OCT2 pre-positioning facilitates cell fate transition and chromatin architecture changes in humoral immunity.

During the germinal center (GC) reaction, B cells undergo profound transcriptional, epigenetic and genomic architectural changes. How such changes are established remains unknown. Mapping chromatin accessibility during the humoral immune response, we show that OCT2 was the dominant transcription factor linked to differential accessibility of GC regulatory elements. Silent chromatin regions destined to become GC-specific super-enhancers (SEs) contained pre-positioned OCT2-binding sites in naive B cells (NBs). These preloaded SE 'seeds' featured spatial clustering of regulatory elements enriched in OCT2 DNA-binding motifs that became heavily loaded with OCT2 and its GC-specific coactivator OCAB in GC B cells (GCBs). SEs with high abundance of pre-positioned OCT2 binding preferentially formed long-range chromatin contacts in GCs, to support expression of GC-specifying factors. Gain in accessibility and architectural interactivity of these regions were dependent on recruitment of OCAB. Pre-positioning key regulators at SEs may represent a broadly used strategy for facilitating rapid cell fate transitions.

Gene-Specific Control of tRNA Expression by RNA Polymerase II.

Increasing evidence suggests that tRNA levels are dynamically and specifically regulated in response to internal and external cues to modulate the cellular translational program. However, the molecular players and the mechanisms regulating the gene-specific expression of tRNAs are still unknown. Using an inducible auxin-degron system to rapidly deplete RPB1 (the largest subunit of RNA Pol II) in living cells, we identified Pol II as a direct gene-specific regulator of tRNA transcription. Our data suggest that Pol II transcription robustly interferes with Pol III function at specific tRNA genes. This activity was further found to be essential for MAF1-mediated repression of a large set of tRNA genes during serum starvation, indicating that repression of tRNA genes by Pol II is dynamically regulated. Hence, Pol II plays a direct and central role in the gene-specific regulation of tRNA expression.

Unique Immune Cell Coactivators Specify Locus Control Region Function and Cell Stage.

Locus control region (LCR) functions define cellular identity and have critical roles in diseases such as cancer, although the hierarchy of structural components and associated factors that drive functionality are incompletely understood. Here we show that OCA-B, a B cell-specific coactivator essential for germinal center (GC) formation, forms a ternary complex with the lymphoid-enriched OCT2 and GC-specific MEF2B transcription factors and that this complex occupies and activates an LCR that regulates the BCL6 proto-oncogene and is uniquely required by normal and malignant GC B cells. Mechanistically, through OCA-B-MED1 interactions, this complex is required for Mediator association with the BCL6 promoter. Densely tiled CRISPRi screening indicates that only LCR segments heavily bound by this ternary complex are essential for its function. Our results demonstrate how an intimately linked complex of lineage- and stage-specific factors converges on specific and highly essential enhancer elements to drive the function of a cell-type-defining LCR.

Transcriptional down-regulation of metabolic genes by Gdown1 ablation induces quiescent cell re-entry into the cell cycle.

Liver regeneration and metabolism are highly interconnected. Here, we show that hepatocyte-specific ablation of RNA polymerase II (Pol II)-associated Gdown1 leads to down-regulation of highly expressed genes involved in plasma protein synthesis and metabolism, a concomitant cell cycle re-entry associated with induction of cell cycle-related genes (including cyclin D1), and up-regulation of p21 through activation of p53 signaling. In the absence of p53, Gdown1-deficient hepatocytes show a severe dysregulation of cell cycle progression, with incomplete mitoses, and a premalignant-like transformation. Mechanistically, Gdown1 is associated with elongating Pol II on the highly expressed genes and its ablation leads to reduced Pol II recruitment to these genes, suggesting that Pol II redistribution may facilitate hepatocyte re-entry into the cell cycle. These results establish an important physiological function for a Pol II regulatory factor (Gdown1) in the maintenance of normal liver cell transcription through constraints on cell cycle re-entry of quiescent hepatocytes.

Unveiling a novel serpinB2-tripeptidyl peptidase II signaling axis during senescence.

