Prediction of Clinical Trajectory in HCV-Related ACLD after SVR: Role of Liver Stiffness in a 5-Years Prospective Study.

The prediction of liver-related events (LRE) after sustained virological response (SVR) in HCV-advanced chronic liver disease (ACLD) patients is crucial. We aimed to evaluate incidence and risk factors of LRE in HCV-cirrhotic patients after SVR and to assess dynamic changes of liver stiffness in participants without LRE at the end of follow-up. We enrolled 575 consecutive patients with HCV-ACLD treated with DAAs and followed up for 5 years after SVR12. Overall, 98 (17%) patients developed any type of event, and HCC was the most frequent LRE. The incidence rate was 1.6 per 100 person-years (p/y) for both HCC and hepatic decompensation. Baseline LSM ≥ 20 kPa was the only independent predictor of hepatic decompensation, while LSM ≥ 20 kPa and male sex were independent predictors of HCC development. Among the 341 participants without LRE and with paired LSM, any LSM reduction was observed in 314 (92.1%), and half of them showed a decrease of LSM ≥ 20%. Among patients without LRE, 27.3% of participants without ≥20% LSM decrease at 2 years achieved the 5-year goal; in contrast, 31.6% of participants with ≥20% LSM decrease at 2 years lost it at 5 years. These findings provide evidence that baseline LSM is a tool to stratify patients at risk of developing LRE; the dynamic changes of LSM value suggest the need for monitoring this parameter over time.

Multiparametric liver assessment in patients successfully treated for hepatitis C: a 4-year follow-up.

BACKGROUND: Hepatitis C virus (HCV) is a major cause of chronic liver disease, in which liver stiffness increases. Liver stiffness measurements (LSM) are therefore essential in diagnosing liver diseases and predicting disease development. The study objective was to perform a comprehensive prospective assessment of the liver before, after and 4 years after treatment for HCV, including an assessment of the long-term outcome of fibrosis, steatosis and inflammation. METHODS AND FINDINGS: Patients eligible for HCV treatment were included prospectively in 2018 (n = 47). Liver stiffness was measured using transient elastography and 2D shear-wave elastography (SWE). Blood tests, B-mode ultrasound (US) and SWE, were performed before, after (end of treatment [EOT]), 3 months after (EOT3) and 4 years after treatment (4Y). At the final visit, we added attenuation imaging and shear-wave dispersion slope (SWDS) measurements to assess steatosis and inflammation. Three months after treatment, the sustained virologic response rate was 93%. The median liver stiffness for baseline, EOT, EOT3 and 4Y was 8.1, 5.9, 5.6 and 6.3 kPa, respectively. There was a significant reduction in liver stiffness from baseline to EOT, and from EOT to EOT3. After 4 years, the mean attenuation coefficient (AC) was 0.58 dB/cm/MHz, and the mean SWDS value was 14.3 (m/s)/kHz. CONCLUSION: The treatment for HCV was highly effective. Measurements of liver stiffness decreased significantly after treatment and remained low after 4 years. AC measurements indicated low levels of liver steatosis. Shear-wave dispersion values indicated inflammation of the liver, but the clinical implication is undetermined and should be explored in larger studies.Clinicaltrials.gov: NCT03434470. ABBREVIATIONS: AC: attenuation coefficient; APRI: aspartate aminotransferase to platelet ratio index; ATI: attenuation imaging; cACLD: compensated advanced chronic liver disease; CAP: controlled attenuation parameter; FIB-4: Fibrosis-4 Index for liver fibrosis; HCC: hepatocellular carcinoma; LSM: liver stiffness measurement; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; SWDS: shear-wave dispersion slope; SWE: shear-wave elastography; US: ultrasound.

RNA-binding protein LSM7 facilitates breast cancer metastasis through mediating alternative splicing of CD44.

