Gastric cancer displays marked molecular heterogeneity with aggressive behavior and treatment resistance. Therefore, good in vitro models that encompass unique subtypes are urgently needed for ...precision medicine development. Here, we have established a primary gastric cancer organoid (GCO) biobank that comprises normal, dysplastic, cancer, and lymph node metastases (n = 63) from 34 patients, including detailed whole-exome and transcriptome analysis. The cohort encompasses most known molecular subtypes (including EBV, MSI, intestinal/CIN, and diffuse/GS, with CLDN18-ARHGAP6 or CTNND1-ARHGAP26 fusions or RHOA mutations), capturing regional heterogeneity and subclonal architecture, while their morphology, transcriptome, and genomic profiles remain closely similar to in vivo tumors, even after long-term culture. Large-scale drug screening revealed sensitivity to unexpected drugs that were recently approved or in clinical trials, including Napabucasin, Abemaciclib, and the ATR inhibitor VE-822. Overall, this new GCO biobank, with linked genomic data, provides a useful resource for studying both cancer cell biology and precision cancer therapy.
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•Living biobank includes 17 normal and 46 gastric cancer organoid lines•Organoid biobank encompasses most of the known molecular subtypes of gastric cancer•Organoids recapitulate the genomic and transcriptomic features of original tumors•High-throughput screen revealed potential target drugs for personalized therapy
Leung and colleagues established a biobank of patient-derived gastric cancer organoids that encompasses a diverse array of subtypes and maintained long-term similarity to the original tumors. They used the organoids to perform large-scale drug screening that identified potential target drugs and could guide patient drug selection.
Background
Approximately one-quarter of patients with Barcelona Clinic Liver Cancer (BCLC) stage 0/A hepatocellular carcinoma (HCC) suffer from tumor relapse within the first year after surgical ...resection. Little data is available for inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI), in predicting the clinical outcome of patients with very early/early stage HCC who underwent curative surgery.
Methods
A retrospective cohort study of 324 patients with BCLC stage 0/A primary HCC undergoing surgical resection was conducted to investigate the prognostic impacts of NLR, PLR, and PNI.
Results
The low-PNI group (<45) had an adverse overall survival (1-year survival rate of 92 vs. 97 %; 5-year survival rate of 57 vs. 82 %;
p
< 0.001) and disease-free survival (1-year survival rate of 69 vs. 85 %; 5-year survival rate of 39 vs. 63 %;
p
< 0.001). It was an independent predictor for disease-specific death, and early and late tumor relapses, with hazard ratios of 2.78 (
p
< 0.001), 1.82 (
p
= 0.011), and 2.55 (
p
= 0.013), respectively. Neither NLR nor PLR had any prognostic significance.
Conclusions
The PNI is a significant prognostic factor for OS and DFS of patients with very early/early stage HCC receiving curative surgery.
Gastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression ...and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (TP53, ARID1A and CDH1) and new (MUC6, CTNNA2, GLI3, RNF43 and others) significantly mutated driver genes. Specifically, we found RHOA mutations in 14.3% of diffuse-type tumors but not in intestinal-type tumors (P < 0.001). The mutations clustered in recurrent hotspots affecting functional domains and caused defective RHOA signaling, promoting escape from anoikis in organoid cultures. The top perturbed pathways in gastric cancer included adherens junction and focal adhesion, in which RHOA and other mutated genes we identified participate as key players. These findings illustrate a multidimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer and provides a road map to facilitate genome-guided personalized therapy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background & Aims Liver biopsy is the gold standard for diagnosing non-alcoholic fatty liver disease (NAFLD) but with practical constraints. Phosphorus magnetic resonance spectroscopy (31 P-MRS) ...allows in vivo assessment of hepatocellular metabolism and has shown potential for biochemical differentiation in diffuse liver disease. Our aims were to describe spectroscopic signatures in biopsy-proven NAFLD and to determine diagnostic performance of31 P-MRS for non-alcoholic steatohepatitis (NASH). Methods31 P-MRS was performed in 151 subjects, comprised of healthy controls (n = 19) and NAFLD patients with non-NASH (n = 37) and NASH (n = 95). Signal intensity ratios for phosphomonoesters (PME) including phosphoethanolamine (PE), phosphodiesters (PDE) including glycerophosphocholine (GPC), total nucleotide triphosphate (NTP) including α-NTP, and inorganic phosphate (Pi), expressed relative to total phosphate (TP) or PME+PDE and converted to percentage, were obtained. Results Compared to controls, both NAFLD groups had increased PDE/TP ( p <0.001) and decreased Pi/TP ( p = 0.011). Non-NASH patients showed decreased PE/PME+PDE ( p = 0.048), increased GPC/PME+PDE ( p <0.001), and normal NTP/TP and α-NTP/TP. Whereas, NASH patients had normal PE/PME+PDE and GPC/PME+PDE, but decreased NTP/TP ( p = 0.004) and α-NTP/TP ( p <0.001). The latter was significantly different between non-NASH and NASH ( p = 0.047) and selected as discriminating parameter, with area under the receiver-operating characteristics curve of 0.71 (95% confidence interval, 0.62–0.79). An α-NTP/TP cutoff of 16.36% gave 91% sensitivity and cutoff of 10.57% gave 91% specificity for NASH. Conclusions31 P-MRS shows distinct biochemical changes in different NAFLD states, and has fair diagnostic accuracy for NASH.
