Cytomegalovirus Diseases of the Gastrointestinal Tract in Immunocompetent Patients: A Narrative Review.

Cytomegalovirus (CMV) is a potential pathogen that causes gastrointestinal (GI) tract diseases regardless of host immunity. In contrast to immunocompromised individuals, immunocompetent patients lack a comprehensive overview of the gastrointestinal manifestations. This study aims to provide a comprehensive summary of the current evidence regarding presentations, diagnostics, management, risk assessment, and outcomes in immunocompetent patients with CMV GI disease. A thorough literature search of English publications up to April 2022 was conducted across electronic databases to identify relevant articles, with eligible case series selected for detailed analysis. The majority of immunocompetent patients affected by CMV GI disease are typically elderly, critically ill, or burdened with comorbidities that compromise immunity. Clinical presentations range from subtle symptoms to severe surgical conditions, including instances of mortality. Specific clinical presentations, blood test results, or endoscopic features are lacking, necessitating reliance on histopathological tests such as immunohistochemistry staining for diagnosis. While antiviral therapy may offer benefits in improving outcomes, careful individual assessment is warranted due to diverse comorbidities and potential side effects. Mortality rates vary considerably based on underlying medical conditions and therapeutic approaches. It is imperative for clinicians to maintain vigilance for CMV GI disease among high-risk groups, despite their baseline immunocompetence, in order to enhance clinical outcomes.

Therapeutic drug monitoring of perampanel: Clinical utility and impact of co-medication on pharmacokinetic variability.

Background: Perampanel (PER) is a newly developed antiseizure medication (ASM). This study aimed to determine the utilization of therapeutic drug monitoring (TDM) for PER in a real-world clinical setting and investigate the influence of concomitant use of ASMs on the plasma concentration profile of PER. Method: We analyzed data from the Chang Gung Research Database, which is the largest multi-institutional electronic medical records database in Taiwan. The main outcomes were the comparisons of PER plasma concentration and the ratio of concentration to the weight-adjusted dose (C/D; [ng/mL]/[mg/kg/d]) among patients received TDM of different clinical indication and among different ASM co-medication subgroups. Results: Overall, 88 plasma samples were collected from 66 epilepsy patients treated with PER. The majority of patients (77.3 %) underwent PER TDM owing to poorly controlled seizures. There was a trend toward a higher plasma concentration and C/D ratio in those suspected of having PER toxicity owing to adverse events than of other indications. The PER concentration exhibited dose linearity. The mean PER plasma concentrations in patients co-medicated with enzyme-inducing ASMs were significantly lower than those in the patients who were not prescribed enzyme-inducing or enzyme-inhibiting ASMs, and co-medication with carbamazepine (CBZ) resulted in a significant reduction in the PER concentration. Conclusion: PER concentration exhibited a linear regression relationship with PER dose, and the plasma concentration of the drug was highly susceptible to the drug's interactions with enzyme-inducing ASMs. TDM with clear indication could help determine the influence of ASMs used concomitantly on PER concentrations and guide clinical adjustments.

Molecular characterization of rifabutin-resistance in refractory Helicobacter pylori infection in Taiwan.

OBJECTIVES: To explore the molecular characteristics of rpoB, encoding ß-subunit of DNA-directed RNA polymerase, and unravel the link to rifabutin-resistance in patients with refractory Helicobacter pylori infection. METHODS: From January 2018-March 2021, a total of 1590 patients were screened for eligibility to participate in the study. Patients with refractory H. pylori infection were confirmed by using the (13C)-urea breath assay. All enrolled patients underwent esophagogastroduodenoscopy, and biopsies were taken for H. pylori culture and antibacterial susceptibility testing. Sequence analysis of rpoB was conducted for all rifabutin-resistant isolates. RESULTS: In total, 70 patients were diagnosed with refractory H. pylori infection, and 39 isolates were successfully cultured. Amongst, 10 isolates were identified as rifabutin-resistance and nine isolates exhibited at least one amino acid substitution in RpoB. Isolates with a minimal inhibitory concentration >32 mg/l displayed a higher number of mutational changes in RpoB than the others. Additionally, more amino acid substitutions in RpoB correlated with developing a higher minimal inhibitory concentration for H. pylori rifabutin-resistance. CONCLUSION: Our findings highlight the relationship between rifabutin-resistance in refractory H. pylori infection and specific mutations in RpoB, which will aid the clinical selection of appropriate antibacterial agents with better therapeutic effects.