AIMS: The RNA-binding protein LSM7 is essential for RNA splicing, acting as a key component of the spliceosome complex; however, its specific role in breast cancer (BC) has not been extensively investigated. MATERIALS AND METHODS: LSM7 expression in BC samples was evaluated through bioinformatics analysis and immunohistochemistry. The impact of LSM7 on promoting metastatic tumor characteristics was examined using transwell and wound healing assays, as well as an orthotopic xenograft model. Additionally, the involvement of LSM7 in alternative splicing of CD44 was explored via RNA immunoprecipitation and third-generation sequencing. The regulatory role of TCF3 in modulating LSM7 gene expression was further elucidated using luciferase reporter assays and chromatin immunoprecipitation. KEY FINDINGS: Our findings demonstrate that LSM7 was significantly overexpressed in metastatic BC tissues and was associated with poor prognostic outcomes in patients with BC. LSM7 overexpression markedly increased the migratory and invasive capabilities of BC cells in vitro and significantly promoted spontaneous lung metastasis in vivo. Furthermore, RIP-seq analysis revealed that LSM7 binded to CD44 RNA, enhancing the expression of its alternatively spliced isoform CD44s, thereby driving BC metastasis and invasion. Additionally, the transcription factor TCF3 was found to activate LSM7 transcription by directly binding to its promoter. SIGNIFICANCE: In summary, this study highlights the pivotal role of LSM7 in the production of the CD44s isoform and the promotion of breast cancer metastasis. Targeting the TCF3/LSM7/CD44s axis may offer a promising therapeutic strategy for breast cancer treatment.

Specific metabolic impairments indicate loss of sustained liver improvements in metabolic dysfunction-associated steatotic liver disease treatment.

Background: High liver fat content (LFC) induces increased risks of both hepatic and extrahepatic progression in metabolic dysfunction-associated steatotic liver disease (MASLD), while maintaining a significant decline in magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) (≥30% decline relative to baseline) without worsening fibrosis results in improved histological severity and prognosis. However, the factors associated with the loss of sustained responses to treatment remain unclear, and we aim to identify them. Methods: Consecutive treatment-naïve MASLD patients between January 2015 and February 2022, with follow-up until April 2023, were included in this prospective cohort study. LFC quantified by MRI-PDFF and liver stiffness measurements (LSM) determined by two-dimensional shear wave elastography (2D-SWE) were evaluated at weeks 0, 24 and 48. MRI-PDFF response was defined as a ≥30% relative decline in PDFF values, and LSM response was defined as a ≥1 stage decline from baseline. Results: A total of 602 MASLD patients were enrolled. Of the 303 patients with a 24-week MRI-PDFF response and complete follow-up of 48 weeks, the rate of loss of MRI-PDFF response was 29.4%, and multivariable logistic regression analyses showed that 24-week insulin resistance (IR), still regular exercise and caloric restriction after 24 weeks, and the relative decline in LFC were risk factors for loss of MRI-PDFF response. Loss of LSM response at 48 weeks occurred in 15.9% of patients, and multivariable analysis confirmed 24-week serum total bile acid (TBA) levels and the relative decline in TBA from baseline as independent predictors. No significant association was found at 48 weeks between loss of MRI-PDFF response and loss of LSM response. Conclusions: MASLD patients with IR and high TBA levels are at higher risks of subsequent diminished sustained improvements of steatosis and fibrosis, respectively.

Increases and decreases in liver stiffness measurement are independently associated with the risk of liver-related events in NAFLD.

BACKGROUND & AIMS: The clinical significance of change in liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) in patients with non-alcoholic fatty liver disease (NAFLD) is not well-understood. We prospectively defined rates of progression to and regression from LSM-defined compensated advanced chronic liver disease (cACLD) and their associations with liver-related events (LREs). METHODS: Participants in the NASH Clinical Research Network-led NAFLD Database 2 and 3 studies were included. Progression to cACLD was defined as reaching LSM ≥10 kPa in participants with LSM <10 kPa on initial VCTE; regression from cACLD was defined as reaching LSM <10 kPa in participants with baseline LSM ≥10 kPa. LREs were defined as liver-related death, liver transplant, hepatocellular carcinoma, MELD >15, development of varices, or hepatic decompensation. Univariate and multivariable interval-censored Cox regression analyses were used to compare the cumulative LRE probability by LSM progression and regression status. RESULTS: In 1,403 participants, 89 LREs developed over a mean follow-up of 4.4 years, with an annual incidence rate for LREs of 1.5 (95% CI 1.2-1.8). In participants at risk, progression to LSM ≥10 or ≥15 kPa occurred in 29% and 17%, respectively, whereas regression to LSM <10 or <15 kPa occurred in 44% and 49%, respectively. Progressors to cACLD (≥10 kPa) experienced a higher cumulative LRE rate vs. non-progressors (16% vs. 4%, adjusted hazard ratio 4.0; 95% (1.8-8.9); p <0.01). Regressors from cACLD (to LSM <10 kPa) experienced a lower LRE rate than non-regressors (7% vs. 32%, adjusted hazard ratio 0.25; 95% CI 0.10-0.61; p <0.01). CONCLUSIONS: Change in LSM over time is independently and bi-directionally associated with risk of LRE and is a non-invasive surrogate for clinical outcomes in patients with NAFLD. IMPACT AND IMPLICATIONS: The prognostic value of change in LSM in patients with NAFLD is not well understood. In this large prospective study of patients with NAFLD and serial vibration-controlled transient elastography exams, baseline and dynamic changes in LSM were associated with the risk of developing liver-related events. LSM is a useful non-invasive surrogate of clinical outcomes in patients with NAFLD.