Background and Aim
Serum albumin and bilirubin are the most significant independent prognostic factors to predict hepatic events in patients with primary biliary cirrhosis (PBC). We aimed to ...investigate the prognostic significance of a new prognostic score, the albumin‐bilirubin (ALBI) score, among PBC patients.
Methods
In a retrospective longitudinal cohort of 61 Chinese PBC patients with follow‐up period up to 18.3 years, the prognostic performance of the ALBI in prediction of hepatic events was compared with other well‐established prognostic scores: Child–Pugh score, model of end‐stage liver disease, Mayo risk score, Yale, European, and Newcastle models.
Results
Fifteen patients (24.6%) developed hepatic events during follow‐up. The c‐index (0.894) and χ2 by likelihood ratio test (36.34) of the ALBI score were highest in comparison to other models. The ALBI score was the only independent prognostic factor by multivariate analysis and its adjusted hazard ratio of developing hepatic event was 27.8 (P < 0.001). There were three prognostically different groups stratified by the ALBI score: ALBI grade 1 (≤ −2.60), grade 2 (> −2.60 to −1.39), and grade 3 (> −1.39) groups. The 2‐, 5‐, and 10‐year event‐free survivals for grade 1, grade 2, and grade 3 groups were 100.0% versus 100.0% versus 57.1%, 100.0% versus 88.5% versus 14.3%, and 100.0% versus 81.7% versus 0.0%, respectively (P < 0.001).
Conclusion
The ALBI score is readily derived from a blood test without using those factors evaluated subjectively or obtained by invasive procedures. It is an independent prognostic factor for PBC patients and provides better/similar prognostic performance compared with other prognostic scores.
Non-human primates are valuable for modelling human disorders and for developing therapeutic strategies; however, little work has been reported in establishing transgenic non-human primate models of ...human diseases. Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor impairment, cognitive deterioration and psychiatric disturbances followed by death within 10-15 years of the onset of the symptoms. HD is caused by the expansion of cytosine-adenine-guanine (CAG, translated into glutamine) trinucleotide repeats in the first exon of the human huntingtin (HTT) gene. Mutant HTT with expanded polyglutamine (polyQ) is widely expressed in the brain and peripheral tissues, but causes selective neurodegeneration that is most prominent in the striatum and cortex of the brain. Although rodent models of HD have been developed, these models do not satisfactorily parallel the brain changes and behavioural features observed in HD patients. Because of the close physiological, neurological and genetic similarities between humans and higher primates, monkeys can serve as very useful models for understanding human physiology and diseases. Here we report our progress in developing a transgenic model of HD in a rhesus macaque that expresses polyglutamine-expanded HTT. Hallmark features of HD, including nuclear inclusions and neuropil aggregates, were observed in the brains of the HD transgenic monkeys. Additionally, the transgenic monkeys showed important clinical features of HD, including dystonia and chorea. A transgenic HD monkey model may open the way to understanding the underlying biology of HD better, and to the development of potential therapies. Moreover, our data suggest that it will be feasible to generate valuable non-human primate models of HD and possibly other human genetic diseases.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Measurement of DNA derived from different tissues in the circulating DNA pool can provide important information regarding the presence of many pathological conditions. However, existing methods ...involving genome-wide bisulfite sequencing are relatively expensive and may present challenges for large-scale analysis.
Through identifying differentially methylated regions in the liver and colon compared with other tissues, we identified 2 markers and developed corresponding droplet digital PCR assays. Plasma concentrations of liver-derived and colon-derived DNA were measured for 13 liver transplant recipients, 40 liver cancer patients, and 62 colorectal cancer (CRC) patients (27 with and 35 without liver metastases).