Oral fecal transplantation enriches Lachnospiraceae and butyrate to mitigate acute liver injury.

While fecal microbiota transplantation (FMT) shows promise in treating human diseases, oral capsule FMT is more accepted and accessible to patients. However, microbe selection in the upper gastrointestinal tract (UGIT) through oral administration remains unclear. Here, we demonstrate that short-term oral fecal gavage (OFG) alleviates acetaminophen-induced acute liver injury (AILI) in mice, regardless of the divergent effects of commensal gut microbes. Pasteurized fecal gavage yields similar therapeutic effects. OFG enriches gut Lachnospiraceae and butyrate compared to donor feces. Butyrate mitigates AILI-induced ferroptosis via AMPK-ULK1-p62 signaling to simultaneously induce mitophagy and Nrf2 antioxidant responses. Combined N-acetylcysteine and butyrate administration significantly improves AILI mouse survival rates. These observations indicate the significance of the UGIT in modulating the implanted fecal microbes through oral administration and its potential biological and clinical impacts. Our findings also highlight a possible strategy for applying microbial metabolites to treat acute liver injury.

Clinical impact of therapeutic drug monitoring for newer anti-seizure medications in patients with epilepsy: A real-world observation study.

BACKGROUND: The clinical value of therapeutic drug monitoring (TDM) for newer anti-seizure medications (ASMs) remains uncertain. This study aimed to assess the impact of newer ASM TDM on clinical decision making in patients with epilepsy. METHODS: We retrospectively identified all plasma requests for newer ASM level measurement as part of routine clinical management in the outpatient departments of seven medical institutes across Taiwan between September 2016 and May 2019. Data collected from reviewed medical records included clinical and medication details, indications for TDM request, test results, interpretation, and impact on patient management. RESULTS: A total of 682 visits with 1051 plasma samples were included. The most frequently analyzed ASMs were levetiracetam (36.1%), oxcarbazepine (18.4%), and lamotrigine (12.0%). Reasons for TDM included poorly controlled seizures (55.3%), concerns about drug-drug interactions (12.3%), and suspicion of drug overdose (10.6%). 68.8% of samples were within the orienting therapeutic range, even for patients with poorly controlled seizures. TDM for non-adherence concerns showed 54.3% below the orienting therapeutic range, while ASM-related adverse events assessment only 8.9% showed levels exceeding the orienting therapeutic range. Following TDM results, 64.2% of cases had medication adjustments, mainly dosage increases. Overall, 55.9% of newer ASM TDM visit showed improved outcomes, including reduced seizures (47.5%) and fewer ASM-related side effects (8.4%). CONCLUSIONS: These findings suggest that appropriate utilization of TDM for newer ASMs provides clinical benefits in adjunct to complement clinical decision making in the management of epilepsy patients in a real-world clinical setting.

Optimizing treatment persistence in epilepsy: a comparative analysis of combined antiseizure medications with different mechanisms of action.

Background: Combination therapy with antiseizure medications (ASMs) is a rational strategy if monotherapy cannot effectively control seizures, thereby aiming to improve tolerance and treatment persistence. Objectives: To compare the efficacy of different ASM combinations among patients. Design: Patients with epilepsy on monotherapy who had a second ASM added as concomitant two-drug therapy from January 2009 to May 2019 in the Chang Gung Research Database, Taiwan, were included in the analysis. Methods: ASM combinations were compared based on their primary mechanism of action (MoA) which are as follows: gamma-aminobutyric acid receptor (G), sodium channel blocker (SC), synaptic vesicle protein 2A (SV2), calcium channel blocker (C), and multiple mechanisms (M). Treatment persistence was compared, and the predictors of persistence were analyzed. Results: In total, 3033 patients were enrolled in this study. Combined ASMs with different MoAs had significantly longer treatment persistence than ASMs with similar MoAs, specifically SC and M combinations. Patients receiving combined ASMs with different MoAs were less likely to discontinue treatment [adjusted hazards ratio: 0.83 (95% CI: 0.75-0.93), p < 0.001]. Among all combinations, the SC + SV2 combination had the longest treatment persistence (mean ± SD: 912.7 ± 841.6 days). Meanwhile, patients receiving the G combination had a higher risk of treatment discontinuation than those receiving the SC + SV2 combination. Underlying malignancies were associated with an increased risk of treatment discontinuation across all MoA categories. Male patients receiving the SC, SV2, and M combinations were more likely to discontinue treatment than female patients. Moreover, patients with renal disease were more likely to discontinue treatment with the SV2 combinations. Conclusion: ASM combinations with different MoAs had superior efficacy and tolerability to ASM combinations with similar MoAs, particularly SC and M combinations. In our cohort, factors associated with treatment discontinuation included underlying malignancy, male sex, and renal disease. These findings may provide valuable insights into the use of ASM combinations if monotherapy cannot adequately control seizures.

