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Oral squamous cell carcinoma (OSCC) is one of the most painful cancers, which interferes with orofacial function including talking and eating. We report that legumain (Lgmn) cleaves protease-activated receptor-2 (PAR2) in the acidic OSCC microenvironment to cause pain. Lgmn is a cysteine protease of late endosomes and lysosomes that can be secreted; it exhibits maximal activity in acidic environments. The role of Lgmn in PAR2-dependent cancer pain is unknown. We studied Lgmn activation in human oral cancers and oral cancer mouse models. Lgmn was activated in OSCC patient tumors, compared with matched normal oral tissue. After intraplantar, facial or lingual injection, Lgmn evoked nociception in wild-type (WT) female mice but not in female mice lacking PAR2in NaV1.8-positive neurons (Par2Nav1.8), nor in female mice treated with a Lgmn inhibitor, LI-1. Inoculation of an OSCC cell line caused mechanical and thermal hyperalgesia that was reversed by LI-1.Par2Nav1.8andLgmndeletion attenuated mechanical allodynia in female mice with carcinogen-induced OSCC. Lgmn caused PAR2-dependent hyperexcitability of trigeminal neurons from WT female mice.Par2deletion, LI-1, and inhibitors of adenylyl cyclase or protein kinase A (PKA) prevented the effects of Lgmn. Under acidified conditions, Lgmn cleaved within the extracellular N terminus of PAR2at Asn30↓Arg31, proximal to the canonical trypsin activation site. Lgmn activated PAR2by biased mechanisms in HEK293 cells to induce Ca2+mobilization, cAMP formation, and PKA/protein kinase D (PKD) activation, but not β-arrestin recruitment or PAR2endocytosis. Thus, in the acidified OSCC microenvironment, Lgmn activates PAR2by biased mechanisms that evoke cancer pain.SIGNIFICANCE STATEMENTOral squamous cell carcinoma (OSCC) is one of the most painful cancers. We report that legumain (Lgmn), which exhibits maximal activity in acidic environments, cleaves protease-activated receptor-2 (PAR2) on neurons to produce OSCC pain. Active Lgmn was elevated in OSCC patient tumors, compared with matched normal oral tissue. Lgmn evokes pain-like behavior through PAR2. Exposure of pain-sensing neurons to Lgmn decreased the current required to generate an action potential through PAR2. Inhibitors of adenylyl cyclase and protein kinase A (PKA) prevented the effects of Lgmn. Lgmn activated PAR2to induce calcium mobilization, cAMP formation, and activation of protein kinase D (PKD) and PKA, but not β-arrestin recruitment or PAR2endocytosis. Thus, Lgmn is a biased agonist of PAR2that evokes cancer pain.

Smoking is a global health problem among health science students. The objectives of this study were to estimate the prevalence of smoking and to examine associated factors among health science students from five universities in Vietnam. Among 5946 participants (95.0% response rate), the smoking prevalence was 19.2% (95% CI:17.4–21.0%) among male students and 2.9% (95% CI:2.4–3.5%) among female students. In the multivariable regression models, significant factors for smoking were the perceived financial burden, the respondent’s year in university, a non-self-determined motivation profile, self-reported depression and/or anxiety, the level of vigorous physical activity, and alcohol drinking.

Oral cancer is very painful and impairs a patient’s ability to eat, talk, and drink. Mediators secreted from oral cancer can excite and sensitize sensory neurons inducing pain. Cancer mediators can also activate Schwann cells, the peripheral glia that regulates neuronal function and repair. The contribution of Schwann cells to oral cancer pain is unclear. We hypothesize that the oral cancer mediator TNFα activates Schwann cells, which further promotes cancer progression and pain. We demonstrate that TNFα is overexpressed in human oral cancer tissues and correlates with increased self-reported pain in patients. Antagonizing TNFα reduces oral cancer proliferation, cytokine production, and nociception in mice with oral cancer. Oral cancer or TNFα alone increases Schwann cell activation (measured by Schwann cell proliferation, migration, and activation markers), which can be inhibited by neutralizing TNFα. Cancer- or TNFα-activated Schwann cells release pro-nociceptive mediators such as TNFα and nerve growth factor (NGF). Activated Schwann cells induce nociceptive behaviors in mice, which is alleviated by blocking TNFα. Our study suggests that TNFα promotes cancer proliferation, progression, and nociception at least partially by activating Schwann cells. Inhibiting TNFα or Schwann cell activation might serve as therapeutic approaches for the treatment of oral cancer and associated pain.

