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Taiwan habu (Protobothrops mucrosquamatus), green bamboo viper (Viridovipera stejnegeri), and Taiwan cobra (Naja atra) are the most venomous snakebites in Taiwan. Patients commonly present with limb swelling but misdiagnosis rates are high, and currently available diagnostic tools are limited. This study explores the immune responses in snakebite patients to aid in differential diagnosis. This prospective observational study investigated the changes in cytokines in snakebite patients and their potential for diagnosis. Elevated pro-inflammatory cytokines IL-6 and TNF-α were observed in all snakebite patients compared to the healthy control group. While no significant disparities were observed in humoral immune response cytokines, there were significant differences in IFN-γ levels, with significantly higher IL-10 levels in patients bitten by cobras. Patients with TNF-α levels exceeding 3.02 pg/mL were more likely to have been bitten by a cobra. This study sheds light on the immune responses triggered by various venomous snakebites, emphasizing the potential of cytokine patterns for snakebite-type differentiation. Larger studies are needed to validate these findings for clinical use, ultimately improving snakebite diagnosis and treatment. [Display omitted] • Taiwan cobra bites show higher IFN-γ and IL-10 levels than bites from other snakes. • Early activation of TNF-α in snakebites suggests their use as diagnostic markers for envenomation. • The study found similar immune responses in Green bamboo viper and Taiwan habu bites. • Monitoring cytokine levels can help identify snakebite types. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Ricolinostat is the first orally available, selective inhibitor of histone deacetylase 6 (HDAC6), currently under evaluation in clinical trials in patients with various malignancies. It is likely that the inevitable emergence of resistance to ricolinostat is likely to reduce its clinical effectiveness in cancer patients. In this study, we investigated the potential impact of multidrug resistance-linked ATP-binding cassette (ABC) transporters ABCB1 and ABCG2 on the efficacy of ricolinostat, which may present a major hurdle to its development as an anticancer drug in the future. We demonstrated that the overexpression of ABCB1 or ABCG2 reduces the intracellular accumulation of ricolinostat, resulting in reduced efficacy of ricolinostat to inhibit the activity of HDAC6 in cancer cells. Moreover, the efficacy of ricolinostat can be fully restored by inhibiting the drug efflux function of ABCB1 and ABCG2 in drug-resistant cancer cells. In conclusion, our results provide some insights into the basis for the development of resistance to ricolinostat and suggest that co-administration of ricolinostat with a modulator of ABCB1 or ABCG2 could overcome ricolinostat resistance in human cancer cells, which may be relevant to its use in the clinic. [ABSTRACT FROM AUTHOR]

Summary: We examined the role of macrophage inflammatory protein (MIP)-3α on oral cavity squamous cell carcinoma (OSCC) and whether it was involved in modulating OSCC cell functions. The study population was comprised of 102 patients with OSCC. MIP-3α levels in tissues were examined by immunohistochemistry and quantitative real-time RT-PCR. Effects of MIP-3α on OSCC cell function were investigated by cell proliferation assays, trans-well migration/invasion assays, and RNA interference. We found that MIP-3α was overexpressed in OSCC tumor cells. MIP-3α expression was significantly higher in tumor cells vs. normal epithelial cells, as determined by both quantitative real-time RT-PCR and immunohistochemistry. Overexpression of MIP-3α was significantly correlated with positive pN status (P =0.036). Nevertheless, there were no correlations related to patient age, pT status, overall pathological stage, cell differentiation, or perineural invasion. The long-term disease-specific survival for patient subgroups stratified by the absence or presence of MIP-3α overexpression was 70.9% vs. 54.7% (P =0.041). Multivariate analysis indicated that MIP-3α overexpression had a significantly lower disease-specific survival (hazard ratio: 2.158; P =0.037). Additionally, in vitro suppression of MIP-3α expression in OECM-1 cells using specific interfering RNAs attenuated cell migration and invasiveness. These findings suggest that MIP-3α overexpression in OSCC is associated with a poorer prognosis for patient survival and contributes to tumor metastasis. [ABSTRACT FROM AUTHOR]

