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Purpose To evaluate the cumulative radiobiological impact of daily megavoltage cone‐beam computed tomography (MV‐CBCT) imaging dose based on normal tissue complication probability (NTCP) and excess absolute risk (EAR) of secondary malignancies among radiotherapy patients treated for breast, pelvic, and head & neck cancers. This study investigated whether MV‐CBCT imaging dose warrants protocol personalization according to patient age, anatomical treatment site, and organ‐specific radiosensitivity. Methods This retrospective study included cohorts of breast (n = 30), pelvic (n = 17), and head & neck (n = 20) cancer patients undergoing radiotherapy with daily MV‐CBCT. Imaging dose distributions employing two common MV‐CBCT protocols (5 and 10 MU per fraction) were analyzed. NTCP values were estimated using logistic models, while EAR were calculated using Schneider's organ equivalent dose (OED)‐based model, integrating organ‐specific dose, patient age, and established tissue‐specific risk coefficients. Comparative statistical analyses were conducted using paired t‐tests, and results were further stratified by patient age (< 40, 40–60, > 60 years). Results In breast cancer patients, NTCP values increased significantly for lung tissue when comparing the 10 MU protocol to the 5 MU one (p < 0.001), while those for heart and breast tissues showed minimal and insignificant differences. EAR estimations revealed substantial risk increases among younger breast cancer patients (< 40 years), with some exceeding 15 cases per 10 000 person‐years under the 10 MU protocol. Conversely, pelvic and head & neck cohorts demonstrated consistently low NTCP and EAR values (< 1%), with no meaningful differences observed between the two imaging protocols. Across all cancer sites, younger age consistently correlated with higher secondary cancer risks. Conclusion Routine daily MV‐CBCT imaging at the 10 MU protocol possesses minimal additional risk in pelvic and head & neck radiotherapy. However, among breast cancer patients, particularly those under 40 years, the 10 MU protocol significantly elevates the theoretical secondary cancer risk estimates and lung NTCP. These findings support transitioning from conventional uniform imaging approach toward personalized MV‐CBCT protocols, tailored according to patient age, anatomical site, and organ radiosensitivity. A stratified imaging framework is proposed to optimize clinical outcomes, balancing treatment accuracy, and long‐term patient safety.

The sodium taurocholate co-transporting polypeptide (NTCP), a bile acids transporter, has been identified as a new therapeutic target for the treatment of liver disease. This paper thoroughly investigates the function of NTCP for regulating bile acid regulation, its correlation with hepatitis B and D infections, and its association with various liver diseases. Additionally, in this review we examine recent breakthroughs in creating NTCP inhibitors and their prospective applications in liver disease treatment. While this review emphasizes the promising potential of targeting NTCP, it concurrently underscores the need for broader and more detailed research to fully understand the long-term implications and potential side effects associated with NTCP inhibition. [Display omitted] •The pathogenesis of various liver diseases is associated with NTCP.•Newly identified lead compounds and promising clinical trials for liver diseases associated with NTCP have emerged.•NTCP will become a promising new target in the therapeutic approach to liver disease.

Sodium taurocholate cotransporting polypeptide (NTCP) is a host cell receptor required for hepatitis B virus (HBV) entry. However, the susceptibility of NTCP-expressing cells to HBV is diverse depending on the culture condition. Stimulation with epidermal growth factor (EGF) was found to potentiate cell susceptibility to HBV infection. Here, we show that EGF receptor (EGFR) plays a critical role in HBV virion internalization. In EGFR-knockdown cells, HBV or its preS1-specific fluorescence peptide attached to the cell surface, but its internalization was attenuated. PreS1 internalization and HBV infection could be rescued by complementation with functional EGFR. Interestingly, the HBV/preS1–NTCP complex at the cell surface was internalized concomitant with the endocytotic relocalization of EGFR. Molecular interaction between NTCP and EGFR was documented by immunoprecipitation assay. Upon dissociation from functional EGFR, NTCP no longer functioned to support viral infection, as demonstrated by either (i) the introduction of NTCP pointmutation that disrupted its interaction with EGFR, (ii) the detrimental effect of decoy peptide interrupting the NTCP–EGFR interaction, or (iii) the pharmacological inactivation of EGFR. Together, these data support the crucial role of EGFR in mediating HBV–NTCP internalization into susceptible cells. EGFR thus provides a yet unidentified missing link from the cell-surface HBV–NTCP attachment to the viral invasion beyond the host cell membrane

Current anti-hepatitis B virus (HBV) drugs are suppressive but not curative for HBV infection, so there is considerable demand for the development of new anti-HBV agents. In this study, we found that fungus-derived exophillic acid inhibits HBV infection with a 50% maximal inhibitory concentration (IC50) of 1.1 µM and a 50% cytotoxic concentration (CC50) of >30 µM in primary human hepatocytes. Exophillic acid inhibited preS1-mediated viral attachment to cells but did not affect intracellular HBV replication. Exophillic acid appears to target the host cells to reduce their susceptibility to viral attachment rather than acting on the viral particles. We found that exophillic acid interacted with the HBV receptor, sodium taurocholate cotransporting polypeptide (NTCP). Exophillic acid impaired the uptake of bile acid, the original function of NTCP. Consistent with our hypothesis that it affects NTCP, exophillic acid inhibited infection with HBV and hepatitis D virus (HDV), but not that of hepatitis C virus. Moreover, exophillic acid showed a pan-genotypic anti-HBV effect. We thus identified the anti-HBV/HDV activity of exophillic acid and revealed its mode of action. Exophillic acid is expected to be a potential new lead compound for the development of antiviral agents.

