The Vitamin C Enantiomers Possess a Comparable Potency in the Induction of Oxidative Stress in Cancer Cells but Differ in Their Toxicity.

The use of vitamin C (VC) in high doses demonstrates a potent tumor suppressive effect by mediating a glucose-dependent oxidative stress in Kirsten rat sarcoma (KRAS) mutant cancer cells. VC with arsenic trioxide (ATO) is a promising drug combination that might lead to the development of effective cancer therapeutics. Considering that a tumor suppressive effect of VC requires its high-dose administration, it is of interest to examine the toxicity of two enantiomers of VC (enantiomer d-optical isomer D-VC and natural l-optical isomer L-VC) in vitro and in vivo. We show that the combinations of L-VC with ATO and D-VC with ATO induced a similar cytotoxic oxidative stress in KrasG12D-expressing mutant cancer cells as indicated by a substantial increase in reactive oxidative species (ROS) production and depolarization of mitochondria. To examine the L-VC and D-VC toxicity effects, we administered high doses of D-VC and L-VC to CD1 mice and carried out an evaluation of their toxic effects. The daily injections of L-VC at a dose of 9.2 g/kg for 18 days were lethal to mice, while 80% of mice remained alive following the similar high-dose administration of D-VC. Following the drug injection courses and histopathological studies, we determined that a natural form of VC (L-VC) is more harmful and toxic to mice when compared to the effects caused by the similar doses of D-VC. Thus, our study indicates that the two enantiomers of VC have a similar potency in the induction of oxidative stress in cancer cells, but D-VC has a distinctive lower toxicity in mice compared to L-VC. While the mechanism of a distinctive toxicity between D-VC and L-VC is yet to be defined, our finding marks D-VC as a more preferable option compared to its natural enantiomer L-VC in clinical settings.

Novel Prevention Approaches of Breast Cancer Surgery Related Complications: Systematic Review and Network Meta-Analysis.

BACKGROUND: Breast cancer surgery related complications are a complex condition influenced by interactions among nerve pathways and the physiological responses to breast surgery. The intensity of this complications displays substantial heterogeneity, dependent on individual patient characteristics, the extent of the surgical procedure performed, and various contributing factors. METHODS: A comprehensive search of electronic databases was conducted to identify relevant randomized controlled trials (RCTs) investigating interventions for post-mastectomy pain syndrome (PMPS). A network meta-analysis was performed to integrate direct and indirect evidence, enabling comparisons of multiple interventions across different outcome measures. RESULTS: The systematic search yielded a total of 26 RCTs investigating 4 groups of different interventions for PMPS. The interventions included pharmacological agents, nerve blocks, physical therapy, and anesthesia regimens. Nerve blocks (OR: 0.34; 95% CrI: 0.24-0.46) and anesthesia (OR: 0.39; 95% CrI: 0.26-0.56) demonstrated improvements in functional outcomes and quality of life. CONCLUSION: This systematic review and network meta-analysis provide a comprehensive evaluation of interventions for PMPS, highlighting their varying efficacy in alleviating pain and improving functional outcomes and quality of life. However, further research with large-scale, well-designed RCTs is warranted to strengthen the evidence base and validate the effectiveness of these interventions in managing PMPS effectively.

Hypopharynx Cancer Incidence in Kazakhstan: 2017-2021.

