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Shu-Hui Lin,1,2,* Hsin-Kai Wang,3,4,* Kun-Tu Yeh,1,5 Hui-Chun Tai,1,6 Hui-Yi Wang,1 Lan-Ru Huang,2 Chun-Wen Chiu,7 Chia-Min Chung,8,9 Bharath Kumar Velmurugan101Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan; 2Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan; 3Public Health Bureau, Tainan City Government, Tainan, Taiwan; 4Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan; 5School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 6Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 7Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan; 8Graduate Institute of BioMedical Sciences, China Medical University, Taichung, Taiwan; 9Environment-Omics-Diseases Research Center, China Medical University Hospital, Taichung, Taiwan; 10Toxicology and Biomedicine Research Group, Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam*These authors contributed equally to this work Purpose: c-MYC has been noted in many tumor types, but its functional significance and clinical utility in oral squamous cell carcinoma (OSCC) are not well known. Here we studied the expression of c-MYC in correlation to clinical outcome in patients with oral squamous cell carcinoma.Methods: The current study, using immunohistochemical staining, first examined c-MYC expression in OSCC patients and further correlated its expression with clinicopathological parameters.Results: c-MYC was expressed in the majority of OSCC patients (n=133). The c-MYC expression is associated with histological grade (P=0.0205) of patients with oral squamous cell carcinoma. Multivariate Cox regression analysis revealed that TN stage (P0.05). Multiplicative-scale interaction between T stage (III/IV) and low c-MYC expression on mortality risk was identified (P=0.0233). Kaplan–Meier survival analysis demonstrated that oral cancer patients (T III/IV stage) with high c-MYC expression had better survival than those with low and medium c-MYC expression (P=0.0270).Conclusion: Our data indicate that c-MYC is a potential biomarker that can be used as a therapeutic target for treating OSCC patients with T stage (III/IV).Keywords: T stage, c-MYC, OSCC, biomarker, survival

Bharath Kumar Velmurugan,1 Hsin-Kai Wang,2,3 Chia-Min Chung,4,5 Chien-Hsun Lee,6 Lan-Ru Huang,7 Kun-Tu Yeh,6,7* Shu-Hui Lin6,8*1Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam; 2Public Health Bureau, Tainan City Government, Tainan City, Taiwan; 3Jenteh Junior College of Medicine, Nursing and Management, Taiwan; 4Graduate Institute of BioMedical Sciences, China Medical University, Taichung, Taiwan; 5Environment-Omics-Diseases Research Center, China Medical University Hospital, Taichung, Taiwan; 6Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan; 7School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 8Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan *These authors contributed equally to this workIntroduction: Oral cancer is a prevalent form of cancer worldwide, particularly in Taiwan, and mechanisms involved in oral squamous cell carcinoma (OSCC) progression remain relatively unknown. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an oncoprotein, is aberrantly expressed in many human malignant tumors including oral cancer. However, the expression and role played by CIP2A in oral cancer pathogenesis remain obscure.Methods: In this study, immunohistochemistry was used to analyze CIP2A expression between OSCC tissues and their adjacent noncancerous tissues. Furthermore, associations between CIP2A expression and histopathological parameters were investigated.Results: In this study, we showed that CIP2A was overexpressed in most of the OSCC tissues. High CIP2A expression was significantly associated with moderate/poor tumor differentiation (P=0.02). No significant association was found between CIP2A expression and other clinical parameters. Kaplan–Meier analysis revealed that high CIP2A expression showed poorer survival rates than those with low CIP2A expression (P=0.047). Multivariate Cox regression analysis indicated that CIP2A expression, N stage, American Joint Committee on Cancer stage and clinical therapy were independent prognostic factors for survival.Conclusion: Thus, our study suggests that CIP2A is an independent prognostic marker for OSCC and a novel target for OSCC treatment.Keywords: CIP2A, OSCC: prognosis, survival, Taiwan

(1) Background: This study investigates the effects of Ursodeoxycholic acid (UDCA) on NF-κB signaling, farnesoid X receptor (FXR) singling, and microRNA-21 in HepG2 cells. (2) Methods: HepG2 cells were treated with lipopolysaccharide (LPS) to simulate hepatic inflammation. The investigation focused on the expression of NF-κB activation, which was analyzed using Western blot, confocal microscopy, and Electrophoretic Mobility-shift Assays (EMSA). Additionally, NF-κB and farnesoid X receptor (FXR) singling expressions of micro-RNA-21, COX-2, TNF-α, IL-6, cyp7A1, and shp were assessed by RT-PCR. (3) Results: UDCA effectively downregulated LPS-induced expressions of NF-κB/65, p65 phosphorylation, and also downregulated FXR activity by Western blot. Confocal microscopy and EMSA results confirmed UDCA's role in modulating NF-κB signaling. UDCA reduced the expressions of LPS-induced COX-2, TNF-α, and IL-6, which were related to NF-κB signaling. UDCA downregulated LPS-induced cyp7A1 gene expression and upregulated shp gene expression, demonstrating selective gene regulation via FXR. UDCA also significantly decreased micro-RNA 21 levels. (4) Conclusions: This study demonstrates UDCA's potent anti-inflammatory effects on NF-κB and FXR signaling pathways, and thus its potential to modulate hepatic inflammation and carcinogenesis through interactions with NF-κB and FXR. The decrease in micro-RNA 21 expression further underscores its therapeutic potential.

As global supply is still inadequate to address the worldwide requirements for HPV vaccines, we assessed the safety and immunogenicity of a new bivalent HPV16/18 vaccine. In this randomized, double-blind, placebo-controlled, phase 2 trial, healthy 9-45-year-old Chinese females in three age cohorts (600 aged 9-17 years; 240 aged 18-26 years; 360 aged 27-45 years) were randomized 1:1 to receive three doses (0,2,6 months) of HPV16/18 vaccine or placebo. We measured neutralizing antibodies against HPV 16 and 18 at 7 months and monitored safety to 12 months in all age cohorts; 9-17-year-old girls were monitored for safety and immunogenicity to 48 months. In vaccinees, 99.8% seroconverted for HPV 16 and 18 types at 7 months; respective GMTs of 5827 (95% CI: 5249, 6468) and 4223 (3785, 4713) were significantly ( p  < .001) higher than controls for all comparisons. GMTs in the 9-17-year-olds, which were significantly higher than in older women at 7 months, gradually declined to 48 months but remained higher than placebo with seropositivity rates maintained at 98.5% and 97.6% against HPV 16 and 18, respectively. Adverse events occurred at similar rates after vaccine and placebo (69.8% vs. 72.5%, p  = .308), including solicited local reactions and systemic adverse events which were mainly mild-to-moderate. The bivalent HPV16/18 vaccine was well tolerated and induced high levels of neutralizing antibodies in all age groups which persisted at high levels to 48 months in the 9-17-year-old age group which would be the target for HPV vaccination campaigns.

Chronic cough is a common complaint in respiratory specialist clinics, with a significant impact on cough-specific quality of life and psychophysiological health. The diagnosis, treatment and management of chronic cough remains a major challenge. We summarized a series of recent advances from clinical studies in the epidemiology, diagnosis and management of chronic cough over the past year.

