Analogue Treatment Research Articles

Treatment satisfaction and patient reported outcomes among people with opioid use disorder participating in an open-label, non-randomised trial of long-acting injectable buprenorphine treatment in Australian custodial settings.

A trial of long-acting injectable buprenorphine (LAIB) in Australian prisons allowed examination of treatment satisfaction and patient-reported outcomes. UNLOC-T was a 16-week non-randomised open-label study. Men and women aged ≥18 years with moderate/severe DSM-5 opioid use disorder currently serving a custodial sentence ≥6 months were recruited. Participants not in opioid agonist treatment (OAT) commenced LAIB (n = 67); those already stable on oral methadone treatment were recruited to a comparison arm (n = 62). The Treatment Satisfaction Questionnaire for Medication (TSQM), Patient Satisfaction Visual Analogue Scale (PS-VAS) and Treatment Burden Questionnaire assessed treatment satisfaction; the Kessler Psychological Distress Scale (K10), 12-Item Short Form Health Survey (SF-12) and the Australian Treatment Outcomes Profile (ATOP) measured mental health, physical health and quality of life. Among participants receiving LAIB, TSQM global satisfaction scores significantly increased from 68.2 (SD 16.6) to 77.0 (SD 18.4) by week 16 (p = 0.0041), as did satisfaction measured by the PS-VAS (62.5 [SD 29.2] vs. 79.4 [SD 25.5], p = 0.0005). Statistically significant improvements between baseline and week 16 were also observed for K10, SF-12 (total) and SF-12 (mental health) scores. By the end of the study, 'successful' treatment outcomes were observed in the ATOP domains of psychological health (84%), physical health (80%) and quality of life (86%). Participants inducted and stabilised on LAIB reported high treatment satisfaction and improved health and wellbeing. Results suggest LAIB is acceptable to people with opioid use disorder in custody, supporting scaleup of this medication to increase coverage of OAT in these settings. https://www.anzctr.org.au ACTRN12618000942257.

Tenofovir vs Entecavir on the Prognosis of Patients With Hepatitis B Virus-Related Hepatocellular Carcinoma After Liver Resection: The Role of HBsAg Levels.

Our study aimed to explore whether hepatitis B surface antigen (HBsAg) levels affected the role of nucleot(s)ide analog treatment (entecavir [ETV] and tenofovir disoproxil fumarate [TDF]) in improving the prognosis of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after liver resection. A total of 865 patients with HBV-related HCC after hepatectomy treated with TDF or ETV were included in our study. Patients were divided into the high HBsAg cohort (n = 681) and the low HBsAg cohort (n = 184). Propensity score matching (PSM) analysis was used to reduce the impact of potential confounding factors. Kaplan-Meier method and competing risk analysis were used to compare the survival outcomes. In the high HBsAg cohort, patients in the TDF group had better recurrence-free survival (RFS) and overall survival (OS) compared with patients in the ETV group both before (RFS: P < 0.001; OS: P < 0.001) and after (RFS: P = 0.005; OS: P = 0.035) PSM. TDF treatment was a favorable factor independently associated with RFS (hazard ratio: 0.58, 95% confidence interval: 0.45-0.75, P < 0.001) and OS (hazard ratio: 0.43, 95% confidence interval: 0.28-0.66, P < 0.001). In the low HBsAg cohort, no difference was observed in RFS and OS between the TDF group and the ETV group both before (RFS: P = 0.140; OS: P = 0.640) and after (RFS: P = 0.480; OS: P = 0.920) PSM. TDF treatment remained superiority after controlling for competing events by competing risk analysis in the high HBsAg cohort. TDF treatment was superior to ETV treatment in improving RFS and OS of HBV-related HCC patients with high HBsAg level after liver resection. Even after controlling for survival competing events, the advantage of TDF treatment remained. Our findings may better help clinicians to assign individualized antiviral regimens to patients with HBV-related HCC after liver resection.

SIRT6 promotes angiogenesis by enhancing VEGFA secretion via demyristoylation in endothelial cell.

