Progressive Acute Lower Extremity Ischemia Resulting From Cardiac Myxoma Embolization: A Case Report.

Cardiac myxomas are the most common primary benign tumors of the heart. The occlusion of peripheral arteries and complete obstruction of the abdominal aorta by a tumor embolus presents with distinct clinical manifestations. Herein, we present the case of a 38-year-old male with acute paresthesia, muscle weakness, erythematous, and violaceous changes in skin color localized to the dorsum of the left forefoot initially treated as cutaneous vasculitis. Further studies revealed the total occlusion of the terminal abdominal aorta by a saddle embolus from a cardiac myxoma. A multidisciplinary team consisting of cardiothoracic and vascular surgeons were involved in treating the patient, which resulted in full resolution of the case. This paper details the progression of acute bilateral limb ischemia to chronic limb threatening ischemia resulting from the total occlusion of the terminal abdominal aorta by a saddle embolus.

Interventions for preventing the progression of autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the leading inherited cause of kidney disease. Clinical management has historically focused on symptom control and reducing associated complications. Improved understanding of the molecular and cellular mechanisms involved in kidney cyst growth and disease progression has resulted in new pharmaceutical agents targeting disease pathogenesis and preventing disease progression. However, the role of disease-modifying agents for all people with ADPKD is unclear. This is an update of a review first published in 2015. OBJECTIVES: We aimed to evaluate the benefits and harms of interventions to prevent the progression of ADPKD and the safety based on patient-important endpoints, defined by the Standardised Outcomes in NephroloGy-Polycystic Kidney Disease (SONG-PKD) core outcome set, and general and specific adverse effects. SEARCH METHODS: We searched the Cochrane Kidney and Transplants Register of Studies up to 13 August 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing any interventions for preventing the progression of ADPKD with other interventions, placebo, or standard care were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study risks of bias and extracted data. Summary estimates of effects were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) or standardised mean difference (SMD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We included 57 studies (8016 participants) that investigated 18 pharmacological interventions (vasopressin 2 receptor (V2R) antagonists, antihypertensive therapy, mammalian target of rapamycin (mTOR) inhibitors, somatostatin analogues, antiplatelet agents, eicosapentaenoic acids, statins, kinase inhibitors, diuretics, anti-diabetic agents, water intake, dietary intervention, and supplements) in this review. Compared to placebo, the V2R antagonist tolvaptan probably preserves eGFR (3 studies, 2758 participants: MD 1.26 mL/min/1.73 m2, 95% CI 0.73 to 1.78; I2 = 0%) and probably slows total kidney volume (TKV) growth in adults (1 study, 1307 participants: MD -2.70 mL/cm, 95% CI -3.24 to -2.16) (moderate certainty evidence). However, there was insufficient evidence to determine tolvaptan's impact on kidney failure and death. There may be no difference in serious adverse events; however, treatment probably increases nocturia, fatigue and liver enzymes, may increase dry mouth and thirst, and may decrease hypertension and urinary and upper respiratory tract infections. Data on the impact of other therapeutic interventions were largely inconclusive. Compared to placebo, somatostatin analogues probably decrease TKV (6 studies, 500 participants: SMD -0.33, 95% CI -0.51 to -0.16; I2 = 11%), probably have little or no effect on eGFR (4 studies, 180 participants: MD 4.11 mL/min/1.73 m3, 95% CI -3.19 to 11.41; I2 = 0%) (moderate certainty evidence), and may have little or no effect on kidney failure (2 studies, 405 participants: RR 0.64, 95% CI 0.16 to 2.49; I2 = 39%; low certainty evidence). Serious adverse events may increase (2 studies, 405 participants: RR 1.81, 95% CI 1.01 to 3.25; low certainty evidence). Somatostatin analogues probably increase alopecia, diarrhoea or abnormal faeces, dizziness and fatigue but may have little or no effect on anaemia or infection. The effect on death is unclear. Targeted low blood pressure probably results in a smaller per cent annual increase in TKV (1 study, 558 participants: MD -1.00, 95% CI -1.67 to -0.33; moderate certainty evidence) compared to standard blood pressure targets, had uncertain effects on death, but probably do not impact other outcomes such as change in eGFR or adverse events. Kidney failure was not reported. Data comparing antihypertensive agents, mTOR inhibitors, eicosapentaenoic acids, statins, vitamin D compounds, metformin, trichlormethiazide, spironolactone, bosutinib, curcumin, niacinamide, prescribed water intake and antiplatelet agents were sparse and inconclusive. An additional 23 ongoing studies were also identified, including larger phase III RCTs, which will be assessed in a future update of this review. AUTHORS' CONCLUSIONS: Although many interventions have been investigated in patients with ADPKD, at present, there is little evidence that they improve patient outcomes. Tolvaptan is the only therapeutic intervention that has demonstrated the ability to slow disease progression, as assessed by eGFR and TKV change. However, it has not demonstrated benefits for death or kidney failure. In order to confirm the role of other therapeutic interventions in ADPKD management, large RCTs focused on patient-centred outcomes are needed. The search identified 23 ongoing studies, which may provide more insight into the role of specific interventions.

