Immune suppression following major thermal injury directly impacts the recovery potential. Limited data from past reports indicate that natural killer cells might be suppressed due to a putative soluble factor that has remained elusive up to date. Here we comparatively study cohorts of patients with Major and Non-Major Burns as well as healthy donors. MICB and ULBP1 are stress ligands of NKG2D that can be induced by heat stress. Remarkably, serum concentration levels of MICB and ULBP1 are increased by 3-fold and 20-fold, respectively, already within 24h post major thermal injury, and are maintained high for 28 days. In contrast, milder thermal injuries do not similarly enhance the serum levels of MICB and ULBP1. This kinetics coincides with a significant downregulation of NKG2D expression among peripheral blood NK cells. Downregulation of NKG2D by high concentration of soluble MICB occurs in cancer patients and during normal pregnancy due to over production by cancer cells or extravillous trophoblasts, respectively, as an active immune-evasion mechanism. In burn patients this seems an incidental outcome of extensive thermal injury, leading to reduced NKG2D expression. Enhanced susceptibility of these patients to opportunistic viral infections, particularly herpes viruses, could be explained by the reduced NKG2D expression. Further studies are warranted for translation into innovative diagnostic or therapeutic technologies.

Intracellular levels of the divalent cations Ca2+ and Mg2+ are important regulators of cell cycle and proliferation. However, the precise mechanisms by which they are regulated in cancer remain incompletely understood. The channel kinases TRPM6 and TRPM7 are gatekeepers of human Ca2+/Mg2+ metabolism. Here, we investigated the human neuroblastoma cell line SHEP-21N in which the MYCN oncogene (encoding N-Myc) can be reversibly expressed under control of an inducible repressor. We report that N-Myc expression increases cell growth and up-regulates both TRPM6 and TRPM7 expression. Membrane current analyses reveal that endogenous TRPM6/TRPM7 currents exhibit reduced Mg·ATP suppression, increased Mg2+ sensitivity, and diminished sensitivity to 2-APB inhibition. These properties are consistent with N-Myc-induced increase of heteromeric TRPM7/TRPM6 channels promoting Ca2+ and Mg2+ uptake. Genetic suppression of TRPM6/TRPM7 through siRNA inhibits cell proliferation, suggesting that N-Myc can promote neuroblastoma cell proliferation through up-regulation of divalent cation-transporting channels.

One of the classical features observed in patients with burn injury is hyperglycemia. There have been previous reports that a cohort of microRNAs (miRNAs) is differentially expressed in the dermis of patients with burn injury. More specifically, it has been shown that the miR-194 can target the insulin-like growth factor receptor 1 (IGF1R) and silence its protein expression resulting in hyperglycemia. The objective of the current study was to discover if additional miRNA-mediated post-transcriptional mechanism exists that lead to suppression of IGF1R protein expression post-burn injury. Using the 30% total body surface area (TBSA) model of burn injury in rats we found that the miRNA let-7b can target IGF1R and downregulate its protein expression, in turn attenuating PI3K/Akt and Gsk3β activation leading to hyperglycemia. Increased let-7b expression was significantly more than the previously reported miR-194 both in the burn rats compared to sham and in patients with burn injury compared to healthy subjects. Serum from burn rats also resulted in decreased IGF1R protein expression in rat L6 myotubes. In vivo targeting of let-7b by antagomir mitigated the effect of increased let-7b expression on IGF1R protein expression and hyperglycemia. Thus targeting let-7b might be a promising approach to treat hyperglycemia in patients with burn injury.