Tripeptidyl peptidase II (TPPII or TPP2) degrades N-terminal tripeptides from proteins and peptides. Studies in both humans and mice have shown that TPPII deficiency is linked to cellular immune-senescence, lifespan regulation and the aging process. However, the mechanism of how TPPII participates in these processes is less clear. In this study, we established a chemical probe-based assay and found that although the mRNA and protein levels of TPPII were not altered during senescence, its enzymatic activity was reduced in senescent human fibroblasts. We also showed that elevation of the levels of the serine protease inhibitor serpinB2 reduced TPPII activity in senescent cells. Moreover, suppression of TPPII led to elevation in the amount of lysosomal contents as in well as TPPI (TPP1) and ß-galactosidase activities, suggesting that lysosome biogenesis is induced to compensate for the reduction of TPPII activity in senescent cells. Together, this study discloses a critical role of the serpinB2-TPPII signaling pathway in proteostasis during senescence. Since serpinB2 levels can be increased by a variety of cellular stresses, reduction of TPPII activity through activation of serpinB2 might represent a common pathway for cells to respond to different stress conditions. This article has an associated First Person interview with the first author of the paper.

The risk factors and clinical outcomes in hepatitis B seropositive and seronegative renal transplant patients.

INTRODUCTION: Hepatitis B virus (HBV) infection is prevalent in Asia including Taiwan. We retrospectively evaluated the risk of HBV reactivation and clinical outcomes in HBV+ and HBV- kidney transplant recipients. METHODS: Patients who underwent kidney transplantation between January 2004 and December 2021 were reviewed. The outcomes of interest included risks of HBV reactivation and patient/graft survival. RESULTS: We identified 337 patients (47.5 ± 12 years) were enrolled in our final cohort. Fifty-two (15.4%) had HBsAg positive at the time of transplantation. Seventeen developed viral reactivations, with 41.2% of them accompanied by active hepatitis. The graft survival, acute rejection rate, and cancer development after kidney transplantation did not differ in terms of HBsAg status. The Cox multivariate analysis indicated the HBV reactivation risk was increased by a lack of pre-transplant anti-HBV medication [hazard ratio (HR), 5.95; 95% confidence interval (CI), 1.31-27.02; P = 0.021 or an absence of lifelong antiviral therapy [HR, 3.14; 95% CI, 1.01-9.74; P = 0.047] Conclusion: Individuals, independent of HBsAg status, had similar prognosis in terms of patient and graft survival, acute rejection rate, and cancer development. The absence of either pre-transplant anti-HBV medication or lifelong antiviral therapy was significantly associated with an increased risk of HBV reactivation.

Severe brain injury and trends of gestational-age-related neurodevelopmental outcomes in infants born very preterm: A population cohort study.

AIM: To investigate the impact of severe neonatal brain injury (SNBI) on gestational age-related trends in neurodevelopmental impairment (NDI) outcome in infants born very preterm. METHOD: A population-based cohort study recruited 1091 infants born at a gestational age of less than 31 weeks between 2011 and 2020. The trends in neonatal morbidities, mortality, and 24-month NDI severity (no/mild, moderate, severe) by epoch (2011-2015, 2016-2020) and gestational age (22-25 weeks, 26-28 weeks, 29-30 weeks) were determined in infants with and without SNBI inclusion. RESULTS: There was increased antenatal steroid use and higher maternal education and socioeconomic status over time. The rates of neonatal morbidities and mortality had no temporal changes. Among 825 infants with follow-up, those in the 22 to 25 weeks gestational age group had declining trends in cerebral palsy and severe cognitive impairment, with decreased rates of severe NDI from 19% to 8% across epochs, particularly in those without SNBI (from 16% to 2%). Relative to its occurrence in epoch 2011 to 2015, risk of severe NDI was significantly reduced in epoch 2016 to 2020 (adjusted relative risk 0.39, 95% confidence interval 0.16-0.96) for infants born at 22 to 25 weeks gestational age, and the risk dropped even lower in these infants without SNBI (0.12, 0.02-0.84). INTERPRETATION: Infants born at 22 to 25 weeks gestational age had decreased rates of severe NDI in the decade between 2011 and 2020, particularly those without SNBI. The improvement might be attributed to better perinatal/neonatal and after-discharge care.

