Kombo knife combined with sorafenib in liver cancer treatment: Efficacy and safety under immune function influence.

BACKGROUND: In the quest to manage hepatocellular carcinoma (HCC), the focus has shifted to a more holistic approach encompassing both data analytics and innovative treatments. Analyzing rich data resources, such as the cancer genome atlas (TCGA), and examining progressive therapies can potentially reshape the trajectory of HCC treatment. AIM: To elucidate the immunological genes and the underlying mechanism of the combined Kombo knife and sorafenib regimen for HCC by analyzing data from TCGA and machine learning data. METHODS: Immune attributes were evaluated via TCGA's postablation HCC RNA sequencing data. Using weighted gene coexpression network analysis and machine learning, we identified genes with high prognostic value. The therapeutic landscape and safety metrics of the integrated treatment were critically evaluated across cellular and animal models. RESULTS: Immune genes-specifically, peptidylprolyl isomerase A and solute carrier family 29 member 3-emerged as significant prognostic markers. Enhanced therapeutic outcomes, such as prolonged progression-free survival and an elevated overall response rate, characterize the combined approach, with peripheral blood mononuclear cells displaying potent effects on HCC dynamics. CONCLUSION: The combination of Kombo knife with sorafenib is an innovative HCC treatment modality anchored in immune-centric strategies.

Drosophila mutants lacking the glial neurotransmitter-modifying enzyme Ebony exhibit low neurotransmitter levels and altered behavior.

Inhibitors of enzymes that inactivate amine neurotransmitters (dopamine, serotonin), such as catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO), are thought to increase neurotransmitter levels and are widely used to treat Parkinson's disease and psychiatric disorders, yet the role of these enzymes in regulating behavior remains unclear. Here, we investigated the genetic loss of a similar enzyme in the model organism Drosophila melanogaster. Because the enzyme Ebony modifies and inactivates amine neurotransmitters, its loss is assumed to increase neurotransmitter levels, increasing behaviors such as aggression and courtship and decreasing sleep. Indeed, ebony mutants have been described since 1960 as "aggressive mutants," though this behavior has not been quantified. Using automated machine learning-based analyses, we quantitatively confirmed that ebony mutants exhibited increased aggressive behaviors such as boxing but also decreased courtship behaviors and increased sleep. Through tissue-specific knockdown, we found that ebony's role in these behaviors was specific to glia. Unexpectedly, direct measurement of amine neurotransmitters in ebony brains revealed that their levels were not increased but reduced. Thus, increased aggression is the anomalous behavior for this neurotransmitter profile. We further found that ebony mutants exhibited increased aggression only when fighting each other, not when fighting wild-type controls. Moreover, fights between ebony mutants were less likely to end with a clear winner than fights between controls or fights between ebony mutants and controls. In ebony vs. control fights, ebony mutants were more likely to win. Together, these results suggest that ebony mutants exhibit prolonged aggressive behavior only in a specific context, with an equally dominant opponent.

The predictive value of MiR-221 in cancer chemoresistance: a systematic review and meta-analysis.

BACKGROUND: Many studies have reported that microRNA-221 (miR-221) is abnormally expressed in various cancers, and there has not been a study to systematically analyze the association between miR-221 and chemoresistance in different cancers. METHODS: We systematically searched PubMed, Web of Science, Ovid, and Cochrane for relevant studies. The pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate. RESULTS: A total of 30 studies with 1670 patients were enrolled in our study. Thirteen cancer types have been studied, and traditional chemotherapy, targeted drugs, endocrine therapy, chemoradiotherapy, and other treatments were used. High miR-221 expression was associated with poor chemotherapy response in most studies, and the meta-analysis confirmed this result (OR = 3.64, 95%CI: 1.73-7.62, p = 0.001). Besides, the higher level of miR-221 was related to shorter overall survival (OS) (HR = 2.16, 95%CI: 1.47-3.16, p < 0.001) and progression-free survival (PFS) (HR = 1.81, 95%CI: 1.51-2.16, p < 0.001) in patients after chemotherapy. CONCLUSION: Our results highlight that high miR-221 expression has possible associations with chemoresistance and poor prognosis in multiple cancers. Further studies are needed to discover the molecular mechanisms underlying these associations to provide a solid evidence base for it being used as biomarkers of response to chemotherapeutic interventions in cancer.