Aldolase B-driven lactagenesis and CEACAM6 activation promote cell renewal and chemoresistance in colorectal cancer through the Warburg effect.

Colorectal cancer (CRC) is a prevalent malignancy worldwide and is associated with a high mortality rate. Changes in bioenergy metabolism, such as the Warburg effect, are often observed in CRC. Aldolase B (ALDOB) has been identified as a potential regulator of these changes, but its exact role in CRC cell behavior and bioenergetic homeostasis is not fully understood. To investigate this, two cohorts of CRC patients were analyzed independently. The results showed that higher ALDOB expression was linked to unfavorable prognosis, increased circulating carcinoembryonic antigen (CEA) levels, and altered bioenergetics in CRC. Further analysis using cell-based assays demonstrated that ALDOB promoted cell proliferation, chemoresistance, and increased expression of CEA in CRC cells. The activation of pyruvate dehydrogenase kinase-1 (PDK1) by ALDOB-induced lactagenesis and secretion, which in turn mediated the effects on CEA expression. Secreted lactate was found to enhance lactate dehydrogenase B (LDHB) expression in adjacent cells and to be a crucial modulator of ALDOB-mediated phenotypes. Additionally, the effect of ALDOB on CEA expression was downstream of the bioenergetic changes mediated by secreted lactate. The study also identified CEA cell adhesion molecule-6 (CEACAM6) as a downstream effector of ALDOB that controlled CRC cell proliferation and chemoresistance. Notably, CEACAM6 activation was shown to enhance protein stability through lysine lactylation, downstream of ALDOB-mediated lactagenesis. The ALDOB/PDK1/lactate/CEACAM6 axis plays an essential role in CRC cell behavior and bioenergetic homeostasis, providing new insights into the involvement of CEACAM6 in CRC and the Warburg effect. These findings may lead to the development of new treatment strategies for CRC patients.

Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly.

Cancer cells exhibit metabolic reprogramming and bioenergetic alteration, utilizing glucose fermentation for energy production, known as the Warburg effect. However, there are a lack of comprehensive reviews summarizing the metabolic reprogramming, bioenergetic alteration, and their oncogenetic links in gastrointestinal (GI) cancers. Furthermore, the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation. This review highlights the interplay between aerobic glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) in cancer cells, as well as hypotheses on the molecular mechanisms that trigger this alteration. The role of hypoxia-inducible transcription factors, tumor suppressors, and the oncogenetic link between hypoxia-related enzymes, bioenergetic changes, and GI cancer are also discussed. This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy, particularly for GI cancers. Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy, the review categorizes these regulators into aerobic glycolysis/ lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS. We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers, as well as the challenges posed by these drugs. Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments, although the diverse metabolic patterns present challenges for targeted therapies. Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes, address side effects, and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.

Juvenile Myoclonic Epilepsy: Seizure and Social Outcomes in Taiwan.

Patients with juvenile myoclonic epilepsy (JME) may not achieve seizure freedom despite optimal treatment with antiseizure medications (ASMs). The aim of this study was to investigate the clinical and social features of patients with JME, and to determine the factors associated with outcomes. We retrospectively identified 49 patients with JME (25 females, mean age 27.6 ± 8.9 years) who were assessed at the Epilepsy Centre of Linkou Chang Gung Memorial Hospital in Taiwan. The patients were divided into two groups, those who were seizure-free and those with ongoing seizures according to their seizure outcome at the last follow-up for one year. Clinical features and social status were compared between these two groups. Twenty-four (49%) of the JME patients were seizure-free for at least one year, while 51% continued to experience seizures despite being treated with multiple ASMs. The presence of epileptiform discharges in the last electroencephalogram and seizures during sleep were significantly associated with worse seizure outcomes (p < 0.05). The patients who were seizure-free had a higher employment rate compared to those who continued to experience seizures (75% vs. 32%, p = 0.004). Despite receiving ASM treatment, a considerable proportion of the patients with JME continued to have seizures. Moreover, poor seizure control was associated with a lower employment rate, which may lead to negative socioeconomic consequences related to JME.