The Quartile Levels of Thyroid-Stimulating Hormone by Newborn Screening Stratified Risks of Neurodevelopmental Impairment in Extremely Preterm Infants - A Population Cohort Study.

BACKGROUND: To evaluate whether thyroid-stimulating hormone (TSH) by newborn screening (NBS) at birth and at discharge can be surrogate markers for neurodevelopmental impairment (NDI) in extremely preterm infants. METHODS: The population cohort enrolled infants born <29 weeks' gestation in 2008 - 2020 in southern Taiwan. Infants with a maternal history of thyroid disorders and infants who required thyroxine supplementation during hospitalization were excluded. TSH levels by NBS at birth and at term-equivalent age (TEA)/discharge were respectively categorized into the lowest quartile, the interquartile range, and the highest quartile, which were correlated to NDI outcomes. RESULTS: Among 392 patients with paired TSH data, 358 (91%) were prospectively followed until corrected age 24 months. At birth, infants with lowest-quartile TSH had higher NDI risks (OR 2.3, 95% CI 1.3 - 4.1, P = 0.004) compared to infants with interquartile-range TSH. Conversely, by TEA/discharge, infants with highest-quartile TSH had increased NDI (OR 1.9, 1.0 - 3.4, P = 0.03). By paired TSH categories, infants persistently in the lowest TSH quartile (48%, aOR 4.4, 1.4 - 14.5, P = 0.01) and those with a shift from interquartile range to the highest quartile (32%, aOR 2.7, 1.0 - 7.4, P = 0.046) had increased NDI risks compared with the reference with consistent interquartile-range TSH. CONCLUSIONS: Extremely preterm infants persistently in the lowest-quartile TSH level at birth and at discharge had the highest NDI risk. TSH quartile levels by NBS may serve as a population surrogate biomarker for assessing NDI risks in infants born extremely preterm.

Mediator subunit MED1 is required for E2A-PBX1-mediated oncogenic transcription and leukemic cell growth.

The chimeric transcription factor E2A-PBX1, containing the N-terminal activation domains of E2A fused to the C-terminal DNA-binding domain of PBX1, results in 5% of pediatric acute lymphoblastic leukemias (ALL). We recently have reported a mechanism for RUNX1-dependent recruitment of E2A-PBX1 to chromatin in pre-B leukemic cells; but the subsequent E2A-PBX1 functions through various coactivators and the general transcriptional machinery remain unclear. The Mediator complex plays a critical role in cell-specific gene activation by serving as a key coactivator for gene-specific transcription factors that facilitates their function through the RNA polymerase II transcriptional machinery, but whether Mediator contributes to aberrant expression of E2A-PBX1 target genes remains largely unexplored. Here we show that Mediator interacts directly with E2A-PBX1 through an interaction of the MED1 subunit with an E2A activation domain. Results of MED1 depletion by CRISPR/Cas9 further indicate that MED1 is specifically required for E2A-PBX1-dependent gene activation and leukemic cell growth. Integrated transcriptome and cistrome analyses identify pre-B cell receptor and cell cycle regulatory genes as direct cotargets of MED1 and E2A-PBX1. Notably, complementary biochemical analyses also demonstrate that recruitment of E2A-PBX1 to a target DNA template involves a direct interaction with DNA-bound RUNX1 that can be further stabilized by EBF1. These findings suggest that E2A-PBX1 interactions with RUNX1 and MED1/Mediator are of functional importance for both gene-specific transcriptional activation and maintenance of E2A-PBX1-driven leukemia. The MED1 dependency for E2A-PBX1-mediated gene activation and leukemogenesis may provide a potential therapeutic opportunity by targeting MED1 in E2A-PBX1+ pre-B leukemia.

Trends in Gestational Age-Related Intelligence Outcomes of School-Age Children Born Very Preterm from 2001 to 2015 in Taiwan.