Correlation of Leptin in Patients With Type 2 Diabetes Mellitus.

The exponential increase in diabetes mellitus (DM) poses serious public health concerns. In this review, we focus on the role of leptin in type 2 DM. The peripheral actions of leptin consist of upregulating proinflammatory cytokines which play an important role in the pathogenesis of type 2 DM and insulin resistance. Moreover, leptin is known to inhibit insulin secretion and plays a significant role in insulin resistance in obesity and type 2 DM. A literature search was conducted on Medline, Cochrane, Embase, and Google Scholar for relevant articles published until December 2023. The following search strings and Medical Subject Headings (MeSH terms) were used: "Diabetes Mellitus," "Leptin," "NPY," and "Biomarker." This article aims to discuss the physiology of leptin in type 2 DM, its glucoregulatory actions, its relationship with appetite, the impact that various lifestyle modifications can have on leptin levels, and, finally, explore leptin as a potential target for various treatment strategies.

Diagnostic accuracy of non-invasive tests to screen for at-risk MASH-An individual participant data meta-analysis.

BACKGROUND & AIMS: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions. METHODS: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported. RESULTS: We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%. CONCLUSIONS: Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations.

The Significance of Xylem Structure and Its Chemical Components in Certain Olive Tree Genotypes with Tolerance to Xylella fastidiosa Infection.

Olive quick decline syndrome (OQDS) is a devastating plant disease caused by the bacterium Xylella fastidiosa (Xf). Exploratory missions in the Salento area led to the identification of putatively Xf-resistant olive trees (putatively resistant plants, PRPs) which were pauci-symptomatic or asymptomatic infected plants belonging to different genetic clusters in orchards severely affected by OQDS. To investigate the defense strategies employed by these PRPs to contrast Xf infection, the PRPs were analyzed for the anatomy and histology of xylem vessels, patterns of Xf distribution in host tissues (by the fluorescent in situ hybridization technique-FISH) and the presence of secondary metabolites in stems. The xylem vessels of the PRPs have an average diameter significantly lower than that of susceptible plants for each annual tree ring studied. The histochemical staining of xylem vessels highlighted an increase in the lignin in the parenchyma cells of the medullary rays of the wood. The 3D images obtained from FISH-LSM (laser scanning microscope) revealed that, in the PRPs, Xf cells mostly appeared as individual cells or as small aggregates; in addition, these bacterial cells looked to be incorporated in the autofluorescence signal of gels and phenolic compounds regardless of hosts' genotypes. In fact, the metabolomic data from asymptomatic PRP stems showed a significant increase in compounds like salicylic acid, known as a signal molecule which mediates host responses upon pathogen infection, and luteolin, a naturally derived flavonoid compound with antibacterial properties and with well-known anti-biofilm effects. Findings indicate that the xylem vessel geometry together with structural and chemical defenses are among the mechanisms operating to control Xf infection and may represent a common resistance trait among different olive genotypes.

BMI and Polycystic Ovary Syndrome: Demographic Trends in Weight and Health.

