The prognostic and predictive relevance of early weight loss (EWL) regarding patient outcomes and treatment side effects were evaluated. Retrospective data on body weight during first 6 months of treatment were evaluated (N = 326). To correlate with efficacy endpoints and treatment side effects, patients were grouped according to clinically significant EWL ≥5% and <5% at Month 3. Age constituted the only significant predictor of EWL following a linear relationship with the corresponding log odds ratio (P = .016). EWL was significantly associated with the incident frequencies of diarrhea, edema, fatigue, nausea and vomiting. Further, a multivariate analysis revealed EWL to be an independent negative prognostic factor for overall survival (32.4 vs 21.1 months; hazard ratio [HR]: 1.64; 95% confidence interval [CI] = 1.13‐2.38; P = .0098) and progression‐free survival (11.8 vs 9.0 months; HR: 1.72; 95% CI = 1.18‐2.5; P = .0048). In conclusion, EWL during systemic treatment against mCRC is significantly associated with patient age. Patients exhibiting EWL had worse survival and higher frequencies of adverse events. Early preventative measures targeted at weight maintenance should be evaluated, especially in elderly patients being at highest risk of EWL.
Plasma Metabolome Profiling Identifies Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma
(2021)
Pancreatic necroses are a major challenge in the treatment of patients with pancreatitis, causing high morbidity. When indicated, these lesions are usually drained endoscopically using plastic or metal stents. However, data on factors associated with the occurrence of failure or adverse events during stent therapy are scarce. We retrospectively analyzed all adverse events and their associated features which occurred in patients who underwent a first-time endoscopic drainage of pancreatic necrosis from 2009 to 2019. During the observation period, a total of 89 eligible cases were identified. Adverse events occurred in 58.4% of the cases, of which 76.9% were minor (e.g., stent dislocation, residual lesions, or stent obstruction). However, these events triggered repeated interventions (63.5% vs. 0%, p < 0.001) and prolonged hospital stays (21.0 [11.8–63.0] vs. 14.0 [7.0–31.0], p = 0.003) compared to controls without any adverse event. Important factors associated with the occurrence of adverse events during endoscopic drainage therapy were positive necrosis cultures (6.1 [2.3–16.1], OR [95% CI], p < 0.001) and a larger diameter of the treated lesion (1.3 [1.1–1.5], p < 0.001). Superinfection of pancreatic necrosis is the most significant factor increasing the likelihood of adverse events during endoscopic drainage. Therefore, control of infection is crucial for successful drainage therapy, and future studies need to consider superinfection of pancreatic necrosis as a possible confounding factor when comparing different therapeutic modalities.
The aberrant activation of the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) pathway is common in pancreatic ductal adenocarcinomas (PDAC). The application of inhibitors against PI3K and AKT has been considered as a therapeutic option. We investigated PDAC cell lines exposed to increasing concentrations of MK-2206 (an AKT1/2/3 inhibitor) and Buparlisib (a pan-PI3K inhibitor). Cell proliferation, metabolic activity, biomass, and apoptosis/necrosis were evaluated. Further, whole-exome sequencing (WES) and RNA sequencing (RNA-seq) were performed to analyze the recurrent aberrations and expression profiles of the inhibitor target genes and the genes frequently mutated in PDAC (Kirsten rat sarcoma virus (KRAS), Tumor protein p53 (TP53)). MK-2206 and Buparlisib demonstrated pronounced cytotoxic effects and limited cell-line-specific effects in cell death induction. WES revealed two sequence variants within the direct target genes (PIK3CA c.1143C > G in Colo357 and PIK3CD c.2480C > G in Capan-1), but a direct link to the Buparlisib response was not observed. RNA-seq demonstrated that the expression level of the inhibitor target genes did not affect the efficacy of the corresponding inhibitors. Moreover, increased resistance to MK-2206 was observed in the analyzed cell lines carrying a KRAS variant. Further, increased resistance to both inhibitors was observed in SU.86.86 carrying two TP53 missense variants. Additionally, the presence of the PIK3CA c.1143C > G in KRAS-variant-carrying cell lines was observed to correlate with increased sensitivity to Buparlisib. In conclusion, the present study reveals the distinct antitumor effects of PI3K/AKT pathway inhibitors against PDAC cell lines. Aberrations in specific target genes, as well as KRAS and TP53, individually or together, affect the efficacy of the two PI3K/AKT pathway inhibitors.
Casein kinase II (CK2) and cyclin-dependent kinases (CDKs) frequently interact within multiple pathways in pancreatic ductal adenocarcinoma (PDAC). Application of CK2- and CDK-inhibitors have been considered as a therapeutic option, but are currently not part of routine chemotherapy regimens. We investigated ten PDAC cell lines exposed to increasing concentrations of silmitasertib and dinaciclib. Cell proliferation, metabolic activity, biomass, and apoptosis/necrosis were evaluated, and bioinformatic clustering was used to classify cell lines into sensitive groups based on their response to inhibitors. Furthermore, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) was conducted to assess recurrent mutations and the expression profile of inhibitor targets and genes frequently mutated in PDAC, respectively. Dinaciclib and silmitasertib demonstrated pronounced and limited cell line specific effects in cell death induction, respectively. WES revealed no genomic variants causing changes in the primary structure of the corresponding inhibitor target proteins. RNA-Seq demonstrated that the expression of all inhibitor target genes was higher in the PDAC cell lines compared to non-neoplastic pancreatic tissue. The observed differences in PDAC cell line sensitivity to silmitasertib or dinaciclib did not depend on target gene expression or the identified gene variants. For the PDAC hotspot genes kirsten rat sarcoma virus (KRAS) and tumor protein p53 (TP53), three and eight variants were identified, respectively. In conclusion, both inhibitors demonstrated in vitro efficacy on the PDAC cell lines. However, aberrations and expression of inhibitor target genes did not appear to affect the efficacy of the corresponding inhibitors. In addition, specific aberrations in TP53 and KRAS affected the efficacy of both inhibitors.
Determination of the Pathological Features of NPC1 Variants in a Cellular Complementation Test
(2019)
Niemann-Pick Type C (NP-C) is a rare disorder of lipid metabolism caused by mutations
within the NPC1 and NPC2 genes. NP-C is a neurovisceral disease leading to a heterogeneous,
multisystemic spectrum of symptoms in those affected. Until now, there is no investigative tool to
demonstrate the significance of single variants within the NPC genes. Hence, the aim of the study
was to establish a test that allows for an objective assessment of the pathological potential of NPC1
gene variants. Chinese hamster ovary cells defective in the NPC1 gene accumulate cholesterol in
lysosomal storage organelles. The cells were transfected with NPC1-GFP plasmid vectors carrying
distinct sequence variants. Filipin staining was used to test for complementation of the phenotype.
The known variant p.Ile1061Thr showed a significantly impaired cholesterol clearance after 12 and
24 h compared to the wild type. Among the investigated variants, p.Ser954Leu and p.Glu1273Lys
showed decelerated cholesterol clearance as well. The remaining variants p.Gln60His, p.Val494Met,
and p.Ile787Val showed a cholesterol clearance indistinguishable from wild type. Further, p.Ile1061Thr
acquired an enhanced clearance ability upon 25-hydroxycholesterol treatment. We conclude that the
variants that caused an abnormal clearance phenotype are highly likely to be of clinical relevance.
Moreover, we present a system that can be utilized to screen for new drugs.