Background: Dengue virus outbreaks are increasing in number and severity worldwide. Viral transmission is assumed to require a minimum time period of viral replication within the mosquito midgut. It is unknown if alternative transmission periods not requiring replication are possible., Methods: We used a mouse model of dengue virus transmission to investigate the potential of mechanical transmission of dengue virus. We investigated minimal viral titres necessary for development of symptoms in bitten mice and used resulting parameters to inform a new model of dengue virus transmission within a susceptible population., Findings: Naïve mice bitten by mosquitoes immediately after they took partial blood meals from dengue infected mice showed symptoms of dengue virus, followed by mortality. Incorporation of mechanical transmission into mathematical models of dengue virus transmission suggest that this supplemental transmission route could result in larger outbreaks which peak sooner., Interpretation: The potential of dengue transmission routes independent of midgut viral replication has implications for vector control strategies that target mosquito lifespan and suggest the possibility of similar mechanical transmission routes in other disease-carrying mosquitoes., Funding: This study was funded by grants from the National Health Research Institutes, Taiwan (04D2-MMMOST02), the Human Frontier Science Program (RGP0033/2021), the National Institutes of Health (1R01AI143698-01A1, R01AI151004 and DP2AI152071) and the Ministry of Science and Technology, Taiwan (MOST104-2321-B-400-016)., Competing Interests: Declaration of interests OSA. is a founder of Agragene, Inc. with equity interest and a founder of Synvect with equity interest. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. All remaining authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The antagonistic Bacillus amyloliquefaciens HY2-1 was a marine microbiology that was isolated previously from the seabed silt of Beibu Gulf in China by dual culture with Penicillium digitatum. As a continuous study, the present work focused on evaluating the antimicrobial activity, identifying the produced active components, and revealing the fermentation characteristics of B. amyloliquefaciens HY2-1, respectively. It was found that B. amyloliquefaciens HY2-1 exhibited a broad-spectrum antimicrobial activity against the tested seven phytopathogenic fungi and five pathogenic bacteria by producing Bacillus lipopeptides such as fengycin A (C 14 to C 19 homologues) and surfactin (C 14 and C 15 homologues). Morphological observation of P. digitatum under light microscope, scanning electron microscopy, transmission electron microscopy, and fluorescence microscope inferred that B. amyloliquefaciens exerted the antagonistic activity by damaging the fungal cell membrane, thus inhibiting the mycelium growth and sporification of phytopathogenic fungi. As a marine microbiology, our results showed that B. amyloliquefaciens could survive and metabolize even at the culture condition with 110 g/L of NaCl concentration, and the produced antimicrobial compounds exhibited excellent thermostability and acid-alkali tolerance. The dynamic models were further constructed to theoretically analyze the fermentation process of B. amyloliquefaciens HY2-1, suggesting that the synthesis of antimicrobial compounds was coupled with both cell growth and cell biomass. In conclusion, the marine lipopeptides-producing B. amyloliquefaciens HY2-1 showed a promising prospect to be explored as a biocontrol agent for plant disease control of crops and postharvest preservation of fruits and vegetables, especially due to its outstanding stress resistance and the broad-spectrum and effective antagonist on various phytopathogenic fungi., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Head and neck cancer is a major cancer type, with high motility rates that reduce the quality of life of patients. Herein, we investigated the effectiveness and mechanism of a combination therapy involving TLR9 activator (CpG-2722) and phosphatidylserine (PS)-targeting prodrug of SN38 (BPRDP056) in a syngeneic orthotopic head and neck cancer animal model. The results showed a cooperative antitumor effect of CpG-2722 and BPRDP056 owing to their distinct and complementary antitumor functions. CpG-2722 induced antitumor immune responses, including dendritic cell maturation, cytokine production, and immune cell accumulation in tumors, whereas BPRDP056 directly exerted cytotoxicity toward cancer cells. We also discovered a novel function and mechanism of TLR9 activation, which increased PS exposure on cancer cells, thereby attracting more BPRDP056 to the tumor site for cancer cell killing. Killed cells expose more PS in tumor for BPRDP056 targeting. Tumor antigens released from the dead cells were taken up by antigen-presenting cells, which enhanced the CpG-272-promoted T cell-mediated tumor-killing effect. These form a positive feed-forward antitumor effect between the actions of CpG-2722 and BPRDP056. Thus, the study findings suggest a novel strategy of utilizing the PS-inducing function of TLR9 agonists to develop combinational cancer treatments using PS-targeting drugs., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: We evaluated the safety and immunogenicity of high and low doses of a novel pichia pastoris-expressed bivalent (types 16 and 18) human papillomavirus (HPV) virus-like particle vaccine., Methods: In this randomized, double-blind, placebo-controlled phase 1 trial, we enrolled 160 healthy females aged 9-45 years in Guangxi, China who were randomized (1:1:2) to receive either low (0.5 mL) or high (1.0 mL) dosages of bivalent HPV vaccine, or placebo (aluminum adjuvant) in a 0, 2, 6 months schedule. Adverse events and other significant conditions that occurred within 30 days after each vaccination were recorded throughout the trial. Sera were collected at days 0, 60, 180 and 210 to measure anti-HPV 16/18 neutralizing antibodies., Results: A total of 160 participants received at least one dose of the HPV vaccine and 152 completed the three dose vaccination series. Reporting rates of adverse events in placebo, low dose (0.5 mL) and high dose (1.0 mL) groups were 47.5 %, 55.0 % and 55.0 %, respectively. No serious adverse events occurred during this trial. 100 % of the participants who received three doses of the HPV vaccine produced neutralizing antibodies against HPV 16/18 vaccine. For HPV 16 and HPV 18, the geometric mean titers (GMTs) were similar between the low dose group (GMT HPV 16  = 10816 [95 % CI: 7824-14953]), GMT HPV 18  = 3966 [95 % CI: 2693-5841]) and high dose group (GMT HPV 16  = 14482 [95 % CI: 10848-19333], GMT HPV 18  = 3428 [95 % CI: 2533-4639])., Conclusion: The pichia pastoris-expressed bivalent HPV vaccine was safe and immunogenic in Chinese females aged 9-45 years. The low dosage (0.5 mL) was selected for further immunogenicity and efficacy study., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: B-W Yu, L-Y Zhou and L Shi were full-time employees of the manufacturer at the time of the study, other authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Scope: This study investigates the effect of epigallocatechin gallate (EGCG) on white and beige preadipocyte growth and explores the involvement of the miR-let-7a/HMGA2 pathway., Methods and Results: 3T3-L1 and D12 cells are treated with EGCG. The effect of EGCG on cell proliferation and viability is evaluated, as well as microRNA (miRNA)-related signaling pathways. EGCG inhibits 3T3-L1 and D12 preadipocyte growth, upregulates miR-let-7a expression, and downregulates high-mobility group AT-hook 2 (HMGA2) mRNA and protein levels in a time- and dose-dependent manner. In addition, overexpression of miR-let-7a significantly inhibits the growth of 3T3-L1 and D12 cells and decreases HMGA2 mRNA and protein levels. MiR-let-7a inhibitor antagonizes the inhibitory effects of EGCG on the number and viability of 3T3-L1 and D12 cells. Furthermore, miR-let-7a inhibitor reverses the EGCG-induced increase in miR-let-7a expression levels and decrease in HMGA2 mRNA and protein levels. HMGA2 overexpression induces an increase in cell number and viability and antagonizes EGCG-suppressed cell growth and HMGA2 expression in 3T3-L1 and D12 preadipocytes., Conclusion: EGCG inhibits the growth of 3T3-L1 and D12 preadipocytes by modulating the miR-let-7a and HMGA2 pathways., (© 2023 Wiley-VCH GmbH.)