Introduction Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women in adolescence and reproductive age. The distribution of PCOS across different body mass index (BMI) categories can vary, and research has shown associations between PCOS and weight status. This study tries to evaluate the distribution of PCOS in relation to BMI in women attending the PCOS clinic in a tertiary hospital in eastern India. Methodology This hospital-based cross-sectional study was carried out in the gynecology outpatient department of a tertiary care center. The study population included all the women in the age group between 15 and 45 years diagnosed as having PCOS using the Rotterdam definition. The various physical, clinical, and biochemical parameters were measured in the study population and compared among the obese and lean PCOS patients. Results and discussion A total of 143 women were included in the study. The mean age of the study population was 26.8 years. Among these, the underweight and normal weight patients were categorized as lean PCOS patients, 35 in number (24.5%), and overweight and obese patients were categorized as obese PCOS patients, 108 in number (75.5%). All the physical parameter measures like age (mean = 28.05, SD = 5.722), height (mean = 153.384, SD = 6.679), weight (mean = 68.182, SD = 11.501), waist circumference (mean = 95.135, SD = 10.291), hip circumference (mean = 101.47, SD = 9.320), waist-to-hip ratio (mean = 0.940, SD = 0.0831), and neck circumference (mean = 34.85, SD = 2.445) were significantly higher in the obese group as compared to the lean group. Menstrual irregularity was significantly more common in the obese PCOS patients as compared to the lean PCOS group (p = 0.02). There was a significant difference (p < 0.05) between the obese and lean PCOS patients when the biochemical parameters like fasting insulin, fasting glucose, and homeostatic model assessment of insulin resistance (HOMA-IR) were compared. There is a strong link between obesity, insulin resistance, and PCOS. Obesity can exacerbate insulin resistance, a common feature of PCOS, leading to increased levels of insulin and androgens. Conclusion The demographic distribution of PCOS in relation to BMI is essential for tailoring interventions and treatments.

Severe hepatic steatosis promotes increased liver stiffness in the early stages of metabolic dysfunction-associated steatotic liver disease.

BACKGROUND & AIMS: The predictors of progression from steatosis to more advanced stages of metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear. We evaluated the association between the quantity of hepatic steatosis and longitudinal changes in liver stiffness measurements (LSMs) using magnetic resonance elastography (MRE) in patients with MASLD. METHODS: We retrospectively analysed patients with MASLD who underwent at least two serial MRE and magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) examinations at least 1 year apart. Fine-Gray competitive proportional hazard regression was used to identify LSM progression and regression factors. RESULTS: A total of 471 patients were enrolled. Factors linked to LSM progression were steatosis grade 3 (MRI-PDFF ≥17.1%, adjusted hazard ratio [aHR] 2.597; 95% confidence interval [CI] 1.483-4.547) and albumin-bilirubin grade 2 or 3 (aHR 2.790; 95% CI 1.284-6.091), while the only factor linked to LSM regression was % decrease rate of MRI-PDFF ≥5% (aHR 2.781; 95% CI 1.584-4.883). Steatosis grade 3 correlated with a higher incidence rate of LSM progression than steatosis grade 1 (MRI-PDFF <11.3%) in patients with LSM stage 0 (<2.5 kilopascal [kPa]), and a % annual decrease rate of MRI-PDFF ≥5% correlated with a higher incidence rate of LSM regression than that of MRI-PDFF >-5% and <5% in patients with LSM stage 1 or 2-4 (≥2.5 kPa). CONCLUSIONS: Severe hepatic steatosis was linked to significant LSM progression in patients with MASLD and low LSM (<2.5 kPa).

Behavioral and neuroanatomical correlates of facial emotion processing in post-stroke depression.