Bile acids (BAs) are important steroidal molecules with a rapidly growing span of applications across a variety of fields such as supramolecular chemistry, pharmacy, and biomedicine. This work provides a systematic review on their transport processes within the enterohepatic circulation and related processes. The focus is laid on the description of specific or less-specific BA transport proteins and their localization. Initially, the reader is provided with essential information about BAs′ properties, their systemic flow, metabolism, and functions. Later, the transport processes are described in detail and schematically illustrated, moving step by step from the liver via bile ducts to the gallbladder, small intestine, and colon; this description is accompanied by descriptions of major proteins known to be involved in BA transport. Spillage of BAs into systemic circulation and urine excretion are also discussed. Finally, the review also points out some of the less-studied areas of the enterohepatic circulation, which can be crucial for the development of BA-related drugs, prodrugs, and drug carrier systems.

Sodium taurocholate cotransporting polypeptide (NTCP, SLC10A1) is a hepatocyte receptor for hepatitis B virus (HBV) infection. The natural NTCP S267F variant causes loss of NTCP HBV receptor function. We assessed the association of S267F with HBV resistance, HBV infection clearance, and HBV-related cirrhosis and hepatocellular carcinoma (HCC). We tested the effects of S267F in 1117 Han Chinese patients with various HBV infection outcomes using multivariate logistic regression analysis. The frequency of S267F (T allele) was higher in HBV-resistant healthy controls (n = 179, 4.0%) compared to HBV-infected patients (n = 648, 1.5%); odds ratio (OR) 0.32 (95% confidence interval [CI] 0.15-0.68; P = .003; dominant model). 267F variant genotypes were also associated with reduced risk for cirrhosis (n = 192, 0.5%) and HCC (n = 258, 1.0%) compared to those with chronic HBV infection (n = 202, 3.0%); OR 0.15 (95% CI, 0.03-0.70) and OR 0.21 (95% CI, 0.062-0.72), respectively. There was no association of the S267F variant with spontaneous HBV clearance. The S267F variant for the HBV cell-entry receptor NTCP was associated with increased resistance to HBV infection and decreased risk for cirrhosis and liver cancer among those with chronic HBV infection.

Abstract Background We investigated the patterns and predictors for virological relapse (VR), clinical relapse (CR), and sustained clinical response (SCR) and the outcomes of retreatment after nucleos(t)ide analogue (NUC) therapy discontinuation. Methods Patients with chronic hepatitis B who were discontinuing NUC therapy were prospectively enrolled. Viral and host predictors of relapse were evaluated, including hepatitis B virus (HBV) surface antigen (HBsAg) level, anti–HBV core antibody level, and presence of single-nucleotide polymorphisms in the genes encoding the receptors NTCP (rs2296651) and CTLA4 (rs231775) and in the 3′ untranslated regions of the genes encoding HLA-DPA1 (rs3077) and HLA-DPB1 (rs9277535); posttherapy predictors of relapse were also investigated. Information about NUC retreatment and outcomes were recorded. Results Overall, 100 patients discontinuing 3-year entecavir (ETV) or tenofovir (TDF) therapy were enrolled. Patients discontinuing TDF exhibited significantly higher rates of VR (52.9% vs 6.1%; P < .001) and CR (15.2% vs. 1.5%, P = .007) at 3 months than those discontinuing ETV, but relapse rates at 12 months were comparable. The end-of-therapy HBsAg levels predicted VR (hazard ratio [HR], 1.62; 95% confidence interval [CI], 1.19–2.21), CR (HR, 1.78; 95% CI, 1.13–2.81), and SCR (OR, 0.57; 95% CI, .35–.94). The CTLA4 (rs231775) non-GG genotype predicted VR (HR, 1.74; 95% CI, 1.01–3.00) and CR (HR, 2.06; 95% CI, 1.04–4.11), while the HLA-DPA1 (rs3077) AA genotype predicted SCR (OR, 10.84; 95% CI, 1.12–105). The HBV DNA 1 month after NUC treatment cessation was an early predictor of subsequent relapse. Conclusions Discontinuation of tenofovir disoproxil fumarate treatment rather than entecavir treatment is associated with earlier relapse, and NUC-specific posttherapy monitoring is necessary. Tenofovir disoproxil fumarate treatment discontinuation is associated with a significantly earlier relapse, compared with discontinuation of entecavir treatment. A low end-of-therapy hepatitis B virus (HBV) surface antigen level predicts a reduced risk of relapse, and the HBV DNA level 1 month after therapy discontinuation serves as an early predictor of relapse.