Transcriptome analysis creates a new era of precision medicine for managing recurrent hepatocellular carcinoma.

The high incidence of hepatocellular carcinoma (HCC) recurrence negatively impacts outcomes of patients treated with curative intent despite advances in surgical techniques and other locoregional liver-targeting therapies. Over the past few decades, the emergence of transcriptome analysis tools, including real-time quantitative reverse transcription PCR, microarrays, and RNA sequencing, has not only largely contributed to our knowledge about the pathogenesis of recurrent HCC but also led to the development of outcome prediction models based on differentially expressed gene signatures. In recent years, the single-cell RNA sequencing technique has revolutionized our ability to study the complicated crosstalk between cancer cells and the immune environment, which may benefit further investigations on the role of different immune cells in HCC recurrence and the identification of potential therapeutic targets. In the present article, we summarized the major findings yielded with these transcriptome methods within the framework of a causal model consisting of three domains: primary cancer cells; carcinogenic stimuli; and tumor microenvironment. We provided a comprehensive review of the insights that transcriptome analyses have provided into diagnostics, surveillance, and treatment of HCC recurrence.

Albumin-Bilirubin Grade as a Novel Predictor of the Development and Short-Term Survival of Post-Banding Ulcer Bleeding Following Endoscopic Variceal Ligation in Cirrhotic Patients.

Background and Objectives: Endoscopic variceal ligation (EVL) is the primary and secondary treatment for acute esophageal variceal bleeding. Post-banding ulcer bleeding (PBUB) may lead to bleeding episodes following EVL, increasing mortality. The aim of this study was to evaluate the risk factors for PBUB and predict the 6-week mortality risk after PBUB. Materials and Methods: We retrospectively analyzed the data collected from cirrhotic patients with EVL from 2015 to 2017. The incidence of PBUB and the 6-week mortality rate were evaluated. Risk factors for PBUB and predictive factors for mortality after PBUB were analyzed. Results: A total of 713 patients were enrolled in this study. Among the studied subjects, the incidence of PBUB was 5.8% (N = 41). The 6-week mortality rate was 63.4% (26/41). In multivariate analysis, MELD score ≥20 (OR: 3.77, 95% CI: 1.94−7.33, p < 0.001), ALBI score of 3 (OR: 2.67, 95% CI: 1.34−5.3, p = 0.005) and the presence of gastric varices (OR: 2.1, 95% CI: 1.06−4.16, p = 0.03) were associated with the development of PBUB. Patients with ALBI grade 3 (OR: 4.8, 95% CI: 1.18−19.6, p = 0.029) and Child-Pugh scores B and C (OR: 16.67, 95% CI: 1.75−158.1, p = 0.014) were associated with 6-week mortality after PBUB. Conclusions: PBUB is a complication with low incidence but increased mortality following EVL. The ALBI grade is a useful score to predict not only the development of PBUB but also the 6-week mortality after PBUB.

Anticoagulant drugs with or without proton pump inhibitor and colorectal cancer risk: a population-based, case-control study.

BACKGROUND: Low-dose aspirin and clopidogrel have demonstrated potential chemoprevention for colorectal cancer (CRC). Proton-pump inhibitors (PPI) are commonly prescribed with anticoagulation drugs, but the relationship between PPI and CRC is unclear. Moreover, evidence of CRC risk under direct oral anticoagulant (DOAC) is limited. This study aimed to investigate the effects of anticoagulation drugs combined with or without PPI on the risks of CRC in Taiwan. METHODS: A retrospective case-control study of 1,024,227 cases based on the Chang Gung Research Database from 2010 to 2017 was performed. Clinical characteristics, indications, duration of anticoagulation and PPI use, and CRC occurrence data were collected. Logistic regression was employed to adjust for known confounders of CRC risk. RESULTS: Monotherapy of clopidogrel decreased the risk of CRC (AOR 0.70; 95% CI 0.60-0.83), while no protective effect was observed in aspirin alone or aspirin plus clopidogrel. DOAC did not affect CRC significantly. The risk of CRC increased in patients with PPI (AOR 1.38; 95% CI 1.28-1.49) and PPI plus DOAC (OR 3.91; 95% CI 1.49-10.27), while PPI plus aspirin decreased the risk of CRC (OR 0.48; 95% CI 0.32-0.73). PPI plus clopidogrel showed no significant effect on the CRC. CONCLUSION: This study suggests clopidogrel alone and PPI plus aspirin offer a preventative benefit against CRC in the Taiwanese population studied. The same effect was not observed in DOAC. Moreover, a significant increase in CRC was observed in patients on PPI monotherapy and PPI plus DOAC, suggesting a possible risk.

