The impact of FOXP3 polymorphisms on oral cancer progression and clinicopathological characteristics.

Oral cancer is the sixth leading cause of cancer mortality worldwide. Genetic, epigenetic, and epidemiological risk factors were suggested to be correlated with the carcinogenesis of oral cancer. In this study, we focused on the correlations of FOXP3 single-nucleotide polymorphisms (SNPs) to oral cancer susceptibility and clinicopathological characteristics. The FOXP3 SNPs rs3761547, rs3761548, rs3761549, and rs2232365 in 1053 controls and 1175 male patients with oral cancer were analyzed with real-time polymerase chain reaction. The results showed that the betel quid chewer who carried the FOXP3 rs3761548 polymorphic variant "T" were significantly associated with lower risk to develop oral cancer [AOR (95% CI) = 0.649 (0.437-0.964); p = 0.032]. The betel quid chewers with genotypic variant "T" of FOXP3 rs3761548 in male oral cancer patients were associated with lower risk of cell differentiated grade [AOR (95% CI) = 0.592 (0.377-0.930); p = 0.023]. The carriers of FOXP3 rs3761548 polymorphic variant "T" in male oral cancer patients with alcohol consumption were associated with lower risk to develop greater tumor [AOR (95% CI) = 0.609 (0.378-0.983); p = 0.042] and lower risk of cell differentiated grade [AOR (95% CI) = 0.440 (0.248-0.779); p = 0.005]. In conclusion, our results have revealed that the FOXP3 rs3761548 polymorphic variant "T" was associated with lower risk of oral cancer susceptibility, greater tumor size, and cell differentiated grade among betel quid chewers. The FOXP3 rs3761548 polymorphisms may play a role as pivotal biomarkers to predict oral cancer disease development and prognosis.

Maternal diabetes mellitus and birth defects in Taiwan: A 5-year nationwide population-based cohort study.

BACKGROUND: Birth defects (BDs) are the main causes of mortality and disability in infants and children. Associations between maternal diabetes mellitus (DM), including gestational DM (GDM) and pregestational DM (type 1 or type 2), and the risk of BDs have been reported. This study aims to determine the relationship between maternal DM and BDs and to investigate whether reducing the incidence of DM can decrease the incidence of BDs. METHODS: We identified all births in Taiwan from the National Birth Defects Surveillance Program between January 1, 2010, and December 31, 2014. Information on the infants' characteristics (sex, gestational age, and birth weight) and mothers' characteristics (age, parity, and associated diseases, including DM) were obtained from the National Birth Registry and National Health Insurance Research Database (NHIRD) in Taiwan. BDs were coded according to the International Classification of Diseases, 9th Revision-Clinical Modification (ICD-9-CM) codes 740-759. RESULTS: Multiple logistic regression analysis with adjusted odds ratio (aOR) and 95% confidence interval (95% CI) for all BDs showed that the aOR (95% CI) was 1.002 (0.965-1.041), and the p -value was 0.9139 in the GDM group. In the type 1 DM group, the aOR (95% CI) was 1.748 (1.110-2.754), and the p -value was 0.016. In the type 2 DM group, the aOR (95%CI) was 1.175 (1.005-1.375), 1.331 (1.196-1.482), and 1.391 (1.216-1.592), and the p -value was 0.0437, <0.0001, and <0.0001 for the duration of mothers with type 2 DM <2, 2 to 5, >5 years, respectively. CONCLUSION: Mothers with pregestational DM (type 1 or type 2) increase the incidence of BD. Appropriate maternal glycemic control may achieve good pregnancy and perinatal outcomes.

Prognostic effects of microcirculation-assisted adjustment of venoarterial blood flow in extracorporeal membrane oxygenation: A prospective, pilot, randomized controlled trial.