BACKGROUND: Emotion processing deficits are known to accompany depressive symptoms and are often seen in stroke patients. Little is known about the influence of post-stroke depressive (PSD) symptoms and specific brain lesions on altered emotion processing abilities and how these phenomena develop over time. This potential relationship may impact post-stroke rehabilitation of neurological and psychosocial function. To address this scientific gap, we investigated the relationship between PSD symptoms and emotion processing abilities in a longitudinal study design from the first days post-stroke into the early chronic phase. METHODS: Twenty-six ischemic stroke patients performed an emotion processing task on videos with emotional faces ('happy,' 'sad,' 'anger,' 'fear,' and 'neutral') at different intensity levels (20%, 40%, 60%, 80%, 100%). Recognition accuracies and response times were measured, as well as scores of depressive symptoms (Montgomery-Åsberg Depression Rating Scale). Twenty-eight healthy participants matched in age and sex were included as a control group. Whole-brain support-vector regression lesion-symptom mapping (SVR-LSM) analyses were performed to investigate whether specific lesion locations were associated with the recognition accuracy of specific emotion categories. RESULTS: Stroke patients performed worse in overall recognition accuracy compared to controls, specifically in the recognition of happy, sad, and fearful faces. Notably, more depressed stroke patients showed an increased processing towards specific negative emotions, as they responded significantly faster to angry faces and recognized sad faces of low intensities significantly more accurately. These effects obtained for the first days after stroke partly persisted to follow-up assessment several months later. SVR-LSM analyses revealed that inferior and middle frontal regions (IFG/MFG) and insula and putamen were associated with emotion-recognition deficits in stroke. Specifically, recognizing happy facial expressions was influenced by lesions affecting the anterior insula, putamen, IFG, MFG, orbitofrontal cortex, and rolandic operculum. Lesions in the posterior insula, rolandic operculum, and MFG were also related to reduced recognition accuracy of fearful facial expressions, whereas recognition deficits of sad faces were associated with frontal pole, IFG, and MFG damage. CONCLUSION: PSD symptoms facilitate processing negative emotional stimuli, specifically angry and sad facial expressions. The recognition accuracy of different emotional categories was linked to brain lesions in emotion-related processing circuits, including insula, basal ganglia, IFG, and MFG. In summary, our study provides support for psychosocial and neural factors underlying emotional processing after stroke, contributing to the pathophysiology of PSD.

Nonalcoholic Fatty Liver Disease, Bone and Muscle Quality in Prolactinoma: A Pilot Study.

OBJECTIVE: Hyperprolactinemia has negative impacts on metabolism and musculoskeletal health. In this study, individuals with active prolactinoma were evaluated for nonalcoholic fatty liver disease (NAFLD) and musculoskeletal health, which are underemphasized in the literature. METHODS: Twelve active prolactinoma patients and twelve healthy controls matched by age, gender, and BMI were included. Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) was used to evaluate hepatic steatosis and magnetic resonance elastography (MRE) to evaluate liver stiffness measurement (LSM). Abdominal muscle mass, and vertebral MRI-PDFF was also evaluated with MRI. Body compositions were evaluated by dual energy X-ray absorptiometry (DXA). The skeletal muscle quality (SMQ) was classified as normal, low and weak by using "handgrip strength/appendicular skeletal muscle mass (HGS/ASM)" ratio based on the cut-off values previously stated in the literature. RESULTS: Prolactin, HbA1c and CRP levels were higher in prolactinoma patients (p<0.001, p=0.033 and p=0.035, respectively). The median MRI-PDFF and MRE-LSM were 3.0% (2.01-15.20) and 2.22 kPa (2.0-2.5) in the prolactinoma group and 2.5% (1.65-10.00) and 2.19 kPa (1.92-2.54) in the control group, respectively and similiar between groups. In prolactinoma patients, liver MRI-PDFF showed a positive and strong correlation with the duration of disease and traditional risk factors for NAFLD. Total, vertebral and pelvic bone mineral density was similar between groups, while vertebral MRI-PDFF tended to be higher in prolactinoma patients (p=0.075). Muscle mass and strength parameters were similar between groups, but HGS/ASM tended to be higher in prolactinoma patients (p=0.057). Muscle mass was low in 33.3% of prolactinoma patients and 66.6 of controls. According to SMQ, all prolactinoma patients had normal SMQ, whereas 66.6% of the controls had normal SMQ. CONCLUSION: Prolactinoma patients demonstrated similar liver MRI-PDFF and MRE-LSM to controls despite their impaired metabolic profile and lower gonadal hormone levels. Hyperprolactinemia may improve muscle quality in prolactinoma patients despite hypogonadism.

METTL3-mediated the m6A modification of SF3B4 facilitates the development of non-small cell lung cancer by enhancing LSM4 expression.