Recent clinical studies have shown that combination therapy of BRAF and MEK inhibition provides more survival benefit than BRAF inhibition monotherapy. However, the adverse events due to BRAF and MEK inhibitors impact the physical comfort and social life of patients. Thus, in this study we have undertaken a meta-analysis of randomized controlled trials to compare the efficacy and adverse events risk between monotherapy and combination therapy. We identified the relevant studies by searching PubMed, EMBASE and Google scholar databases, between the year January 2000 and May 2016. Based on the heterogeneity, the fixed- or random-effects models were employed to analyze the efficacy and the incidence rate of adverse events. In addition, the subgroup analyses were conducted to overcome the effects of heterogeneity. Finally, our study included five RCTs, involving 1730 patients for this meta-analysis. The fixed-effects model demonstrated that combination therapy of BRAF and MEK inhibition provided more survival benefit in terms of ORR, PFS and OS (P < 0.00001). But, the combination therapy also significantly increased the incidences of pyrexia, chills, vomiting, chorioretinopathy, retinal detachment, hypertension, night sweats, increased aspartate aminotransferase and creatine kinase levels (P < 0.05) as compared to monotherapy. But, based on the significantly better survival outcomes, the combined BRAF and MEK inhibition will obviously be the mainstay therapy for the BRAF V600-mutant melanoma. However, a set of adverse events should be paid attention when physicians consider combination therapy.

Tec kinase, a prototypical member of the Tec tyrosine kinases family, was shown to mainly govern lymphocyte proliferation. In the present study, we investigated the role of Tec kinase in acute inflammatory response in lipopolysaccharide (LPS) challenge. First, we demonstrate that Tec kinase activity was observed in RAW264.7 macrophages exposed to LPS. Tec and phosphorylated Tec expression were upregulated in a dose- and time-dependent manner after LPS stimulation. LPS increased monocyte chemotactic protein (MCP)-1 secretion and intercellular adhesion molecule (ICAM)-1 expression, and increasing mRNA expression was consistently observed. LPS also induced IκBα phoshporylaytion and its degradation, increased NF-κB p65 phoshporylaytion and translocation to nuclei in RAW264.7 cells. Pretreatment with LFM-A13 decreased LPS-induced cytokines and chemokines production and mRNA levels, blocked NF-κB transactivation. These effects of LPS were also prevented by Tec-siRNA. Additionally, LFM-A13 or Tec-siRNA obviously inhibited LPS-induced TGFβ-activated kinase 1(TAK1) phosphorylation. Taken together, our results suggest that Tec kinase involves in acute inflammation process in LPS-stimulated RAW264.7 cells, at least mediated by activating TAK1/ NF-κB signal pathway.

Hypertrophic scar is characterized by the overgrowth of fibroblasts and often considered as a kind of benign skin tumor, thus chemotherapeutic drugs have been used to treat scars. In view of the similarity, this study aims to investigate whether drug resistance in cancer that contributes to the failure of chemotherapy also exists in hypertrophic scar, and what is the possible mechanism. Fibroblasts derived from hypertrophic scar and normal skin tissues were first compared for their resistance to verapamil and etoposide phosphate. Scar fibroblasts showed stronger resistance to both verapamil and etoposide than normal fibroblasts, also scar fibroblasts expressed more P-glycoprotein and MRP1 than normal fibroblasts. When scar fibroblasts were pre-treated with PSC833 or probenecid, a P-glycoprotein or MRP1 inhibitor respectively, the resistance to verapamil or etoposide was strongly attenuated. Moreover, co-immunoprecipitation revealed more association of P-glycoprotein/MRP1 with actin filaments in scar fibroblasts than normal fibroblasts. The resistance in scar fibroblasts to verapamil and etoposide was almost abolished when pre-treated with latrunculin-A or a specific anti-actin antibody. Taken together, this study suggests that the enhanced expression of drug resistance-related transporters and their increased association with actin cytoskeleton contribute to the resistance to chemotherapeutic drugs in hypertrophic scar. Thus, down-regulating the expession of drug transporters or disrupting drug transporter-actin filament interaction might be novel and effective ways for hypertrophic scar treatment.