CCL18 promotes migration and invasion of multiple myeloma cells and is associated with poor prognosis.

CCL18 has recently been implicated in malignancies and is increasingly mentioned as a potential tumoral biomarker and furtherly a molecular target for therapeutic intervention, but its expression and clinical significance in multiple myeloma have not been explored. Serum CCL18 levels were measured by ELISA method in 254 newly diagnosed multiple myeloma (NDMM), 21 monoclonal gammopathy of undetermined significance (MGUS) and 22 healthy adults. The study suggests that the serum CCL18 level in NDMM patients was significantly higher than that in MGUS and healthy adults. High level of CCL18 were associated with advanced ISS and R-ISS stages in MM. Patients with high serum CCL18 displayed a significantly more frequent occurrence of renal impairment and hypercalcemia, while the proportion of achieving complete remission (CR) was lower. More importantly, Cox analysis identified CCL18 and LDH as independent predictors of PFS in MM patients, whereas CCL18, creatinine and LDH were independent predictors of OS. Finally, we show that CCL18 can promote migration and invasion of myeloma cell lines RPMI8226 and MM.1S. CCL18 may play a tumor-promoting role by increasing the migration and invasion abilities of myeloma cells.

Prognostic nomogram incorporating cytokines for overall survival in patients with newly diagnosed multiple myeloma.

OBJECTIVE: The purpose of this study was to explore the relationship between pretreatment cytokine status and overall survival and establish a prognostic nomogram incorporating cytokines in newly diagnosed multiple myeloma (NDMM) patients. METHODS: A total of 121 patients with NDMM from the Wuhan Union Hospital were included in our study. Patient serum levels of cytokines, including macrophage inflammatory protein 1 alpha (MIP-1α), migration inhibitory factor (MIF), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor-α (VEGF-α), monocyte chemoattractant protein-1 (MCP-1) and soluble interleukins IL-17A, IL-6, IL-21 and IL-10 were assessed before treatment. Based on the results of the multivariate Cox proportional hazards model, we developed a prognostic nomogram. We used the concordance index (C-index) and a calibration curve to measure the predictive performance of the nomogram. RESULTS: Three important variables (lactate dehydrogenase, MIP-1α and creatinine) were incorporated in the nomogram using multivariate Cox analysis. The 3-year overall survival (OS) rate and progression-free survival (PFS) rate were 83.8% and 21.8% in the low-risk group of the nomogram and 17.4% and 8.4% in the high-risk group, respectively. The C-index of the nomogram for OS prediction was 0.80 (95% CI: 0.68-0.92), showing superiority over the predictive power of the Durie-Salmon staging system (C-index = 0.58; 95% CI: 0.49-0.67), International Staging System (C-index = 0.70; 95% CI: 0.61-0.79) and Revised-International Staging System (C-index = 0.71; 95% CI: 0.63-0.80). The calibration curve showed that the nomogram accurately predicted the 1-year, 2-year and 3-year OS of NDMM patients. CONCLUSION: The established nomogram provides accurate and individualized OS risk estimation for NDMM patients.

Comparative study of two Chinese versions of Montreal Cognitive Assessment for Screening of Mild Cognitive Impairment.