Angiogenesis plays a pivotal role in ischemic cardiovascular disease, accompanied by epigenetic regulation during this process. Sirtuin 6 (SIRT6) has been implicated in the regulation of DNA repair, transcription and aging, with its deacetylase activity fully studied. However, the role of SIRT6 demyristoylase activity remains less clear, with even less attention given to its myristoylated substrates. In this study, we report that endothelial specific SIRT6 knockout attenuated angiogenesis in mice, while SIRT6 was observed to promote migration and tube formation in endothelial cell. Notably, we further determined that SIRT6 affects the intracellular VEGFA and global myristoylation level under hypoxia. Moreover, ALK14 (myristic acids analogue) treatment and SIRT6 knockdown results in a significant decrease in VEGFA secretion under hypoxia, implying the involvement of SIRT6 demyristoylase activity in angiogenesis. Mechanistically, CLICK IT assay verified that VEGFA is a myristoylated substrate of SIRT6. Further, overexpression of SIRT6 mutants (R65A, G60A and H133Y) results in profound differences in VEGFA secretion, indicating that SIRT6 promotes VEGFA secretion through demyristoylation but not deacetylation. Finally, overexpression of SIRT6 rescued the diminishment of endothelial migration, tube formation and sprouting caused by ALK14 treatment. Overall, our study demonstrates that SIRT6 regulates angiogenesis by demyristoylating VEGFA and increasing VEGFA secretion. Therefore, modulation of SIRT6 demyristoylase activity may represent a therapeutic strategy for ischemic cardiovascular disease.

Roles for Prlhr/GPR10 and Npffr2/GPR74 in feeding responses to PrRP.

Several groups of neurons in the NTS suppress food intake, including Prlh-expressing neurons (NTSPrlh cells). Not only does the artificial activation of NTSPrlh cells decrease feeding, but also the expression of Prlh (which encodes the neuropeptide PrRP) and neurotransmission by NTSPrlh neurons contributes to the restraint of food intake and body weight, especially in animals fed a high fat diet (HFD). We set out to determine roles for putative PrRP receptors in the response to NTS PrRP and exogenous PrRP-related peptides. We used animals lacking PrRP receptors GPR10 and/or GPR74 (encoded by Prlhr and Npffr2, respectively) to determine roles for each in the restraint of food intake and body weight by the increased expression of Prlh in NTSPrlh neurons (NTSPrlhOX mice) and in response to the anorectic PrRP analog, p52. Although Prlhr played a crucial role in the restraint of food intake and body weight in HFD-fed control animals, the combined absence of Prlhr and Npffr2 was required to abrogate the restraint of food intake in NTSPrlhOX mice. p52 suppressed feeding independently of both receptors, however. Hence, each receptor can participate in the NTSPrlh-mediated suppression of food intake and body weight gain, while PrRP analog treatment can mediate its effects via distinct systems. While Prlhr plays a crucial role in the physiologic restraint of weight gain, the action of either receptor is capable of ameliorating obesity in response to enhanced NTSPrlh signaling.

Association of fibronectin serum levels with loss of hepatitis B surface antigen in patients with chronic hepatitis B during nucleos(t)ide analogue treatment

Association of fibronectin serum levels with loss of hepatitis B surface antigen in patients with chronic hepatitis B during nucleos(t)ide analogue treatment

Cytidine analogs in plant epigenetic research and beyond.

Cytosine (DNA) methylation plays important roles in silencing transposable elements, plant development, genomic imprinting, stress responses, and maintenance of genome stability. To better understand the functions of this epigenetic modification, several tools have been developed to manipulate DNA methylation levels. These include mutants of DNA methylation writers and readers, targeted manipulation of locus-specific methylation, and the use of chemical inhibitors. Here, we summarize the effects of commonly used cytidine analog chemical inhibitors represented by zebularine, 5-azacytidine, and their related compounds on plants. These analogs are incorporated into the chromosomal DNA, where they block the activity of the replicative CG DNA methyltransferase 1 (MET1). This leads to manifold alterations in plant epigenome, modified developmental programs, or suppression of hybridization barriers. We also highlight the DNA-damaging effects of cytidine analogs, particularly the formation of stable DNA-protein crosslinks between DNA and MET1. This sheds new light on specific phenotypes observed upon cytidine analog treatments. In conclusion, cytidine analogs remain a vital tool for plant genome research and have the potential to open new promising avenues for applications in plant biotechnology and breeding.