Background: Despite the success in decreasing varicella-related disease burden, live-attenuated Oka vaccine strain of varicella-zoster virus (vOka) remains neuro-virulence and may establish latency and reactivate, raising safety concerns. Here we aimed to evaluate the safety and immunogenicity of a skin- and neuro-attenuated varicella vaccine candidate (v7D)., Methods: This is a randomized, double-blind, placebo-controlled, dose-escalation and age de-escalation phase 1 clinical trial conducted in Liuzhou, China (ChiCTR1900022284). Eligible healthy participants aged 1-49 years, with no history of varicella vaccination and had no history of varicella or herpes zoster were sequentially enrolled and allocated to subcutaneously receive one of the three doses (3.3, 3.9, and 4.2 lg PFU) of v7D, vOka or placebo in a dose-escalation and age de-escalation manner. The primary outcome was safety, assessed by adverse events/reactions within 42 days after vaccination and serious adverse events (SAEs) throughout six months after vaccination. The secondary outcome was immunogenicity, assessed by the VZV IgG antibodies measured with fluorescent antibody to membrane antigen (FAMA) assay., Findings: Between April 2019 and March 2020, totally 224 participants were enrolled. Within 42 days post-vaccination, the incidences of adverse reactions were 37.5%-38.7% in the three doses of v7D groups which were similar to that of the vOka (37.5%) and placebo (34.4%) groups. No SAE has been judged as causally related to vaccination. At 42 days post-vaccination, 100% of children aged 1-12 years in the per-protocol set of immunogenicity cohort of the v7D groups became seropositive. Meanwhile, in the intent-to-treat set of immunogenicity cohort of subjects aged 1-49 years, the geometric mean increases of the three groups of v7D vaccine were 3.8, 5.8 and 3.2, respectively, which were similar to that of the vOka vaccine group (4.4) and significantly higher than that of the placebo group (1.3)., Interpretation: The candidate v7D vaccine has been preliminarily shown to be well-tolerated and immunogenic in humans. The data warrant further evaluation of the safety advantage and efficacy of v7D as a varicella vaccine., Funding: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, and Beijing Wantai CO., LTD., Competing Interests: The authors declare the following financial interests/personal relationships that may be considered potential competing interests: The study funder, Beijing Wantai Biological Pharmacy Enterprise, prepared the vaccines in the phase 1 trial. Q-Q S, J-Z J, J-L H, Y-M L and X-Z Y are employees of Beijing Wantai Biological Pharmacy Enterprise. X-Z Y and Y-M L have stock options in Beijing Wantai Biological Pharmacy Enterprise CO. All other authors declare no competing interests., (© 2023 The Author(s).)

Background: Zika virus (ZIKV) infection is clinically known to induce testicular swelling, termed orchitis, and potentially impact male sterility, but the underlying mechanisms remain unclear. Previous reports suggested that C-type lectins play important roles in mediating virus-induced inflammatory reactions and pathogenesis. We thus investigated whether C-type lectins modulate ZIKV-induced testicular damage., Methods: C-type lectin domain family 5 member A (CLEC5A) knockout mice were generated in a STAT1-deficient immunocompromised background (denoted clec5a -/- stat1 -/- ) to enable testing of the role played by CLEC5A after ZIKV infection in a mosquito-to-mouse disease model. Following ZIKV infection, mice were subjected to an array of analyses to evaluate testicular damage, including ZIKV infectivity and neutrophil infiltration estimation via quantitative RT-PCR or histology and immunohistochemistry, inflammatory cytokine and testosterone detection, and spermatozoon counting. Furthermore, DNAX-activating proteins for 12 kDa (DAP12) knockout mice (dap12 -/- stat1 -/- ) were generated and used to evaluate ZIKV infectivity, inflammation, and spermatozoa function in order to investigate the potential mechanisms engaged by CLEC5A., Results: Compared to experiments conducted in ZIKV-infected stat1 -/- mice, infected clec5a -/- stat1 -/- mice showed reductions in testicular ZIKV titer, local inflammation and apoptosis in testis and epididymis, neutrophil invasion, and sperm count and motility. CLEC5A, a myeloid pattern recognition receptor, therefore appears involved in the pathogenesis of ZIKV-induced orchitis and oligospermia. Furthermore, DAP12 expression was found to be decreased in the testis and epididymis tissues of clec5a -/- stat1 -/- mice. As for CLEC5A deficient mice, ZIKV-infected DAP12-deficient mice also showed reductions in testicular ZIKV titer and local inflammation, as well as improved spermatozoa function, as compared to controls. CLEC5A-associated DAP12 signaling appears to in part regulate ZIKV-induced testicular damage., Conclusions: Our analyses reveal a critical role for CLEC5A in ZIKV-induced proinflammatory responses, as CLEC5A enables leukocytes to infiltrate past the blood-testis barrier and induce testicular and epididymal tissue damage. CLEC5A is thus a potential therapeutic target for the prevention of injuries to male reproductive organs in ZIKV patients., (© 2023. The Author(s).)

Copper-based catalysts are widely explored in electrochemical CO 2 reduction (CO 2 RR) because of their ability to convert CO 2 into high-value-added multicarbon products. However, the poor stability and low selectivity limit the practical applications of these catalysts. Here, we proposed a simple and efficient asymmetric low-frequency pulsed strategy (ALPS) to significantly enhance the stability and the selectivity of the Cu-dimethylpyrazole complex Cu 3 (DMPz) 3 catalyst in CO 2 RR. Under traditional potentiostatic conditions, Cu 3 (DMPz) 3 exhibited poor CO 2 RR performance with the Faradaic efficiency (FE) of 34.5% for C 2 H 4 and FE of 5.9% for CH 4 as well as the low stability for less than 1 h. We optimized two distinguished ALPS methods toward CH 4 and C 2 H 4 , correspondingly. The high selectivities of catalytic product CH 4 (FE CH4 = 80.3% and above 76.6% within 24 h) and C 2 H 4 (FE C2H4 = 70.7% and above 66.8% within 24 h) can be obtained, respectively. The ultralong stability for 300 h (FE CH4 > 60%) and 145 h (FE C2H4 > 50%) was also recorded with the ALPS method. Microscopy (HRTEM, SAED, and HAADF) measurements revealed that the ALPS method in situ generated and stabilized extremely dispersive and active Cu-based clusters (∼2.7 nm) from Cu 3 (DMPz) 3 . Meanwhile, ex situ spectroscopies (XPS, AES, and XANES) and in situ XANES indicated that this ALPS method modulated the Cu oxidation states, such as Cu(0 and I) with C 2 H 4 selectivity and Cu(I and II) with CH 4 selectivity. The mechanism under the ALPS methods was explored by in situ ATR-FTIR, in situ Raman, and DFT computation. The ALPS methods provide a new opportunity to boost the selectivity and stability of CO 2 RR.

Ligand-targeting drug delivery systems have made significant strides for disease treatments with numerous clinical approvals in this era of precision medicine. Herein, we report a class of small molecule-based immune checkpoint-targeting maytansinoid conjugates. From the ligand targeting ability, pharmacokinetics profiling, in vivo anti-pancreatic cancer, triple-negative breast cancer, and sorafenib-resistant liver cancer efficacies with quantitative mRNA analysis of treated-tumor tissues, we demonstrated that conjugate 40a not only induced lasting regression of tumor growth, but it also rejuvenated the once immunosuppressive tumor microenvironment to an "inflamed hot tumor" with significant elevation of gene expressions that were not accessible in the vehicle-treated tumor. In turn, the immune checkpoint-targeting small molecule drug conjugate from this work represents a new pharmacodelivery strategy that can be expanded with combination therapy with existing immune-oncology treatment options.

