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Review Article Open Access
Zhuoya Sun, Lupeng Qiu, Xiao Zhao, Shunchang Jiao
Published online June 25, 2024
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Oncology Advances. doi:10.14218/OnA.2023.00043
Abstract
The tumor microenvironment is a dynamic cellular landscape critical to cancer progression. Within it, tumor-infiltrating lymphocytes hold a dual role, contributing to both tumor [...] Read more.

The tumor microenvironment is a dynamic cellular landscape critical to cancer progression. Within it, tumor-infiltrating lymphocytes hold a dual role, contributing to both tumor suppression and progression. This review synthesized current knowledge on tumor-infiltrating lymphocytes, emphasizing their prognostic significance and therapeutic potential. By dissecting their interactions within the tumor microenvironment and with cancer cells, we sought to uncover the complexities of the immune response in cancer and explored the future direction of immunotherapeutic strategies.

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Illuminating and Instructive Clinical Case Open Access
Monica Dahiya, Teresa Tai, Trana Hussaini, Gordon Ritchie, Nancy Matic, Eric M. Yoshida, Christopher F. Lowe
Published online December 12, 2024
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Journal of Clinical and Translational Hepatology. doi:10.14218/JCTH.2024.00248
Abstract
Few cases of tenofovir resistance have been reported, and the appropriate treatment for such cases remains unclear. We aimed to share a case of a chronic hepatitis B mono-infected [...] Read more.

Few cases of tenofovir resistance have been reported, and the appropriate treatment for such cases remains unclear. We aimed to share a case of a chronic hepatitis B mono-infected patient with potential tenofovir resistance who required combined lamivudine and tenofovir therapy to achieve adequate viral suppression. The patient’s viral load (plasma) was monitored using the cobas® hepatitis B virus Test on the cobas® 6800 system. Hepatitis B antiviral drug resistance (AVDR) mutations were assessed by amplicon-based sequencing. Plasma was extracted using the MagNa Pure 24 system, and polymerase chain reaction targeting the polymerase gene (860bp) was performed. Sequencing was conducted on GridION R10.4.1 flow cells, and the resulting FASTQ files were analyzed using DeepChek®-HBV Software. We describe a female patient in her 60s with chronic hepatitis B who was e-antigen positive. She met treatment criteria in May 2020, when her alanine transaminase levels were 1.5 times above the upper limit of normal. She was initially started on entecavir but had to switch to tenofovir alafenamide in June 2020 due to a rash. Despite three years of tenofovir therapy, her viral load remained unsuppressed. AVDR testing identified two suspected tenofovir resistance mutations (V191I and A317S). Since no mutations associated with lamivudine resistance were detected, the patient was treated with a combination of lamivudine and tenofovir, achieving viral suppression after four months. Although rare, tenofovir resistance should be considered in patients with persistent viremia despite long-term therapy. AVDR sequencing facilitated the detection of potential tenofovir resistance and guided treatment decisions, leading to successful viral suppression in this case.

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Original Article Open Access
Fengping Wu, Chenrui Liu, Ling He, Yikai Wang, Xin Zhang, Miaoxian Li, Rui Lu, Pei Kang, Mei Li, Yaping Li, Xiaoli Jia, Shuangsuo Dang
Published online December 6, 2024
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Journal of Clinical and Translational Hepatology. doi:10.14218/JCTH.2024.00240
Abstract
T lymphocytes play a pivotal role in resolving hepatitis B virus infection. This study aimed to investigate the dynamics of peripheral blood T lymphocyte subsets during peginterferon [...] Read more.

T lymphocytes play a pivotal role in resolving hepatitis B virus infection. This study aimed to investigate the dynamics of peripheral blood T lymphocyte subsets during peginterferon alpha (peg-IFN-α) therapy and their association with hepatitis B surface antigen (HBsAg) clearance in inactive HBsAg carriers (IHCs).

This prospective observational study enrolled 197 IHCs treated with peg-IFNα-2a/2b for 48 weeks and followed for 24 weeks (treatment group), and 221 IHCs who were regularly monitored for 72 weeks without treatment (IHC control group). Peripheral blood T lymphocyte subsets were evaluated using flow cytometry at baseline, and at 12, 24, 48, and 72 weeks in both groups. At 72 weeks, IHCs in the treatment group were categorized into an HBsAg clearance group and an HBsAg persistence group. Differences in T lymphocyte subsets among these groups were compared, and correlations between T lymphocyte subsets and HBsAg clearance were analyzed.