Estimation of Break and Noise Variance and the Maximum Distance of Climate Stations Allowed in Relative Homogenisation of Annual Temperature Anomalies

ABSTRACTRelative homogenisation uses the difference time series of neighbouring climate stations in order to reduce the dominating variance of the climate signal. Larger distances between the stations reduce the signal‐to‐noise ratio (SNR) because the noise variance increases while the break variance remains constant. For different continents, we derive the distance where noise and break variance become equal (SNR = 1). This is an estimate for the maximum allowed distance because SNRs below 1 bear the risk that the homogenisation produces nonsense results. Technically, the break variance is derived by extrapolating the autocovariance to zero temporal distance. An analogous treatment of the variance provides an estimate of the sum of break and noise variance, so that the SNR can be concluded. However, the unavoidable usage of anomalies and limited time series shifts and bends the commonly assumed simple functions (decreasing exponential for the covariance and constant for the variance) in a complex manner. The actually occurring functions are theoretically derived and then fitted to observational data. Above that, we show that also in North America, the inhomogeneity levels themselves and not the jumps between them can be described as a random variable. Consequently, no Brownian‐motion‐type inhomogeneities seem to exist, as it was suggested in earlier studies.

CO82 Long-Acting Somatostatin Analogues Treatment Patterns and Outcomes in Neuroendocrine Tumor Patients: An Italian Propensity Score Matched Cohort Study

CO82 Long-Acting Somatostatin Analogues Treatment Patterns and Outcomes in Neuroendocrine Tumor Patients: An Italian Propensity Score Matched Cohort Study

SOMATOSTATIN ANALOGUES VS ACTIVE SURVEILLANCE IN SMALL PANCREATIC NEUROENDOCRINE TUMORS.

The best strategy for non-functioning, sporadic, G1-G2 pancreatic neuroendocrine tumors ≤2 cm is unknown. An active surveillance is usually recommended. The PROMID and the CLARINET studies proved the value of somatostatin analogue (SSA) treatment in advanced gastro-entero-pancreatic neuroendocrine tumors. Aim of this study is to assess the value of SSA in PanNET≤2 cm. We retrospectively collected data from 72 patients with sporadic non-functioning G1-G2 PanNETs≤2 cm, that were either treated with somatostatin analogues (n = 31) or underwent active surveillance (n = 41) at our Institution. At a median follow-up of 53.7 months, the median progression free survival was not reached in the treatment group versus an estimated PFS of 85 months in the control group (HR 0.11, p = 0.01), with a rate of progression or death up to 21.9% in the active surveillance group. Additionally, in the group of patients treated with somatostatin analogues the response rate was 16.1% with one complete response. Our monocentric experience demonstrated a significant antiproliferative activity of somatostatin analogues in patients with sporadic, non-functionating G1-G2 PanNETs ≤2 cm delaying tumor progression and distant spread in small lesions that sometimes may reveal unpredictable aggressiveness.

Role of Air Pollution in Development of Hepatocellular Carcinoma Among Chronic Hepatitis B Patients Treated With Nucleotide/Nucleoside Analogues.

To investigate the association between air pollution and hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with nucleotide/nucleoside analogues. We enrolled 1298 CHB patients treated with nucleotide/nucleoside analogues and analysed the incidence and risk factors for HCC. Daily estimates of air pollutants were estimated since the previous year from the enrolment date. The annual incidence of HCC was 2.1/100 person-years after a follow-up period of over 4840.5 person-years. Factors with the strongest association with HCC development were liver cirrhosis (hazard ratio [HR]/95% confidence interval [CI]: 3.00/1.55-5.81; p = 0.001), male sex (2.98/1.51-5.90; p = 0.02), body mass index (1.11/1.04-1.18; p = 0.002) and age (1.06/1.04-1.09; p < 0.001). Among patients with cirrhosis, the factors associated with HCC development were male sex (HR/95% CI: 2.10/1.00-4.25; p = 0.04) and NO2 (per one-unit increment, parts per billion; 1.07/1.01-1.13; p = 0.01). Moreover, patients with the highest quartile of annual NO2 exposure had more than a three-fold risk of HCC than those with the lowest quartile of annual exposure (HR/95% CI: 3.26/1.34-7.93; p = 0.01). Among patients without cirrhosis, the strongest factors associated with HCC development were male sex (HR/95% CI: 5.86/1.79-19.23; p = 0.004), age (1.12/1.07-1.17; p < 0.001) and platelet count (0.99/0.98-1.00; p = 0.04). Air pollution influences HCC development in CHB patients who receive nucleotide/nucleoside analogue therapy. Long-term NO2 exposure might accelerate HCC development in CHB patients with cirrhosis receiving nucleotide/nucleoside analogue treatment.