Our aim was to compare the utility and accuracy of the Chinese Version of Montreal Cognitive Assessment Basic (MoCA-BC) and the Montreal Cognitive Assessment-Beijing Version (MoCA-BJ) in the identification of mild cognitive impairment (MCI) under different education levels. A sample of individuals with MCI (n = 295), Alzheimer's disease (AD; n = 254), and normal controls (NC; n = 259) at 2 Memory Clinics and communities was administered the MoCA-BC, MoCA-BJ, Mini-Mental State Examination (MMSE), and other neuropsychological tests. The discriminant validity of the MoCA-BC and MoCA-BJ as diagnostic instruments was ascertained. The overall discriminant validity for detection of MCI from NC (receiver operating characteristic area under the curve [95% confidence interval]) was that the MoCA-BC (0.95 [0.93, 0.97]) had better sensitivity and accuracy than MoCA-BJ (0.87 [0.84, 0.90]). In addition, we provide an easy to use table that enables the conversion of MoCA-BC to the MoCA-BJ scores or to MMSE scores. The MoCA-BC and MoCA-BJ provided good diagnostic accuracy when compared to MMSE. The MoCA-BC, which was proved to be an appropriate tool when screening for MCI among elderly subjects, can now be compared directly with the MoCA-BJ.

Role of Moesin Phosphorylation in Retinal Pericyte Migration and Detachment Induced by Advanced Glycation Endproducts.

Proliferative diabetic retinopathy (PDR) involves persistent, uncontrolled formation of premature blood vessels with reduced number of pericytes. Our previous work showed that advanced glycation endproducts (AGEs) induced angiogenesis in human umbilical vein endothelial cells, mouse retina, and aortic ring, which was associated with moesin phosphorylation. Here we investigated whether moesin phosphorylation may contribute to pericyte detachment and the development of PDR. Primary retinal microvascular pericytes (RMPs) were isolated, purified from weanling rats, and identified by cellular markers α-SMA, PDGFR-ß, NG2, and desmin using immunofluorescence microscopy. Effects of AGE-BSA on proliferation and migration of RMPs were examined using CCK-8, wound healing, and transwell assays. Effects on moesin phosphorylation were examined using western blotting. The RMP response to AGE-BSA was also examined when cells expressed the non-phosphorylatable Thr558Ala mutant or phospho-mimicking Thr558Asp mutant of moesin or were treated with ROCK inhibitor Y27632. Colocalization and interaction between CD44, phospho-moesin, and F-actin were observed. Experiments with cultured primary RMPs showed that AGE-BSA inhibited the proliferation, enhanced the migration, and increased moesin phosphorylation in a dose- and time-dependent manner. AGE-BSA also triggered the rearrangement of F-actin and promoted the interaction of CD44 with phospho-moesin in RMPs. These effects were abrogated in cells expressing the non-phosphorylatable moesin mutant and the application of ROCK inhibitor Y27632 attenuated AGE-induced alteration in cultured RMPs by abolishing the phosphorylation of moesin. However, those AGE-induced pathological process occurred in RMPs expressed the phospho-mimicking moesin without AGE-BSA treatment. It is concluded that AGEs could activate ROCK to mediate moesin phosphorylation at Thr558, and resulting phospho-moesin interacts with CD44 to form CD44 cluster, which might stimulate the migration of RMPs and subsequent RMP detachment in microvessel. This pathway may provide new drug targets against immature neovessel formation in PDR.

Impact of tenofovir antiviral treatment on survival of chronic hepatitis B related hepatocellular carcinoma after hepatectomy in Chinese individuals from Qingdao municipality.