Green tea epigallocatechin gallate (EGCG) and microRNA (miRNA) molecules modulate obesity. Nevertheless, it is still unknown whether EGCG modulates fat cell growth via miRNA-related signaling. In this study, white preadipocytes were used to examine whether the antimitogenic effect of EGCG on fat cells is regulated by the miR-143/MAPK7 pathway. We showed that EGCG upregulated the levels of miR-143, but not miR-155, in 3T3-L1 preadipocytes. Moreover, EGCG downregulated MAPK7 mRNA and protein levels time- and dose-dependently. MAPK7 expression increased during 3T3-L1 cell proliferation. miR-143 overexpression in the absence of EGCG mimicked the effects of EGCG to suppress preadipocyte growth and MAPK7 expression, whereas knockdown of miR-143 antagonized the EGCG-altered levels of miR-143, MAPK7, and pERK1/2 and reversed the EGCG-inhibited cell growth. These findings suggest that EGCG inhibits 3T3-L1 cell growth via miR-143/MAPK7 pathway.

The COVID-19 pandemic has robustly affected global education environments, so higher education institutions need to emphasize innovation and creativity in educational methods for teachers to improve their teaching performance as well as enhance the engagement and motivation of students in this changing environment. Accordingly, it is essential to discuss the role of teaching innovation in the setting of the COVID-19 pandemic compared to the pre-COVID-19 period. The aim of this study is to empirically validate the importance of teaching innovation in student evaluation of teaching before and during the COVID-19 pandemic. Data were collected from the medical college of a comprehensive university in Taiwan and were subjected to t -tests and multiple linear regression analysis. Findings from a quantitative study with 44 teachers revealed that teaching innovation was positively correlated to student evaluation of teaching. We also found that teachers who implemented teaching innovation strategies performed better than those teachers who used conventional teaching strategies on student evaluation of teaching. In particular, teaching innovative teachers had improvement in student evaluation of teaching during the time of the COVID-19 pandemic, but not non-teaching innovative teachers. The evidence from this study suggests that teaching innovation can not only enhance teachers' teaching development and performance but also boost students' motivation for learning, especially in the time of the COVID-19 pandemic. Our findings have important implications for future research on teaching innovation and for higher education institutions and faculty wishing to provide high-quality learning environments to their students., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lin, Huang and Lin.)

We report the design, synthesis and evaluation of a class of phosphatidylserine-targeting zinc (II) dipicolylamine drug conjugates and show that conjugate 16b elicits immune cell infiltration and remodels the "cold" hepatic tumor microenvironment to the inflamed "hot" tumor. Structure-property relationship study via linker modifications and subsequent pharmacokinetics profiling were carried out to improve the solubility and stability of the conjugates in vivo. In a spontaneous hepatocellular carcinoma mouse model, we showed that conjugate 16b exhibited better antitumor efficacy than sorafenib. In particular, significant increase of CD8 + T cell infiltration and granzyme B level was observed, providing insights in sensitizing tumors from intrinsic immune suppressive microenvironment. Evaluation of tumor inflammation-related mRNA expression profile revealed that conjugate 16b, through inductions of key gene expressions including STAT1, CXCL9, CCL5, and PD-L1, rejuvenated tumor microenvironment with enhancement in T cell-, macrophage-, NK cell-, chemokines and cytokines'- functions. Our study establishes that an apoptosis-targeting theranostic enables enrichment of multifaceted immune cells into the tumor mass, which provides potential therapeutic strategies in the combination with immune checkpoint blockade treatment., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ligand-targeting drug conjugates are a class of clinically validated biopharmaceutical drugs constructed by conjugating cytotoxic drugs with specific disease antigen targeting ligands through appropriate linkers. The integrated linker-drug motif embedded within such a system can prevent the premature release during systemic circulation, thereby allowing the targeting ligand to engage with the disease antigen and selective accumulation. We have designed and synthesized new thioester-linked maytansinoid conjugates. By performing in vitro cytotoxicity, targeting ligand binding assay, and in vivo pharmacokinetic studies, we investigated the utility of this new linker-drug moiety in the small molecule drug conjugate (SMDC) system. In particular, we conjugated the thioester-linked maytansinoids to the phosphatidylserine-targeting small molecule zinc dipicolylamine and showed that Zn8&#95;DM1 induced tumor regression in the HCC1806 triple-negative breast cancer xenograft model. Moreover, in a spontaneous sorafenib-resistant liver cancer model, Zn8&#95;DM1 exhibited potent antitumor growth efficacy. From quantitative mRNA analysis of Zn8&#95;DM1 treated-tumor tissues, we observed the elevation of gene expressions associated with a "hot inflamed tumor" state. With the identification and validation of a plethora of cancer-associated antigens in the "omics" era, this work provided the insight that antibody- or small molecule-based targeting ligands can be conjugated similarly to generate new ligand-targeting drug conjugates.

There are few well-characterized syngeneic murine models for hepatocellular carcinoma (HCC), which limits immunological studies and the development of immunotherapies for HCC. We previously established an oncogene-induced spontaneous HCC mouse model based on transposon-mediated oncogene ( AKT and NRASV12 ) insertion into the genome of hepatocytes to induce tumorigenesis. Two tumor clones with different levels of lipid droplets (LDs) showed similar in vitro growth but distinctive in vivo phenotypes, including divergent proliferative capability and varying induction of myeloid-derived suppressor cells (MDSCs). The two clones showed distinct gene expression related to lipid metabolism, glycolysis, and cancer stemness. Endogenous fatty acid (FA) synthesis and exogenous monounsaturated fatty acid (MUFA) consumption promoted both tumor proliferation and cancer stemness, and upregulated c-Myc in the HCC cell lines. Moreover, the LD hi HCC cell line expressed a higher level of type II IL-4 receptor, which promoted tumor proliferation through binding IL-4 or IL-13. The chromosomal DNA of two tumor clones, NHRI-8-B4 (LD hi ) and NHRI-1-E4 (LD lo ) showed five identical AKT insertion sites in chromosomes 9, 10, 13, 16 and 18 and two NRAS integration sites in chromosomes 2 and 3. Herein, we describe two novel HCC cell lines with distinct features of lipid metabolism related to cancer stemness and differential interplay with the immune system, and present this syngeneic HCC mouse model as a practical tool for the study of cancer stemness and discovery of new therapies targeting liver cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cheng, Ko, Ku, Huang, Yao, Liao, Chen, Huang and Huang.)

The formation of new blood vessels in solid tumors is regulated by various endothelial trophic factors. We identified that CLEC11A, an extracellular C-type lectin, was over-expressed in lung cancer cell lines harboring mutated EGFR . CLEC11A expression was also frequently elevated in lung adenocarcinoma (LAC) tissues with EGFR mutation. CLEC11A-expressing H1299 cells formed larger tumors in nude mice than did the control cells. The CLEC11A-expressing tumors contained more CD31-positive cells, suggesting that they had a higher angiogenic activity. CLEC11A per se did not induce blood vessel formation, but enhanced angiogenesis triggered by VEGF-A or basic FGF in vivo. Additionally, the expression of small hairpin RNA against CLEC11A (shCLEC11A) in HCC827 LAC cells suppressed their tumorigenic ability. Purified CLEC11A exhibited a chemotactic ability, which is dependent on its integrin-binding RGD and LDT motifs, toward endothelial cells. This chemotactic activity was not affected by the presence of a VEGFR inhibitor. Conditioned medium produced by HCC827-shCLEC11A cells had diminished chemotactic ability toward endothelial cells. CLEC11A treatments increased the levels of active integrin β1 that were not associated with activation of focal adhesion kinases in endothelial cells. Our results indicated that CLEC11A was a factor of angiogenic potential and was involved in lung cancer tumorigenesis.

