Nevin Manimala

Cell Rep. 2024 Dec 24;44(1):115093. doi: 10.1016/j.celrep.2024.115093. Online ahead of print.

ABSTRACT

Hepatocytes are organized into distinct zonal subsets across the liver lobule, yet their contributions to liver homeostasis and regeneration remain controversial. Here, we developed multiple genetic lineage-tracing mouse models to systematically address this. We found that the liver lobule can be divided into two major zonal and molecular hepatocyte populations marked by Cyp2e1 or Gls2. Pericentral Cyp2e1⁺ and periportal Gls2⁺ hepatocytes maintain their own lineage during adult homeostasis, while Cyp2e1⁺ hepatocytes fuel neonatal liver growth. The Gls2⁺ and Cyp2e1⁺ populations can rapidly regenerate one another when one of the populations is severely damaged. Midlobular Ccnd1⁺ hepatocytes are enriched in the Cyp2e1⁺ zone in adult liver but have limited contributions to regeneration upon partial hepatectomy and severe pericentral injury. Remarkably, Lgr5⁺ hepatocytes, a unique Cyp2e1⁺ subset, contribute significantly to liver replenishment upon periportal injuries. Our findings unravel that zonal hepatocytes mainly self-maintain during homeostasis but exhibit complex plasticity in repair upon injury.

PMID:39721024 | DOI:10.1016/j.celrep.2024.115093

Mil Med. 2024 Dec 25:usae554. doi: 10.1093/milmed/usae554. Online ahead of print.

ABSTRACT

INTRODUCTION: Military body fat standards were implemented in the 1980s to prevent obesity and associated poor military readiness. In the past 2 decades, enforcement of existing Army body composition standards has been eroded by the steady increase in national obesity rates, the demand for new recruits especially during the 2007 surge in Iraq, and the COVID epidemic in 2020. The diminishing qualified recruit pool puts a new focus on accession standards. The purpose of accession standards is to ensure that recruits will meet soldier standards, but accession standards have been relaxed to improve recruitment with an assumption that most recruits will achieve the retention standards during initial entry training. A new method of percent body fat estimation (%BF) adopted by the Army in 2024 further liberalizes both accession and retention standards. This study examined the impact of current accession and retention %BF standards on the proportion of the US population that would be disqualified from Army service.

METHODS: This analysis was based on National Health and Nutrition Examination Survey (NHANES) statistical sampling of the US population, where height, weight, abdominal circumferences, and dual-energy x-ray absorptiometry (DXA) %BF data were available (n = 26,090, including 13,302 men and 12,788 women). The proportion of individuals in the NHANES data failing to meet weight screen and %BF standards based on age and sex categories were calculated using DXA and the new Army anthropometric method. A recent large dataset from another service was used to compare the new method to DXA.

RESULTS: Near one-third to one-half of American men and women failed to meet the current Army body composition standard (29, 39, 48, and 50% of men and 39, 45, 46, and 50% of women for age groups 17-20, 21-27, 28-29, and 40-59). More men than women benefited from more liberal accession standards to enter the Army above the retention standard to which they will be held after initial entry training (an additional 12, 11, 15, and 15% of men and 7, 1, 2, and 1% of women who met accession standards exceeded retention standards and would be expected to lose %BF after entry). Approximately one-fourth of women exceeded %BF but were under the height-weight screen; <10% of men were in this category. No men but 16% of the youngest women had low lean mass (<35 kg).

DISCUSSION: Army body composition standards are generous, extending to the limits of increased metabolic health risks and providing underestimates of actual %BF based on the behavior of circumference-based methods of body fat estimation. However, current standards do not accurately select or track physical readiness, especially for women, and should be updated. Modernization of physical readiness standards to meet the needs of the Army of 2030 could include adoption of new technologies that directly assess central adiposity, adequate muscle mass, and replace fitness testing with cardiac output metrics. With half of US adults projected to be obese by 2030, it is time for a review of the strategic goals of modernized military readiness standards.

PMID:39721003 | DOI:10.1093/milmed/usae554

J Vis Commun Med. 2024 Dec 25:1-6. doi: 10.1080/17453054.2024.2438635. Online ahead of print.