BACKGROUND: Splicing factor B subunit 4 (SF3B4) has been confirmed to participate in the progression of many cancers and is considered to be a potential target for non-small cell lung cancer (NSCLC). Thus, the role and molecular mechanism of SF3B4 in NSCLC progression deserves further study. METHODS: Quantitative real-time PCR and western blot were employed to detect the mRNA and protein levels of SF3B4, Sm-like protein 4 (LSM4) and methyltransferase-like 3 (METTL3). Cell proliferation, apoptosis, invasion, migration and stemness were tested by cell counting kit-8, colony formation, flow cytometry, transwell, wound healing, and sphere formation assays. The interaction between SF3B4 and METTL3 or LSM4 was confirmed by MeRIP, RIP and Co-IP assays. Mice xenograft models were constructed to assess the effects of METTL3 and SF3B4 on NSCLC tumorigenesis. RESULTS: SF3B4 had high expression in NSCLC tissues and was associated with the shorter overall survival of NSCLC patients. Knockdown of SF3B4 suppressed NSCLC cell proliferation, invasion, migration and stemness, while inducing apoptosis. METTL3 promoted SF3B4 mRNA stability by m6A modification, and its knockdown inhibited NSCLC cell growth, metastasis and stemness by downregulating SF3B4. SF3B4 could interact with LSM4, and sh-SF3B4-mediated the inhibition on NSCLC cell functions could be reversed by LSM4 overexpression. In addition, reduced METTL3 expression restrained NSCLC tumor growth, and this effect was reversed by SF3B4 overexpression. CONCLUSION: METTL3-stablized SF3B4 promoted NSCLC cell growth, metastasis and stemness via positively regulating LSM4.

ALT poorly predicts Nonalcoholic Fatty Liver Disease (NAFLD) and liver fibrosis as determined by vibration-controlled transient elastography in adult National Health and Nutrition Examination Survey 2017-2018.

BACKGROUND: Non-alcoholic fatty liver disease is a growing problem in the United States, contributing to a range of liver disease as well as cardiovascular disease. ALT is the most widely used liver chemistry for NAFLD evaluation. We hypothesized that the normal range many laboratories use was too high, missing many patients with clinically important steatosis and/or fibrosis. METHODS: This study utilized 2017-2018 NHANES data including 9254 participants. We compared four different upper limits of normal for ALT with specific measurements of steatosis and liver stiffness as determined by liver elastography with FibroScan®. Liver stiffness was further characterized as showing any fibrosis or advanced fibrosis. After exclusions, our final pool was 4184 for liver stiffness measurement and 4183 for steatosis grade as measured by Controlled Attenuation Parameter (CAP). Using these variables, we performed logistic regression between ALT and CAP, and ALT and fibrosis/advanced fibrosis, and did a Receiver Operating Characteristic curve. RESULTS: Based on three of the most widely used cut off values for ALT, we found that ALT does not reliably rule out NAFLD in over 50% of cases. It also missed 45.9-64.2% of patients with liver fibrosis. CONCLUSIONS: Our study revealed that ALT is an inaccurate marker for NAFLD as measured by FibroScan® with CAP greater than or equal to 300 dB/m. Accuracy improved specific risk factors were considered. These data also showed that ALT was a poor marker for liver fibrosis. We conclude that there is no single ALT level that accurately predicts hepatic steatosis or fibrosis.

Effect of Concurrent Metabolic Dysfunction-Associated Steatotic Liver Disease on Serial Non-invasive Fibrosis Markers in Chronic Hepatitis B.