Loss of key components that form cell-cell adherens junctions, such as α-catenin, triggers severe epidermal hyperproliferation. However, the underlying molecular mechanisms remain largely unknown. We report here that neuroblastoma breakpoint family (NBPF) genes are upregulated and that NBPF7 specifically promotes cellular proliferation of α-catenin-silenced HaCaT cells through functional linkage with the NF-κB pathway. Genome-wide profiling of HaCaT cells shows that NBPF genes are upregulated following α-catenin knockdown. Data from western blot analyses are consistent with the activation of the NF-κB pathway as well as increased expression of NBPF7 by α-catenin knockdown. Co-immunoprecipitation assays indicate that NBPF7 could be detected in endogenous activated NF-κB immunoprecipitates. Immunoflurence analyses demonstrate that NBPF7 co-localizes with activated NF-κB in the nucleus after α-catenin silencing. Moreover, inhibition of NBPF7 decreases the proliferation of HaCaT cells and abolishes the enhanced proliferation associated with α-catenin knockdown in HaCaT cells. These results indicate that NBPF7 plays a key role in the α-catenin signaling pathway that regulates cell proliferation of keratinocytes. Our findings suggest that the classical NF-κB pathway plays a critical role in cellular proliferation and that NBPF7 is a functional mediator for α-catenin in the regulation of keratinocyte growth.

Current knowledge of the molecular mechanism driving tumor budding is limited. Here, we focused on elucidating the detailed mechanism underlying tumor budding in urothelial cancer of the bladder. Invasive urothelial cancer was pathologically classified into three groups as follows: nodular, trabecular, and infiltrative (tumor budding). Pathohistological analysis of the orthotopic tumor model revealed that human urothelial cancer cell lines MGH-U3, UM-UC-14, and UM-UC-3 displayed typical nodular, trabecular, and infiltrative patterns, respectively. Based on the results of comprehensive gene expression analysis using microarray (25 K Human Oligo chip), we identified two collagens, COL4A1 and COL13A1, which may contribute to the formation of the infiltrative pattern. Visualization of protein interaction networks revealed that proteins associated with connective tissue disorders, epithelial-mesenchymal transition, growth hormone, and estrogen were pivotal factors in tumor cells. To evaluate the invasion pattern of tumor cells in vitro, 3-D collective cell invasion assay using Matrigel was performed. Invadopodial formation was evaluated using Gelatin Invadopodia Assay. Knockdown of collagens with siRNA led to dramatic changes in invasion patterns and a decrease in invasion capability through decreased invadopodia. The in vivo orthotopic experimental model of bladder tumors showed that intravesical treatment with siRNA targeting COL4A1 and COL13A1 inhibited the formation of the infiltrative pattern. COL4A1 and COL13A1 production by cancer cells plays a pivotal role in tumor invasion through the induction of tumor budding. Blocking of these collagens may be an attractive therapeutic approach for treatment of human urothelial cancer of the bladder.

Interest has emerged in the therapeutic potential of inhibiting store operated calcium (Ca2+) entry (SOCE) for melanoma and other cancers because malignant cells exhibit a strong dependence on Ca2+ flux for disease progression. We investigated the effects of deleting Selenoprotein K (SELENOK) in melanoma since previous work in immune cells showed SELENOK was required for efficient Ca2+ flux through the endoplasmic reticulum Ca2+ channel protein, inositol 1,4,5-trisphosphate receptor (IP3R), which is due to the role SELENOK plays in palmitoylating and stabilizing the expression of IP3R. CRISPR/Cas9 was used to generate SELENOK-deficiency in human melanoma cells and this led to reduced Ca2+ flux and impaired IP3R function, which inhibited cell proliferation, invasion, and migration. Ca2+-dependent signaling through calcineurin was inhibited with SELENOK-deficiency, and gene array analyses together with evaluation of transcript and protein levels showed altered transcriptional programs that ultimately disrupted stemness and pro-growth properties. In vivo investigations were conducted using the Grm1-Tg transgenic mouse strain that develops spontaneous metastatic melanoma, which was crossed with SELENOK-/- mice to generate the following littermates: Grm1-Tg/SELENOK-/-, Grm1-Tg/SELENOK-/+, Grm1-Tg/SELENOK+/+. SELENOK-deficiency in Grm1-Tg/SELENOK-/- male and female mice inhibited primary tumor growth on tails and ears and reduced metastasis to draining lymph nodes down to levels equivalent to non-tumor control mice. Cancer stem cell pools were also decreased in Grm1-Tg/SELENOK-/- mice compared to littermates. These results suggest that melanoma requires SELENOK expression for IP3R dependent maintenance of stemness, tumor growth and metastasic potential, thus revealing a new potential therapeutic target for treating melanoma and possibly other cancers.