Ginger-derived nanovesicles attenuate osteoarthritis progression by inhibiting oxidative stress via the Nrf2 pathway.

Aim: Osteoarthritis (OA) is a common degenerative joint disease. Previous studies demonstrated ginger-derived exosome-like nanovesicles (GDN) showed therapeutic effects in degenerative diseases. However, it remains unknown whether GDN could alleviate OA progression.Materials & methods: In this study, GDN were obtained and characterized. Then we evaluated the effects of GDN in tert-butyl hydroperoxide (TBHP)-induced chondrocytes, posttraumatic OA rat model and ex vivo cultured human OA cartilage explants.Results: We demonstrated GDN promoted cartilage anabolism and alleviated oxidative stress in TBHP-induced chondrocytes and OA rat. Our results also showed GDN exhibited protective effects in cultured cartilage explants. Furthermore, we verified the Nrf2 pathway was associated with protective effects of GDN.Conclusion: Altogether, our findings demonstrated GDN hold great potential for OA treatment.

[Box: see text].

Compromised macrophages contribute to progression of MASH to hepatocellular carcinoma in FGF21KO mice.

Metabolic dysfunction-associated steatohepatitis is well accepted as a potential precursor of hepatocellular carcinoma. Previously, we reported that fibroblast growth factor 21 (FGF21) revealed a novel anti-inflammatory activity via inhibiting the TLR4-IL-17A signaling, which could be a potential anticarcinogenetic mechanism to prevent to MASH-HCC transition. Here, we set out to determine whether FGF21 has a major impact on Kupffer cells' (KCs) ability during MASH-HCC transition. We found aberrant hepatic FGF21 and KC pool in human MASH-HCC. Lack of FGF21 up-regulated ALOX15, which converted the oxidized fatty acids to induce excessive KC death and mobilization of monocyte-derived macrophages (MoMFs) for KC replacement. Lack of FGF21 oversupplied free fatty acids for sphingosine-1-phosphate (S1P) cascade synthesis to mediate MASH-HCC transition via S1P-YAP signaling and cross-talk between tumor cells and macrophages. In conclusion, lack of FGF21 accelerated MASH-HCC transition via the S1P-AP signaling. Compromised MoMFs could present as tumor-associated macrophage phenotype rendering tumor immune microenvironment for MASH-HCC transition.

Ghrelin is involved in regulating the progression of Echinococcus Granulosus-infected liver lesions through suppression of immunoinflammation and fibrosis.

BACKGROUND: Cystic Echinococcosis (CE) is a zoonotic disease causing fibrosis and necrosis of diseased livers caused by infection with Echinococcus granulosus (E.g). There is evidence that E.g is susceptible to immune escape and tolerance when host expression of immunoinflammation and fibrosis is suppressed, accelerating the progression of CE. Ghrelin has the effect of suppressing immunoinflammation and fibrosis, and whether it is involved in regulating the progression of E.g-infected liver lesions is not clear. METHODS: Serum and hepatic Ghrelin levels were observed in E.g-infected mice (4, 12 and 36 weeks) and compared with healthy control groups. Co-localization analysis is performed between protein expression of Ghrelin in and around the hepatic lesions of E.g-infected 12-week mice and protein expression of different hepatic histiocytes by mIHC. HepG2 cells and protoscoleces (PSCs) protein were co-cultured in vitro, as well as PSCs were alone in vitro, followed by exogenously administered of Ghrelin and its receptor blocker, [D-Lys3]-GHRP-6, to assess their regulatory effects on immunoinflammation, fibrosis and survival rate of PSCs. RESULTS: Serum Ghrelin levels were increased in E.g-infected 4- and 12-week mice, and reduced in 36-week mice. E.g-infected mice consistently recruited Ghrelin in and around the hepatic lesions, which was extremely strongly co-localized with the protein expression of hepatic stellate cells (HSCs), T cells and the TGF-ß1/Smad3 pathway. The secretion of Ghrelin was increased with increasing concentrations of PSCs protein in HepG2 cells culture medium. Moreover, Ghrelin could significantly inhibit the secretion of IL-2, INF-γ and TNF-α, as well as the expression of Myd88/NF-κB and TGF-ß1/Smad3 pathway protein, and promoted the secretion of IL-4 and IL-10. Blocking Ghrelin receptor could significantly inhibit PSCs growth in in vitro experiment. CONCLUSION: Ghrelin is highly expressed in the early stages of hepatic E.g infection and may be involved in regulating the progression of liver lesions by suppression immunoinflammation and fibrosis.