The Effect of Prostaglandin F2 Analog Treatment on the Immunoexpression of Fibrosis-Associated Factors in Patients with Glaucoma Undergoing Deep Sclerotomy.

Long-term use of topical prostaglandins might initiate chronic conjunctival inflammation, leading to poor outcomes of glaucoma surgery. The aim of this study was to evaluate the immunoexpression pattern of HSP70, CTGF, SNAIL, aSMA, cMYB, and HIFa in the conjunctiva, episclera, and deep sclera in patients with glaucoma undergoing deep sclerectomy in order to establish an association between staining intensities and prostaglandin F2 (PGF2) treatment. Double immunofluorescence (HSP70, CTGF, SNAIL, aSMA, cMYB, and HIFa) was performed on conjunctiva, episclera, and deep sclera samples, which were obtained from 23 patients treated with PGF2 and 8 patients without PGF2 treatment. When comparing the ocular tissues of patients regarding treatment with PGF2 analogs, we found a significant increase in the immunoexpression of HSP70 in the conjunctival epithelium of patients treated with PGF2 analogs compared to those without PGF2 treatment. These patients also had an increase in SNAIL immunoexpression and a decrease in aSMA immunoexpression in the deep sclera. There were no significant differences in HIFa, CTGF, or cMYB immunoexpression levels between the two groups. Further research into the regulation of these factors in ocular tissues could lead to the development of potential novel therapeutic approaches in glaucoma management.

Real-world experience with glucagon-like peptide 2 analogues in patients with short bowel syndrome and chronic intestinal failure: Results from an international survey in expert intestinal failure centers

Background and AimsGlucagon-like peptide 2 (GLP-2) analogues are the first available disease-modifying treatments for patients with intestinal failure (IF) due to short bowel syndrome (SBS). Efficacy in terms of reduction of parenteral support (PS) has been demonstrated in multiple studies and real-world reports. However, it remains unclear how many patients are eligible to receive the treatment, when treatment is started after intestinal resection, how treatment efficacy is assessed outside of clinical trials, and how the treatment is modified in case of non-response or adverse events. The aim of this study was to investigate the real-world management of patients treated with GLP-2 analogues in expert centers around the world. MethodsA survey questionnaire was developed by a multidisciplinary working group consisting of 52 questions related to various aspects of multidisciplinary care of SBS-IF patients. The 17 questions related to the use of GLP-2 analogues in clinical practice were analyzed for this study. The online survey was sent to 33 participating centers in a phase 3 study of a long-acting GLP-2 analogue. Only responses from countries with access to commercially available GLP-2 analogues were included in the study. A descriptive analysis was performed for each question. Results are presented as median (interquartile range). ResultsThe responses from the 19 expert IF centers with access to GLP-2 analogues indicated that 10 (10-20) % of patients with SBS-IF were treated with a GLP-2 analogue, which was less than the number of eligible patients (30 (25-40) %). In most centers (10 centers, 53%), GLP-2 therapy was started 6-12 months after the last intestinal resection, with 5 centers (26%) starting later (12-24 months). Multiple parameters were used in combination to determine the response to GLP-2 analogues of which the three most common were >20% decrease in PS (95%), at least 1 day of PS reduction per week (84%) and increased urinary output (68%). In non-responders GLP-2 therapy was stopped within the first year by 67% of the centers. Finally, strategies in case of significant adverse events include stopping the GLP-2 analogue (used by 79% of experts), dose reduction (67%) and temporary treatment interruption (62%). ConclusionThe results of this survey completed by expert IF centers show the real-life use of GLP-2 analogues in clinical practice. Key learning points identified include the accounting for a period of intestinal adaptation before starting GLP-2 analogues and not stopping the treatment too early in case of non-response. The best strategy in case of adverse effects should be studied further.