Suppressed adaptive immune function is one of the major concerns responsible for the development of opportunistic infections and subsequent sepsis with high mortality in severe burns. Endoplasmic reticulum stress (ERS) is the endogenous self-protective mechanism, and it plays an important role in almost every process of living by regulating the balance between homeostasis and apoptosis. The current study investigated the involvement of ERS in the pathogenesis of dysfunction of dendritic cells (DCs) in burn mice. Our results show a significant ERS response in splenic DC after burn injury. Treatment with salubrinal (Sal, reported to protect cells against ERS-induced apoptosis.) decrease the apoptotic rate of DC induced by burns, and promote maturation and activation of DC, as well as the ability to promote T cell proliferation and polarization towards Th1 immunity (all P<0.05). Gene silence of XBP-1 (key molecular in ERS response) results in the increased apoptosis and suppressed phenotypical maturation of splenic DC in burn mice. These results show that the excessive ERS is essential for immunosuppression during severe thermal injury. XBP-1 plays a pivotal role in DC functional immunomodulation in burn mice. Inhibition of apoptotic ERS response benefits mice from major burns.

To explore the profibrotic characteristics of the autografted dermis, acellular dermal matrix, and dermal fibroblasts from superficial/deep layers of pig skin, 93 wounds were established on the dorsa of 7 pigs. 72 wounds autografted with the superficial/deep dermis and acellular dermal matrix served as the superficial/deep dermis and acellular dermal matrix group, respectively, and were sampled at 2, 4, and 8 weeks post-wounding. 21 wounds autografted with/without superficial/deep dermal fibroblasts served as the superficial/deep dermal fibroblast group and the control group, respectively, and were sampled at 2 weeks post-wounding. The hematoxylin and eosin staining showed that the wounded skin thicknesses in the deep dermis group (superficial acellular dermal matrix group) were significantly greater than those in the superficial dermis group (deep acellular dermal matrix group) at each time point, the thickness of the cutting plane in the deep dermal fibroblast group was significantly greater than that in the superficial dermal fibroblast group and the control group. The western blots showed that the α-smooth muscle actin expression in the deep dermis group (superficial acellular dermal matrix group) was significantly greater than that in the superficial dermis group (deep acellular dermal matrix group) at each time point. In summary, the deep dermis and dermal fibroblasts exhibited more profibrotic characteristics than the superficial ones, on the contrary, the deep acellular dermal matrix exhibited less profibrotic characteristics than the superficial one.

