The Induction of Combined Hyperthermal Ablation Effect of Irreversible Electroporation with Polydopamine Nanoparticle-Coated Electrodes.

Irreversible electroporation (IRE) is a prominent non-thermal ablation method widely employed in clinical settings for the focal ablation therapy of solid tumors. Utilizing high-voltage, short-duration electric pulses, IRE induces perforation defects in the cell membrane, leading to apoptotic cell death. Despite the promise of irreversible electroporation (IRE) in clinical applications, it faces challenges concerning the coverage of target tissues for ablation, particularly when compared to other thermal ablation therapies such as radiofrequency ablation, microwave ablation, and cryoablation. This study aims to investigate the induced hyperthermal effect of IRE by applying a polydopamine nanoparticle (Dopa NP) coating on the electrode. We hypothesize that the induced hyperthermal effect enhances the therapeutic efficacy of IRE for cancer ablation. First, we observed the hyperthermal effect of IRE using Dopa NP-coated electrodes in hydrogel phantom models and then moved to in vivo models. In particular, in in vivo animal studies, the IRE treatment of rabbit hepatic lobes with Dopa NP-coated electrodes exhibited a two-fold higher increase in temperature (ΔT) compared to non-coated electrodes. Through a comprehensive analysis, we found that IRE treatment with Dopa NP-coated electrodes displayed the typical histological signatures of hyperthermal ablation, including the disruption of the hepatic cord and lobular structure, as well as the infiltration of erythrocytes. These findings unequivocally highlight the combined efficacy of IRE with Dopa NPs for electroporation and the hyperthermal ablation of target cancer tissues.

Combination of Melatonin and Small Molecules Improved Reprogramming Neural Cell Fates via Autophagy Activation.

Reprogramming cell fates towards mature cell types are a promising cell supply for treating degenerative diseases. Recently, transcription factors and some small molecules have turned into impressive modulating elements for reprogramming cell fates. Melatonin, a pineal hormone, has neuroprotective functions including neural stem cell (NSC) proliferative and differentiative modulation in both embryonic and adult brain. We developed a protocol that could be implemented in the direct reprogramming of human skin fibroblast towards neural cells by using histone deacetylase (HDAC) inhibitor, glycogen synthase kinase-3 (GSK3) inhibitor (CHIR99021), c-Jun N-terminal kinase (JNK) inhibitor, rho-associated protein kinase inhibitor (Y-27632), cAMP activator, and melatonin treatment. We found that melatonin enhanced neural-transcription factor genes expressions, including brain-specific homeobox/POU domain protein 2 (BRN2), Achaete-Scute Family BHLH transcription Factor 1 (ASCL1), and Myelin Transcription Factor 1 Like (MYT1L). Melatonin also increased the expression of different neural-specific proteins such as doublecortin (DCX), Sex determining region Y-box 2 (Sox2), and neuronal nuclei (NeuN) compared with other five small molecules (valproic acid (VPA), CHIR99021, Forskolin, 1,9 pyrazoloanthrone (SP600125), and Y-27632) combination in the presence and absence of melatonin. A noticeable upregulation of autophagy proteins (microtubule-associated protein 1A/1B-light chain 3 (LC3) and Beclin-1) were seen in the melatonin treatment during the induction period while these were reverted in the presence of L-leucine, an autophagy inhibitor. In addition, the expression of NeuN was also significantly reduced by L-leucine. Collectively, our findings revealed an activation of autophagy during neural induction; melatonin enhanced reprogramming efficiency for neuron induction through the modulation of autophagy activation.

Association of the selenoprotein 15-kDa (SEP15) polymorphisms with cancer risk: a meta-analysis.