Background: Hepatitis B surface antigen (HBsAg) seroclearance is the most important milestone indicating favourable clinical outcomes in patients with chronic hepatitis B (CHB). However, it is difficult to achieve due to the impaired HBV-specific immunity, such as programmed cell death 1 (PD-1)-associated T cell exhaustion. We assessed soluble PD-1 (sPD-1) as a novel seromarker for predicting spontaneous HBsAg loss., Methods: Serial serum levels of sPD-1 were evaluated in 1046 untreated hepatitis B e antigen (HBeAg)-seronegative individuals who had achieved undetectable serum HBV DNA. Multiple regression analyses were applied to assess associations among baseline and subsequent sPD-1 levels, HBsAg decline during follow-up, and spontaneous HBsAg seroclearance., Results: A total of 390 individuals achieved spontaneous HBsAg seroclearance during 6464.4 person-years of follow-up. Baseline sPD-1 levels were inversely associated with baseline HBsAg levels (qHBsAg) as well as a greater decline in qHBsAg during follow-up. Incidence rates of HBsAg seroclearance were 11.5, 61.7, 96.7 and 151.0 per 1000 person-years for sPD-1 levels of ≥4000, 536-3999, 125-535 and <125 pg/mL, respectively (P trend  < 0.0001). Compared with baseline sPD-1 levels ≥4000 pg/mL, the rate ratio (95% CI) of HBsAg seroclearance was 2.1 (1.1-3.9), 3.0 (1.6-5.5) and 5.1 (2.8-9.5), for baseline sPD-1 levels of 536-3999, 125-535 and <125 pg/mL, respectively, after adjustment for sex, age and serum alanine aminotransferase and HBsAg levels., Conclusion: sPD-1 level is a novel marker which independently predicts spontaneous HBsAg seroclearance of HBeAg-negative inactive CHB patients with undetectable HBV DNA. (word count: 234, <250)., (© 2022 John Wiley & Sons Ltd.)

Chronic hepatitis B affects more than 250 million individuals worldwide, putting them at risk of developing liver cirrhosis and liver cancer. While antiviral immune responses are key to eliminating hepatitis B virus (HBV) infections, insufficient antiviral immunity characterized by failure to eliminate HBV-infected hepatocytes is associated with chronic hepatitis B. Prophylactic vaccination against hepatitis B successfully established protective immunity against infection with the hepatitis B virus and has been instrumental in controlling hepatitis B. However, prophylactic vaccination schemes have not been successful in mounting protective immunity to eliminate HBV infections in patients with chronic hepatitis B. Here, we discuss the current knowledge on the development and efficacy of therapeutic vaccination strategies against chronic hepatitis B with particular emphasis on the pathogenetic understanding of dysfunctional anti-viral immunity. We explore the development of additional immune stimulation measures within tissues, in particular activation of immunogenic myeloid cell populations, and their use for combination with therapeutic vaccination strategies to improve the efficacy of therapeutic vaccination against chronic hepatitis B.

Zirconium (Zr)-based porphyrinic metal-organic frameworks (PCN-223-M) were employed as the electrocatalysts to explore the effect of uncoordinated Zr sites on the performance of the CO 2 reduction reaction (CO 2 RR). PCN-223-AA with the lowest uncoordinated number of 0.79 exhibited the highest FE(CO) of 90.7%. It was demonstrated that the catalytic performance of PCN-223-M showed negative correlation to the uncoordinated Zr sites. This research provided a rational strategy to design efficient MOF electrocatalysts with few uncoordinated metal sites for highly selective CO 2 RR.

Background/aim: Casein kinase 1 epsilon (CK1ε) is a member of the casein kinase 1 family, which includes highly conserved and ubiquitous serine/threonine protein kinases. Recent research has revealed that CK1ε plays an important role in a variety of human cancer types; however, its role in human melanoma remains unclear. The aim of this study was to elucidate the clinical role of CK1ε in patients with melanoma., Patients and Methods: Samples from 34 patients with melanoma were analyzed by immunohistochemical staining. Formalin-fixed paraffin-embedded tissue microarrays were also examined by two histopathologists to assess CK1ε protein expression in humans., Results: Cytoplasmic CK1ε protein expression was significantly lower in tumor tissue than in normal tissue. Lack of cytoplasmic CK1ε protein was significantly correlated with distant metastasis (p=0.022) and poorer survival (p=0.030). However, Kaplan-Meier survival analysis revealed that elevated expression of cytoplasmic CK1ε protein was not significantly associated with the overall survival of patients with melanoma. Univariate and multivariate analyses demonstrated that lack of cytoplasmic CK1ε protein expression was related to distant metastasis (p<0.001 and p=0.004), showing that CK1ε was a prognostic factor., Conclusion: CK1ε protein expression might serve as a prognostic indicator in the treatment of patients with melanoma., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Interstitial lung diseases (ILDs) include a wide variety of chronic progressive pulmonary diseases characterized by lung inflammation, fibrosis and hypoxemia and can progress to respiratory failure and even death. ILDs are associated with varying degrees of quality of life impairments in affected people. Studies on the quality of life in patients with ILDs are still limited, and there are few studies with long-term follow-up periods in these patients., Methods: Data from patients who were clinically diagnosed with ILDs in the Respiratory Department, Beijing Chaoyang Hospital, Capital Medical University from January 2017 to February 2018 were collected. Clinical status and HRQoL were assessed at baseline and subsequently at 6- and 12-month intervals with the LCQ, mMRC, HADS, SF-36, and SGRQ. Multivariate linear regression was used to evaluate the determinants of the decline in HRQoL., Results: A total of 139 patients with idiopathic interstitial pneumonia (IIP) and 30 with connective tissue disease-associated ILD (CTD-ILD) were enrolled, 140 of whom completed the follow-up. The mean age was 63.7 years, and 92 patients were men. At baseline, the decline in HRQoL assessed by the SF-36 and SGRQ was significantly associated with the mMRC, LCQ and HADS depression score. In the follow-up, changes in FVC%, DLco%, mMRC and LCQ were significantly associated with changes in HRQoL., Conclusions: HRQoL in both IIP and CTD-ILD patients deteriorates to varying degrees, and the trend suggests that poor HRQoL in these patients is associated with many determinants, primarily dyspnea, cough and depression. Improving HRQoL is the main aim when treating patients living with ILDs., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate the accuracy of bedside transthoracic lung ultrasonography (TLU) in different typical high resolution computed tomography (HRCT) signs of interstitial lung diseases (ILDs). Methods: Fifty patients first diagnosed with ILDs were enrolled from January 2016 to December 2018. There were 21 males and 29 females. The mean age was (56±14) years(rang 42-73 years). TLU was performed in inspiration for the characters of A-lines and B-lines as well as pleural at anterior, lateral and dorsal chest walls, respectively. HRCT was selected at three levels according to the upper, middle, and lower lung fields. The range of each level needing to be evaluated corresponded to the TLU scanning field one by one, and recording the signs of HRCT. Early change of ILDs was definite as the HRCT score was no more than 1 and no honeycomb was present. The correlation between A-lines, B-lines, pleural abnormal and HRCT signs was evaluted. Spearman's correlation coefficient was used to evaluate the relationship between B-lines and HRCT score. Results: The sensitivity and specificity of A-lines for HRCT normality were 83.9% and 84.9%, respectively. Coincidence rate was 84.6%. The sensitivity and specificity of B-lines for HRCT abnormality were 84.9% and 83.9%, respectively. Coincidence rate was 84.6%. Interlobular septal thickening shadow had fewer B-lines and narrower interval than other HRCT signs, while the other HRCT signs had no differences in B-lines. And the sensitivity and specificity of B-lines for detection the early change of HRCT in ILDs were 89.5% and 89.2%, respectively. Coincidence rate was 89.3%. A positive correlation was found between the number of B-lines and HRCT scores ( R =0.827, P< 0.001), and the width of B-lines and HRCT score ( R =0.951, P< 0.001). Meanwhile, a negative correlation was found between the interval of B-lines and HRCT score ( R =-0.831, P< 0.001). The sensitivity and specificity of TLU for HRCT pleural abnormality were 100.0% and 90.0%, respectively. Coincidence rate was 93.6%. Conclusions: TLU showed high sensitivity and specificity in finding interstitial changes of the lung. It gives a new view on the diagnostic possibilities of ILDs and may be used to evaluate the severity and the therapeutic effect of treatment. However, TLU could not differentiate HRCT signs of ILDs.