OBJECTIVE: The study explored the clinical efficacy of microcirculation-assisted blood flow adjustment in patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO). METHODS: This prospective, pilot, randomized controlled trial was conducted from 2018 to 2021; enrolled patients were randomly assigned to the microcirculation or control group at a 1:1 ratio. Microcirculatory and clinical data were collected within 24 h (T1) and at 24-48 h (T2), 48-72 h (T3), and 72-96 h (T4) after ECMO initiation and were compared between the groups following the intention-to-treat (ITT) principle. The primary outcome was the Sequential Organ Failure Assessment (SOFA) score at T2. In addition to ITT analysis, analysis based on the as-treated (AT) principle was performed. RESULTS: A total of 35 patients were enrolled in this study. At T2, the SOFA score did not significantly differ between the microcirculation and control groups (16 [14.8-17] vs. 16 [12.5-18], P = 0.782). Generalized estimating equation analysis demonstrated a significantly greater reduction in the SOFA score over time in the microcirculation-AT group than in the control-AT group (estimated difference: -0.767, standard error: 0.327, P = 0.019). The lactate level at T2 was significantly lower in the microcirculation-AT group (2.7 [2.0-3.6] vs. 4.1 [3.0-6.6] mmol/L, P = 0.029). No significant difference in the 30-day survival rate was noted between the groups. CONCLUSION: This prospective pilot study demonstrated the feasibility of microcirculation-assisted VA-ECMO blood flow adjustment despite no significant clinical benefit for critically ill patients. More efforts in personnel training and newer technologies may help achieve microcirculation optimization.

Reducing Birth Defects by Decreasing the Prevalence of Maternal Chronic Diseases-Evaluated by Linked National Registration Dataset.

Birth defects (BDs) are an important cause of abortion, stillbirth, and infant mortality that may cause lifelong disability. The defects can be caused by genetics, environmental exposure, or maternal chronic diseases. We conducted a study to analyze the association between maternal chronic diseases and BDs and to evaluate the effect of decreasing the prevalence of maternal chronic diseases on reducing BDs. The data of newborns and their mothers were concatenated and analyzed from three national population databases: the National Health Insurance Research Database, the Birth Certificate Application, and the Birth Registration Database in Taiwan during the period of 2005 to 2014. Codes 740-759 of the International Classification of Diseases 9th Revision­Clinical Modification (ICD-9-CM) were used as the diagnosis of BDs. The prevalence of BDs was 2.72%. Mothers with cardiovascular diseases, hypertension, anemia, genitourinary tract infections, renal diseases, neurotic or psychotic disorders, gestational diabetes mellitus (DM), and pregestational type 1 or type 2 DM had a significantly higher prevalence of BDs. The population attributable risk percent (PAR%) of BDs was 1.63%, 0.55%, 0.18%, 1.06%, 0.45%, 0.22%, 0.48%, and 0.24% for maternal hypertension, cardiovascular disease, renal disease, genitourinary infection, anemia, neurotic and psychotic disorders, gestational DM, and pregestational type 1 or type 2 DM, respectively. The percentage change (−1%, −5%, and −10% of prevalence in 2034 compared with the prevalence in 2005−2014) of maternal disease and the predicted number of live births was used to estimate the decrease in the number of newly diagnosed BDs in 2034. By using the middle-estimated number of live births in 2034, we predicted that the number of BDs would decrease by 302, 102, 33, 196, 83, 41, 89, and 44 with a −5% prevalence of maternal hypertension, cardiovascular disease, renal disease, genitourinary infection, anemia, neurotic and psychotic disorders, gestational DM, and pregestational type 1 or type 2 DM, respectively. We conclude that mothers with chronic diseases, including cardiovascular diseases, hypertension, anemia, genitourinary tract infections, renal diseases, neurotic or psychotic disorders, gestational DM, and pregestational type 1 or type 2 DM, have a significantly higher (p < 0.01) prevalence of having offspring with BDs. Mothers with chronic diseases are associated with BDs. It is very important to set up a policy to decrease the prevalence of these maternal chronic diseases; then, we can reduce the incidence of BDs.

Association of dipeptidyl peptidase IV polymorphism with clinicopathological characters of oral cancer.

OBJECTIVE: To evaluate the associations between dipeptidyl peptidase IV (DPP4) single-nucleotide polymorphism (SNP) and clinicopathological characteristics of oral cancer. METHODS: Four loci of DPP4 SNPs (rs7608798 A/G, rs3788979 C/T, rs2268889 T/C, and rs6741949 G/C) were genotyped by using the TaqMan allelic discrimination in 1238 oral cancers patients and 1197 non-cancer individuals. RESULTS: The percentage of DPP4 SNP rs2268889 TC + CC was significantly higher in the oral cancer participants compared to the control group (odds ratio [OR]: 1.178, 95% confidence interval (CI): 1.004-1.382, p = 0.045). Among 1676 smokers, DPP4 polymorphisms carriers with betel quid chewing were found to have an 8.785- to 10.903-fold risk to have oral cancer compared to DPP4 wild-type carriers without betel quid chewing. Similar trend was found in individuals with alcohol consumption. Moreover, the oral cancer individuals without cigarette smoking history with at least one varied C allele of DPP4 rs2268889 had a significantly higher percentage of large tumor size with the wild-type TT homozygote (p = 0.011). CONCLUSIONS: The DPP4 SNP may correlate to the development of oral cancer in those with cigarette smoking and alcohol consumption. Besides, the DPP4 SNP rs2268889 could relate to worse clinical course of oral cancer in non-smokers.