From colon wall to tumor niche: Unraveling the microbiome's role in colorectal cancer progression.

Colorectal cancer (CRC) is influenced by perturbations in the colonic microbiota, characterized by an imbalance favoring pathogenic bacteria over beneficial ones. This dysbiosis contributes to CRC initiation and progression through mechanisms such as carcinogenic metabolite production, inflammation induction, DNA damage, and oncogenic signaling activation. Understanding the role of external factors in shaping the colonic microbiota is crucial for mitigating CRC progression. This study aims to elucidate the gut microbiome's role in CRC progression by analyzing paired tumor and mucosal tissue samples obtained from the colon walls of 17 patients. Through sequencing of the V3-V4 region of the 16S rRNA gene, we characterized the tumor microbiome and assessed its association with clinical variables. Our findings revealed a significant reduction in alpha diversity within tumor samples compared to paired colon biopsy samples, indicating a less diverse microbial environment within the tumor microenvironment. While both tissues exhibited dominance of similar bacterial phyla, their relative abundances varied, suggesting potential colon-specific effects. Fusobacteriota enrichment, notably in the right colon, may be linked to MLH1 deficiency. Taxonomy analysis identified diverse bacterial genera, with some primarily associated with the colon wall and others unique to this region. Conversely, several genera were exclusively expressed in tumor tissue. Functional biomarker analysis identified three key genes with differential abundance between tumor microenvironment and colon tissue, indicating distinct metabolic activities. Functional biomarker analysis revealed three key genes with differential abundance: K11076 (putrescine transport system) and K10535 (nitrification) were enriched in the tumor microenvironment, while K11329 (SasA-RpaAB circadian timing mediator) dominated colon tissue. Metabolic pathway analysis linked seven metabolic pathways to the microbiome. Collectively, these findings highlight significant gut microbiome alterations in CRC and strongly suggest that long-term dysbiosis profoundly impacts CRC progression.

The link between fear of disease progression and health promotion behaviors in patients with obstructive sleep apnea hypoventilation syndrome (OSAHS): the mediating role of social support.

OBJECTIVE: This study aims to assess the levels of social support, fear of disease progression (FOP) and health promotion behaviors in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS), and to examine the associations between FOP, social support, and health promotion behaviors in OSAHS patients, with a focus on exploring the mediating role of social support. The findings aim to provide insights for enhancing health promotion behaviors among OSAHS patients in China and to offer a theoretical foundation for healthcare professionals in devising intervention strategies to promote health behaviors in individuals with OSAHS. METHODS: This cross-sectional study included 307 patients diagnosed with OSAHS in Jinzhou City, Liaoning province. The survey instruments utilized included the Demographic Characteristics Questionnaire, Social Support Rating Scale (SSRS), Fear of Disease Progression Scale (Fop-Q-SF), and Health-Promoting Lifestyle Scale (HPLP II). Pearson correlation analysis was employed to assess correlations, while multiple linear regression and structural equation modeling were utilized to explore potential mediation effects. RESULTS: In the OSAHS patient population, FOP (r=-0.55, p<0.001) and social support (r = 0.60, p<0.001) were found to be significantly correlated with health promotion behaviors. In the mediated effects model, social support was identified as a partial mediator in the association between FOP and health promotion behaviors among OSAHS patients, accounting for 59.00% of the total effect. CONCLUSION: FOP demonstrates a direct relationship with health promotion behaviors in patients with OSAHS, with social support playing a mediating role in this connection. Healthcare professionals are advised to underscore the significance of social support in promoting the health of OSAHS patients to mitigate FOP and consequently improve health promotion behaviors.

Effect of a nurse-led integrated care intervention on quality of life and rehospitalisation in patients with severe exacerbation of COPD-a pilot study.