The impact of different antiviral regimen on prognosis of chronic hepatitis B (CHB) related hepatocellular carcinoma (HCC) remains to be explored.A total of 479 CHB-related HCC patients after curative liver resection were enrolled receiving tenofovir (TDF, TDF group) or lamivudine, telbivudine, and entecavir (non-TDF group). Both the overall survival and diseases-free survival were analyzed and compared.A total of 242 patients received TDF treatment and 237 patients received other antiviral regimen. Child-Pugh score, serum α-fetoprotein (AFP) level, total bilirubin level, status of hepatitis B e antigen (HBeAg), and cirrhosis were compared between groups. Kaplan-Meier analysis revealed that patients with TDF treatment had significantly longer overall survival than those of patients with other regimen (P = .015). Similarly, compared with patients with non-TDF treatment, disease-free survival time was longer (P = .042) in those with TDF treatment. Multivariate analysis showed that TDF treatment (P = .04), AFP level (P = .03) were significant independent factors associated with overall survival of CHB-related HCC patients. While TDF treatment (P = .04) and serum AFP level (P = .03) were independent factors associated with disease-free survival.Anti-virus treatment with TDF benefits for both overall survival and disease-free survival of CHB-related patients than other Nucleos(t)ide analogues.

Serum soluble VSIG4 as a surrogate marker for the diagnosis of lymphoma-associated hemophagocytic lymphohistiocytosis.

Lymphoma-associated haemophagocytic lymphohistiocytosis (L-HLH) is characterized by excessively activated macrophages and cytotoxic T lymphocytes, but few reliable markers for activated macrophages are available clinically. This study, designed to discover novel biomarkers for the diagnosis of lymphoma patients with L-HLH, was initiated between 2016 and 2018. Fifty-seven adult lymphoma patients were enrolled - 39 without HLH and 18 with HLH. The differential serum protein expression profile was first screened between lymphoma patients with and without L-HLH by a quantitative mass spectrometric approach. Soluble V-set and immunoglobulin domain-containing 4 (sVSIG4), specifically expressed by macrophages, was significantly upregulated in the L-HLH group. Subsequently, sVSIG4 concentration was confirmed by enzyme-linked immunosorbent assay to be significantly increased in lymphoma patients with L-HLH. When it was exploited for the diagnosis of lymphoma patients with L-HLH, the area under a receiver operating characteristic curve was 0·98 with an optimal cut-off point of 2195 pg/ml and the corresponding sensitivity and specificity were 94·44% and 94·87% respectively. In addition, the one-year overall survival was significantly worse in patients with a sVSIG4 concentration above 2195 pg/ml compared with those below 2195 pg/ml (5·3% vs. 72·2%, P < 0·0001). sVSIG4 may be a surrogate marker of activated macrophages for the diagnosis of lymphoma patients with L-HLH.

Comparison of cryoballoon ablation for atrial fibrillation guided by real-time three-dimensional transesophageal echocardiography vs. contrast agent injection.

BACKGROUND: Pulmonary vein (PV) occlusion generally depends on repetitive contrast agent injection when cryoballoon ablation for atrial fibrillation (AF). The present study was to compare the effect of cryoballoon ablation for AF guided by transesophageal echocardiography (TEE) vs. contrast agent injection. METHODS: Eighty patients with paroxysmal AF (PAF) were enrolled in the study. About 40 patients underwent cryoballoon ablation without TEE (non-TEE group) and the other 40 underwent cryoballoon ablation with TEE for PV occlusion (TEE group). In the TEE group during the procedure, PVs were displayed in 3-dimensional images to guide the balloon to achieve PV occlusion. The patients were followed up at regularly scheduled visits every 2 months. RESULTS: No differences were identified between the groups in regard to the procedure time and cryoablation time for each PV. The fluoroscopy time (6.7 ±â€Š4.2 min vs. 17.9 ±â€Š5.9 min, P < 0.05) and the amount of contrast agent (3.0 ±â€Š5.1 mL vs.18.1 ±â€Š3.4 mL, P < 0.05) in the TEE group were both less than the non-TEE group. At a mean of 13.0 ±â€Š3.3 mon follow-up, success rates were similar between the TEE group and non-TEE group (77.5% vs. 80.0%, P = 0.88). CONCLUSIONS: Cryoballoon ablation with TEE for occlusion of the PV is both safe and effective. Less fluoroscopy time and a lower contrast agent load can be achieved with the help of TEE for PV occlusion during procedure.