Selenoproteins are involved in antioxidant defense, the redox signaling pathway and cell homeostasis. Primary studies have shown that single-nucleotide polymorphisms in the selenoprotein gene (SEP15) are associated with cancer risk. However, conflicting outcomes warrant a meta-analysis to obtain more precise estimates. Literature search yielded 18 case-control studies from 12 articles. We calculated pooled odds ratios (OR) and 95% confidence intervals (CI) of two SEP15 polymorphisms (rs5845 and rs5859) using standard genetic models (homozygous, recessive, dominant and codominant). Subgroup analysis was based on statistical power (80% cutoff) and cancer type (breast/respiratory/genitourinary/colorectal). Heterogeneity of the outcomes necessitated examining their sources (outlier treatment). Multiple comparison outcomes were corrected with the False Discovery Rate (PaF). Our core findings lay in the post-outlier recessive subgroup outcomes, where risks in the powered study (≥ 80%) was increased (OR 1.26, 95% CI 1.02-1.57, PaF = 0.047) while that in genitourinary cancer was protective (OR 0.29, 95% CI 0.20-0.43, PaF < 10-4). The potency of outlier treatment in unmasking significant associations and generating homogeneity provides good evidence of SEP15's role in cancer. In the clinical sense, selenium chemo-intervention may be of benefit among persons with particular SEP15 genotypes.AbbreviationsAnumber of unduplicated articles that contributed to instabilityAManalysis modelBnumber of robust comparisonsBCbreast cancerBLCbladder cancercDNAcomplementary deoxyribonucleic acidCIconfidence intervalCIDconfidence interval differenceCRCcolorectal cancerDdecreased riskEHeliminated heterogeneityFfixed-effectsFDRFalse Discovery RateGUCgenitourinary cancersGSgained significanceHBhospital-basedHWEHardy-Weinberg EquilibriumIincreased riskI2measure of heterogeneitykDakiloDaltonLAClaryngeal cancerLUClung cancermafminor allele frequencynnumber of studiesNnumber of comparisonsNMnot mentionedNOSNewcastle-Ottawa ScaleORodds ratioPaP value for associationPaδP value for association (pre-FDR)PaFP value for association FDR-correctedPbP value for heterogeneityPBpopulation-basedPCprostate cancerPRISMAPreferred Reporting Items for Systematic Reviews and Meta-AnalysesPROpre-outlierPSOpost-outlierRrandom-effects[R]referenceRCrespiratory cancersRNSretained non-significanceROSreactive oxygen speciesSEPselenoproteinsSEP15selenoprotein geneSNPsingle nucleotide polymorphismSWShapiro-Wilk testUSAUnited States of Americavvvariantwvheterozygouswwwild-type.

Genetic Polymorphisms of Vitamin D Receptor Gene are Associated with Cervical Cancer Risk in Northeastern Thailand.

OBJECTIVE: This study aimed to explore whether VDR polymorphisms (Fok1, Apa1 and Taq1) are associated to the cervical cancer in Thai population. MATERIALS AND METHODS: Subjects of 204 cervical cancer patient and 204 age-matched healthy control were enrolled in the case-control study. VDR polymorphisms were detected by using real-time PCR. Haplotype analysis of three loci was applied to the obtained genotypes. RESULTS: Significantly increased risk for cervical cancer was observed in carriers of TT genotype (p = 0.0388) and T allele (p = 0.0357) of Fok1 and TC genotype (p = 0.0001), CC genotype (p = 0.0160) and the C allele of Taq1 (p = 0.0001). Haplotype analyses revealed a significant correlation between C-T-C, T-G-C and T-T-C haplotypes and elevated risk for cervical cancer (OR = 2.06; 95%CI = 1.06-4.00; p = 0.0313, OR = 2.15; 95%CI = 1.22-3.80; p = 0.0078 and OR = 2.81; 95%CI = 1.53-5.16; p = 0.0006, respectively). Furthermore, haplotype carrying C allele of Taq1 (C-G-C + C-T-C + T-G-C + T-T-C) significantly increased cervical cancer risk with OR of 1.92 (95%CI = 1.32-2.79, p = 0.0006). CONCLUSION: Our finding revealed an association between VDR polymorphisms and cervical cancer risk. Taq1 C allele might be a molecular marker for cervical cancer development.
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Genetic Polymorphisms of the Human Cytochrome P450 1A1 (CYP1A1) and Cervical Cancer Susceptibility among Northeast Thai Women.

BACKGROUND: CYP1A1 is an enzyme in phase I of the cytochrome P450 (CYP) superfamily, and plays a key role in detoxification of carcinogens. Host genetic predisposition in the CYP1A1 may be associated with an increased susceptibility to cervical cancer.The study aimed to evaluate four common polymorphisms of the CYP1A1 and cervical cancer susceptibility among Northeast Thai women. METHODS: A case-control study was conducted involving 204 patients with squamous cell cervical cancer (SCCA) and 204 age-matched healthy controls. DNA was extracted from peripheral blood leucocytes. CYP1A1 m1, m3, and m4 genotypes were detected using PCR-RFLP, whereas the CYP1A1 m2 genotype was investigated using real-time PCR. Haplotype analysis was performed using PHASE algorithm version 2.1.1. RESULTS: CYP1A1 m3 was monomorphic. Association between the common CYP1A1 polymorphisms, m1 and m2, and cervical cancer risk was not observed (p>0.05), nor was any association found between the m1-m2-m4 haplotype and cervical cancer risk (p>0.05). Interestingly, the CA genotype of CYP1A1 m4 was observed in 30.88% of the cervical cancer patients but was absent in healthy controls. CONCLUSION: Our results demonstrated a possible involvement of the CYP1A1 m4 polymorphism but no other common polymorphisms (viz., m1, m2, and m3) in the risk for cervical cancer.This finding may be useful when screening for risk of cervical cancer among Northeast Thai women.
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Genetic Polymorphism of the Glutathione S-transferase Pi 1 (GSTP1) and Susceptibility to Cervical Cancer in Human Papilloma Virus Infected Northeastern Thai Women