ABSTRACT

Four versions of the novel Moletest on-device signal-processing analysis software, delivered on a single-application iPadPro11, were evaluated in pigmented skin lesions of patients sent for biopsy comparing its results with the lesion histology. The primary objective was to demonstrate that the nomela^® test provided at least 95 ± 2% sensitivity for not-melanoma. Proprietary software recognised the lesion perimeter, rejecting images with uncertain border, and performed analysis using non-scalar metrics of the image within the perimeter. From five algorithms any one reading outside the predefined melanoma range assigned the lesion to ‘no evidence of melanoma’ or otherwise to ‘melanoma not excluded’. 1365 participants provided 1573 lesions. 1389 valid cases had a valid signal-processing test result and a valid histology report defined as ‘not-melanoma’ (n = 1205) or ‘melanoma’ (n = 184). Statistical analysis for the four versions were: sensitivity (ability of the signal-processing analysis to assign ‘No evidence of melanoma’ to a lesion with ‘not-melanoma’ histology) 8.6/48.4/76.9/52.1%; specificity (ability to assign ‘Melanoma not excluded’ to a lesion with ‘melanoma’ histology) 100/79.6/75.0/65.2%. The performance of the Moletest signal-processing analysis as a diagnostic support for rule-out of melanoma showed limited value in all four versions.

PMID:39720991 | DOI:10.1080/17453054.2024.2438635

Apoptosis. 2024 Dec 25. doi: 10.1007/s10495-024-02049-x. Online ahead of print.

ABSTRACT

Gastric cancer remains a leading cause of cancer-related mortality worldwide. The prognosis often depends on early detection and understanding the molecular mechanisms involved in its progression. Periodic tryptophan protein 1 (PWP1) has emerged as a novel diagnostic marker, potentially linked to gastric cancer progression. This study aims to elucidate the impact of PWP1 on gastric cancer development, focusing on apoptosis, cell cycle regulation, and the role of p53. This study utilized gastric cancer cell lines to investigate the expression and functional role of Pwp1. Quantitative PCR and Western blot analyses were conducted to measure PWP1 expression levels. Apoptosis was assessed by using flow cytometry and TUNEL assays, and cell cycle analysis was performed to evaluate the impact of PWP1 modulation. Additionally, animal experiments were conducted using mouse models injected with gastric cancer cells, with PWP1 knockdown or overexpression, to observe tumor growth and progression. Statistical significance was evaluated using t-tests and ANOVA where appropriate. Elevated PWP1 expression was observed in gastric cancer tissues compared to normal tissues. PWP1’s knockdown resulted in increased apoptosis and cell cycle arrest at the G1 phase, suggesting its role in promoting invasion and proliferation. Furthermore, animal experiments demonstrated reduced tumor growth in mice with PWP1 knockdown. PWP1 was found to transcriptionally regulate p53, affecting its expression and thereby influencing apoptosis and cell cycle pathways in gastric cancer. Our study identifies PWP1 as a novel oncogene frequently overexpressed in gastric cancer (GC). Through transcriptional regulation of p53, PWP1 enhances cell growth by influencing apoptosis and inducing G1 phase cell cycle arrest. These findings underscore PWP1 as a promising therapeutic target for treating GC, suggesting its potential for future clinical applications.

PMID:39720977 | DOI:10.1007/s10495-024-02049-x

Arch Gynecol Obstet. 2024 Dec 25. doi: 10.1007/s00404-024-07890-8. Online ahead of print.

ABSTRACT

PURPOSE: We aimed to evaluate if ovarian stimulation with individualized dosing of recombinant follicle-stimulating hormone (rec-FSH) with follitropin delta compared with standard gonadotropin dosing reduce occurrence of follicular asynchrony in women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF).

METHODS: Matched case-control study analyzed occurrence of follicular growth asynchrony during ovarian stimulation and IVF outcomes in women with PCOS. Follicular growth was considered to be asynchronous when one or two leading follicles were at least 4 mm larger in diameter than the rest of the cohort on day 5 and 9 of stimulation. Analysis encompassed 44 women stimulated with individualized rec-FSH dosing, and 88 women treated with standard dosing. The patients were matched in terms of age, Anti-Müllerian hormone levels and body weight.

RESULTS: Early and late follicular asynchrony were present less frequently in individualized dosing compared to standard dosing group (4.5% vs 17%, p = 0.04 and 2.3% vs 37.5%, p < 0.001, on stimulation day 5 and 9, respectively). Multivariate logistic regression on follicular asynchrony revealed that individualized dosing significantly decreases the occurrence and chances for late follicular asynchrony (Odds Ratio 0.28, p < 0.001). Shorter duration of stimulation (9.6 vs 10.4 days, p = 0.001), lower total gonadotropin dose (1118 vs 1940 IU, p < 0.001), higher number of metaphase II oocytes (7.1 + 4.3 vs 5.4 ± 3.0, p = 0.001), good quality embryos (3.8 vs 2.0, p < 0.001), and implantation rates (31.0 vs 23.4, p = 0.04) were observed in the individualized dosing group.

CONCLUSION: Individualized rec-FSH dosing reduces asynchronous follicular growth and improves ovarian stimulation efficiency in women with PCOS undergoing IVF.