OBJECTIVE: To investigate whether gestational age (GA)-related intelligence outcomes of children born very preterm improved over time. STUDY DESIGN: A multicenter cohort study recruited 4717 infants born at GA <31 weeks and admitted to neonatal intensive care units between 2001 and 2015 in Taiwan. Intelligence outcomes at age 5.5 years were classified by intelligent quotient (IQ) into no cognitive impairment (IQ > -1 SD), mild cognitive impairment (IQ = -1∼-2 SD), and moderate/severe cognitive impairment (IQ < -2 SD). Trends were assessed for neonatal morbidities, mortality, and intelligence outcomes by birth epoch (2001-2003, 2004-2006, 2007-2009, 2010-2012, 2013-2015) and GA (23-24, 25-26, 27-28, 29-30 weeks). RESULTS: Maternal education levels increased and rates of brain injury and mortality decreased over time. Among the 2606 children who received IQ tests, the rates of no, mild, and moderate/severe cognitive impairment were 54.5%, 30.5%, and 15.0%, respectively. There were significant trends in the increasing rates of no cognitive impairment and declining rates of mild and moderate/severe cognitive impairment in all GA groups across the 5 birth epochs. Relative to the occurrence in 2001-2003, the odds were significantly reduced for moderate/severe cognitive impairment from 2007-2009 (aOR 0.49, 95% CI 0.30-0.81) to 2013-2015 (0.35, 0.21-0.56) and for mild cognitive impairment from 2010-2012 (0.54, 0.36-0.79) to 2013-2015 (0.36, 0.24-0.53). CONCLUSIONS: For children born very preterm between 2001 and 2015 in Taiwan, the improvement of maternal education levels and improvements in neonatal brain injury and mortality were temporally associated with trends of decreasing intellectual impairment at school age across all GA groups.

Utility of the Kidney Failure Risk Equation and Estimated GFR for Estimating Time to Kidney Failure in Advanced CKD.

RATIONALE & OBJECTIVE: The Kidney Failure Risk Equation (KFRE) predicts the 2-year risk of kidney failure for patients with chronic kidney disease (CKD). Translating KFRE-predicted risk or estimated glomerular filtration rate (eGFR) into time to kidney failure could inform decision making for patients approaching kidney failure. STUDY DESIGN: Retrospective cohort. SETTING & PARTICIPANTS: CKD Outcomes and Practice Patterns Study (CKDOPPS) cohort of patients with an eGFR<60mL/min/1.73m2 from 34 US nephrology practices (2013-2021). EXPOSURE: 2-year KFRE risk or eGFR. OUTCOME: Kidney failure defined as initiation of dialysis or kidney transplantation. ANALYTICAL APPROACH: Accelerated failure time (Weibull) models used to estimate the median, 25th, and 75th percentile times to kidney failure starting from KFRE values of 20%, 40%, and 50%, and from eGFR values of 20, 15, and 10mL/min/1.73m2. We examined variability in time to kidney failure by age, sex, race, diabetes status, albuminuria, and blood pressure. RESULTS: Overall, 1,641 participants were included (mean age 69±13 years; median eGFR of 28mL/min/1.73m2 [IQR 20-37mL/min/1.73 m2]). Over a median follow-up period of 19 months (IQR, 12-30 months), 268 participants developed kidney failure, and 180 died before reaching kidney failure. The median estimated time to kidney failure was widely variable across patient characteristics from an eGFR of 20mL/min/1.73m2 and was shorter for younger age, male sex, Black (versus non-Black), diabetes (vs no diabetes), higher albuminuria, and higher blood pressure. Estimated times to kidney failure were comparably less variable across these characteristics for KFRE thresholds and eGFR of 15 or 10mL/min/1.73m2. LIMITATIONS: Inability to account for competing risks when estimating time to kidney failure. CONCLUSIONS: Among those with eGFR<15mL/min/1.73m2 or KFRE risk>40%), both KFRE risk and eGFR showed similar relationships with time to kidney failure. Our results demonstrate that estimating time to kidney failure in advanced CKD can inform clinical decisions and patient counseling on prognosis, regardless of whether estimates are based on eGFR or the KFRE. PLAIN-LANGUAGE SUMMARY: Clinicians often talk to patients with advanced chronic kidney disease about the level of kidney function expressed as the estimated glomerular filtration rate (eGFR) and about the risk of developing kidney failure, which can be estimated using the Kidney Failure Risk Equation (KFRE). In a cohort of patients with advanced chronic kidney disease, we examined how eGFR and KFRE risk predictions corresponded to the time patients had until reaching kidney failure. Among those with eGFR<15mL/min/1.73m2 or KFRE risk > 40%), both KFRE risk and eGFR showed similar relationships with time to kidney failure. Estimating time to kidney failure in advanced CKD using either eGFR or KFRE can inform clinical decisions and patient counseling on prognosis.