Objective: We aimed to investigate any association between a genetic polymorphism of the detoxification GSTP1 gene and risk of cervical cancer in northeastern Thailand. Materials and Methods: Genotyping of GSTP1 was performed for 198 squamous cell cervical cancer (SCCA) patients and 198 age-matched healthy controls with the PCR-RFLP method. Results: The respective frequencies of the G allele were 0.33 and 0.26 in the controls and cases, the difference being significant (OR = 0.69 [95% CI: 0.50-0.95, p=0.0192]). Among women infected with high-risk types of HPV, being a heterozygous carrier was associated with a reduced risk of cervical cancer (adjusted OR = 0.32 [95% CI: 0.12-0.91, p=0.031]). Similarly, a decreased risk was observed in heterozygous women with a non-smoking partner (adjusted OR = 0.27 [95% CI: 0.09-0.83, p=0.023]). Conclusions: GSTP1 polymorphism could influence susceptibility to cervical cancer among northeast Thai women; either as a independent factor or in combination with high-risk HPV infection. Dual-testing of HPV and the GSTP1 might prove an effective screening tool for cervical cancer.

Haplotype Analysis of MDR1 and Risk for Cervical Cancer in Northeastern Thailand

Objective: The aim of this study was to investigate the association between genotype and haplotype of MDR1 (C1236T, G2677T/A and C3435T) and the risk for cervical cancer in Northeastern Thai women. Methods: An age-matched case-control study involving squamous cell cervical cancer (SCCA) patients (n=204) and healthy controls (n=204) was enrolled for MDR1 genotyping by real-time PCR method. Results: The genotype distribution of MDR1 in both patients and controls was not significantly different (p>0.05). The haplotype analysis showed that T-T-T was the most common haplotype in this population. Significantly increased risk of cervical cancer was observed in carriers of T-T-C and C-G-T haplotypes with ORs of 1.86 (95%CI=1.02-3.39, p=0.0416) and 2.00 (95%CI=1.18-3.40, p=0.0140), respectively. Analysis of 2677-3435 haplotype showed increased risk for cervical cancer in G-T (OR=1.55; 95% CI=1.12-2.13, p=0.0432) and T-C (OR=1.91; 95%CI=1.05-3.47, p=0.0325). Conclusion: The results provide evidence that haplotype of MDR1 may be an important risk factor for cervical cancer development in Northeastern Thai women.

Preliminary Study of the GSTM1 Null Polymorphism and History of Tobacco Smoking among Oral Cancer Patients in Northeastern Thailand.

Risks with GSTM1 genotypes and potential roles of smoking in the susceptibility to oral squamous cell carcinoma (OSCC) were studied in Northeastern Thailand. Study subjects were 79 histologically-confirmed OSCC cases (31 men, 48 women) and 79 age- and sex-matched healthy controls ranging in age from 25 to 84 years. GSTM1 genotyping was achieved by two independent PCR assays. The GSTM1 null allele and the homozygous genotype did not increase risk of OSCC vs the wild type allele and the remaining genotypes. When the focus was on the smoking habit, male subjects who smoked ≥10 or ≥35 years were at significantly increased risk for OSCC with adjusted ORs of 4.88 [95%CI, 1.41-16.87, p=0.012] or 4.94 [95%CI, 1.62-15.12, p=0.005], respectively. A higher risk for OSCC was found for smoking amount; those who smoked >5 or >10 pack-years were at a higher risk with adjusted OR of 4.46 [95%CI; 1.45-13.74, p=0.009] or 3.89 [95%CI; 1.34-11.28, p=0.012], respectively. There are certain smoking patterns that give greater risks and thus both smoking duration and pack-years should be taken into consideration in tobacco related cancer prevention.

Lack of participation of the GSTM1 polymorphism in cervical cancer development in Northeast Thailand.