Immunotherapy using checkpoint blockade has revolutionized cancer treatment, improving patient survival and quality of life. Nevertheless, the clinical outcomes of such immunotherapy are highly heterogeneous between patients. Depending on the cancer type, the patient response rates to this immunotherapy are limited to 20-30%. Based on the mechanism underlying the antitumor immune response, new therapeutic strategies have been designed with the aim of increasing the effectiveness and specificity of the antitumor immune response elicited by checkpoint blockade agents. The activation of toll-like receptor 9 (TLR9) by its synthetic agonists induces the antitumor response within the innate immunity arm, generating adjuvant effects and priming the adaptive immune response elicited by checkpoint blockade during the effector phase of tumor-cell killing. This review first describes the underlying mechanisms of action and current status of monotherapy using TLR9 agonists and immune checkpoint inhibitors for cancer immunotherapy. The rationale for combining these two agents is discussed, and evidence indicating the current status of such combination therapy as a novel cancer treatment strategy is presented., (Copyright © 2020 Chuang, Tseng, Huang, Huang, Huang and Chuang.)

There is a positive feedback loop driving tumorigenesis and tumor growth through coordinated regulation of epigenetics, inflammation, and stemness. Nevertheless, the molecular mechanism linking these processes is not well understood. In this study, we analyzed the correlation of de-ubiquitinases (DUBs) expression with survival data from the OncoLnc database. Among the DUBs analyzed, ubiquitin specific protease 4 (USP4) had the lowest negative Cox coefficient. Low expression of USP4 was associated with poor survival among lung cancer patients and was inversely correlated with expression of stemness and inflammation markers. Expression of USP4 were reduced at more advanced stages of lung cancer. Mechanistically, expression of USP4 was downregulated in snail1-overexpressing and stemness-enriched lung cancer cells. Snail1 was induced in lung cancer cells by interaction with macrophages, and epigenetically suppressed USP4 expression by promoter methylation. Stable knockdown of USP4 in lung cancer cells enhanced inflammatory responses, stemness properties, chemotherapy resistance, and the expression of molecules allowing escape from immunosurveillance. Further, mice injected with USP4 knockdown lung cancer cells demonstrated enhanced tumorigenesis and tumor growth. These results reveal that the Snail1-mediated suppression of USP4 is a potential mechanism to orchestrate epigenetic regulation, inflammation and stemness for macrophage-promoted tumor progression.

Asymmetric transmission (AT) devices are fundamental elements for optical computing and information processing. We here propose an AT device consisting of a pair of coupled complementary subwavelength gratings. Different from previous works, asymmetric dielectric environment is employed for unidirectional excitation of surface plasmon polaritons (SPPs) and thus asymmetric optical transmission, and near-field coupling effect inherent in the coupled complementary structure is exploited to enhance forward transmission and AT behavior, and determine operation bandwidth as well. The influence of asymmetric dielectric environment, effect of vertical and lateral couplings, interactions of electric- and magnetic-dipole moments and the realization of Kerker conditions, are investigated in depth to unearth the AT mechanism and performance. High-performance AT with large forward transmittance of 0.96 and broad bandwidth of 174 nm is achieved at wavelength 1250 nm. Our work helps people to gain a better understanding of near-filed coupling effect in coupled complementary structures, expand their application fields, and it also offers an alternate way to high-performance AT devices.

Objective: Recently, the vital role of circular RNAs (circRNAs) in human diseases has attracted much attention. The aim of this research was to verify the potential role of circRNA&#95;0000285 in the development of cervical cancer (CC)., Patients and Methods: CircRNA&#95;0000285 expression in both CC cells and tissue samples was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Functional experiments were performed, including cell counting kit-8 (CCK-8) assay, cell cycle assay and transwell assay. Meanwhile, the underlying mechanism was explored through qRT-PCR and Western blot assay, respectively. In addition, the function of circRNA&#95;0000285 was identified in vivo., Results: CircRNA&#95;0000285 expression level was significantly higher in CC samples than that of corresponding normal tissues. Moreover, the growth and migration abilities of CC cells were significantly inhibited after circRNA&#95;0000285 was knocked down in vitro. Furthermore, the expression of FUS was remarkably down-regulated after knockdown of circRNA&#95;0000285. Subsequent results indicated that the expression level of FUS was positively correlated with the expression of circRNA&#95;0000285 in CC tissues. In addition, the knockdown of circRNA&#95;0000285 significantly inhibited the formation and metastasis of CC in nude mice., Conclusions: CircRNA&#95;0000285 could enhance the proliferation and metastasis of CC by up-regulating FUS, which might be a potential therapeutic target for CC treatment.

The aim of this study is to review the natural course, clinical features, and reproductive prognosis of ovarian tumors associated with hyperandrogenemia. We retrospect 33 patients of ovarian tumors with hyperandrogenemia. Thirty cases (91%) were sex cord-stromal tumors. Sertoli-Leydig cell tumors, Leydig cell tumors, and steroid cell tumors were the most common types. It is not possible, to predict the pathological subtypes based on androgen levels alone. Most of these tumors were solid masses, with an average diameter of 3.9 cm. These tumors are soft or fragile, no clear boundary with normal tissue, thus excision is superior to exfoliation. The average disease course of the top three tumors was 32.6, 35.4, and 67.7 months, respectively. Among 11 married women with a desire to get pregnant, nine cases resumed menstrual periods after surgery and became pregnant naturally. Hyperandrogenemia might predict a better prognosis. The asynchronism of hyperandrogenemia and undetectable tumor may cause irreversible change and emotional depress, the methods of early diagnosis need further study.

Potential function of UNC13C in variety of cancers including, oral squamous cell carcinoma (OSCC) remains obscure. In the present study, immunohistochemical staining in tissue microarrays containing 268 OSCC samples showed that UNC13C protein levels were inversely correlated with AJCC Stage III and IV ( P = 0.002) and death ( P = 0.0134). Patients with lower UNC13C expression had a significantly shorter survival ( P = 0.0231) than those with higher UNC13C expression. We also identified decreased overall UNC13C expression in oral cancer cell lines. In addition, our functional analysis of UNC13C shows that overexpression of UNC13C inhibited migration and invasion capacities of SCC-9 and SAS cells compared with the empty plasmid transfected cells. Further experiments suggested that transcription factors (Slug, Snail, Twist, and ZEB1) and mesenchymal marker (Vimentin) were down regulated and Tight Junction Protein (Claudin1) was up regulated after UNC13C overexpression in SCC9 and SAS cells. The novel role of UNC13C is revealed for the first time in OSCC. In summary, these results suggest that UNC13C as a novel tumor suppressor and an essential regulator of EMT signaling pathway during OSCC progression, and thus it could be used as a target for preventing oral cancer metastasis.