Effectiveness of telbivudine antiviral treatment in patients with hepatitis B virus-associated glomerulonephritis: A 104-week pilot study.

The aim of this study was to evaluate clinical efficacy of telbivudine in treatment of hepatitis B virus-associated glomerulonephritis (HBV-GN).A total of 43 HBV-GN patients combined with chronic hepatitis B were treated with telbivudine for 104 weeks. Serum levels of HBV DNA viral load, HBeAg, HBeAb, alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (Cr), and 24-hour urinary protein were evaluated after telbivudine treatment of 12, 24, 52, 76, and 104 weeks. Estimated glomerular filtration rate (eGFR) was calculated at baseline, 24 weeks, 52 weeks, and 104 weeks of treatment, respectively. Complete remission (CR) was defined as urinary protein <0.3 g/day, with normal ALT, AST, Cr, and eGFR. Criteria for partial remission include: 24-hour urinary protein excretion decreased by >50% compared with baseline level, and ALT and AST decreased >50%.Proteinuria level gradually decreased in patients with HBV-GN after telbivudine treatment. The percentages of PR + CR were 90.7% and 95.3%, respectively, at 52 and 104 weeks. Compared to baseline, eGFR were significantly increased from 69.2 ±â€Š23.1 mL/min/1.73 m to 116.2 ±â€Š26.3 mL/min/1.73 m at 104 weeks of treatment. Multivariate analysis indicated that baseline HBV DNA viral load (odds ratio [OR] = 1.19, 95% confidence interval [CI] 1.11-2.19, P = .02) and baseline urinary protein (OR = 1.08, 95% CI 1.04-2.44, P = .03) were independent risk factors associated with CR after telbivudine treatment among patients with HBV-GN.Our study demonstrates that telbivudine can be used to treat HBV-GN and effectively improve eGFR in these patients.

Automated analysis of long-term grooming behavior in Drosophila using a k-nearest neighbors classifier.

Despite being pervasive, the control of programmed grooming is poorly understood. We addressed this gap by developing a high-throughput platform that allows long-term detection of grooming in Drosophila melanogaster. In our method, a k-nearest neighbors algorithm automatically classifies fly behavior and finds grooming events with over 90% accuracy in diverse genotypes. Our data show that flies spend ~13% of their waking time grooming, driven largely by two major internal programs. One of these programs regulates the timing of grooming and involves the core circadian clock components cycle, clock, and period. The second program regulates the duration of grooming and, while dependent on cycle and clock, appears to be independent of period. This emerging dual control model in which one program controls timing and another controls duration, resembles the two-process regulatory model of sleep. Together, our quantitative approach presents the opportunity for further dissection of mechanisms controlling long-term grooming in Drosophila.

Updated concepts on the pathophysiology and the clinical management of trauma hemorrhage and coagulopathy.

Uncontrolled hemorrhage and subsequent trauma-induced coagulopathy (TIC) are still the principle causes for preventable death after trauma and early detection and aggressive management have been associated with reduced mortality. Despite increasing knowledge about trauma resuscitation, best practice to treat this newly defined entity is still under debate. A synopsis of best current knowledge with reference to the updated European trauma guideline on the management of severe trauma hemorrhage and TIC is presented. The implementation of evidence-based local protocols and algorithms including clinical quality and safety management systems together with parameters to assess key measures of bleeding control and outcome is advocated.

Role of moesin, Src, and ROS in advanced glycation end product-induced vascular endothelial dysfunction.