Reduced Sleep Quality Is Related to Poor Quality of Life in Patients with Juvenile Myoclonic Epilepsy, a Case-Control Study.

Juvenile myoclonic epilepsy (JME) is a primary generalized epilepsy which is closely related to the sleep-wake cycle. This study aimed to investigate whether sleep disturbance is more common among patients with JME and the impact this may have on their quality of life (QOL). Thirty-four patients with JME and age- and gender-matched controls were recruited into this case control study, and assessed using validated sleep questionnaires including the Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and Stanford Sleepiness Scale (SSS). QOL was assessed using the Quality of Life in Epilepsy Inventory (QOLIE-31). The patients had a significantly higher PSQI score and higher proportion of abnormal PSQI scores than the controls. They also had higher ESS and SSS scores, but without statistical significance. The patients with poor sleep quality had significantly lower overall QOL, emotional well-being, and energy/fatigue subscale scores. The use of a higher number of antiseizure medications, dosage of levetiracetam, and usage of antiseizure medication polytherapy were associated with sleep disorders. Our results showed that sleep disturbance is common in patients with JME, and also that it has an impact on their QOL.

Functional Role of Mitochondrial DNA in Cancer Progression.

Mitochondrial DNA (mtDNA) has been identified as a significant genetic biomarker in disease, cancer and evolution. Mitochondria function as modulators for regulating cellular metabolism. In the clinic, mtDNA variations (mutations/single nucleotide polymorphisms) and dysregulation of mitochondria-encoded genes are associated with survival outcomes among cancer patients. On the other hand, nuclear-encoded genes have been found to regulate mitochondria-encoded gene expression, in turn regulating mitochondrial homeostasis. These observations suggest that the crosstalk between the nuclear genome and mitochondrial genome is important for cellular function. Therefore, this review summarizes the significant mechanisms and functional roles of mtDNA variations (DNA level) and mtDNA-encoded genes (RNA and protein levels) in cancers and discusses new mechanisms of crosstalk between mtDNA and the nuclear genome.

Cytomegalovirus Diseases of the Gastrointestinal Tract.

Cytomegalovirus (CMV) infection of the gastrointestinal (GI) tract can be fatal. However, very few studies have provided comprehensive analyses and specified the differences in symptoms observed in different parts of the GI tract. This study aimed to comprehensively analyze clinical manifestations and management of GI CMV disease. This retrospective cohort study enrolled the patients who had CMV diseases of the GI tract proved by CMV immunohistochemistry stain from the pathology database in a 4000-bed tertiary medical center between January 2000 and May 2021. The patient characteristics, clinical manifestations, endoscopic features, treatments, outcomes, and prognostic factors were analyzed. A total of 356 patients were enrolled, including 46 infected in the esophagus, 76 in the stomach, 30 in the small intestine, and 204 in the colon. In total, 49.4% patients were immunocompromised. The overall in-hospital mortality rate was 20.8%: CMV enteritis had the highest rate (23.3%). Sixty percent of patients received antiviral treatment and 16% were administered both intravenous and oral anti-viral drugs (Combo therapy, minimal and mean treatment duration were 14 and 39.9 ± 25 days). Prognostic factors of in-hospital mortality included age, immune status, albumin level, platelet count, GI bleeding, time-to-diagnosis, and Combo therapy. In the survival analysis, immunocompetent patients receiving Combo therapy had the best survival curve, and immunocompromised patients receiving non-Combo therapy had the worst survival curve. Combo therapy ≥14 days resulted in a better outcome for both immunocompromised and immunocompetent patients. In conclusion, CMV GI diseases affect both immunocompromised and immunocompetent hosts, and a complete treatment course should be considered for patients with poor prognostic factors.

The Role of Clips in Preventing Delayed Bleeding After Colorectal Polyp Resection: An Individual Patient Data Meta-Analysis.