Purpose: The main purposes of this manuscript are to report a surprising and interesting degradation reaction of glucagon from a specific vendor in which glucagon underwent cleavage among several peptide bonds quickly under near neutral to basic conditions, and to propose the root cause of mechanism for the degradation reaction., Methods: The degradation reaction was monitored by HPLC and the fragment structures were confirmed by LC-MS. Possible impurities responsible for the degradation were either confirmed or excluded by a variety of techniques such as addition of chelator EDTA and transitional metal ions or separation by ultrafiltration., Results: This type of degradation was rarely reported in literature, especially considering its extreme cleavage efficiency. Contamination by a thermostable high molecular impurity (such as a peptidase with molecular weight between 10 and 30 KDa) during the manufacturing process was the main reason for this interesting phenomenon., Conclusions: The degradation phenomenon described here could be used as an excellent example showing that products ordered from vendors meeting the rudimentary quality standards might contain impurities which could cause significant degradation. We suggest that a simple solution, i.e. additional tests of stability under real or accelerated conditions by manufacturers and inclusion of the "accelerated stability criteria" in the Certificate of Analysis (CoAs), especially for sensitive biological reagents prone to faster degradation, would be very helpful for avoiding losses for both vendors and users.

Immunotherapy has ushered in a new era of cancer therapy, and this is also applicable to therapy of hepatocellular carcinoma (HCC). In this context, effective development of therapeutic strategies requires an HCC mouse model with known tumor-associated antigens (TAAs) and an HCC growth reporter. We created such a model using hydrodynamic injection and a transposon system to introduce AKT and NRAS and open reading frames (ORFs) encoding surrogate tumor antigens and luciferase into chromosomes of hepatocytes to induce nodular and diffuse tumors in the liver. TAA-specific CD8 + T cells were detected during HCC progression; however, these showed exhausted-like phenotypes and were unable to control tumor growth. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAM) from the tumor microenvironment were found to contribute to the suppression of the CD8 + T-cell response. The transposon-based Akt/N-Ras-induced HCC mouse model we developed enables researchers to monitor tumor growth non-invasively and to quantify and characterize endogenous or adoptively transferred TAA-specific CD8 + T-cell responses. These features make it a suitable preclinical model for exploration and evaluation of immune checkpoint inhibitors and cell-based immunotherapies for HCC treatment.

Macrophage accumulation and inflammation in the lung owing to stresses and diseases is a cause of lung cancer development. However, molecular mechanisms underlying the interaction between macrophages and cancer cells, which drive inflammation and stemness in cancers, are poorly understood. In this study, we investigated the expression of ubiquitin-specific peptidase 17 (USP17) in lung cancers, and role of elevated USP17 in the interaction between macrophages and lung cancer cells. USP17 expression in lung cancers was associated with poor prognosis, macrophage, and inflammatory marker expressions. Macrophages promoted USP17 expression in cancer cells. TNFR-associated factor (TRAF) 2-binding and TRAF3-binding motifs were identified in USP17, through which it interacted with and disrupted the TRAF2/TRAF3 complex. This stabilized its client proteins, enhanced inflammation and stemness in cancer cells, and promoted macrophage recruitment. In different animal studies, co-injection of macrophages with cancer cells promoted USP17 expression in tumors and tumor growth. Conversely, depletion of macrophages in host animals by clodronate liposomes reduced USP17 expression and tumor growth. In addition, overexpression of USP17 in cancer cells promoted tumor growth and inflammation-associated and stemness-associated gene expressions in tumors. These results suggested that USP17 drives a positive-feedback interaction between macrophages and cancer cells to enhance inflammation and stemness in cancer cells, and promotes lung cancer growth.

Activated T cells undergo metabolic reprogramming and effector-cell differentiation but the factors involved are unclear. Utilizing mice lacking DUSP6 (DUSP6 -/- ), we show that this phosphatase regulates T cell receptor (TCR) signaling to influence follicular helper T (T FH ) cell differentiation and T cell metabolism. In vitro, DUSP6 -/- CD4 + T FH cells produced elevated IL-21. In vivo, T FH cells were increased in DUSP6 -/- mice and in transgenic OTII-DUSP6 -/- mice at steady state. After immunization, DUSP6 -/- and OTII-DUSP6 -/- mice generated more T FH cells and produced more antigen-specific IgG2 than controls. Activated DUSP6 -/- T cells showed enhanced JNK and p38 phosphorylation but impaired glycolysis. JNK or p38 inhibitors significantly reduced IL-21 production but did not restore glycolysis. TCR-stimulated DUSP6 -/- T cells could not induce phosphofructokinase activity and relied on glucose-independent fueling of mitochondrial respiration. Upon CD28 costimulation, activated DUSP6 -/- T cells did not undergo the metabolic commitment to glycolysis pathway to maintain viability. Unexpectedly, inhibition of fatty acid oxidation drastically lowered IL-21 production in DUSP6 -/- T FH cells. Our findings suggest that DUSP6 connects TCR signaling to activation-induced metabolic commitment toward glycolysis and restrains T FH cell differentiation via inhibiting IL-21 production., Competing Interests: The authors declare no conflict of interest.

The importance of miRNAs in the progression of prostate cancer (PCa) has further been supported by the finding that miRNAs have been identified as potential oncogenes or tumor suppressors in PCa. Indeed, in eukaryotes, miRNAs have been found to regulate and control gene expression by degrading mRNA at the post-transcriptional level. In this study, we investigated the expression of miR-34 family members, miR-34b and miR-34c, in different PCa cell lines, and discussed the molecular mechanism of miR-34b in the invasion and migration of PCa cells in vitro. The difference analyses of the transcriptome between the DU145 and PC3 cell lines demonstrated that both miR-34b and -34c target critical pathways that are involved in metabolism, such as proliferation, and migration, and invasion. The molecular expression of miR-34b/c were lower in PC3 cells. Moreover, over-expression of miR-34b/c in PC3 cells caused profound phenotypic changes, including decreased cell proliferation, migration and invasion. Moreover, the players that regulate expression levels of transforming growth factor-β (TGF-β), TGF-β receptor 1 (TGF-βR1), and p53 or phosphorylation levels of mothers against decapentaplegic 3 (SMAD3) in the TGF-β/Smad3 signaling pathway have yet to be elucidated, and will provide novel tools for diagnosis and treatment of metastatic PCa., Competing Interests: The authors declare no conflict of interest.