PMID:39720974 | DOI:10.1007/s00404-024-07890-8

Breast Cancer Res Treat. 2024 Dec 25. doi: 10.1007/s10549-024-07578-2. Online ahead of print.

ABSTRACT

PURPOSE: In early-stage breast cancer, steatotic liver disease (SLD) is associated with increased recurrence, cardiovascular events, and non-cancer death. Endocrine therapy (ET) increases the risk of SLD. The impact of cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) on SLD and prognostic association in metastatic breast cancer is unknown. We characterized the presence of SLD, risk factors, and treatment outcomes of SLD in metastatic HR+/HER2- breast cancer receiving CDK4/6i.

METHODS: This single institution, retrospective, cohort study included patients with metastatic HR+/HER2- breast cancer receiving first-line ET and CDK4/6i from January 2018 to June 2022. SLD was defined as a Liver Attenuation Index (LAI) > 25 HU on contrast-enhanced CT scans and/or > 10 HU on plain CT scans. Univariable binary-logistic regression was used to assess associations with SLD. Time to treatment failure (TTF) and overall survival (OS) were analyzed using Cox proportional hazards modeling.

RESULTS: Among 87 patients with a median age of 58 years and 65.5% postmenopausal, 50 (57.5%) had SLD at anytime (24 at baseline, 26 acquired). SLD at baseline was statistically associated with post-menopausal status. It was quantitatively but not statistically associated with age > 65, diabetes, smoking, and HER2-low. SLD at anytime was statistically significantly associated with longer TTF (median 470 vs 830.5 days, HR = 0.38, p < 0.001). No significant differences in OS or grade 3/4 adverse events were observed between groups.

CONCLUSION: This study demonstrated a high prevalence of SLD in this population, with SLD presence correlated with longer TTF. SLD may be an indicator of better outcomes in metastatic HR+/HER2- breast cancer patients treated with CDK4/6i.

PMID:39720971 | DOI:10.1007/s10549-024-07578-2

J Echocardiogr. 2024 Dec 25. doi: 10.1007/s12574-024-00674-8. Online ahead of print.

ABSTRACT

BACKGROUND: The current guidelines recommend patient stratification based on transthoracic echocardiography (TTE) to identify individuals with potential pulmonary hypertension (PH). We validated the relationship between PH and the pulmonary artery diameter (PAD) on computed tomography (CT) with peak tricuspid regurgitant velocity (TRV) measured by TTE for referral of patients with suspected PH for TTE screening.

METHODS: We performed a retrospective analysis of CT-based PAD of 2356 patients who underwent TTE from February 2, 2013 to December 25, 2019 at our institution. The thresholds for suspected PH based on TRV were determined using receiver operating characteristic curves based on PAD. Pearson’s rank correlation coefficient was used to assess the relationship between PAD and TRV.

RESULTS: The area under the curve (AUC) of the PAD for suspected PH was statistically greater or comparable to others. The sex-specific PAD threshold for high PH probability were 29.4 mm (male: AUC, 0.86; sensitivity, 84.9%; specificity, 72.3%) and 27.8 mm (female: AUC, 0.83; sensitivity, 78%; specificity, 75.6%). Pearson’s rank correlation coefficient showed a correlation between the PAD and TRV (male: ρ = 0.40, P < 0.001, female: ρ = 0.43, P < 0.001).

CONCLUSIONS: The main PAD on CT findings served as a suitable marker for referral of patients with suspected PH for TTE screening. Patients exceeding the CT-derived PAD threshold, even incidentally, should undergo additional TTE for a comprehensive PH assessment.

PMID:39720970 | DOI:10.1007/s12574-024-00674-8

Cell Physiol Biochem. 2024 Dec 19;58(6):739-755. doi: 10.33594/000000746.

ABSTRACT

BACKGROUND/AIMS: Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that severely affects cognitive functions and memory. Early detection is crucial for timely intervention and improved patient outcomes. However, traditional diagnostic tools, such as MRI and PET scans, are costly and less accessible. This study aims to develop an automated, cost-effective digital diagnostic approach using deep learning (DL) and computer-aided detection (CAD) methods for early AD identification and classification.

METHODS: The proposed framework utilizes pretrained convolutional neural networks (CNNs) for feature extraction, integrated with two classifiers: multi-class support vector machine (MSVM) and artificial neural network (ANN). A dataset categorized into four groups-non-demented, very mild demented, mild demented, and moderate demented-was employed for evaluation. To optimize the classification process, a texture-based algorithm was applied for feature reduction, enhancing computational efficiency and reducing processing time.