BACKGROUND & AIMS: Concurrent hepatic steatosis has diverse effects on chronic hepatitis B (CHB), however the combined effects of metabolic dysfunction-associated steatotic liver disease (MASLD) and CHB on liver fibrosis progression remains unclear. The primary aim of this study was to utilize serial fibrosis measurements to compare the dynamic change in fibrosis in CHB patients with/without concurrent MASLD. The secondary aim was to investigate factors associated with steatosis development and regression in CHB patients. METHODS: This was a retrospective cohort study of all non-cirrhotic CHB patients identified from 1/1/2011 to 31/12/2016. Hepatic steatosis was diagnosed by ultrasound. Fibrosis markers included liver stiffness (LSM) by transient elastography, APRI and FIB-4. General linear mixed effects modelling was used to fit polynomial and linear estimates. RESULTS: Of 810 CHB patients (n = 2,373 LSM measurements; median age 44.4y; 48% male; 24% HBeAg positive), 14% had concurrent MASLD. LSM was higher at baseline but decreased in MASLD patients over time, while LSM remained stable in non-MASLD patients, such that all patients had similar LSM beyond 4-5 years. MASLD patients had lower APRI compared to non-MASLD patients, which was predominately due to a higher platelet count and higher ALT over time. There was substantial discordance between LSM, APRI and FIB-4. Baseline BMI was the only factor that predicted steatosis development and regression. CONCLUSIONS: We found no evidence of an association between concurrent MASLD and fibrosis progression amongst CHB patients without baseline advanced liver disease. APRI and FIB-4 may have reduced accuracy in MASLD patients.

Analysis of Lsm Protein-Mediated Regulation in the Haloarchaeon Haloferax mediterranei.

The Sm protein superfamily includes Sm, like-Sm (Lsm), and Hfq found in the Eukarya, Archaea, and Bacteria domains. Archaeal Lsm proteins have been shown to bind sRNAs and are probably involved in various cellular processes, suggesting a similar function in regulating sRNAs by Hfq in bacteria. Moreover, archaeal Lsm proteins probably represent the ancestral Lsm domain from which eukaryotic Sm proteins have evolved. In this work, Haloferax mediterranei was used as a model organism because it has been widely used to investigate the nitrogen cycle and its regulation in Haloarchaea. Predicting this protein's secondary and tertiary structures has resulted in a three-dimensional model like the solved Lsm protein structure of Archaeoglobus fulgidus. To obtain information on the oligomerization state of the protein, homologous overexpression and purification by means of molecular exclusion chromatography have been performed. The results show that this protein can form hexameric complexes, which can aggregate into 6 or 12 hexameric rings depending on the NaCl concentration and without RNA. In addition, the study of transcriptional expression via microarrays has allowed us to obtain the target genes regulated by the Lsm protein under nutritional stress conditions: nitrogen or carbon starvation. Microarray analysis has shown the first universal stress proteins (USP) in this microorganism that mediate survival in situations of nitrogen deficiency.

Sound Touch Elastography for Noninvasive Assessment of Liver Stiffness in Patients With Chronic Heart Failure.

Heart failure (HF) can damage various organs, including the liver, a phenomenon known as "cardiohepatic syndrome." The latter is characterized by liver congestion and hepatic artery hypoperfusion, which can lead to liver damage. In this study, we aimed to assess liver damage quantitatively in chronic HF (CHF) with sound touch elastography (STE). A total of 150 subjects were enrolled, including HF with reduced ejection fraction (HFrEF) groups (left ventricular ejection fraction ≤40%, n = 45), HF with mildly reduced ejection fraction (HFmrEF) groups (left ventricular ejection fraction between 41% and 49%, n = 40), and right-sided HF (RHF) groups (n = 25); normal groups (n = 40). Liver stiffness measurement (LSM) was performed in all subjects by STE. The other hepatic parameters were also measured. The LSM was 5.4 ± 1.1 kPa in normal subjects and increased slightly to 5.9 ± 0.7 kPa in patients with HFmrEF. However, the HFrEF and RHF groups had significantly higher LSMs of 8.4 ± 2.0 kPa and 10.3 ± 2.7 kPa, respectively. The LSM of HFrEF was significantly higher than that of HFmrEF, whereas the increase in LSM in patients with RHF was significant relative to HFmrEF and HFrEF. In addition, the other parameters showed abnormal values in only RHF and HFrEF. In conclusion, STE is a useful clinical technique for the noninvasive evaluation of liver stiffness associated with CHF, which could help patients with CHF manage their treatment regimens.

LSM14B coordinates protein component expression in the P-body and controls oocyte maturation.