At 72 weeks, intention-to-treat analysis showed significantly higher HBsAg clearance (46.7%) and seroconversion rates (34.5%) in the treatment group compared to the IHC control group (HBsAg clearance rate of 1.4%, seroconversion rate of 0.9%; both p < 0.001). The median absolute counts of CD3+, CD4+, and CD8+ cells significantly decreased at 12, 24, and 48 weeks in both the HBsAg clearance and persistence groups, returning to baseline at 72 weeks (all p < 0.001). IHCs with HBsAg clearance had higher median percentages of CD3+ CD8+ cells and lower median percentages of CD3+ CD4+ cells and CD4+/CD8+ ratios at 12, 24, and 48 weeks compared to the HBsAg persistence and IHC control groups (all p < 0.001). Baseline HBsAg levels (below 2.0 log10 IU/mL) and hepatitis B virus DNA levels (below 20 IU/mL), alanine aminotransferase elevation at 12 weeks (greater than 2×upper limit of normal), and CD4+/CD8+ ratios (less than 1.5 at 12 weeks and below 1.4 at 24 weeks) were predictive of HBsAg clearance.

Peripheral blood CD4+/CD8+ ratios at 12 and 24 weeks may serve as predictive markers for HBsAg clearance in IHCs treated with peg-IFN-α.

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Original Article Open Access
Jeremiah Onubi, Oluwagbenga Adebayo Adeola, Patricia Eseigbe, Adesegun Elisha, Grace O Sheyin, Anyuku A George Chima
Published online September 6, 2024
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Exploratory Research and Hypothesis in Medicine. doi:10.14218/ERHM.2024.00018
Abstract
Depression can lead to poor outcomes during antiretroviral therapy, and current evidence suggests high rates of depression among people living with human immunodeficiency virus [...] Read more.

Depression can lead to poor outcomes during antiretroviral therapy, and current evidence suggests high rates of depression among people living with human immunodeficiency virus (PLHIV), especially in low-and middle-income countries. This study was designed to investigate the sociodemographic factors associated with depression among PLHIV on antiretroviral therapy in a Nigerian cosmopolitan city.

A hospital-based, cross-sectional study was conducted among 592 consenting, randomly selected adult PLHIV receiving treatment at a university teaching hospital in Jos, Nigeria, in 2022, using the PHQ-9 questionnaire and an interviewer-administered sociodemographic questionnaire. Associated variables in univariate analysis were used in multivariable binary logistic regression to obtain adjusted odds ratios (AOR) with a significance level set at α = 0.05.

Depression was found to be highly prevalent among study participants, with 44.9% of them affected. Findings revealed that being male [AOR = 0.62; 95% confidence interval (CI): 0.42–0.92], being employed (AOR = 0.55; 95%CI: 0.31–0.97), and earning a monthly income of ₦50,000–100,000 ($65–130) (AOR = 0.49; 95% CI: 0.27–0.91) and >₦100,000–200,000(>$130–260) (AOR = 0.33; 95% CI: 0.13–0.77) were significantly associated with reduced odds of depression.

The significant association of being male, having formal employment, and earning a moderate monthly income with reduced odds of depression may have implications for policy and strategies for managing mental health issues among PLHIV in cosmopolitan areas like Jos, which face peculiar challenges such as cultural tensions, traffic congestion, and gentrification. PLHIV categories with a relatively higher likelihood of depression may benefit from targeted mental health support systems, in addition to other mental health management strategies generally available to PLHIV.

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Mini Review Open Access
Fernando Bessone, Geraldine L. Hillotte, Norberto Tamagnone, Daiana Arnedillo, Marcelo G. Roma
Published online January 21, 2025
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Journal of Clinical and Translational Hepatology. doi:10.14218/JCTH.2024.00325
Abstract
Drug-induced liver injury (DILI) is a harmful reaction to medications, herbs, and dietary supplements that results in liver dysfunction. Based on the distinct clinical patterns [...] Read more.