Picrasidine I Triggers Heme Oxygenase-1-Induced Apoptosis in Nasopharyngeal Carcinoma Cells via ERK and Akt Signaling Pathways.

Nasopharyngeal carcinoma (NPC) has a higher incidence in Taiwan than worldwide. Although it is a radiosensitive malignancy, cancer recurrence is still high in the advanced stages because of its ability to induce lymph node metastasis. Picrasidine I from Picrasma quassioides has been reported as a potential drug for targeting multiple signaling pathways. The present study aimed to explore the role of picrasidine I in the apoptosis of NPC cells. Our results show that picrasidine I induced cytotoxic effects in NPC cells and caused cell cycle arrest in the sub-G1, S, and G2/M phases. Western blot analysis further demonstrated that the modulation of apoptosis through the extrinsic and intrinsic pathways was involved in picrasidine I-induced cell death. Downregulation of the ERK1/2 and Akt signaling pathways was also found in picrasidine I-induced apoptosis. Additionally, the apoptosis array showed that picrasidine I significantly increased heme oxygenase-1 (HO-1) expression, which could act as a critical molecule in picrasidine I-induced apoptosis in NPC cells. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets also revealed that the HMOX1 mRNA level (HO-1) is lower in patients with head and neck squamous carcinoma (HNSCC) and NPC than in patients without cancer. Our study indicated that picrasidine I exerts anticancer effects in NPC by modulating HO-1 via the ERK and Akt signaling pathways.

Causative organisms and antimicrobial susceptibility in jaundiced infants with significant bacteriuria.

BACKGROUND: Jaundice may be one of the first signs of urinary tract infection (UTI) in infants. The most common pathogen is Escherichia coli. Currently recommended antibiotic treatment for neonatal UTI is ampicillin and an aminoglycoside. Recently, increasing ampicillin and gentamicin resistance in strains of E. coli has been isolated. The aim of this study was to determine causative organisms and antimicrobial susceptibility in jaundiced infants with significant bacteriuria (SB). METHODS: We evaluated admitted afebrile, asymptomatic infants younger than 1-month old with hyperbilirubinemia (total bilirubin >15 mg/dl) requiring phototherapy between January 2011 and December 2015. A total of 615 asymptomatic jaundiced infants were enrolled. Urinalysis and urine cultures were performed on all jaundiced infants. A urine culture was defined as SB if a single pathogen with more than 105-colony forming units per milliliter (CFU/ml) by sterile urinary collection bag or 104 CFU/ml by catheterization was isolated. RESULTS: A total of 88 (14.3%) of 615 asymptomatic jaundiced infants had positive urinary culture. E coli was the most common cultured bacteria (40 cases, [45.5%]). Enterococcus faecalis was the second most common bacteria (17 cases, [19.3%]). Seven cases (8.0%) of Streptococcus agalactiae and six cases (6.8%) of Klebsiella pneumoniae were also identified. Ampicillin sensitivity was found in 22.5% of E. coli infections, gentamicin sensitivity was found in 84.2%, and extended-spectrum ß-lactamases were found in 7.5%. CONCLUSION: E. coli was the most common causative organism for infants with SB. We suggest modifying current empiric antibiotics by changing gentamicin to amikacin for neonatal Gram-negative bacterial infections.