In the present study, we examined the activity of p53 protein in Jurkat cells treated with high mobility group box-1 protein (HMGB1), thereafter we investigated the mechanism of extracellular HMGB1 mediated p53 expression in immune dysfunction of T lymphocytes. mRNA expression of p53, mdm2, and p21 was determined by Real-time reverse transcription-polymerase chain reaction(RT-PCR). The apoptotic rate of Jurkat cells was analyzed by flow cytometry. Expressions of bcl-2, bax, caspase-3, phosphorylated (p) extracellular signal-regulated kinase (ERK)1/2, ERK1/2, p-p38 mitogen-activated protein kinase (MAPK), p38 MAPK, and p-c-jun amino-terminal kinase (JNK)1/2 and JNK1/2 were simultaneously determined by Western blotting. After treatment with HMGB1 (100 ng/ml or 1000 ng/ml), the proliferative activity of Jurkat cells was significantly decreased, and a low and medium concentration of HMGB1 induced an up-regulation of p53 mRNA, p-p53 and p53 protein expression. Meanwhile, levels of mdm2 and p21 were elevated by incubated with HMGB1 (100 ng/ml) for 24 or 48 hours. Moreover, the proliferation of Jurkat cells in response to HMGB1 (100 ng/ml) in the vector group was significantly depressed. The bax and caspase-3 levels in p53 shRNA-expressed cells treated with HMGB1 (100 ng/ml) was markedly decreased, whereas expression of bcl-2 was obviously enhanced. Among ERK1/2, p38 MAPK and JNK1/2 signaling, only p38 MAPK pathway could be significantly activated by treatment with HMGB1, and the specific inhibitor of p38 MAPK was used, p53 and p-p53 expression induced by HMGB1 were significantly down-regulated. Taken together, our data strongly indicated that HMGB1 might enhance p53 expression, which was associated with both the proliferative activity as well as apoptosis of T cells.

Tumor necrosis factor-alpha (TNF-α) is a multifunctional pro-inflammatory cytokine that plays an important role in cancer development. We performed a meta-analysis to assess the relationship between single nucleotide polymorphisms in the TNF-α promoter region (rs1800629 and rs361525) and susceptibility to squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and melanoma. After database retrieval, article selection, data extraction, and quality assessment, 20 articles comprising 4865 cases and 6329 controls were included in this study. rs1800629 was associated with an increased overall risk of SCC, lung SCC, and oral SCC in the AA vs G and AA vs GG+GA genetic models (all OR>1, Passociation <0.05). No increased risk of skin SCC, skin BCC or melanoma was observed (all Passociation >0.05). Rs361525 was not associated with overall SCC risk in the allele, heterozygote, dominant, recessive, or carrier model (all Passociation >0.05). Begg's and Egger's tests (PBegg>0.05; PEgger>0.05) demonstrated there was no significant publication bias. These data indicate that the AA genotype of TNF-α rs1800629, but not rs361525, is associated with an increased risk of SCC, suggesting it could potentially serve as a prognostic marker for predicting SCC risk.

Acute myeloid leukemia (AML) is a heterogeneous disorder of the hematopoietic system with no common genetic "Achilles heel" that can be targeted. Most patients respond well to standard therapy, while a majority relapse, and development of an effective therapy for AML patients is still urgently needed. In this study, we demonstrated that betulinic acid (BA) significantly increased Aryl hydrocarbon receptor (AHR) expression through demethylation on the AHR promoter in AML cells, and the increased AHR expression interacts with and sequesters ARNT, subsequently suppressing hypoxia-inducible factor-1α (HIF1α) pathway. We also found that histone deacetylase inhibitor chidamide (CDM) treatment significantly increased p300 over-acetylation in AML cells with dissociation of p300 with HIF1α, and subsequently suppressed the HIF1α pathway. Further investigation showed that BA/CDM combination additively increased generation of reactive oxygen species (ROS) with DNA damage, apoptosis and mitochondrial dysfunction. Also, BA/CDM combination additively suppressed the HIF1α pathway with decreased VEGF expression. in vivo mice study showed that BA/CDM combination significantly suppressed AML tumor growth, and overexpression of SOD2 and a constitutive HIF1α (HIF1C) completely diminished this effect. We conclude that a BA/CDM combination inhibits AML tumors through ROS over-generation and HIF1α pathway suppression. This is the first time we have shown the potential effect and possible mechanism of BA and CDM on the inhibition of AML tumor growth.