Drug-induced liver injury (DILI) is a harmful reaction to medications, herbs, and dietary supplements that results in liver dysfunction. Based on the distinct clinical patterns of liver damage, DILI can be categorized into hepatocellular, cholestatic, and mixed types. Hepatocellular DILI is linked to inflammation, apoptosis, and necrosis, while cholestatic DILI is commonly associated with bile plugs and, in rare cases, ductopenia. Ursodeoxycholic acid (UDCA) is the therapeutic agent most widely used for the treatment of cholestatic hepatopathies of diverse etiologies and has been mainly used as a supportive treatment in cholestatic DILI. In this review, we presented a more structured and systematic framework for the potential application of this hepatoprotective agent across a broader range of DILI scenarios. A MEDLINE search of the literature from 1995 to the present retrieved 41 preliminary clinical studies suggesting that UDCA may offer curative and preventive benefits for hepatocellular DILI as well. This aligns with preclinical studies in rodents, showing beneficial effects of UDCA in experimental DILI irrespective of the clinical patterns of injury involved. This could be due to the broad range of potentially beneficial effects of UDCA, which may address the various types of liver damage with different causes and mechanisms seen in all forms of DILI. UDCA’s beneficial properties include anticholestatic, antioxidant, anti-inflammatory, anti-apoptotic, anti-necrotic, mitochondrial protective, endoplasmic reticulum stress-relieving, and immunomodulatory effects. Controlled studies with systematic use of standardized causality assessments are eagerly awaited to properly validate the use of UDCA in DILI. Meanwhile, we hope this article helps clarify and systematize the use of this versatile and safe hepatoprotective medication for different types of liver toxicity.

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Original Article Open Access
Juan Deng, Kai Ding, Shuqing Liu, Fei Chen, Ru Huang, Bonan Xu, Xin Zhang, Weifen Xie
Published online December 20, 2024
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Journal of Clinical and Translational Hepatology. doi:10.14218/JCTH.2024.00197
Abstract
The transcription factor sex-determining region Y-related high-mobility group-box gene 9 (SOX9) plays a critical role in organ development. Although SOX9 has been implicated in [...] Read more.

The transcription factor sex-determining region Y-related high-mobility group-box gene 9 (SOX9) plays a critical role in organ development. Although SOX9 has been implicated in regulating lipid metabolism in vitro, its specific role in metabolic dysfunction-associated steatohepatitis (MASH) remains poorly understood. This study aimed to investigate the role of SOX9 in MASH pathogenesis and explored the underlying mechanisms.

MASH models were established using mice fed either a methionine- and choline-deficient (MCD) diet or a high-fat, high-fructose diet. To evaluate the effects of SOX9, hepatocyte-specific SOX9 deletion or overexpression was performed. Lipidomic analyses were conducted to assess how SOX9 influences hepatic lipid metabolism. RNA sequencing was employed to identify pathways modulated by SOX9 during MASH progression. To elucidate the mechanism further, HepG2 cells were treated with an adenosine monophosphate-activated protein kinase (AMPK) inhibitor to test whether SOX9 acts via AMPK activation.

SOX9 expression was significantly elevated in hepatocytes of MASH mice. Hepatocyte-specific SOX9 deletion exacerbated MCD-induced MASH, whereas overexpression of SOX9 mitigated high-fat, high-fructose-induced MASH. Lipidomic and RNA sequencing analyses revealed that SOX9 suppresses the expression of genes associated with lipid metabolism, inflammation, and fibrosis in MCD-fed mice. Furthermore, SOX9 deletion inhibited AMPK pathway activation, while SOX9 overexpression enhanced it. Notably, administration of an AMPK inhibitor negated the protective effects of SOX9 overexpression, leading to increased lipid accumulation in HepG2 cells.

Our findings demonstrate that SOX9 overexpression alleviates hepatic lipid accumulation in MASH by activating the AMPK pathway. These results highlight SOX9 as a promising therapeutic target for treating MASH.

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Original Article Open Access
Alshymaa A. Hassnine, Yasser Fouad, Zienab M. Saad, Alaa M. Mostafa, Hend M. Moness, Nehal I. Abbas, Nasr M. Osman, Wafaa Abdelghany
Published online May 29, 2024
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Gene Expression. doi:10.14218/GE.2023.00047
Abstract
Metabolic-associated fatty liver disease (MAFLD) may increase the risk of cardiovascular events. In this study, we assessed the predictive value of pentraxin 3 (PTX3) for severe [...] Read more.

Metabolic-associated fatty liver disease (MAFLD) may increase the risk of cardiovascular events. In this study, we assessed the predictive value of pentraxin 3 (PTX3) for severe fibrosis and carotid intima-media thickness (CIMT) in patients with MAFLD.

188 patients (114 with MAFLD, 74 with dual etiology MAFLD and chronic hepatitis C) were included. All participants underwent clinical history and examination, metabolic parameter assessment, serum level evaluation of PTX3, Fibrosis-4 index and nafld fibrosis score scores, abdominal ultrasound, and CIMT assessment.