OBJECTIVE: To explore the feasibility and effect of a nurse-led integrated care intervention on health-related quality of life (QoL) and unplanned 90-day rehospitalisation in patients hospitalised due to acute exacerbation of COPD (AECOPD). METHOD: A monocentric non-randomized parallel cluster design was applied. The primary endpoint was the difference between Chronic Respiratory Questionnaire (CRQ) Mastery Scores at hospital discharge and 13 weeks post-discharge. Secondary endpoints were differences between other CRQ scores, numbers of rehospitalisations and self-reported exacerbations. The study would end either 13 weeks after the full sample size was achieved or when study time ran out. RESULTS: The study was terminated before reaching the targeted sample size. Of 174 invitees, 69 (39.7%, 30 control, 39 intervention) consented to participate. Of those, 47 completed the study, 45 of whom had complete data sets for the primary endpoint. No differences in QoL scores, unplanned COPD-related rehospitalisations or unplanned all-cause rehospitalisations were detected. The mean number of self-reported moderate exacerbations was higher in the intervention group (p = 0.006). CONCLUSION: The pilot study had slow recruitment, high drop-out rates, and no significant effect on 3-month outcomes. Further research should focus on enhancing the current understanding of how to motivate and recruit patients in this setting. CLINICALTRIALS.GOV ID: NCT04011332.

Temporal Dynamics of Cardiovascular Risk in Patients with Chronic Obstructive Pulmonary Disease During Stable Disease and Exacerbations: Review of the Mechanisms and Implications.

Introduction: Exacerbations of chronic obstructive pulmonary disease (COPD) are risk factors for severe cardiovascular (CV) events, with the risk remaining significantly elevated long after the symptomatic phase of the exacerbation. The pathophysiology underpinning the relationship between acute events of both COPD and CV diseases has been understudied. Our objectives were to review the mechanisms by which COPD exacerbations increase the risk of CV events and understand the temporality of this risk. Methods: A pragmatic and targeted literature review was conducted with a focus on identifying recent, high-impact papers up to June 2023, guided by insights from subject matter experts including pulmonologists and cardiologists. Results: A substantial number of inter-related mechanisms underpin the spiral of anatomical and functional deterioration of lung and heart affecting COPD patients during stable state. In turn, an exacerbation of COPD may trigger a CV event, during and beyond the symptomatic phase, due to ventilation/perfusion mismatch, oxygen supply-demand imbalance, oxidative stress, systemic inflammation, hypercoagulable state, dynamic hyperinflation, pulmonary hypertension, and sympathetic activation. However, no study was identified that explored the mechanisms by which an exacerbation confers a sustained risk of CV event. Conclusion: While our review identified multiple dynamic and interacting pathophysiological mechanisms during and after an exacerbation of COPD that contribute to increasing the risk of a wide range of cardiac events, little is known regarding the precise long-term mechanisms after acute exacerbation to explain the persistent increased CV event risk beyond the symptomatic phase. The temporal changes in static and dynamic substrates need further characterization to better understand the different risk factors and risk periods for a CV event following the onset of an exacerbation. Moreover, guideline-directed cardiopulmonary therapies should be implemented at every opportunity; preventing exacerbations and intensively treating traditional CV risk factors should be a focus in COPD management.

Biomarkers of Prothrombotic State and Risk Assessment of Exacerbations in Patients with Chronic Obstructive Pulmonary Disease.

Background: Epidemiologic studies have shown that patients with acute exacerbation of COPD (AECOPD) suffer from morbidity and mortality from venous thromboembolism (VTE) and poor diagnosis. Von Willebrand factor (vWF) and plasminogen activator inhibitor type-1 (PAI-1) are frequently investigated in COPD as crucial parameters for coagulation and fibrinolysis. Nevertheless, the role of vWF and PAI-1 in AECOPD needs further exploration. Objective: We sought to evaluate the hypercoagulability in AECOPD and investigate the association of plasma vWF and PAI-1 with occurrence and exacerbation risk of AECOPD patients. Methods: Fifty-seven AECOPD patients and 34 control subjects were enrolled in our study. The concentrations of plasma vWF and PAI-1 antigens were measured by ELISA kit. Independent samples t-test or Wilcoxon rank sum test was applied for group comparison. Spearman correlation analysis, subject work curve (ROC) analysis, and Logistic regression were used to evaluate the role of the plasma vWF and PAI-1 in AECOPD. Results: We observed increased vWF (770.15 ± 325.52 vs 327.62 ± 210.97 ng/mL, P < 0.001) and PAI-1 (0.47 vs 0.17 ng/mL, P < 0.001) levels in AECOPD patients compared with control subjects. Both vWF and PAI-1 are closely related to COPD (vWF: AUC = 0.8741, P < 0.001; PAI-1: AUC = 0.8222, P < 0.001). Moreover, elevated vWF could be an independent risk factor for COPD (OR = 1.01, 95% CI: 1.00-1.01, P = 0.01). We also discovered higher plasma levels of vWF and PAI-1 in the COPD "E" group in contract to "AB" group (vWF: 966.29 ± 251.18 vs 552.21 ± 253.28, P < 0.0001; PAI-1: 1.02 vs 0.38, P = 0.003). And vWF levels increased with increasing COPD exacerbation risk, moreover, plasma vWF positively related with patients' CAT scores and SGRQ scores. In addition, plasma vWF and PAI-1 correlated with each other in total participants and AECOPD subgroup analysis. Conclusion: This study demonstrated that AECOPD patients have a prothrombotic state, as demonstrated by vWF and PAI-1 levels in plasma compared with those in control subjects, and the prothrombotic state increases with increasing COPD exacerbation risk.