Abstract: Glucose-6-phosphate dehydrogenase (G6PD) plays a key role in the regeneration of NADPH and maintenance of cellular redox balance. In the present study, we investigate the effect of G6PD deficiency on H2O2-elicited signaling in HepG2 cells. H2O2 was found to inhibit cellular protein tyrosine phosphatase (PTP) activity, resulting in activation of MAPKs. MKP-1 expression increased in the late phase of H2O2 signaling. Using RNAi technology, we found that G6PD knockdown enhanced the inhibitory effect of H2O2 on PTPs and led to sustained MAPK activation. This was accompanied by delayed expression and inhibition of MKP-1. Using a pharmacological inhibitor and siRNA, we demonstrate that MKP-1 acts as a regulator of MAPK activation in H2O2 signaling. The prolonged MAPK activation in G6PD-knockdown cells was associated with an increased susceptibility to H2O2-induced apoptosis and growth retardation. Treatment with p38 and JNK inhibitors or N-acetylcysteine ameliorated such cellular effect, while triptolide and MKP-1-siRNA did the opposite. Glucose oxidase treatment had similar effects as addition of H2O2. Taken together, these findings suggest that G6PD knockdown enhances the magnitude and duration of H2O2-induced MAPK signaling through inhibition of cellular PTPs, and the resultant anomalous signaling may lead to cell demise. [Copyright &y& Elsevier]

Summary: This hospital-based cohort study evaluated the efficacy of three Epstein-Barr virus (EBV) – associated assays for nasopharyngeal carcinoma (NPC) primary screening and monitoring treatment outcome. Five hundred and seventeen consecutive subjects, including 156 NPC patients, 264 healthy volunteers and 97 patients with head and neck squamous cell carcinoma (HNSCC) were enrolled. The sensitivity and specificity of EBV IgAs to viral capsid antigen (VCA), complementary EBV IgAs to early antigen and nuclear antigen-1 (EA+EBNA-1), and EBV DNA load were examined by immunofluorescent assays, enzyme-linked immunosorbent assays, and quantitative real-time PCR, respectively. After constructing the receiver operating characteristics to demonstrate screening efficacy, EBV EA+EBNA-1 IgA (AUC: 0.952; 95% CI, 0.930–0.974) was proved superior to EBV VCA IgA (AUC: 0.888; 95% CI, 0.854–0.922) or EBV DNA load (AUC: 0.893; 95% CI, 0.854–0.932) in differentiating NPC patients from controls. Comparison of screening efficacy between NPC patients and HNSCC patients revealed EBV EA+EBNA-1 IgA (AUC: 0.964; 95% CI, 0.943–0.985) still outperformed EBV VCA IgA (AUC: 0.884; 95% CI, 0.845–0.923). In subjects with higher serum titer or level equal to or above 1:80 and 6EU/ml for EBV VCA IgA and EA+EBNA-1 IgA, the specificity reached as high as 99.2% and 95.1%, respectively, in the control groups. However, correlation of these three assays with clinicopathological manifestations of NPC, revealed only EBV DNA load significantly associated with N stage and overall stage in NPC patients. Additionally, EBV DNA load could be used to further raise the specificity of EBV EA+EBNA-1 IgA assays and was also the only assay to be consistently predictive of tumor relapse in post-treatment patients according to serial test results by time frame. Consequently, an EBV EA+EBNA-1 IgA-based protocol is recommended for mass screening, but EBV DNA load should be used solely for post-treatment monitoring for NPC in endemic areas. [Copyright &y& Elsevier]

Abstract: Deregulation of protein kinase-mediated signaling events is one of the major causes to malignant transformation. In this work, we tried to purify protein kinase inhibitory activity and antitumor activity from ethanol extracts of the seeds of Livistona chinensis R. Brown (LC), a traditional herb used for the treatment of nasopharyngeal carcinoma (NPC). Both activities were found to be co-purified in various chromatography steps, and a highly purified fraction, LC-X, was obtained and its biological effects were characterized further. LC-X inhibited the activities of various protein kinases in vitro, including PAK2, PKA, PKC, GSK-3α, CK2, mitogen-activated protein kinase (MAPK), and JNK1, with IC50 between ∼1 and 40μg/ml. The proliferation of two NPC (NPC-TW02 and -TW04) and one breast cancer (MCF-7) cell lines, but not the epidermoid (A431) and cervical (HeLa) carcinoma cell lines, were significantly blocked by LC-X at the dose of >50μg/ml. Cell cycle arrested at G2/M phase and apoptosis were detected in NPC-TW02 cells treated with LC-X for 24h. Further studies revealed that epidermal growth factor (EGF)-induced activation of epidermal growth factor receptor (EGFR) and MAPK could be potently inhibited by LC-X in both NPC-TW02 and A431cells in a dose-dependent manner. More interestingly, the level of EGFR protein detected by Western blot decreased drastically in LC-X-treated A431 and NPC-TW02 cells in a dose- and time-dependent fashion. Further analysis of the plasma membrane and cytosolic fractions from LC-X-treated and untreated A431 cells showed that a 170kDa protein selectively disappeared from the plasma membrane of LC-X-treated cells. The protein was identified as EGFR by MALDI-TOF mass spectrometry, indicating EGFR as a selective target for LC-X. Moreover, the electrophoretic mobility of purified EGFR in SDS–PAGE was altered dramatically post LC-X treatment, suggesting that LC-X may chemically modify EGFR. In conclusion, the active components with both antitumor and protein kinases inhibitor activities were highly purified from LC, which can inhibit the EGF signaling events mainly through EGFR modification. Blockage of the functions of EGFR may account for the antitumor activity of these active components. [Copyright &y& Elsevier]