The efficacy and safety of addition of pegylated interferon to long-term nucleos(t)ide analogue therapy on functional cure of chronic hepatitis B patient: a systematic review and meta-analysis.

This meta-analysis aims to assess the efficacy and safety of adding pegylated interferon (Peg-IFN) to long-term nucleos(t)ide analogs (NAs) treatment for achieving functional cure in patients with chronic hepatitis B (CHB). This meta-analysis was registered in PROSPERO (CRD42024519116). We searched PubMed, Embase, Cochrane Library and Web of Science for randomized controlled trials that compared adding Peg-IFN to long-term NAs with NAs alone for the treatment of CHB. Relative risks (RR) and 95% confidence interval (CI) were pooled using a random-effects model. Seven trials with 692 participants were included. Compared to NAs monotherapy, sequential combination therapy significantly increased the HBsAg seroclearance rate (RR 4.37, 95%CI: 1.92-9.55; I2 = 0%) and HBsAg seroconversion rate (RR 3.98, 95%CI: 1.50-10.54; I2 = 0%), and the results reached statistical significance. Compared to NAs monotherapy, sequential combination therapy showed a significant increase in HBeAg seroclearance rate (RR 2.04; 95%CI: 0.47-8.82; I2 = 73%) and HBeAg seroconversion rate (RR 2.10; 95%CI: 0.41-10.71; I2 = 67%), but did not reach statistical significance. Sequential combination therapy was more likely to experience adverse events. Although most reactions are mild and reversible, vigilant monitoring for treatment-related adverse events is essential, with prompt intervention when needed. For CHB patients on long-term NAs treatment, sequential combination therapy boosts HBsAg seroclearance and HBsAg seroconversion rates compared to monotherapy. However, it may increase adverse events. Additional studies are needed to thoroughly evaluate its clinical effectiveness, given the current limited research available. PROSPERO, identifier CRD42024519116.

Chronic Hepatitis B Costs and Healthcare Resource Utilization in a Japanese Patient Population: A Retrospective Cross-Sectional Analysis

Introduction: Data on the economic burden of chronic hepatitis B infection in Japan are lacking. This study investigated healthcare resource utilization and costs of chronic hepatitis B infection and liver complications in Japan. Methods: This non-interventional study used the Medical Data Vision database. For the first analysis, a population with prevalent chronic hepatitis B infection and absence of liver complications was identified and further stratified by nucleos(t)ide analog treatment history. In the second analysis, patients with prevalent chronic hepatitis B infection and incident liver complications were identified. Patients were followed for 1 year in the first analysis and 2 years in the second analysis. Numbers of all-cause outpatient, inpatient, emergency hospitalizations, medication use, and associated costs per person-year were described across patients without/with nucleos(t)ide analog treatment and in those without/with liver complications. Results: For patients with chronic hepatitis B infection, 75,967 had no liver complications while 17,678 patients had liver complications. All-cause outpatient visits were the largest contributor to healthcare resource utilization and costs, for patients without and with liver complications, and were numerically higher for patients on nucleos(t)ide analog than not. Patients with liver complications had numerically higher all-cause healthcare resource utilization and total costs than patients without complications. Conclusions: Japan has a high economic burden of chronic hepatitis B infection, particularly in patients with liver complications. Optimizing treatment to prevent complications may reduce this burden.

Structural dynamics of human deoxyuridine 5’-triphosphate nucleotidohydrolase (dUTPase)

Structural- and functional heterogeneity, as well as allosteric regulation, in homo-monomeric enzymes is a highly active area of research. One such enzyme is human nuclear-associated deoxyuridine 5’-triphosphate nucleotidohydrolase (dUTPase), which has emerged as an interesting drug target in combination therapy with traditional nucleotide analogue treatment of cancer. We report, for the first time, a full structural dynamics study of human dUTPase by NMR. dUTPase has been investigated in terms of structural dynamics in its apo form, in complex with the modified substrate resistant to hydrolysis, 2’-deoxyuridine 5’-α,β-imido-triphosphate (dUpNHpp), as well as the product, 2’-deoxy-uridine-monophosphate (dUMP). The apo form of the enzyme displayed slow dynamics in the milli- to microsecond regime in relaxation dispersion experiments, which was further slowed down to observable heterogeneity upon substrate-analogue binding. The results suggest that the non-hydrolysable substrate-analogue traps the enzyme in the conformational isomerization step that has been previously suggested to be part of the enzyme catalysis kinetics cycle. The observed heterogeneity fits well with the pattern expected to emerge from the suggested kinetic model, and no evidence for homotropic allosterism was found. The heatmaps of the slow dynamics, chemical shift perturbation upon substrate binding and conserved regions of the enzyme sequence all displayed a similar pattern, which suggests that the structural dynamics is finely tuned and important for the biological function of the enzyme for binding, conformational shift, catalysis and substrate release.