LAMP-based electrochemical platform for monitoring HPV genome integration at the mRNA level associated with higher risk of cervical cancer progression.

Human papillomaviruses (HPVs) represent a diverse group of double-stranded DNA viruses associated with various types of cancers, notably cervical cancer. High-risk types of HPVs exhibit their oncogenic potential through the integration of their DNA into the host genome. This integration event contributes significantly to genomic instability and the progression of malignancy. However, traditional detection methods, such as immunohistochemistry or PCR-based assays, face inherent challenges, and thus alternative tools are being developed to fasten and simplify the analysis. Our study introduces an innovative biosensing platform that combines loop-mediated amplification with electrochemical (EC) analysis for the specific detection of HPV16 integration. By targeting key elements like the E7 mRNA, a central player in HPV integration, and the E2 viral gene transcript lost upon integration, we show clear distinction between episomal and integrated forms of HPV16. Our EC data confirmed higher E7 expression in HPV16-positive cell lines having integrated forms of viral genome, while E2 expression was diminished in cells with fully integrated genomes. Moreover, we revealed distinct expression patterns in cervical tissue of patients, correlating well with digital droplet PCR, qRT-PCR, or immunohistochemical staining. Our platform thus offers insights into HPV integration in clinical samples and facilitates further advancements in cervical cancer research and diagnostics.

[Choice of fractionation regimen for Grade IV gliomas depending on rapid early progression]. / Vybor rezhima fraktsionirovaniya pri gliomakh IV stepeni zlokachestvennosti v zavisimosti ot bystrogo rannego progressirovaniya (REP).

OBJECTIVE: To investigate the effect of two fractionation regimens on survival in patients with Grade IV gliomas depending on rapid early progression (REP). MATERIAL AND METHODS: Fractionation with prescribed doses of 2 and 3 Gy was alternately used in 140 patients with morphologically confirmed Grade IV glioma using a pairwise modeling strategy. RESULTS: REP was diagnosed in 60 (42.9%) out of 140 patients with Grade IV gliomas and 55 (45.5%) out of 121 patients with glioblastomas. Fatal outcome was observed in 111 (79.3%) patients, 99 (70.7%) ones died from progression of glioma. In case of no REP, the median overall survival as of December 2023 was 32.20 (95% CI 25.7-38.7) months, with REP - only 16.03 (95% CI 13.5-18.6) months (p<0.0001). Median survival was slightly lower in patients with glioblastoma - 28.2 and 16.5 months, respectively (p<0.0001).In patients with Grade IV gliomas and no REP, 3 Gy (n=40) fractionation regimen was followed by median overall survival 44.98 (95% Cl 15.3-74.6) months, 2 Gy (n=40) - 20.99 (95% CI 9.2-32.7) months (p=0.027). In case of glioblastoma, differences between fractionation regimes lose significance - medians 33.7 and 19.7 months, respectively (p=0.081). According to multivariate analysis, 3 Gy fractionation regimen is more effective than standard radiotherapy (p=0.009) in patients without REP, while significance of isoeffective doses <59.5Gy≥ is slightly lower (p=0.020). Radiotherapy on the background of temozolomide is equally important (p=0.007).In patients with grade 4 gliomas and REP, 3 Gy (n=30) fractionation regimen was followed by median overall survival 17.18 (95% CI 14.2-20.2) months, 2 Gy (n=30) - 12.88 (95% CI 5.4-20.3) months (p=0.849). In case of glioblastoma, Cox model classification matrix looks as follows: fractionation variant (p=0.423), isoeffective dose <59.5Gy≥ (p<0.0001), temozolomide during radiotherapy (p=0.701), functional status (p=0.485). CONCLUSION: In patients with Grade IV gliomas and no REP, 3 Gy fractionation regimen has significant advantages over standard radiotherapy regarding overall survival. In case of more aggressive course of tumor (REP), higher single dose does not improve treatment outcomes. Isoeffective dose ≥59.5Gy is of great importance.