In liver transplant recipients, the fractional concentration of liver-derived DNA measured using the liver-specific methylation marker and donor-specific alleles showed good correlation (Pearson
= 0.99). In liver cancer patients, the concentration of liver-derived DNA correlated positively with the maximal dimension of the tumor (Spearman
= 0.74). In CRC patients with and without liver metastasis, the plasma concentrations of colon-derived DNA (median, 138 copies/mL and 4 copies/mL, respectively) were increased compared with the 30 healthy controls (26 had undetectable concentrations). The absolute concentration of liver-derived DNA provided a better differentiation between CRC patients with and without liver metastasis compared with the fractional concentration (area under ROC curve, 0.85 vs 0.75).
Quantitative analysis of plasma DNA with tissue-specific methylation patterns using droplet digital PCR is applicable for the investigation of cancers and assessing organ transplantation. This approach is useful for differentiating patients with and without metastases to other organs.
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by the expansion of polyglutamine (polyQ) tract that leads to motor, cognitive and psychiatric impairment. Currently there ...is no cure for HD. A transgenic HD nonhuman primate (HD-NHP) model was developed with progressive development of clinical and pathological features similar to human HD, which suggested the potential preclinical application of the HD-NHP model. Elevated expression of miR-196a was observed in both HD-NHP and human HD brains. Cytotoxicity and apoptosis were ameliorated by the overexpression of miR-196a in HD-NHP neural progenitor cells (HD-NPCs) and differentiated neural cells (HD-NCs). The expression of apoptosis related gene was also down regulated. Mitochondrial morphology and activity were improved as indicated by mitotracker staining and the upregulation of CBP and PGC-1α in HD-NPCs overexpressing miR-196a. Here we demonstrated the amelioration of HD cellular phenotypes in HD-NPCs and HD-NCs overexpressing miR-196a. Our results also suggested the regulatory role of miR-196a in HD pathogenesis that may hold the key for understanding molecular regulation in HD and developing novel therapeutics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Concurrent fatty liver in hepatitis B virus (HBV)-infected patients without significant alcohol intake is a frequent and increasingly alarming problem because of the non-alcoholic fatty liver disease ...pandemic. The risk of HBV-related hepatocellular carcinoma (HCC) development was increased by concomitant obesity and diabetes. Direct evidence of the hepatocarcinogenic effect of fatty liver in chronic HBV remains elusive. We aimed to evaluate the risk of concurrent histologically proven fatty liver in HBV hepatocarcinogenesis.
We conducted a retrospective cohort study on a liver biopsy cohort of HBV-infected patients without significant alcohol intake to evaluate the prevalence of concurrent histologically proven fatty liver and its association with subsequent HCC development. We also examined nine polymorphisms on six non-alcoholic fatty liver disease-related candidate genes (ADIPOQ, APOC3, GCKR, LEPR, PNPLA3, and PPARG).
Among 270 HBV-infected patients, concurrent fatty liver was found in 107 patients (39.6%) and was associated with metabolic risks, cirrhosis (P = 0.016) and PNPLA3 rs738409 CG/GG genotype (P = 0.002). At a median follow-up of 79.9 months, 11 patients (4.1%) developed HCC, and nine of them had concurrent fatty liver. By multivariable Cox analysis, concurrent fatty liver (HR 7.27, 95% confidence interval: 1.52-34.76; P = 0.013), age, cirrhosis, and APOC3 rs2854116 TC/CC genotype (HR 3.93, 95% confidence interval: 1.30-11.84; P = 0.013) were independent factors predicting HCC development.
Concurrent fatty liver is common in HBV-infected patients and an independent risk factor potentiating HBV-associated HCC development by 7.3-fold. The risk of HBV-related HCC is increased by APOC3 gene polymorphism, and further characterization is required by its role.
Aspiration of gastric contents can be a serious perioperative complication, attributing up to 9% of all anesthesia-related deaths. However, there is currently no practical, noninvasive bedside test ...to determine gastric content and volume in the perioperative period.
The current study evaluates the feasibility of using bedside ultrasonography for assessing gastric content and volume. In the pilot phase, 18 healthy volunteers were examined to assess the gastric antrum, body, and fundus in cross-section in five prandial states: fasting and after ingestion of 250 mL of water, 500 mL of water, 500 mL of effervescent water, and a solid meal. In the phase II study, the authors concentrated on ultrasound examination of the gastric antrum in 36 volunteers for whom regression analysis was used to determine the correlation between gastric volume and antral cross-sectional area.
The gastric antrum provided the most reliable quantitative information for gastric volume. The antral cross-sectional area correlated with volumes of up to 300 mL in a close-to-linear fashion, particularly when subjects were in the right lateral decubitus position. Sonographic assessment of the gastric antrum and body provides qualitative information about gastric content (empty or not empty) and its nature (gas, fluid, or solid). The fundus was the gastric area least amenable to image and measure.
Our preliminary results suggest that bedside two-dimensional ultrasonography can be a useful noninvasive tool to determine gastric content and volume.
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