Nucleos(t)ide analogs to treat patients with positive hepatitis B virus deoxyribonucleic acid and normal alanine transaminase: protocol for an open-label single-center randomized parallel controlled trial

BackgroundDirect high-quality evidence remains absent on the benefits of HBeAg-negative chronic hepatitis B patients (CHB) with normal alanine transaminase (ALT) and positive HBV DNA after nucleos(t)ide analogs (NAs) treatment.MethodsThis is a single-center, open-label, randomized parallel controlled trial with a follow-up duration of 96 weeks. An estimated 300 patients will be recruited at West China Hospital of Sichuan University, China. After stratified by serum HBV DNA (< 2000 vs. ≥ 2000 IU/ml), eligible patients will be randomized (allocation ratio 1:1) to receive either antiviral therapy (the treatment group) or regular examination alone (the control group). The primary outcomes are rates of virological response and changes in the levels of serum HBV pregenomic RNA (pgRNA) and scores of health-related qualities of life.DiscussionThis randomized controlled trial focuses on HBeAg-negative patients with normal ALT, including those of the inactive carrier phase and the grey zone, whose antiviral treatment remains controversial. Additionally, a health-related quality of life scale is introduced to comprehensively estimate the benefit of antiviral treatment apart from virological response and adverse liver events. Meaningfully, the study findings will provide high-quality and direct evidence for optimal clinical management in such populations.Trial registrationThis trial was registered with the Chinese Clinical Trial Registry (ChiCTR2300069391) on 15 March 2023.Graphical

Evaluation of the Effect of Topical Prostaglandin Analog Treatment on Orbital Structures in Open-Angle Glaucoma with Computed Tomography

Background/Objectives: This study aims to evaluate the computed tomography (CT) scans of glaucoma patients using prostaglandin analogs (PGA) in one eye, investigate findings associated with prostaglandin-associated periorbitopathy (PAP), and compare these findings with those of the contralateral eyes. Methods: Patients with open-angle glaucoma who had CT images of the orbital region taken for another reason at least one month after starting PGA treatment in one eye were included in the study. Enophthalmos measurements from thin-slice CT images, along with 3D volume measurements of orbital fat tissue, periorbital muscles, and the optic nerve, were performed. Ophthalmological examination findings and treatment information were collected. The values were compared with those of the contralateral eyes of the same patients not using PGA. Intraclass correlation coefficients (ICCs) were computed to evaluate measurement repeatability. Results: Forty patients were included in the study. Among them, 29 (72.5%) used latanoprost, 9 (22.5%) used bimatoprost, and 2 (5%) used travoprost. The mean enophthalmos values on the treated side (15.5 ± 2.0 mm) were lower than on the untreated side (16.1 ± 1.4 mm), but this difference was not statistically significant (p = 0.07). In 29 patients (72.5%), enophthalmos measurements were smaller on the treated side, with 7 patients (17.5%) showing a difference of 2 mm or more. No significant correlation was found between the duration of PGA use and enophthalmos measurements (p = 0.768 r = −0.048). Additionally, no significant differences were found in orbital fat volume, total extraocular muscle volume, and optic nerve volume (p &gt; 0.05). ICC values demonstrated excellent reliability (ICC &gt; 0.75) for all measurements. Conclusions: We did not find significant differences in enophthalmos measurements, orbital fat volume, total muscle volume, and optic nerve volume between the PGA-treated and untreated eyes.

High serum growth differentiation factor 15 is a risk factor for the occurrence of hepatocellular carcinoma in chronic hepatitisB patients treated with nucleos(t)ide analogs.