The Double-Edged Sword Property of Mesenchymal Stem Cell-Derived Exosomal microRNAs in Colorectal Cancer.

Mesenchymal stem cells (MSCs)-based therapies are promising therapeutic strategies for cancer treatment, because of their strong immunomodulatory and tissue regeneration abilities. In case of colorectal cancer (CRC), MSCs indicate a double-edged sword activity. Some reports declared the inhibitory effects of MSCs on the proliferation, migration, and infiltration of cancer cells to suppress the CRC initiation and development, whereas others showed the tumor-promoter impacts of MSCs on the progression of CRC. Recent investigations have revealed that exosomal microRNAs (Exo-miRs) derived from MSCs (MSCs-Exo-miRs) are attributed to such paradoxical effect. Thus, the current review aimed to seek the role of MSCs-Exo-miRs in CRC progression and their therapeutic potential for the CRC treatment.

lncRNA POLR2J4 Plays a Biomarker Role in Hepatitis B Virus-Related Hepatocellular Carcinoma Through Regulating miR-214-3p.

Identifying novel therapeutic targets for hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) has become a key goal in liver cancer research. Even though long non-coding RNAs (lncRNAs) do not code proteins, they could regulate the expression of functional genes and thus mediate disease development. The aim of this study was to estimate the role of lncRNA POLR2J4 (POLR2J4) in the progression of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) to pinpoint a potential biomarker. This study included 109 patients diagnosed with HBV-positive HCC, from whom tissue samples were collected. The expression level of POLR2J4 was evaluated by qPCR. The significance of POLR2J4 in HBV-HCC development and prognosis was estimated by Chi-square, Kaplan-Meier, and Cox analysis. In vitro, POLR2J4 was regulated in HBV-HCC cells, and its effect on cell growth and metastasis was assessed by CCK8 and Transwell assay. The interaction between POLR2J4 and miR-214-3p was evaluated through the luciferase reporter and RNA immunoprecipitation assays. In tumor tissues of HBV-HCC patients, there was an observed increase in the expression of POLR2J4. The increase was closely related with patients' presence of cirrhosis and vascular invasion, higher AFP, and advanced Edmondson grade and TNM stage. An upregulation of POLR2J4 predicted a poor prognosis for HBV-HCC patients and served as an independent indicator. In HBV-related HCC cells, silencing POLR2J4 suppressed cell proliferation, migration, and invasion. Furthermore, POLR2J4 negatively regulated miR-214-3p reversing the inhibition of cellular processes. POLR2J4 acted as a prognostic biomarker and a tumor promoter of HBV-HCC by modulating miR-214-3p.

Effect of telomere shortening on disease progression in patients with inflammatory bowel disease: A systematic review and meta-analysis protocol.

INTRODUCTION: Inflammatory bowel disease (IBD) remains a major public health challenge worldwide. In recent years, it has been discovered that a link between telomere shortening and disease progression in IBD patients has been present. However, there is controversy as to whether telomere shortening precipitates disease progression or disease progression causes telomere shortening. There is also a shortage of systematic reviews and data synthesis to explain the association between telomere shortening and disease progression in individuals with IBD. We aimed to systematically review the association between telomere shortening and disease advancement in individuals with IBD to inform future studies. METHODS AND ANALYSIS: We will undertake a thorough search of the electronic database from the beginning until December 31, 2023. We will search the databases: MEDLINE/PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), VIP, Wanfang Database (Wanfang), CMB, Cochrane Library, Cochran Clinical Trials Registry, and the World Health Organization International Clinical Trials Registry Platform. Two reviewers will assess the discovered citations for eligibility based on the title and abstract before proceeding to the full-text and data extraction phases. These reviewers will debate and settle any conflicts that arise during the inclusion process; a third reviewer will settle any issues that remain. The validated data extraction form will be used to collect data for eligible research. The included studies will undergo a quality and bias check and will proceed meta-analysis. DISCUSSION: This systematic review and meta-analysis will reveal a positive correlation between illness progression and telomere shortening in individuals with IBD, perhaps demonstrating three causal links between them. This study will conduct the first systematic review and meta-analysis examining the correlation between telomere shortening and illness advancement in individuals with IBD. Exploring the connection between these two situations can enhance the comprehension of the development and advancement of IBD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42024501171.