Measurement of the 5S1/2 to 5D5/2 two-photon clock transition frequency of rubidium-85 in high vacuum.

We present a scheme to precisely resolve the unperturbed line shape of an optical rubidium clock transition in a high vacuum, by which we avoided the systematic errors of "collision shift" and "modulation shift." The spectral resolution resolved by this scheme is significantly improved such that we can use "Zeeman broadening" to inspect the stray magnetic field, through which we were able to compensate the magnetic field inside the Rb cells to be below 10-3 Gauss. We thus update the absolute frequency of the clock transition and propose a standard operation procedure (SOP) for the clock self-calibration.

Preceding risks and mortality outcomes of different neonatal acute kidney injury in preterm infants.

BACKGROUND: The aim of the study was to examine preceding risks and mortality outcomes of oliguric and non-oliguric acute kidney injury (AKI) in very preterm infants. METHODS: Infants born ≤30 weeks' gestation were included. AKI was diagnosed based on neonatal Kidney Disease: Improving Global Outcomes criteria and was classified as oliguric and non-oliguric according to the urine-output criteria. We used modified Poisson and Cox proportional-hazards models for statistical comparisons. RESULTS: Of 865 enrolled infants (gestational age 27.2 ± 2.2 weeks and birth weight 983 ± 288 gm), 204 (23.6%) developed AKI. Before AKI, the oliguric AKI group had significantly higher prevalence of small-for-gestational age (p = 0.008), lower 5-min Apgar score (p = 0.009) and acidosis (p = 0.009) on admission, and hypotension (p = 0.008) and sepsis (p = 0.001) during admission than the non-oliguric AKI group. Oliguric (adjusted risk ratio 3.58, 95% CI 2.33-5.51; adjusted hazard ratio 4.93, 95% CI 3.14-7.72) instead of non-oliguric AKI had significantly higher mortality risks than no AKI. Oliguric AKI showed significantly higher mortality risks than non-oliguric AKI, irrespective of serum creatinine and severity of AKI. CONCLUSIONS: Categorizing AKI as oliguric and non-oliguric was crucial because of the distinct preceding risks and mortality outcomes of these two types of AKI in very preterm neonates. IMPACT: The differences of the underlying risks and prognosis between oliguric and non-oliguric AKI in very preterm infants remain unclear. We found that oliguric AKI, but not non-oliguric AKI, carries higher mortality risks than infants without AKI. Oliguric AKI possessed higher mortality risks than non-oliguric AKI, irrespective of concomitant serum creatinine elevation and severe AKI. Oliguric AKI is more associated with prenatal small-for-the-gestational age and perinatal and postnatal adverse events, while non-oliguric AKI is associated with nephrotoxins exposures. Our finding highlighted the importance of oliguric AKI and is helpful in developing future protocol in neonatal critical care.

Risk patterns associated with transient hearing impairment and permanent hearing loss in infants born very preterm: A retrospective study.