Epstein-Barr virus (EBV) has widely infected more than 90% of human populations. Currently, there is no efficient way to remove the virus because the EBV carriers are usually in a latent stage that allows them to escape the immune system and common antiviral drugs. In the effort to develop an efficient strategy for the removal of the EBV virus, we have shown that betulinic acid (BA) slightly suppresses EBV replication through SOD2 suppression with subsequent reactive oxygen species (ROS) generation and DNA damage in EBV-transformed LCL (lymphoblastoid cell line) cells. Chidamide (CDM, CS055), a novel histone deacetylase inhibitor (HDACi), could significantly switch EBV from the latent stage to the lytic stage with increased gene expression of BZLF1 and BMRF1, but has a small effect on EBV replication due to the suppression effect of CDM-mediated ROS generation. Interestingly, a combination of BA and CDM synergistically inhibits EBV replication with ROS over-generation and subsequent DNA damage and apoptosis. Overexpression of SOD2 diminishes this effect, while SOD2 knockdown mimics this effect. An in vivo xenograft tumor development study with the tail vein injection of EBV-transformed LCL cells in nude mice proves that the combination of BA and CDM synergistically increases superoxide anion release in tumor tissues and suppresses EBV replication and tumor growth, and significantly prolongs mouse survival. We conclude that the combination of BA and CDM could be an efficient strategy for clinical EBV removal.

Metastatic melanoma is the most deadly skin neoplasm in the United States. Outcomes for this lethal disease have improved dramatically due to the use of both targeted and immunostimulatory drugs. Immunogenic cell death (ICD) has emerged as another approach for initiating antitumor immunity. ICD is triggered by tumor cells that display damage-associated molecular patterns (DAMPs). These DAMP molecules recruit and activate dendritic cells (DCs) that present tumor-specific antigens to T cells which eliminate neoplastic cells. Interestingly, the expression of DAMP molecules occurs in an endoplasmic reticulum (ER) stress-dependent manner. We have previously shown that ER stress was required for the cytotoxic activity of the endocannabinoid metabolite, 15-deoxy, Δ12,14 prostamide J2 (15dPMJ2). As such, the current study investigates whether 15dPMJ2 induces DAMP signaling in melanoma. In B16F10 cells, 15dPMJ2 caused a significant increase in the cell surface expression of calreticulin (CRT), the release of ATP and the secretion of high-mobility group box 1 (HMGB1), three molecules that serve as surrogate markers of ICD. 15dPMJ2 also stimulated the cell surface expression of the DAMP molecules, heat shock protein 70 (Hsp70) and Hsp90. In addition, the display of CRT and ATP was increased by 15dPMJ2 to a greater extent in tumorigenic compared to non-tumorigenic melanocytes. Consistent with this finding, the activation of bone marrow-derived DCs was upregulated in co-cultures with 15dPMJ2-treated tumor compared to non-tumor melanocytes. Moreover, 15dPMJ2-mediated DAMP exposure and DC activation required the electrophilic cyclopentenone double bond within the structure of 15dPMJ2 and the ER stress pathway. These results demonstrate that 15dPMJ2 is a tumor-selective inducer of DAMP signaling in melanoma.

Three-dimensional (3D) culture, which can simulate in vivo microenvironments, has been increasingly used to study tumor cell biology. Since most preclinical anti-glioma drug tests still rely on conventional 2D cell culture, we established a collagen scaffold for 3D glioma cell culture. Glioma cells cultured on these 3D scaffolds showed greater degree of dedifferentiation and quiescence than cells in 2D culture. 3D-cultured cells also exhibited enhanced resistance to chemotherapeutic alkylating agents, with a much higher proportion of glioma stem cells and upregulation of O6-methylguanine DNA methyltransferase (MGMT). Importantly, tumor cells in 3D culture showed chemotherapy resistance patterns similar to those observed in glioma patients. Our results suggest that 3D collagen scaffolds are promising in vitro research platforms for screening new anti-glioma therapeutics.