BACKGROUND & AIMS: Nonpedunculated colorectal polyps are normally endoscopically removed to prevent neoplastic progression. Delayed bleeding is the most common major adverse event. Clipping the resection defect has been suggested to reduce delayed bleedings. Our aim was to determine if prophylactic clipping reduces delayed bleedings and to analyze the contribution of polyp characteristics, extent of defect closure, and antithrombotic use. METHODS: An individual patient data meta-analysis was performed. Studies on prophylactic clipping in nonpedunculated colorectal polyps were selected from PubMed, Embase, Web of Science, and Cochrane database (last selection, April 2020). Authors were invited to share original study data. The primary outcome was delayed bleeding ≤30 days. Multivariable mixed models were used to determine the efficacy of prophylactic clipping in various subgroups adjusted for confounders. RESULTS: Data of 5380 patients with 8948 resected polyps were included from 3 randomized controlled trials, 2 prospective, and 8 retrospective studies. Prophylactic clipping reduced delayed bleeding in proximal polyps ≥20 mm (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.44-0.88; number needed to treat = 32), especially with antithrombotics (OR, 0.59; 95% CI, 0.35-0.99; number needed to treat = 23; subgroup of anticoagulants/double platelet inhibitors: n = 226; OR, 0.40; 95% CI, 0.16-1.01; number needed to treat = 12). Prophylactic clipping did not benefit distal polyps ≥20 mm with antithrombotics (OR, 1.41; 95% CI, 0.79-2.52). CONCLUSIONS: Prophylactic clipping reduces delayed bleeding after resection of nonpedunculated, proximal colorectal polyps ≥20 mm, especially in patients using antithrombotics. No benefit was found for distal polyps. Based on this study, patients can be identified who may benefit from prophylactic clipping. (PROSPERO registration number CRD42020104317.).

SYNE1 Exonic Variant rs9479297 Contributes to Concurrent Hepatocellular and Transitional Cell Carcinoma Double Primary Cancer.

Unexpected high risk of synchronous/metachronous hepatocellular carcinoma (HCC) and transitional cell carcinoma (TCC) co-occurrence has been discovered previously. Here, we searched for genetic variation contributing to the co-occurrence of this double primary cancer (DPC). Using targeted exome sequencing, a panel of variants associated with concurrent DPC was identified. However, only a nonsynonymous variant within the Spectrin Repeat Containing Nuclear Envelope Protein 1 (SYNE1) gene was associated with DPC occurrence (p = 0.002), compared with that in the healthy population. Further independent cohort verification analysis revealed that the SYNE1-rs9479297-TT genotype (versus TC + CC genotypes) was enriched in patients with DPC, compared with that in those with TCC alone (p = 0.039), those with HCC alone (p = 0.006), those with non-HCC/non-TCC (p < 0.001), and healthy population (p < 0.001). SYNE1 mRNA expression reduced in both patients with HCC and TCC, and its lower expression in HCC was associated with shorter recurrence-free (p = 0.0314) and metastasis-free (p = 0.0479) survival. SYNE1-rs9479297 genotypes were correlated with tissue SYNE1 levels and clinical outcomes in HCC patients. Finally, SYNE1 silencing enhanced the cell proliferation and migration of HCC/TCC cells. In conclusion, SYNE1-rs9479297 genotypes were associated with HCC/TCC DPC co-occurrence and correlated with SYNE1 expression, which in turn contributed to HCC/TCC cell proliferation and migration, thereby affecting clinical outcomes.

Risk of Enteric Infection in Patients with Gastric Acid Supressive Drugs: A Population-Based Case-Control Study.