Targeting cancer-associated fibroblasts/tumor cells cross-talk inhibits intrahepatic cholangiocarcinoma progression via cell-cycle arrest.

BACKGROUND: Cancer-associated fibroblasts (CAFs), mainly responsible for the desmoplastic reaction hallmark of intrahepatic Cholangiocarcinoma (iCCA), likely have a role in tumor aggressiveness and resistance to therapy, although the molecular mechanisms involved are unknown. Aim of the study is to investigate how targeting hCAF/iCCA cross-talk with a Notch1 inhibitor, namely Crenigacestat, may affect cancer progression. METHODS: We used different in vitro models in 2D and established new 3D hetero-spheroids with iCCA cells and human (h)CAFs. The results were confirmed in a xenograft model, and explanted tumoral tissues underwent transcriptomic and bioinformatic analysis. RESULTS: hCAFs/iCCA cross-talk sustains increased migration of both KKU-M213 and KKU-M156 cells, while Crenigacestat significantly inhibits only the cross-talk stimulated migration. Hetero-spheroids grew larger than homo-spheroids, formed by only iCCA cells. Crenigacestat significantly reduced the invasion and growth of hetero- but not of homo-spheroids. In xenograft models, hCAFs/KKU-M213 tumors grew significantly larger than KKU-M213 tumors, but were significantly reduced in volume by Crenigacestat treatment, which also significantly decreased the fibrotic reaction. Ingenuity pathway analysis revealed that genes of hCAFs/KKU-M213 but not of KKU-M213 tumors increased tumor lesions, and that Crenigacestat treatment inhibited the modulated canonical pathways. Cell cycle checkpoints were the most notably modulated pathway and Crenigacestat reduced CCNE2 gene expression, consequently inducing cell cycle arrest. In hetero-spheroids, the number of cells increased in the G2/M cell cycle phase, while Crenigacestat significantly decreased cell numbers in the G2/M phase in hetero but not in homo-spheroids. CONCLUSIONS: The hCAFs/iCCA cross-talk is a new target for reducing cancer progression with drugs such as Crenigacestat.

The pharmacological management of alcohol-related cirrhosis: what's new?

INTRODUCTION: Alcohol use disorder (AUD) is present in the majority of patients with alcohol-associated liver disease (ALD), which leads to about 50% of cirrhosis-related hospitalizations and over 25% of deaths worldwide. Patients with ALD often present at an advanced stage, like cirrhosis with its complications and alcohol-associated hepatitis (AH), which has high short-term mortality. Current treatments are limited, with the limited benefit of glucocorticoids only in the short-term among patients with AH, highlighting an urgent need for novel therapies. AREAS COVERED: This review applies the PIRO (Predisposition, Injury, Response, Organ dysfunction) concept to ALD, understanding an ongoing process of liver damage, and opportunities to address and halt the progression. We also highlight the significance of treating AUD to improve long-term outcomes in ALD. EXPERT OPINION: Personalized therapies targeting specific genetic profiles and multiple pathogenic pathways are crucial in managing ALD. Emerging therapies like gut-liver-brain axis modulators like fecal microbiota transplant and probiotics, interleukin-22, granulocyte-colony stimulating factor (G-CSF) and stem cells, epigenetic regulators of inflammation and regeneration are encouraging with the potential of efficacy in patients with ALD. Liver transplantation (LT) is a definitive therapy for advanced cirrhosis with increasing impetus on early LT select patients with active alcohol use.

Effect of Ocular Perfusion Pressure on Incidence of Diabetic Retinopathy in Type 2 Diabetes: A Two-Year Prospective Study.