AIM: To determine the risk patterns associated with transient hearing impairment (THI) and permanent hearing loss (PHL) of infants born very preterm who failed hearing screenings. METHOD: We enrolled 646 infants (347 males, 299 females) born at no more than 30 weeks' gestation between 2006 and 2020 who received auditory brainstem response screening at term-equivalent age. Audiological examinations of infants who failed the screening revealed THI, when hearing normalized, or PHL, defined as a persistent unilateral or bilateral hearing threshold above 20 dB. Principal component analysis (PCA) was used to characterize risk patterns. RESULTS: Among the 646 infants, 584 (90.4%) had normal hearing, 42 (6.5%) had THI, and 20 (3.1%) had PHL. Compared with the group with normal hearing, the THI and PHL groups had significantly higher rates of neurodevelopmental impairment at 24 months corrected age. PCA of risk patterns showed the THI group and especially the PHL group had more severe haemodynamic and respiratory instability. Moreover, severe intraventricular haemorrhage (IVH) was also a risk for PHL. Propensity score matching revealed an association of haemodynamic and respiratory instability with PHL. INTERPRETATION: In infants born preterm, the severity and duration of haemodynamic and respiratory instability are risk patterns for both THI and PHL; severe IVH is an additional risk for PHL. WHAT THIS PAPER ADDS: Neurodevelopmental delay was more common in infants born preterm who failed hearing screening. Principal component analysis revealed the risk patterns associated with hearing impairment. Haemodynamic-respiratory instability was associated with transient and permanent hearing impairment outcomes. Severe haemodynamic-respiratory instability and intraventricular haemorrhage was associated with permanent hearing loss.

Health Care Trainees' and Professionals' Perceptions of ChatGPT in Improving Medical Knowledge Training: Rapid Survey Study.

BACKGROUND: ChatGPT is a powerful pretrained large language model. It has both demonstrated potential and raised concerns related to knowledge translation and knowledge transfer. To apply and improve knowledge transfer in the real world, it is essential to assess the perceptions and acceptance of the users of ChatGPT-assisted training. OBJECTIVE: We aimed to investigate the perceptions of health care trainees and professionals on ChatGPT-assisted training, using biomedical informatics as an example. METHODS: We used purposeful sampling to include all health care undergraduate trainees and graduate professionals (n=195) from January to May 2023 in the School of Public Health at the National Defense Medical Center in Taiwan. Subjects were asked to watch a 2-minute video introducing 5 scenarios about ChatGPT-assisted training in biomedical informatics and then answer a self-designed online (web- and mobile-based) questionnaire according to the Kirkpatrick model. The survey responses were used to develop 4 constructs: "perceived knowledge acquisition," "perceived training motivation," "perceived training satisfaction," and "perceived training effectiveness." The study used structural equation modeling (SEM) to evaluate and test the structural model and hypotheses. RESULTS: The online questionnaire response rate was 152 of 195 (78%); 88 of 152 participants (58%) were undergraduate trainees and 90 of 152 participants (59%) were women. The ages ranged from 18 to 53 years (mean 23.3, SD 6.0 years). There was no statistical difference in perceptions of training evaluation between men and women. Most participants were enthusiastic about the ChatGPT-assisted training, while the graduate professionals were more enthusiastic than undergraduate trainees. Nevertheless, some concerns were raised about potential cheating on training assessment. The average scores for knowledge acquisition, training motivation, training satisfaction, and training effectiveness were 3.84 (SD 0.80), 3.76 (SD 0.93), 3.75 (SD 0.87), and 3.72 (SD 0.91), respectively (Likert scale 1-5: strongly disagree to strongly agree). Knowledge acquisition had the highest score and training effectiveness the lowest. In the SEM results, training effectiveness was influenced predominantly by knowledge acquisition and partially met the hypotheses in the research framework. Knowledge acquisition had a direct effect on training effectiveness, training satisfaction, and training motivation, with ß coefficients of .80, .87, and .97, respectively (all P<.001). CONCLUSIONS: Most health care trainees and professionals perceived ChatGPT-assisted training as an aid in knowledge transfer. However, to improve training effectiveness, it should be combined with empirical experts for proper guidance and dual interaction. In a future study, we recommend using a larger sample size for evaluation of internet-connected large language models in medical knowledge transfer.

The outcomes and prognostic factors of patients with hepatocellular carcinoma and normal serum alpha fetoprotein levels.