Abstract: Corneal angiogenesis is associated with a variety of corneal diseases, and is sometimes vision threatening. In recent years, with the discovery of major pro- and anti-angiogenic factors in the cornea, details of the angiogenic process are gradually unveiled. Of note, corneal inflammation and neovascularization associated with severe limbal stem cell (LSC) deficiency is a clinically challenging issue in that the condition persists long after the initial insult, and will not improve without transplantation of LSCs. However, to date the molecular mechanism by which LSC transplantation restores corneal avascularity is not fully understood. In addition to discussing major pro-angiogenic factors involved in corneal neovascularization, this review article also focuses on possible molecular mechanisms underlying persistent inflammation and neovascularization following severe LSC deficiency, and anti-angiogenic factors expressed by human limbo-corneal epithelial cells (HLCECs). Most of the recently discovered corneal anti-angiogenic factors belong to extracellular matrix proteins that aquire angio-inhibitory activity only after proper proteolytic processing. Our recent findings showed that the secretion of endostatin (derived from basement membrane collagen XVIII) and restin (from collagen XV) by HLCECs were enhanced when HLCECs were cultivated on amniotic membrane (AM). This adds to the advantage of transplanting ex vivo expanded HLCECs cultivated on AM in that the anti-angiogenic activity of the epithelial cells is augmented in a physiological way. Furthermore, proteomic profiling of HLCECs and human conjunctival epithelial cells (HCECs) identified a 14-3-3 protein (stratifin) preferentially expressed by HLCECs. In addition to functioning as a cell cycle controller, keratinocyte-derived stratifin induces MMPs which are involved in the generation of restin (by MMP-1) and endostatin (by MMP-3). These findings highlight the significance of delicate epithelial–matrix interactions in the maintenance of corneal avascularity. [Copyright &y& Elsevier]

LY3023414 (samotolisib) is a promising new dual inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR). Currently, multiple clinical trials are underway to evaluate the efficacy of LY3023414 in patients with various types of cancer. However, the potential mechanisms underlying acquired resistance to LY3023414 in human cancer cells still remain elusive. In this study, we investigated whether the overexpression of ATP-binding cassette (ABC) drug transporters such as ABCB1 and ABCG2, one of the most common mechanisms for developing multidrug resistance, may potentially reduce the efficacy of LY3023414 in human cancer cells. We demonstrated that the intracellular accumulation of LY3023414 in cancer cells was significantly reduced by the drug efflux function of ABCB1 and ABCG2. Consequently, the cytotoxicity and efficacy of LY3023414 for inhibiting the activation of the PI3K pathway and induction of G0/G1 cell-cycle arrest were substantially reduced in cancer cells overexpressing ABCB1 or ABCG2, which could be restored using tariquidar or Ko143, respectively. Furthermore, stimulatory effect of LY3023414 on the ATPase activity of ABCB1 and ABCG2, as well as in silico molecular docking analysis of LY3023414 binding to the substrate-binding pockets of these transporters provided additional insight into the manner in which LY3023414 interacts with both transporters. In conclusion, we report that LY3023414 is a substrate for ABCB1 and ABCG2 transporters implicating their role in the development of resistance to LY3023414, which can have substantial clinical implications and should be further investigated. [ABSTRACT FROM AUTHOR]