Patients with chronic hepatitisB (CHB) remain at risk for hepatocellular carcinoma (HCC) even with nucleos(t)ide analog therapy. We evaluated risk factors for HCC development, including serum hepatitisB virus (HBV) RNA, hepatitis B core-related antigen level, and growth differentiation factor 15 (GDF15) level, a predictor of HCC development in patients with chronic hepatitisC. We collected clinical data and stored serum from CHB patients without a history of HCC who were receiving nucleos(t)ide analog treatment for more than 1year and whose HBV DNA level was less than 3.0 log IU/mL. We measured the serum levels of HBV RNA and GDF15. Among 242 CHB patients, 57 had detectable HBV RNA, and GDF15 was quantified in all patients. The median GDF15 level was 0.86ng/mL. Cox proportional hazards analysis revealed that male sex and higher GDF15, FIB-4 index, alpha-fetoprotein and gamma-glutamyl transpeptidase were independent risk factors for HCC. The presence of HBV RNA above the lower limit of quantification was not a risk factor. When we set cutoff values based on the Youden index, the cumulative incidence of HCC was significantly higher in the male, AFP ≥3.0ng/mL, gamma-glutamyl transpeptidase ≥22U/L, FIB-4 index≥1.93, and GDF-15≥1.17ng/mL groups. In patients with no or more than three of these five risk factors, the 10-year HCC cumulative incidence rates were 0% and 41.0%, respectively. High serum GDF15 is an independent risk factor for the occurrence of HCC in CHB patients treated with nucleos(t)ide analogs.

LAT1 supports mitotic progression through Golgi unlinking in an amino acid transport activity-independent manner

Amino acid transporters play a vital role in cellular homeostasis by maintaining protein synthesis. L-type amino acid transporter 1 (LAT1/SLC7A5/CD98lc) is a major transporter of large neutral amino acids in cancer cells because of its predominant expression. Although amino acid restriction with various amino acid analog treatments is known to induce mitotic defects, the involvement of amino acid transporters in cell division remains unclear. In this study, we identified that LAT1 is responsible for mitotic progression in a transport activity-independent manner. LAT1 knockdown activates the spindle assembly checkpoint, leading to a delay in metaphase. LAT1 maintains proper spindle orientation with confinement of the lateral cortex localization of the NuMA protein, which mediates the pulling force against the mitotic spindle toward the lateral cortex. Unexpectedly, JPH203, an inhibitor of LAT1 amino acid transport activity, does not affect mitotic progression. Moreover, the transport activity-deficient LAT1 mutant maintains the proper spindle orientation and mitotic progression. LAT1 forms a heterodimer with CD98 (SLC3A2/CD98hc) both in interphase and mitosis. Although CD98 knockdown decreases the plasma membrane localization of LAT1, it does not affect mitotic progression. LAT1 is localized to the Golgi and ER not only at the plasma membrane in interphase, and promotes Golgi unlinking during the mitotic entry, leading to centrosome maturation. These results suggest that LAT1 supports mitotic progression in an amino acid transport activity-independent manner and that Golgi-localized LAT1 is important for mitotic progression through the acceleration of Golgi unlinking and centrosome maturation. These findings reveal a novel LAT1 function in mitosis.

MCMVDRP: a multi-channel multi-view deep learning framework for cancer drug response prediction.

Drug therapy remains the primary approach to treating tumours. Variability among cancer patients, including variations in genomic profiles, often results in divergent therapeutic responses to analogous anti-cancer drug treatments within the same cohort of cancer patients. Hence, predicting the drug response by analysing the genomic profile characteristics of individual patients holds significant research importance. With the notable progress in machine learning and deep learning, many effective methods have emerged for predicting drug responses utilizing features from both drugs and cell lines. However, these methods are inadequate in capturing a sufficient number of features inherent to drugs. Consequently, we propose a representational approach for drugs that incorporates three distinct types of features: the molecular graph, the SMILE strings, and the molecular fingerprints. In this study, a novel deep learning model, named MCMVDRP, is introduced for the prediction of cancer drug responses. In our proposed model, an amalgamation of these extracted features is performed, followed by the utilization of fully connected layers to predict the drug response based on the IC50 values. Experimental results demonstrate that the presented model outperforms current state-of-the-art models in performance.