BACKGROUND: Alpha fetoprotein (AFP) is the most widely used tumor marker for hepatocellular carcinoma (HCC). Nevertheless, few studies have investigated the prognostic factors of HCC patients with normal serum AFP levels. METHODS: We retrospectively enrolled 2198 patients with HCC and normal serum AFP levels (<20 ng/mL) from 2007 to 2020. Overall survival (OS) rates were calculated by the Kaplan-Meier method, and analyses of the prognostic factors were performed using a Cox proportional hazard model. RESULTS: Among the enrolled patients, 1385 (63%) patients were in the low-normal AFP group (serum AFP levels ≤7 ng/mL), and 813 (37%) patients were in the high-normal AFP group (serum AFP levels between 7 and 20 ng/mL). The high-normal AFP group had poorer liver functional reserve, more multiple tumors, and smaller tumor size compared to those in the low-normal AFP group. After a median follow-up of 32.4 months, 942 patients died, and the 5-year OS rate was 54.4%. The 5-year OS rates were 57.4% and 49.8% in the low-normal AFP group and high-normal AFP group, respectively (p = 0.001). A multivariate analysis showed the independent prognostic factors of poor OS were no anti-viral therapy, advanced albumin-bilirubin grades, the presence of vascular invasion, tumor size ≥5 cm, and non-curative treatment modalities. Serum AFP levels were not associated with OS according to the multivariate analysis. CONCLUSION: Liver functional reserve, anti-viral therapy, tumor size, vascular invasion, and treatment modalities, determined the outcomes of HCC patients with normal serum AFP levels, but serum AFP levels did not.

Effect of the Ligation and Reperfusion Timeframe on Maximal Ischemia-Reperfusion Injury in Diverse Rat Models.

Background: Little is known about the effect that different time sequences for coronary ligation and reperfusion have on ischemic-reperfusion (IR) injury. Objective: To investigate the relationship between the extent of IR injury and the timeframe for coronary ligation/reperfusion in three animal models. Methods: Three rat models were used: normal Sprague-Dawley rats, diabetes mellitus (DM) rats, and fat rats. The rats in each model were divided into four groups based on the coronary ligation period (L): 30, 60, 120, and 180 min, and then divided into seven sub-groups based on the reperfusion period (R): 0, 30, 60, 120, 180, 270, and 360 min. R0 was the IR injury baseline for each sub-group. The hearts were harvested and stained with Evans blue and 2,3,5-triphenyl tetrazolium chloride dye to distinguish the different myocardial injury areas: area at risk (AAR) and myocardial necrosis. The difference between each subgroup and baseline (R0) for the necrotic area/AAR was calculated. Results: In the normal rats, the highest IR injury differences compared with the baseline group occurred at L120, with a reperfusion time of > 180 min. The highest IR injury difference compared to the baseline group occurred at L30, with a reperfusion time of > 180 min in the DM rats and at L60R270, L120R180 in the fat rats. Conclusions: IR injury, as induced by different coronary ligation and reperfusion time intervals, had diverse expression profiles in the different animal models. Optimal animal models with optimal coronary ligation/reperfusion protocols to achieve maximal IR injury will affect the results and interpretation of future studies.

Ledipasvir/Sofosbuvir for Patients Coinfected With Chronic Hepatitis C and Hepatitis B in Taiwan: Follow-up at 108 Weeks Posttreatment.