Vascular hyporeactivity is one of the major causes responsible for refractory hypotension and associated mortality in severe hemorrhagic shock. Mitochondrial permeability transition (mPT) pore opening in arteriolar smooth muscle cells (ASMCs) is involved in the pathogenesis of vascular hyporeactivity. However, the molecular mechanism underlying mitochondrial injury in ASMCs during hemorrhagic shock is not well understood. Here we produced an in vivo model of severe hemorrhagic shock in adult Wistar rats. We found that sirtuin (SIRT)1/3 protein levels and deacetylase activities were decreased in ASMCs following severe shock. Immunofluorescence staining confirmed reduced levels of SIRT1 in the nucleus and SIRT3 in the mitochondria, respectively. Acetylation of cyclophilin D (CyPD), a component of mPT pore, was increased. SIRT1 activators suppressed mPT pore opening and ameliorated mitochondrial injury in ASMCs after severe shock. Furthermore, administration of SIRT1 activators improved vasoreactivity in rats under severe shock. Our data suggest that epigenetic mechanisms, namely histone post-translational modifications, are involved in regulation of mPT by SIRT1/SIRT3- mediated deacetylation of CyPD. SIRT1/3 is a promising therapeutic target for the treatment of severe hemorrhagic shock.

Varicella zoster virus (VZV) is the etiological agent of shingles, a painful skin rash that affects a significant proportion of the elderly population. In the present study, we used two aging cell models, Hutchinson-Gilford progeria syndrome (HGPS) fibroblasts and stress or replicative senescence-induced normal human dermal fibroblasts (NHDFs), to investigate age-associated susceptibility to VZV infection. VZV infectivity titers were significantly associated with donor age in HGPS fibroblasts and senescence induction in NHDFs. High throughput RNA-sequencing (RNA-seq) analysis was performed to assess global and dynamic changes in the host transcriptomes of VZV-infected aging cells. Analysis of differentially expressed genes (DEGs) indicated that VZV infection in aged HGPS fibroblasts resembled that in senescent NHDFs, particularly in terms of genes associated with pattern recognition receptors in virus sensing network, providing novel insights into the mechanisms of senescence-associated susceptibility to VZV infection. Additionally, we identified stimulator of interferon genes (STING) as a potential VZV sensing receptor. Knockdown of STING expression resulted in increased viral replication in primary fibroblasts, whereas STING overexpression led to suppression of VZV plaque formation. In conclusion, our findings highlight the important role of immunosenescence following VZV infection and provide significant insights into the mechanisms underlying cellular sensing of VZV infection and the induction of immune responses in aged skin cells.

Despite a good initial response to front-line chemotherapy, majority of the ovarian cancer patients relapse with consecutive phases of recurrences; and nearly 60% die within 5 years due to the development of a chemoresistant disease. This study investigated whether inhibition of the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway by momelotinib is sufficient in suppressing tumor burden and prolonging the disease-free survival period in a mouse model of ovarian cancer. We demonstrate that paclitaxel treatment enhanced JAK2/STAT3 activation which resulted in the enrichment of cancer stem cell (CSC)-like phenotype in the surviving ovarian cancer cells in vitro and in in vivo mouse xenografts. Combined treatment with paclitaxel and momelotinib inhibited paclitaxel-induced JAK2/STAT3 activation and CSC-like development in mice xenografts, and consequently reduced the tumor burden significantly greater than that achieved by paclitaxel-treatment alone. However, robust recurrent tumor growth with enhanced JAK2/STAT3 activation and CSC-like phenotype was observed in all mice groups after termination of treatments, but was delayed significantly in the paclitaxel and momelotinib treated group compared to other treatment groups. Daily oral gavage of momelotinib after termination of paclitaxel treatment showed sustained inhibition of tumor growth and a prolonged disease-free survival period in 50% of the mice. The other 50% of mice that developed tumors with ongoing momelotinib treatment also showed significantly increased survival benefit and a smaller tumor burden. These preliminary findings may have a profound clinical impact in developing an effective momelotinib-based 'maintenance-therapy' in ovarian cancer patients' post-chemotherapy treatment.