RESULTS: The system demonstrated high statistical performance, achieving an accuracy of 91%, precision of 95%, and recall of 90%. Among the initial set of twenty-two texture features, seven were identified as particularly effective in differentiating normal cases from mild AD stages, significantly streamlining the classification process. These results validate the robustness and efficacy of the proposed DL-based CAD system.

CONCLUSION: This study presents a reliable and affordable solution for early AD detection and diagnosis. The proposed system outperforms existing state-of-the-art models and offers a valuable tool for timely treatment planning. Future research should explore its application to larger, more diverse datasets and investigate integration with other imaging modalities, such as MRI, to further enhance diagnostic precision.

PMID:39720940 | DOI:10.33594/000000746

Eur J Endocrinol. 2024 Dec 25:lvae166. doi: 10.1093/ejendo/lvae166. Online ahead of print.

ABSTRACT

OBJECTIVE: We have shown that men aged 50 years+ at high risk of type 2 diabetes treated with testosterone together with a lifestyle program reduced the risk of type 2 diabetes at two years by 40% compared to a lifestyle program alone. To develop a personalized approach to treatment, we aimed to explore a prognostic model for incident type 2 diabetes at two years and investigate biomarkers predictive of the testosterone effect.

DESIGN: Model development in 783 men with impaired glucose tolerance but not type 2 diabetes from T4DM; a multicenter, 2-year trial of Testosterone vs placebo. External validation performed in 236 men from the EXamining OuTcomEs in chroNic Disease in the 45 and Up Study (EXTEND-45, n=267,357).

METHODS: Type 2 diabetes at two years defined as 2-hour fasting glucose by oral glucose tolerance test (OGTT) ≥ 11.1mmol/L. Risk factors, including predictive biomarkers of testosterone treatment, were assessed using penalized logistic regression.

RESULTS: Baseline HbA1c and 2-hour OGTT glucose were dominant predictors, together with Testosterone, age, and an interaction between Testosterone and HbA1c (p=0.035, greater benefit with HbA1c≥5.6%, 38mmol/mol). The final model identified men who developed type 2 diabetes, with C-statistics 0.827 in development and 0.798 in validation. After recalibration, the model accurately predicted a participant’s absolute risk of type 2 diabetes.

CONCLUSIONS: Baseline HbA1c and 2-hour OGTT glucose predict incident type 2 diabetes at 2 years in high-risk men, with risk modified independently by Testosterone treatment. Men with HbA1c≥5.6% (38mmol/mol) benefit most from Testosterone treatment, beyond a lifestyle program.

PMID:39720906 | DOI:10.1093/ejendo/lvae166

J Cell Mol Med. 2024 Dec;28(24):e70322. doi: 10.1111/jcmm.70322.

ABSTRACT

Increasingly, emerging research evidence has demonstrated that nonalcoholic fatty liver disease (NAFLD) is a disease closely associated with systemic inflammation. However, the specific upstream inflammatory factors engaged in the pathogenesis of NAFLD remain unclear. Our study aimed to identify the inflammatory regulators causally associated with NAFLD pathogenesis through Mendelian randomisation. A two-sample Mendelian randomisation method was applied to analyse the causal association between 91 circulating inflammatory proteins and NAFLD. Data on circulating inflammatory proteins were derived from samples of European ancestry (14,824 samples) and NAFLD data were obtained from the FinnGen consortium (2025 cases and 284,826 controls). Instrumental variables were selected from the genetic variance and F-statistics were calculated to avoid bias. We adopted the random-effects inverse variance weighting (IVW) method as our primary analytical approach. Supplementary analyses were also implemented, including weighted median, MR-Egger and weighted mode. Moreover, we conducted pleiotropy and heterogeneity analyses to validate the accuracy of the findings. The application of Mendelian randomisation analysis identified four inflammatory factors that might be causally associated with NAFLD at the genetic level. Elevated levels of eotaxin (or = 1.27, 95% CI: 1.05-1.53, p = 0.014), osteoprotegerin (OPG) (or = 1.29, 1.03-1.60, p = 0.023) and TNFRSF9 (or = 1.32, 95% CI: 1.06-1.64, p = 0.014) may be causally related to an increasing risk of NAFLD. Conversely, heightened leukaemia inhibitory factor (LIF) levels (or = 0.63, 0.44-0.92, p = 0.016) were linked to a lower risk of NAFLD onset. There was no causal relationship between levels of other circulating inflammatory proteins and NAFLD. Our analysis uncovered four upstream inflammatory factors genetically associated with the pathogenesis of NAFLD. These results highlight the potential involvement of inflammation in NAFLD, which provides partial insights for further research in this field in the future.

PMID:39720899 | DOI:10.1111/jcmm.70322