Purpose: To investigate the association between mean ocular perfusion pressure (MOPP), estimated cerebrospinal fluid pressure (CSFP), and changes in diabetic retinopathy (DR) in a Southern Chinese population with type 2 diabetes (T2DM). Methods: A total of 1224 subjects from the Guangzhou Diabetic Eye Study were enrolled. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and intraocular pressure (IOP) were measured. MOPP was calculated with the formula: MOPP = 2/3 [DBP + 1/3 (SBP - DBP)] - IOP. CSFP was calculated using the formula: CSFP = 0.44 × body mass index (kg/m2) + 0.16 × DBP - 0.18 × age (years) - 1.91. Incidence, progression, and regression of DR were graded based on seven-field 45° conventional fundus photographs at baseline and during two-year follow-up examinations according to the United Kingdom National Diabetic Eye Screening Program guidelines. Results: Higher MOPP was associated with DR incidence in the multivariate model (per 1 mm Hg increase: relative risk, 1.05; 95% confidence interval, 1.01-1.09; P = 0.02) and was not associated with DR development and DR regression in two-year follow-up of T2DM patients. However, CSFP was not associated with DR changes (incidence, progression, or regression). Conclusions: The higher MOPP is an independent risk factor for DR incidence among T2DM patients in a Southern Chinese cohort. Monitoring MOPP and managing blood pressure can be part of a comprehensive approach to prevent or delay the onset of DR in T2DM patients. Translational Relevance: MOPP might be an indicator for the detection of DR incidence.

Baseline Diameter Does Not Predict Growth Rate in a Presurgical Ascending Thoracic Aortic Aneurysm Population.

BACKGROUND: Patients with ascending thoracic aortic aneurysm are recommended to undergo routine imaging surveillance. Although maximal diameter is the primary metric of disease severity, recent American College of Cardiology/American Heart Association guidelines emphasize the importance of aortic growth in determining surgical candidacy and risk. As diameter increases, it is assumed that aortic growth rate accelerates because of increased wall tension; however, this relationship is poorly studied. We aim to investigate the relationship between ascending thoracic aortic aneurysm diameter and growth rate using vascular deformation mapping, a validated technique for 3-dimensional growth mapping with submillimeter accuracy. METHODS AND RESULTS: We retrospectively identified adult patients with ascending aortic dilation (≥4.0 cm) and serial gated computed tomography angiograms separated by ≥2 years, excluding confirmed heritable thoracic aortic disease. Ascending growth rate was defined as 90th percentile radial wall deformation by vascular deformation mapping. Maximal diameter measurements were derived from the baseline computed tomography angiogram, and aortic length and body size-adjusted indexes were calculated. Among 258 included patients (63.2% men; age of 63 years [interquartile range, 55-69 years]), mean±SD baseline diameter was 46.3±3.6 mm and median growth rate was 0.21 mm/year (interquartile range, 0.13-0.38 mm/year). No correlation was noted between growth rate and baseline diameter (r=0.02, P=0.74) or other aortic size metrics. On multivariate analysis, age was independently predictive of growth rate (ß=-0.007, P=0.021), alongside weight (ß=0.003, P=0.016) and the presence of moderate or severe aortic valve insufficiency (ß=0.146, P=0.049). CONCLUSIONS: Maximal aortic diameter is not predictive of aortic growth rate, in this contemporary cohort of patients with sizes under current surgical thresholds (<55 mm).

SEVERE DISEASE PROGRESSION OF POSTMOLAR GESTATIONAL NEOPLASM IN A VIETNAMESE YOUNG FEMALE PATIENT AFTER TREATMENT REFUSAL: INSIGHTS FROM A CASE REPORT AND LITERATURE REVIEW.

Choriocarcinoma is characterized as the most aggressive malignant alternation of gestational trophoblastic neoplasm; however, this illness is a curable malignancy. Although a rarity, this disease affects a female patient's life and causes a fatal condition. Choriocarcinoma is a life-threatening disease since it is initially insidious and can rapidly lead to masive hemorrhage, even death. Choriocarcinoma should be suspected in childbearing-age women with the high-risk scores according to FIGO. The study aims to report a severe case of widespread metastatic choriocarcinoma to optimize the treatment with multiagent chemotherapy and a multidisciplinary cooperation at our center. A G1P0 20-year-old woman was referred to the hospital for suspicion of metastatic choriocarcinoma after self-stopping chemotherapy because of the COVID-19 pandemic. During hospitalization, the tumor metastasized and presented profuse intraabdominal hemorrhage. The patient underwent immediate surgical intervention to control bleeding, and a definitive diagnosis was accurately established by the histopathological examination. After surgery, the EMA/CO regimen was administered as the first line of treatment, despite the patient being in a coma and requiring a ventilator machine. After 6 cycles of the EMA/CO regimen, her serum ß-hCG level decreased to 8 mUI/mL, however, her ß-hCG concentration was not down to a negative value. Thus, the patient received paclitaxel/cisplatin alternating with paclitaxel/etoposide (TP/TE regimen) for complete remission following 2 cycles. The delays in choriocarcinoma treatment are prognostic factors for worse outcomes, whereas chemotherapy may be considered a suitable treatment even in a patient's coma, thus improving a prognosis substantially.