Luteolin-7-O-glucoside inhibits cell proliferation and modulates apoptosis through the AKT signaling pathway in human nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is an unnoticeable malignant tumor with a high potential of lymphatic metastasis, and its prevalence is high in Asia. Ionizing radiation is the mainstay of treatment for patients with NPC without metastasis. However, patients with metastatic lesions require advanced treatments such as chemotherapy. The present study investigated the apoptotic effect of luteolin-7-O-glucoside on NPC cells and elucidated its underlying signaling mechanisms. The results revealed that luteolin-7-O-glucoside significantly reduced the proliferation of NPC cell lines (NPC-039 and NPC-BM). Flow cytometry and morphological analysis results demonstrated that luteolin-7-O-glucoside treatment induced S and G2 /M cell cycle arrest, chromatin condensation, and apoptosis. In addition, mitochondrial membrane potential was observed to be depolarized with an increasing concentration of luteolin-7-O-glucoside. Proteins involved in the extrinsic and intrinsic pathways of apoptosis, such as death receptor, caspase-3, caspase-8, caspase-9, and Bcl-2 family proteins (Bax, t-Bid, Bcl-2, and Bcl-xL), were downregulated and upregulated after treatment with luteolin-7-O-glucoside, respectively. Moreover, the addition of a PI3K/AKT inhibitor enhanced the activation of poly-ADP-ribose-polymerase (PARP) and attenuated cell viability, indicating that luteolin-7-O-glucoside induced apoptosis in NPC cells through the AKT signaling pathway. These results indicated that the apoptosis of NPC cells modulated by luteolin-7-O-glucoside may be preceded by mitochondrial depolarization, cell cycle arrest, extrinsic and intrinsic apoptosis pathway activation, and AKT signaling modulation. Thus, luteolin-7-O-glucoside can be a promising anticancer agent against human NPC.

Effect of Periodontitis and Scaling and Root Planing on Risk of Pharyngeal Cancer: A Nested Case-Control Study.

This study investigated the association between periodontitis and the risk of pharyngeal cancer in Taiwan. For this population-based nested case-control study using the Longitudinal Health Insurance Database derived from Taiwan's National Health Insurance Research Database, we identified patients (n = 1292) who were newly diagnosed with pharyngeal cancer between 2005 and 2013 and exactly paired them with propensity score matched control subjects (n = 2584). Periodontitis and scaling and root planing (SRP) were identified before the index date. Pharyngeal cancer was subdivided into 3 subgroups on the basis of anatomic location: nasopharyngeal cancer, oropharyngeal cancer, and hypopharyngeal cancer. A multiple conditional logistic regression model was applied to analyze the adjusted odds ratio (aOR). Periodontitis was associated with an increased risk of pharyngeal cancer (aOR, 1.57; 95% confidence interval (CI), 1.17 to 2.10), especially oropharyngeal cancer (aOR, 2.22; 95% CI, 1.07 to 4.60). We found a decreased risk of pharyngeal cancer in patients who had undergone SRP (aOR, 0.77; 95% CI, 0.61 to 0.96). In conclusion, this study showed that periodontitis was associated with an increased risk of pharyngeal cancer and SRP exerted a protective effect against pharyngeal cancer. Our results suggest that treating periodontitis and performing SRP, which are modifiable factors in oral health, in clinical practice may provide an opportunity to decrease the disease burden of pharyngeal cancer in Taiwan.

Epithelial growth factor receptor tyrosine kinase inhibitors alleviate house dust mite allergen Der p2-induced IL-6 and IL-8.

Steroid-insensitive asthma-related airway inflammation is associated with the expression of epidermal growth factor receptor (EGFR) tyrosine kinase in asthmatic bronchial epithelium. Proinflammatory cytokines IL-6 and IL-8 are related to steroid-insensitive asthma. It is currently unknown how EGFR-tyrosine kinase inhibitors (EGFR-TKIs) affects house dust mite (HDM)-induced asthma in terms of inflammatory cytokines related to steroid-resistant asthma and further signaling pathway. Cytokine expressions and EGFR signaling pathway were performed by ELISA, reverse transcriptase PCR, real-time PCR, and Western blot in cell-line models. AMP-activated protein kinase (AMPK) pathway-related inhibitors were applied to confirm the association between EGFR-TKI and AMPK pathway. HDM induced IL-6 and IL-8 in a dose-dependent manner. Both Erlotinib (Tarceva) and Osimertinib (AZD-9291) reduced the levels of HDM-stimulated IL-6 and IL-8 levels in BEAS-2B cells. AZD-9291 was more effective than Erlotinib in inhibiting phospho-EGFR, and downstream phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and phopho-signal transducer and activator of transcription 3 (p-STAT3) pathway signaling. In addition, AMPK pathway-related inhibitor, Calcium-/calmodulin-dependent protein kinase kinase ß (CaMKKß) inhibitor, down-regulated IL-8, but EGFR-TKI had no effect on AMPK pathway. Our findings highlight EGFR-TKIs, Tarceva, and AZD-9291, attenuate HDM-induced inflammatory IL-6 and IL-8 cytokines via EGFR signaling axis pathway, but not AMPK signaling pathway.