Oral cancer patients experience pain at the site of the primary cancer. Patients with metastatic oral cancers report greater pain. Lack of pain identifies patients at low risk of metastasis with sensitivity = 0.94 and negative predictive value = 0.89. In the same cohort, sensitivity and negative predictive value of depth of invasion, currently the best predictor, were 0.95 and 0.92, respectively. Cancer pain is attributed to cancer-derived mediators that sensitize neurons and is associated with increased neuronal density. We hypothesized that pain mediators would be overexpressed in metastatic cancers from patients reporting high pain. We identified 40 genes overexpressed in metastatic cancers from patients reporting high pain (n = 5) compared to N0 cancers (n = 10) and normal tissue (n = 5). The genes are enriched for functions in extracellular matrix organization and angiogenesis. They have oncogenic and neuronal functions and are reported in exosomes. Hierarchical clustering according to expression of neurotrophic and axon guidance genes also separated cancers according to pain and nodal status. Depletion of exosomes from cancer cell line supernatant reduced nociceptive behavior in a paw withdrawal assay, supporting a role for exosomes in cancer pain. The identified genes and exosomes are potential therapeutic targets for stopping cancer and attenuating pain.

Oral squamous cell carcinoma (SCC) pain is more prevalent and severe than pain generated by any other form of cancer. We previously showed that protease-activated receptor-2 (PAR2) contributes to oral SCC pain. Cathepsin S is a lysosomal cysteine protease released during injury and disease that can activate PAR2. We report here a role for cathepsin S in PAR2-dependent cancer pain. We report that cathepsin S was more active in human oral SCC than matched normal tissue, and in an orthotopic xenograft tongue cancer model than normal tongue. The multiplex immunolocalization of cathepsin S in human oral cancers suggests that carcinoma and macrophages generate cathepsin S in the oral cancer microenvironment. After cheek or paw injection, cathepsin S evoked nociception in wild-type mice but not in mice lacking PAR2 in Nav1.8-positive neurons (Par2Nav1.8), nor in mice treated with LY3000328 or an endogenous cathepsin S inhibitor (cystatin C). The human oral SCC cell line (HSC-3) with homozygous deletion of the gene for cathepsin S (CTSS) with CRISPR/Cas9 provoked significantly less mechanical allodynia and thermal hyperalgesia, as did those treated with LY3000328, compared to the control cancer mice. Our results indicate that cathepsin S is activated in oral SCC, and that cathepsin S contributes to cancer pain through PAR2 on neurons.

This study aimed to describe the status of antenatal depression and its associated factors among pregnant women in Vietnam. A cross-sectional study was conducted in four obstetric hospitals in Vietnam from January to September 2019. A total of 1260 pregnant women were interviewed using a structured questionnaire. A Tobit regression model was used to determine factors associated with antenatal depression. Results showed that pregnant women were at high risk of antenatal depression (24.5%). Women with fetus abnormalities and higher education were at higher risk of antenatal depression. We highlighted the need for implementing formal screening programs to early detect antenatal depression.

OBJECTIVES: The average alcohol consumption per capita among Vietnamese adults has consistently increased. Although alcohol-related disorders have been extensively studied, there is a paucity of research shedding light on this issue among Internet users. The study aimed to examine the severity of alcohol-related disorders and other associated factors that might predispose individuals towards alcohol usage in a sample of youths recruited online. METHODS: An online cross-sectional study was conducted with 1,080 Vietnamese youths. A standardized questionnaire was used. Respondent-driven sampling was applied to recruit participants. Multivariate logistic and Tobit regressions were utilized to identify the associated factors. RESULTS: About 59.5% of the males and 12.7% of the total youths declared that they were actively using alcohol. From the total sample, a cumulative total of 32.3% of the participants were drinking alcohol, with 21.8% and 25.0% of the participants being classified as drinking hazardously and binge drinkers, respectively. The majority of the participants (60.7%) were in the pre-contemplative stage. CONCLUSIONS: A high prevalence of hazardous drinking was recognized among online Vietnamese youths. In addition, we found relationships between alcohol use disorder and other addictive disorders, such as tobacco smoking and water-pipe usage. Our results highlighted that the majority of the individuals are not receptive to the idea of changing their alcohol habits, and this would imply that there ought to be more government effort towards the implementation of effective alcohol control policies. Language: en