The potential association between the GSTM1 deletion polymorphism and risk of cervical cancer was investigated in Northeastern Thailand. DNA was extracted from buffy coat specimens of 198 patients with squamous cell carcinoma of the cervix and 198 age-matched healthy controls. Genotyping of the GSTM1 was conducted by using two PCR methods, a short- and a long-PCR. Distribution of the GSTM1 genotypes in between the cases and the controls was not significantly different (p>0.5 by χ2 test). The results suggest that the GSTM1 deletion polymorphism is not a risk factor for squamous cell carcinoma of the cervix in the northeast Thai women.

Human papillomavirus genotypes and cervical cancer in northeast Thailand.

Human papillomavirus (HPV) is a major cause of cervical cancer. More than 100 HPV genotypes have been identified; however the distribution varies geographically and according to ethnicity. The purpose of this study was to investigate the prevalence and distribution of HPV subtypes among Northeast Thai women. Subjects included 198 cases of SCCA and 198 age-matched, healthy controls. HPV-DNA was amplified by PCR using the consensus primers GP5+/6+ system followed by reverse line blot hybridization genotyping. The prevalence of high-risk HPV infection was 21 (10.1%) and 152 (76.8%) in the controls and in the cases, respectively. High-risk HPV significantly increased the risk for cervical cancer with an OR of 42.4 (95%CI: 22.4-81.4, p<0.001) and an adjusted OR of 40.7-fold (95%CI: 21.5-76.8, p <0.001). HPV-16 was the most prevalent HPV type in the SCCA (56.2%) followed by HPV-58 (17.8%) and HPV-18 (13.6%); whereas HPV-58 (46.4%) was a prominent genotype in the controls followed by HPV-16 (39.3%) and unidentified HPV types (25.0%). These findings indicate that HPV infection remains a critical risk factor for SCCA; particularly, HPV-16, HPV-58 and HPV-18. In order to eradicate cervical cancer, sustained health education, promoted use of prophylactics and a HPV-58 vaccine should be introduced in this region.

Risk factors for cervical cancer in northeastern Thailand: detailed analyses of sexual and smoking behavior.

Cervical cancer is a serious public health problem in Thailand. We investigated possible risk factors for cervical cancer including HPV infection, p53 polymorphism, smoking and reproductive history among women in Northeast Thailand using a case control study with 177 cases and age-matched controls. Among the HPV carriers, a significantly increased risk for cervical cancer with an OR of 36.97 (p<0.001) and an adjusted OR of 38.07 (p<0.001) were observed. Early age at first sexual exposure, and multiple sexual partners increased the risk of cervical cancer with ORs ranging between 1.73-2.78 (p<0.05). The interval between menarche and first sexual intercourse<6 years resulted in a significant increase in the risk for cervical cancer with ORs ranging between 3.32-4.09 and the respective adjusted OR range for the 4-5 and 2-3 year-old groups were 4.09 and 2.92. A higher risk was observed among subjects whose partner had smoking habits, whether currently or formerly; with respective ORs of 3.36 (p<0.001) and 2.17 (p<0.05); and respective adjusted ORs of 2.90 (p<0.05) and 3.55 (p<0.05). Other smoking characteristics of the partners including smoking duration≥20 years, number of cigarettes smokes≥20 pack-years and exposure time of the subject to passive smoking≥5 hrs per day were found to be statistically significant risks for cervical cancer with adjusted ORs of 3.75, 4.04 and 11.8, respectively. Our data suggest that the risk of cervical cancer in Thai women is substantially associated with smoking characteristics of the partner(s), the interval between menarche and first sexual intercourse as well as some other aspects of sexual behavior.

Genetic risk of DNA repair gene polymorphisms (XRCC1 and XRCC3) for high risk human papillomavirus negative cervical cancer in Northeast Thailand.

To identify risk factors other than high risk human papillomavirus infection for the development of cervical cancer, functional polymorphisms of DNA repair genes, XRCC1 Arg399Gln and Arg194Trp and XRCC3 Thr241Met, were studied among Northeastern Thai women. Cases (n=111) were defined as squamous cell cervical cancer and controls (n=118) were recruited from healthy women without cervical abnormalities. The XRCC1 194Trp/Trp genotype significantly increased the risk for cervical cancer (OR=5.52; 95%CI=1.14-26.64; p=0.03). Among the HPV infection negative group, significantly higher risks for cervical cancer were visualized for XRCC1 399Arg/Gln (adjusted OR=3.69; 95%CI=1.04-13.06; p=0.04) and XRCC1 194Arg/Trp (adjusted OR=4.13; 95%CI=1.13-15.12; p=0.03). This study indicates that variant types of DNA repair genes play partial roles in modifying individual susceptibility to cervical cancer. Since cervical cancer is a multi-factorial disease, the contribution of DNA repair enzymes to the development of cervical cancer, if it exists may be concealed by HPV infection.