Chronic hepatitis B virus (HBV) infection is a global public health issue. There are >250 million people chronically infected with HBV, and these chronic carriers are at high risk of developing end-stage liver diseases and hepatocellular carcinoma. Patients with chronic hepatitis B (CHB) usually acquire the virus perinatally, while most patients infected during adulthood develop acute hepatitis B (AHB), which usually results in viral clearance. HBV infection is noncytopathic, and liver injury is mostly contributed by host immune responses. The virus is stealthy, since the infection rarely induces type I interferon response in the early phase. In AHB, viral infection is detected and restrained by the innate immune response, which is followed by a strong and robust adaptive immune response and accompanied by viral clearance. In patients with CHB, both innate and adaptive immune responses are weak and thus rarely lead to viral clearance. Interferon α and nucleos(t)ide analogues are 2 classes of approved antiviral therapies. The former treatment activates nature killer (NK) cells and NK T cells, which partially enhances the innate immune response, while the later treatment suppresses viral replication by inhibiting reverse transcriptase, which may restore the HBV-specific adaptive immune response. However, single or combined treatment are still far from achieving seroclearance of HBV surface antigen. Although the treatment response is unsatisfactory in current clinical trials using several immunomodulators for boosting antiviral immunity, immunotherapy that is able to induce immune surveillance is still the most promising modality for HBV cure in the future., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Immunotherapy aiming to rescue or boost antitumor immunity is an emerging strategy for treatment of cancers. The efficacy of immunotherapy is strongly controlled by the immunological milieu of cancer patients. Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cell populations with immunosuppressive functions accumulating in individuals during tumor progression. The signaling mechanisms of MDSC activation have been well studied. However, there is little known about the metabolic status of MDSCs and the physiological role of their metabolic reprogramming. In this study, we discovered that myeloid cells upregulated their glycolytic genes when encountered with tumor-derived factors. MDSCs exhibited higher glycolytic rate than their normal cell compartment did, which contributed to the accumulation of the MDSCs in tumor-bearing hosts. Upregulation of glycolysis prevented excess reactive oxygen species (ROS) production by MDSCs, which protected MDSCs from apoptosis. Most importantly, we identified the glycolytic metabolite, phosphoenolpyruvate (PEP), as a vital antioxidant agent able to prevent excess ROS production and therefore contributed to the survival of MDSCs. These findings suggest that glycolytic metabolites have important roles in the modulation of fitness of MDSCs and could be potential targets for anti-MDSC strategy. Targeting MDSCs with analogs of specific glycolytic metabolites, for example, 2-phosphoglycerate or PEP may diminish the accumulation of MDSCs and reverse the immunosuppressive milieu in tumor-bearing individuals.

Digital refocusing has a tradeoff between complexity and quality when using sparsely sampled light fields for low-storage applications. In this paper, we propose a fast physically correct refocusing algorithm to address this issue in a twofold way. First, view interpolation is adopted to provide photorealistic quality at infocus-defocus hybrid boundaries. Regarding its conventional high complexity, we devised a fast line-scan method specifically for refocusing, and its 1D kernel can be 30× faster than the benchmark View Synthesis Reference Software (VSRS)-1D-Fast. Second, we propose a block-based multi-rate processing flow for accelerating purely infocused or defocused regions, and a further 3- 34× speedup can be achieved for high-resolution images. All candidate blocks of variable sizes can interpolate different numbers of rendered views and perform refocusing in different subsampled layers. To avoid visible aliasing and block artifacts, we determine these parameters and the simulated aperture filter through a localized filter response analysis using defocus blur statistics. The final quadtree block partitions are then optimized in terms of computation time. Extensive experimental results are provided to show superior refocusing quality and fast computation speed. In particular, the run time is comparable with the conventional single-image blurring, which causes serious boundary artifacts.

Background: Proton pump inhibitors (PPIs) are widely applied for acid related disorders, and possess pleiotropic biological functions. The effect of PPIs on the gastric mucosa, neutrophil and Helicobacter pylori (H. pylori) infiltration and glandular atrophy has not been well investigated, particularly the duration of the effects of PPIs., Objectives: To investigate the effects of PPIs on neutrophil infiltration, H. pylori infiltration and the gastric mucosa., Material and Methods: A total of 76 adult patients with gastrointestinal symptoms who had undergone upper gastrointestinal endoscopy were enrolled in the study. Each patient's history was recorded, including smoking, alcohol consumption and the duration of PPI use prior to gastric biopsy. Endoscopic biopsies of gastric antral mucosa were performed and evaluated by histology. Neutrophil and H. pylori infiltration were graded by H & E staining in accordance with the updated Sydney system., Results: Among the 76 patients, 44 patients had H. pylori infection and 19 patients had taken PPIs for varying durations prior to gastric biopsy. Neutrophil infiltration was significantly inhibited by PPIs (p = 0.005). The duration of PPI use was correlated with inhibition of neutrophil and H. pylori infiltration. A logistical regression analysis demonstrated that PPIs significantly inhibited neutrophil infiltration in the gastric mucosa and were associated with atrophy of the mucosa., Conclusions: PPIs attenuated neutrophil infiltration of gastric mucosa, and may be related to atrophy of the mucosa.

To get inside the properties of N,N-disubstituted Schiff bases, we synthesized three high-yielding benzaldehyde Schiff bases. We used the reaction between salicylaldehyde and different diamine compounds, including diamine, ethanediamine, and o -phenylenediamine, determining the structure of obtained molecules by nuclear magnetic resonance spectroscopy and electrospray ionization mass spectroscopy. We thus evaluated the microbicidal and antitumor activity of these compounds, showing that salicylaldehyde-hydrazine hydrate Schiff base (compound 1a ) significantly inhibited the growth of S. aureus ; salicylaldehyde- o -phenylenediamine Schiff base (compound 1c ) displayed a strong capability to inhibit the proliferation of leukemia cell lines K562 and HEL. Moreover, we observed that the antibacterial action of 1a might be associated with the regulation of the expression of key virulence genes in S. aureus . Compound 1c resulted in a strong apoptotic activity against leukemia cells, also affecting the cell cycle distribution. Overall, our novel N,N-disubstituted Schiff bases possess unique antibacterial or antitumor activities that exhibit the potent application prospect in prophylactic or therapeutic interventions, providing new insights for developing new antibacterial and anticancer chemical agents.

Oleanolic acid (OA), one of the major pentacyclic triterpenes abundantly present in nature, is a promising compound with various biological activities, including anti-inflammatory, anti-ulcer, hepatoprotective, antidiabetic, fungicidal and antiparasitic properties. Therefore, a series of derivatives of 1α,2α-epoxy-3β-hydroxyl oleanolic acid derivatives were designed and synthesized, and their antibacterial activities were investigated in vitro. Based on these results, the compounds with antibacterial activity were screened by RT-PCR to determine whether they can regulate the expression of genes related to metabolism, haemolysis, and β-lactamase in vitro, and the structure-microbicidal activity relationship of each compound was analyzed. Our study shows that some of the modifications in the synthetic compounds, such as the introduction of an ortho-cyano-substituted benzyl group and a short chain alkyl ester at the 28-carboxyl, as well as the introduction of an acetyl group at the 3-hydroxyl group of ring A, could enhance antibacterial activity. This provides basic evidence for the optimization of 1α,2α-epoxy-3β-hydroxyl oleanolic acid derivatives. The antibacterial mechanism of the active OA derivatives appears to involve the regulation of expression of metabolism-associated genes in Escherichia coli, haemolysis-associated genes in Bacillus subtilis, metabolism-related genes in Klebsiella pneumonia and β-lactamase-associated genes in Acinetobacter baumannii. Some OA derivatives were bactericidal to three of the strains and appeared to regulate gene expression associated with metabolism, haemolysis, and β-lactamase in vitro. These newly designed OA derivatives possess unique antibacterial activities and may be potentially useful for prophylactic or therapeutic intervention of bacterial infections., (Copyright © 2016. Published by Elsevier Ltd.)

This paper presents a LED driver for VLC. The main purpose is to solve the low data rate problem used to be in switching type LED driver. The GaN power device is proposed to replace the traditional silicon power device of switching LED driver for the purpose of increasing switching frequency of converter, thereby increasing the bandwidth of data transmission. To achieve high efficiency, the diode-connected GaN power transistor is utilized to replace the traditional ultrafast recovery diode used to be in switching type LED driver. This work has been experimentally evaluated on 350-mA output current. The results demonstrate that it supports the data of PWM dimming level encoded in the PPM scheme for VLC application. The experimental results also show that system's efficiency of 80.8% can be achieved at 1-Mb/s data rate.