The generation of mature and healthy oocytes is the most critical event in the entire female reproductive process, and the mechanisms regulating this process remain to be studied. Here, we demonstrate that Smith-like (LSM) family member 14B (LSM14B) regulates oocyte maturation, and the loss of LSM14B in mouse ovaries leads to abnormal oocyte MII arrest and female infertility. Next, we find the aberrant transcriptional activation, indicated by abnormal non-surrounded nucleolus and surrounded nucleolus oocyte proportions, and abnormal chromosome assembly and segregation in Lsm14b-deficient mouse oocytes. The global transcriptome analysis suggests that many transcripts involved in cytoplasmic processing body (P-body) function are altered in Lsm14b-deficient mouse oocytes. Deletion of Lsm14b results in the expression and/or localization changes of P-body components (such as LSM14A, DCP1A, and 4E-T). Notably, DDX6, a key component of the P-body, is downregulated and accumulates in the nuclei in Lsm14b-deficient mouse oocytes. Taken together, our data suggest that LSM14B links mouse oocyte maturation to female fertility through the regulation of the P-body.

Predictors of controlled attenuation parameter in metabolic dysfunction.

BACKGROUND & AIMS: Hepatic fat content can be non-invasively estimated by controlled attenuation parameter (CAP) during transient elastography. The aim of this study was to examine the determinants and predictors of CAP values in individuals with metabolic dysfunction. METHODS: We enrolled 1230 consecutive apparently healthy individuals (Liver-Bible-2022 cohort) with ≥3 metabolic dysfunction features. CAP was measured by Fibroscan. CAP determinants and predictors were identified using backward stepwise analysis and introduced in generalized linear models. RESULTS: Participants were predominantly males (82.9%), mean age was 53.8 ± 6.4 years, 600 (48.8%) had steatosis (CAP ≥ 275 dB/m), and 27 had liver stiffness measurement (LSM) ≥ 8 kPa. CAP values correlated with LSM (p < 10-22). In multivariable analysis, fasting insulin and abdominal circumference (AC) were the main determinants of CAP (p < 10-6), together with body mass index (BMI; p < 10-4), age, diabetes, triglycerides, ferritin, and lower HDL and thyroid stimulating hormone (TSH; p < 0.05 for all). In a subset of 592 participants with thyroid hormone measurement, we found an association between higher free triiodothyronine levels, correlating with lower TSH, and CAP values, independent of TSH and of levothyroxine treatment (p = 0.0025). A clinical CAP score based on age, BMI, AC, HbA1c, ALT, and HDL predicted CAP ≥ 275 dB/m with moderate accuracy (AUROC = 0.73), which was better than that of the Fatty Liver Index and of ALT (AUROC = 0.70/0.61, respectively) and validated it in multiple cohorts. CONCLUSION: Abdominal adiposity and insulin resistance severity were the main determinants of CAP in individuals with metabolic dysfunction and may improve steatotic liver disease risk stratification. CAP values were modulated by the hypophysis-thyroid axis.

The role of LSM1 in breast cancer: Shaping metabolism and tumor-associated macrophage infiltration.

LSM1 is part of the cytoplasmic protein complex Lsm1-7-Pat1 and is likely involved in pre-mRNA degradation by aiding U4/U6 snRNP formation. More research is needed to uncover LSM1's potential in breast cancer (BRCA) clinical pathology, the tumor immune microenvironment, and precision oncology. We discovered LSM1 as a diagnostic marker for advanced BRCA with poor survival, using a multi-omics approach. We studied LSM1 expression across BRCA regions and its link to immune cells through various methods, including spatial transcriptomics and single-cell RNA-sequencing. We also examined how silencing LSM1 affects mitochondrial function and energy metabolism in the tumor environment. These findings were confirmed using 54 BRCA patient biopsies and tissue microarrays. Immunofluorescence and bioinformatics assessed LSM1's connection to clinicopathological features and prognosis. This study uncovers gene patterns linked to breast cancer, with LSM1 linked to macrophage energy processes. Silencing LSM1 in breast cancer cells disrupts mitochondria and energy metabolism. Spatial analysis aligns with previous results, showing LSM1's connection to macrophages. Biopsies confirm LSM1 elevation in advanced breast cancer with increased macrophage presence. To summarize, LSM1 changes may drive BRCA progression, making it a potential diagnostic and prognostic marker. It also influences energy metabolism and the tumor's immune environment during metastasis, showing promise for precision medicine and drug screening in BRCA.