BACKGROUND: For patients coinfected with hepatitis C virus (HCV) and hepatitis B virus (HBV), HCV treatment with direct-acting antivirals can lead to HBV reactivation. We evaluated HBV reactivation during ledipasvir/sofosbuvir treatment and 108-week follow-up. METHODS: In Taiwan, 111 patients with HCV genotype 1 or 2 and HBV received ledipasvir/sofosbuvir (90mg/400mg) once daily for 12 weeks. HBV virologic reactivation was defined as postbaseline increase in HBV DNA from either less than the lower limit of quantification (LLOQ, 20 IU/mL) to equal to or more than LLOQ or equal to or more than LLOQ to >1 log10 IU/mL. HBV clinical reactivation was HBV virologic reactivation with alanine aminotransferase (ALT) >2× upper limit of normal. Factors associated with development of HBV virologic or clinical reactivation were evaluated with logistic regression analysis. RESULTS: All patients (100%, 111/111) maintained HCV suppression through 108 weeks after treatment. HBV virologic reactivation occurred in 73% of patients (81/111). Clinical reactivation occurred in 9% (10/111). The majority of HBV virologic reactivations (86%, 70/81) occurred by follow-up week 12, whereas clinical reactivation was generally more delayed. Eight (7%, 8/111) initiated HBV therapy. In regression analyses, baseline HBV DNA and hepatitis B surface antigen (HBsAg) levels were associated with HBV virologic reactivation and baseline ALT and HBV DNA, and HBsAg levels were associated with HBV clinical reactivation. CONCLUSION: Among HCV/HBV coinfected patients treated with direct-acting antivirals for HCV, HBV virologic reactivation occurred in a majority of patients during treatment and follow-up. In most patients, HBV virologic reactivation was asymptomatic; only a small proportion initiated HBV treatment. Notably, clinical reactivation may still occur >3 months after end of therapy. CLINICAL TRIALS REGISTRATION: NCT02613871.

From GWAS to drug screening: repurposing antipsychotics for glioblastoma.

BACKGROUND: Glioblastoma is currently an incurable cancer. Genome-wide association studies have demonstrated that 41 genetic variants are associated with glioblastoma and may provide an option for drug development. METHODS: We investigated FDA-approved antipsychotics for their potential treatment of glioblastoma based on genome-wide association studies data using a 'pathway/gene-set analysis' approach. RESULTS: The in-silico screening led to the discovery of 12 candidate drugs. DepMap portal revealed that 42 glioma cell lines show higher sensitivities to 12 candidate drugs than to Temozolomide, the current standard treatment for glioblastoma. CONCLUSION: In particular, cell lines showed significantly higher sensitivities to Norcyclobenzaprine and Protriptyline which were predicted to bind targets to disrupt a certain molecular function such as DNA repair, response to hormones, or DNA-templated transcription, and may lead to an effect on survival-related pathways including cell cycle arrest, response to ER stress, glucose transport, and regulation of autophagy. However, it is recommended that their mechanism of action and efficacy are further determined.

Genome-wide association study reveals ethnicity-specific SNPs associated with ankylosing spondylitis in the Taiwanese population.

BACKGROUND: Ankylosing spondylitis (AS) is an autoimmune disease affecting mainly spine and sacroiliac joints and adjacent soft tissues. Genome-wide association studies (GWASs) are used to evaluate genetic associations and to predict genetic risk factors that determine the biological basis of disease susceptibility. We aimed to explore the race-specific SNP susceptibility of AS in Taiwanese individuals and to investigate the association between HLA-B27 and AS susceptibility SNPs in Taiwan. METHODS: Genotyping data were collected from a medical center participating in the Taiwan Precision Medicine Initiative (TPMI) in the northern district of Taiwan. We designed a case-control study to identify AS susceptibility SNPs through GWAS. We searched the genome browser to find the corresponding susceptibility genes and used the GTEx database to confirm the regulation of gene expression. A polygenic risk score approach was also applied to evaluate the genetic variants in the prediction of developing AS. RESULTS: The results showed that the SNPs located on the sixth chromosome were related to higher susceptibility in the AS group. There was no overlap between our results and the susceptibility SNPs found in other races. The 12 tag SNPs located in the MHC region that were found through the linkage disequilibrium method had higher gene expression. Furthermore, Taiwanese people with HLA-B27 positivity had a higher proportion of minor alleles. This might be the reason that the AS prevalence is higher in Taiwan than in other countries. We developed AS polygenic risk score models with six different methods in which those with the top 10% polygenic risk had a fivefold increased risk of developing AS compared to the remaining group with low risk. CONCLUSION: A total of 147 SNPs in the Taiwanese population were found to be statistically significantly associated with AS on the sixth pair of chromosomes and did not overlap with previously published sites in the GWAS Catalog. Whether those genes mapped by AS-associated SNPs are involved in AS and what the pathogenic mechanism of the mapped genes is remain to be further studied.