Radiobiological indices can provide insights into treatment efficacy beyond traditional physical dose metrics and potentially facilitate the comparison between various radiotherapy plans. This study investigates the integration of radiobiological indices with standard physical dose criteria to improve high-dose-rate (HDR) brachytherapy plan evaluation and selection process for the treatment of prostate cancers in a multicriteria optimization (MCO) framework. This is accomplished within the framework of a graphics processing unit-based multicriteria optimization algorithm, gMCO. 2000 Pareto-optimal plans for 200 patients were optimized for a 15 Gy HDR brachytherapy boost after external beam radiation therapy (44 Gy in 22 fractions). Tumour control probability (TCP), normal tissue complication probability (NTCP), and uncomplicated tumour control probability (UTCP) were calculated for each plan. Maximizing UTCP alone resulted in insufficient target coverage (target$$V_{100} < 90\\%$$) according to clinical guidelines. Conversely, maximizing target coverage while meeting institutional criteria compromised UTCP significantly (reduction of about 0.09). Selecting plans that met all institutional criteria first, then maximizing UTCP, achieved a balanced compromise between tumour control and normal tissue safety. While combining UTCP and standard dose metrics based on dose-volume histogram (i.e., absorbed dose or physical dose constraints) with MCO can enhance brachytherapy plan optimization, exclusive reliance on standard TCP and NTCP models, using recommended parameters, yields clinically unacceptable plans.

A novel analytical approach for the targeted profiling of bile acids (BAs) in human serum/plasma based on liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) is presented. Reversed-phase chromatography enabled the baseline separation of 15 human BA species which could be readily detected by accurate mass analysis in negative ion mode. Blood proteins were removed by methanol precipitation in the presence of deuterium-labeled internal standards which allowed BA quantification in 50 μl plasma/serum. The assay was validated according to FDA guidance achieving quantification limits from 7.8 to 156 nM. Calibration curves prepared in charcoal-stripped serum/plasma showed excellent regression coefficients (R ² > 0.997) and covered quantities from 7.8 to 10,000 nM depending on the analyzed species. Intra- and inter-day accuracy and precision were below 15 % for all analytes. Apparent extraction recoveries were above 97 %, and ion suppression rates were between 4 and 53 %. Mean BA level in serum/plasma from healthy volunteers ranged from 11 ± 4 nM (tauroursodeoxycholic acid) to 1321 ± 1442 nM (glycochenodeoxycholic acid). As a proof of concept, the assay was applied to plasma samples derived from a clinical phase I study of myrcludex B, a novel first-in-class virus entry inhibitor for the treatment of chronic hepatitis B and D. The results demonstrate that myrcludex-induced inhibition of the hepatic BA transporter Na⁺-taurocholate cotransporting polypeptide (NTCP) significantly affects plasma BA level. These observations provide novel insights into drug-induced metabolic responses and will be indispensable for the assessment of side effects and dose-finding processes during future clinical trials.

The SLC10A transporter gene family consists of seven members and substrates transported by three members ( SLC10A1 , SLC10A2 and SLC10A6 ) are Na + -dependent. SLC10A1 (sodium taurocholate cotransporting polypeptide [NTCP]) and SLC10A2 (apical sodium-dependent bile salt transporter [ASBT]) transport bile salts and play an important role in maintaining enterohepatic circulation of bile salts. Solutes other than bile salts are also transported by NTCP. However, ASBT has not been shown to be a transporter for non-bile salt substrates. While the transport function of NTCP can potentially be used as liver function test, interpretation of such a test may be complicated by altered expression of NTCP in diseases and presence of drugs that may inhibit NTCP function. Transport of bile salts by NTCP and ASBT is inhibited by a number of drugs and it appears that ASBT is more permissive to drug inhibition than NTCP. The clinical significance of this inhibition in drug disposition and drug–drug interaction remains to be determined. Both NCTP and ASBT undergo post-translational regulations that involve phosphorylation/dephosphorylation, translocation to and retrieval from the plasma membrane and degradation by the ubiquitin–proteasome system. These posttranslational regulations are mediated via signaling pathways involving cAMP, calcium, nitric oxide, phosphoinositide-3-kinase (PI3K), protein kinase C (PKC) and protein phosphatases. There appears to be species difference in the substrate specificity and the regulation of plasma membrane localization of human and rodent NTCP. These differences should be taken into account when extrapolating rodent data for human clinical relevance and developing novel therapies. NTCP has recently been shown to play an important role in HBV and HDV infection by serving as a receptor for entry of these viruses into hepatocytes.