Long-term use of gastric-acid-suppressive drugs is known to be associated with several adverse effects. However, the association between enteric infection and acid suppression therapy is still uncertain. This study aimed to evaluate the association between gastric acid suppression and the risk of enteric infection. Materials and Methods: We conducted a population-based case-control study using the data from Chang Gung Research Database (CGRD) in Taiwan. Between January 2008 and December 2017, a total of 154,590 adult inpatients (age > 18) were identified. A pool of potential eligible controls according to four propensity scores matching by sex, age, and index year were extracted (n = 89,925). Subjects with missing data or who received less than 7 days of proton pump inhibitors (PPIs) and/or H2-receptor antagonists (H2RAs) were excluded. Finally, 17,186 cases and 69,708 corresponding controls were selected for analysis. The use of PPIs and H2RAs, the result of microbiological samples, and co-morbidity conditions have been analyzed. Confounders were controlled by conditional logistic regression. Results: 32.84% of patients in the case group used PPIs, compared with 7.48% in the control group. Of patients in the case group, 9.9% used H2RAs, compared with 6.9% in the control group. Of patients in the case group, 8.3% used a combination of PPIs and H2RAs, compared with 2.7% in the control group. The most common etiological pathogens were Enterococcus (44.8%), Clostridioides difficile (34.5%), and Salmonella spp. (10.2%). The adjusted odds ratio (OR) for PPI use with enteric infection was 5.526 (95% confidence interval [CI], 5.274-5.791). For H2RAs, the adjusted odds ratio was 1.339 (95% confidence interval [CI], 1.261-1.424). Compared to the control group, persons with enteric infection had more frequent acid-suppressive agent usage. Conclusions: This study demonstrates that gastric-acid-suppressive drug use is associated with an increased risk of enteric infection after adjusting for potential biases and confounders.

Tissue Architecture Influences the Biological Effectiveness of Boron Neutron Capture Therapy in In Vitro/In Silico Three-Dimensional Self-Assembly Cell Models of Pancreatic Cancers.

Pancreatic cancer is a leading cause of cancer death, and boron neutron capture therapy (BNCT) is one of the promising radiotherapy techniques for patients with pancreatic cancer. In this study, we evaluated the biological effectiveness of BNCT at multicellular levels using in vitro and in silico models. To recapture the phenotypic characteristic of pancreatic tumors, we developed a cell self-assembly approach with human pancreatic cancer cells Panc-1 and BxPC-3 cocultured with MRC-5 fibroblasts. On substrate with physiological stiffness, tumor cells self-assembled into 3D spheroids, and the cocultured fibroblasts further facilitated the assembly process, which recapture the influence of tumor stroma. Interestingly, after 1.2 MW neutron irradiation, lower survival rates and higher apoptosis (increasing by 4-fold for Panc-1 and 1.5-fold for BxPC-3) were observed in 3D spheroids, instead of in 2D monolayers. The unexpected low tolerance of 3D spheroids to BNCT highlights the unique characteristics of BNCT over conventional radiotherapy. The uptake of boron-containing compound boronophenylalanine (BPA) and the alteration of E-cadherin can partially contribute to the observed susceptibility. In addition to biological effects, the probability of induced α-particle exposure correlated to the multicellular organization was speculated to affect the cellular responses to BNCT. A Monte Carlo (MC) simulation was also established to further interpret the observed survival. Intracellular boron distribution in the multicellular structure and related treatment resistance were reconstructed in silico. Simulation results demonstrated that the physical architecture is one of the essential factors for biological effectiveness in BNCT, which supports our in vitro findings. In summary, we developed in vitro and in silico self-assembly 3D models to evaluate the effectiveness of BNCT on pancreatic tumors. Considering the easy-access of this 3D cell-assembly platform, this study may not only contribute to the current understanding of BNCT but is also expected to be applied to evaluate the BNCT efficacy for individualized treatment plans in the future.

Direct-acting Antiviral Therapy Improves the Outcome of Chronic Hepatitis C/intermediate-stage B Hepatocellular Carcinoma Patients.

BACKGROUND/AIM: The benefit of direct-acting antiviral therapy (DAA) in chronic hepatitis C (CHC) infected patients who received curative treatment for early-stage hepatocellular carcinoma (HCC) is well known, but is unclear for intermediate stage HCC. PATIENTS AND METHODS: CHC patients with Barcelona Clinic Liver Cancer (BCLC) stage B HCC receiving chemoembolization were identified. Univariate, multivariate analyses, and Kaplan-Meier curve were used to identify factors associated with survival outcomes. RESULTS: Among 113 included patients, the median survival of DAA treated group (n=14) and non-treated group (n=99) were 40.1 months and 22.9 months, respectively. Multivariate analysis showed that Eastern Cooperative Oncology Group (ECOG) score, DAA, and serum albumin were key independent factors associated with overall survival. Moreover, the time-to-complete remission (TTCR) was improved in the DAA treated group. CONCLUSION: ECOG, DAA, and serum albumin were prognostic factors for CHC/intermediate-stage HCC patients. DAA was also a beneficial factor for TTCR.