The disruption of endothelial integrity and the occurrence of angiogenesis in response to AGEs contribute greatly to micro- and macrovascular complications associated with DM. Among human dermal, brain, and retinal vascular ECs, activation of ERM, moesin, by phosphorylation of Thr-558 is involved in AGE-induced hyperpermeability and angiogenesis via the Rho and ROCK (Rho/ROCK) and p38 pathways. Src also plays an important role in AGE-induced endothelial barrier dysfunction by phosphorylating moesin, VE-cadherin, and FAK. Furthermore, recent studies have demonstrated that ROS serve as a key mediator of the AGE-induced endothelial response. ROS inhibition would greatly benefit ECs. This review focuses on the role of moesin in microvascular permeability and angiogenesis, and on the involvement of Src and ROS in endothelial barrier disruption.

Glucagon-like peptide-1 inhibits the receptor for advanced glycation endproducts to prevent podocyte apoptosis induced by advanced oxidative protein products.

OBJECTIVE: To investigate whether and how glucagon-like peptide-1 (GLP-1) can protect podocytes from apoptosis induced by advanced oxidative protein products (AOPPs). METHODS: Murine podocytes were stimulated with 200 µg/ml AOPP for 48 h in the presence or absence of GLP-1. Cell viability was assessed using the cell counting kit-8 assay. Podocyte apoptosis was detected by flow cytometry and Hoechst 33258 staining. Superoxide radical production was assayed using lucigenin-enhanced chemiluminescence, and Western blotting was used to measure expression of RAGE, NADPH oxidase subunits p47phox and gp91phox, as well as apoptosis-associated proteins p53, Bax, Bcl-2 and caspase-3. RESULTS: Incubating podocytes with AOPPs reduced cell viability, triggered changes in cell morphology and promoted apoptosis. GLP-1 partially inhibited AOPP-induced apoptosis, O2- overproduction, and AOPP-induced expression of RAGE. GLP-1 inhibited expression of p47phox and gp91phox in AOPP-treated podocytes, and it attenuated AOPP-induced expression of p53, Bax and cleaved caspase-3, whereas it restored expression of Bcl-2. CONCLUSION: GLP-1 partially inhibits AOPP-induced apoptosis in podocytes, perhaps by interfering with the AOPP-RAGE axis, decreasing oxidative stress and inhibiting the downstream p53/Bax/caspase-3 apoptotic pathway. GLP-1 may be a useful anti-apoptotic agent for early intervention in diabetic nephropathy.

Effect of salvianolic acid B on TNF-α induced cerebral microcirculatory changes in a micro-invasive mouse model.

PURPOSE: To investigate the effects of salvianolic acid B (SAB) on tumor necrosis factor a (TNF-α) induced alterations of cerebral microcirculation with a bone-abrading model. METHODS: The influences of craniotomy model and bone-abrading model on cerebral microcirculation were compared. The bone-abrading method was used to detect the effects of intracerebroventricular application of 40 µg/kg·bw TNF-α on cerebral venular leakage of fluorescein isothiocyanate (FITC)- albulmin and the rolling and adhesion of leukocytes on venules with fluorescence tracer rhodamine 6G. The therapeutical effects of SAB on TNF-α induced microcirculatory alteration were observed, with continuous intravenous injection of 5 mg/kg·h SAB starting at 20 min before or 20 min after TNF-α administration, respectively. The expressions of CD11b/CD18 and CD62L in leukocytes were measured with flow cytometry. Immunohistochemical staining was also used to detect E-selectin and ICAM-1 expression in endothelial cells. RESULTS: Compared with craniotomy method, the bone-abrading method preserved a higher erythrocyte velocity in cerebral venules and more opening capillaries. TNF-α intervention only caused responses of vascular hyperpermeability and leukocyte rolling on venular walls, without leukocyte adhesion and other hemodynamic changes. Pre- or post-SAB treatment attenuated those responses and suppressed the enhanced expressions of CD11b/CD18 and CD62L in leukocytes and E-selectin and ICAM-1 in endothelial cells induced by TNF-α. CONCLUSIONS: The pre- and post-applications of SAB during TNF-α stimulation could suppress adhesive molecular expression and subsequently attenuate the increase of cerebral vascular permeability and leukocyte rolling.