The serum PTX3 was significantly elevated in patients with advanced fibrosis compared to those with mild/moderate fibrosis (1.8 vs 1.4, p = 0.006). The PTX3 level was independently associated with advanced fibrosis (odds ratio = 1.26, 95% confidence interval 1.008–1.040). In MAFLD patients, the PTX3 levels in patients with low fibrosis compared to those with advanced fibrosis were 1.4 (1–2.1) and 1.9 (1.3–3.8), respectively (p = 0.027). A significantly greater CIMT was noted in patients with elevated PTX3 levels (3.85 (3.42–4) vs 4.05 (3.7–4.67), p = 0.0001) compared to those with low PTX3 levels.

Serum PTX3 levels can accurately predict advanced fibrosis and CIMT in MAFLD patients. Thus, it could be useful for management and risk stratification.

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Case Series Open Access
Kenji Miki, Masayoshi Yamanishi, Satoko Mibayashi, Shinsaku Imashuku
Published online May 14, 2024
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Journal of Clinical and Translational Pathology. doi:10.14218/JCTP.2023.00064
Abstract
Disseminated carcinomatosis of bone marrow (DCBM) occurs mostly in stomach cancer patients; however, characterizing tumor cells morphologically and phenotypically in the bone marrow [...] Read more.

Disseminated carcinomatosis of bone marrow (DCBM) occurs mostly in stomach cancer patients; however, characterizing tumor cells morphologically and phenotypically in the bone marrow is not an easy task. In addition, among patients with DCBM, an unknown primary site (CUPS) is rarely noted despite standard clinical evaluation, imaging studies, and endoscopic findings. This study aimed to clarify the diagnosis/outcome of DCBM in elderly patients we have treated.

Here, we report eight DCBM cases. Once tumor clumps were noted in the bone marrow, we performed serum tumor markers, immunostaining of tumor cells in the bone marrow clot, or biopsy preparations. In addition, imaging studies (CT/MRI/ FDG PET-CT) were performed.

Of eight cases, two were diagnosed with DCBM/CUPS. Among the eight cases, six fatal cases had a median survival time of 2 months (ranging from <0.5 to 8 months) from DCBM detection to death or the time of this writing, while the CUPS cases were still alive at 2+ and 3+ months, respectively. The outcomes of DCBM and DCBM/CUPS, particularly in elderly patients, were dismal, and comprehensive genomic profiling could not be perform in these cases.

The use of conventional morphological/phenotypical characteristics to improve the prognosis of DCBM patients is limited. Consequently, the application of comprehensive genomic profiling is recommended to enhance diagnostic and therapeutic approaches.

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Short Communication Open Access
Majed Saeed Nassar, Sayed Wajid, Nawal Alkatheeri, Ibrahim A. Wasfi
Published online August 20, 2024
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Journal of Exploratory Research in Pharmacology. doi:10.14218/JERP.2023.00013S
Abstract
Camels are commonly administered butylscopolamine (BSA), an antimuscarinic quaternary ammonium derivative, to reduce spasms in the smooth muscles of their urinary and gastrointestinal [...] Read more.

Camels are commonly administered butylscopolamine (BSA), an antimuscarinic quaternary ammonium derivative, to reduce spasms in the smooth muscles of their urinary and gastrointestinal tracts. However, its presence in body fluids after racing is prohibited by animal racing authorities. The current study aimed to conduct a pilot pharmacokinetic study of BSA in healthy camels. The goal was to obtain initial pharmacokinetic parameters and use these parameters to predict plasma concentrations from the dose and clearance. This will help advise on a withdrawal time for BSA administration before camel racing. The pharmacokinetics of BSA were evaluated in three healthy camels after a single intravenous dose of 0.2 mg/kg body weight. Sensitive liquid chromatography with tandem mass spectrometry was used for the quantification of BSA and the internal standard, ipratropium, in plasma. BSA concentration versus time data were best described by a two-compartment open model. The pharmacokinetic parameters (median and range) were as follows: terminal elimination half-life was 2.29 (1.48–2.46) h, plasma clearance was 1,018.5 (772.4–1,024.0) mL/h/kg, volume of distribution at steady state was 931.9 (700.0–1,068.7) mL/kg, Cmax was 443.9 (351.1–443.9) ng/mL, and Tmax was 0.5 (0.25–0.75) h. BSA’s irrelevant plasma concentration was estimated to be 20 ng/mL. Consequently, it can be concluded that plasma would not contain BSA at the screening level of 20 ng/mL at the usual dose of 0.2 mg/kg body weight 24 h before camel racing.

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Letter to the Editor Open Access
David Yardeni, Asif Hitawala, Lilian Howard, Theo Heller, Meryl Waldman
Published online July 19, 2024
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Journal of Clinical and Translational Hepatology. doi:10.14218/JCTH.2024.00169
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