OBJECTIVE: The article studies the geographical features of the incidence of hypopharynx cancer (HPC) in Kazakhstan. METHODS: The retrospective study was done for the period 2017-2021. Descriptive and analytical methods of ecoepidemiology were used. Crude (CR), age-specific (ASIR), age-standardized (ASR), equalized incidence rates and approximation were calculated. The dynamics of indicators was investigated using component analysis according to methodological recommendations. The method of drawing up a cartogram based on the determination of the standard deviation (σ) from the mean (x) was applied. RESULT: During the study period, 814 new cases of HPC were registered. The incidence rate decreased from 0.898 (2017) to 0.895 in 2021 and the overall decline was 0.003 per 100,000 population, including due to the age structure - ∑ΔA=+0.04, due to the risk of acquiring illness - ∑ΔR=-0.05 and their combined effect - ∑ΔRA=+0.01. The component analysis revealed that the increase in the number of patients with HPC was mainly due to the growth of the population (ΔP=+37.0%), changes in its age structure (ΔA=+106.1%) and changes associated with the risk of acquiring illness (ΔR=-133.4%). The cartograms were allocated according to the following criteria: low - up to 0.730/0000, average - from 0.73 to 1.180/0000, high - above 1.180/0000. The results of the spatial assessment showed the highest levels of HPC incidence in following regions: Atyrau (1.960/0000) and West Kazakhstan (1.580/0000). CONCLUSION: Thus, this is the first epidemiological study of HPC, which assessed the role of the influence of various factors, including demographic and risk of acquiring illness, on the dynamics of incidence, taking into account gender differences and geographical variability.

Efficacy of Tibial Nerve Stimulation on Fecal Incontinence in Patients With Low Anterior Resection Syndrome Following Surgery for Colorectal Cancer.

OBJECTIVE: To systematically review the available literature on the efficacy of tibial nerve stimulation on faecal incontinence and quality of life in adult patients with low anterior resection syndrome following surgery for colorectal cancer. METHODS: A primary search of electronic databases was conducted adopting a combination of search terms related to the following areas of interest: "efficacy", "tibial nerve stimulation" and "low anterior resection syndrome". A secondary search of the grey literature was performed in addition to checking the reference list of included studies and review papers. The review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A descriptive analysis was used to integrate the review findings. RESULTS: Five distinct studies involving 116 patients met the inclusion criteria for the review. The included studies suggest that tibial nerve stimulation may have a positive effect on faecal incontinence and quality of life in some patients with low anterior resection syndrome and might be considered as an additional treatment option. CONCLUSION: There were a limited number of studies and a great degree of heterogeneity of evidence due to differences in participants' baseline characteristics, dropout rates, and follow-up periods. Further research adopting validated, consistent, and complex outcome assessment methods is recommended to determine the efficacy of tibial nerve stimulation for treatment of patients with low anterior resection syndrome.

The Oxidative Drug Combination for Suppressing KRAS G12D Inducible Tumour Growth.

Background: Kirsten rat sarcoma (KRAS) protein is an essential contributor to the development of pancreatic ductal adenocarcinoma (PDAC). KRAS G12D and G12V mutant tumours are significant challenges in cancer therapy due to high resistance to the treatment. Objective: To determine how effective is the ATO/D-VC combination in suppression of PDAC the mouse transgenic model. This study investigated the antitumour effect of a novel combination of arsenic trioxide (ATO) and D-ascorbic acid isomer (D-VC). Such a combination can be used to treat KRAS mutant cancer by inducing catastrophic oxidative stress. Methods: In this study, we examined the effectiveness of ATO and D-VC on xenograft models-AK192 cells transplanted into mice. Previously, it has been shown that a high concentration of Vitamin C (VC) selectively can kill the cells expressing KRAS. Results: The results of this study demonstrated that the combination of VC with a low dose of the oxidizing drug ATO led to the enhancement of the therapeutic effect. These findings suggest that the combined treatment using ATO and D-VC is a promising approach to overcome the limitation of drug selectivity and efficacy.

Association of polymorphisms in TP53 and the promoter region of IL10 with gastric cancer in a Kazakh population.

The emerging evidence indicates that single nucleotide polymorphisms (SNPs) of the tumor necrosis factor (TNF), interleukin 10 (IL10), tumor protein p53 (TP53), and cluster of differentiation 14 (CD14) genes may determine individual susceptibility to gastric cancer (GC). We aimed to investigate the associations for polymorphisms of the TNF, IL10, TP53, and CD14 genes in a population of Kazakhs, to identify potential risk or protective associations of the SNPs with GC. A case group of 143 patients hospitalized for GC was enrolled. Controls were 355 volunteers with no history of any cancer and frequency matched with cases by age. Differences in proportions for categorical variables and the assessment of genotypic frequencies conforming to the Hardy-Weinberg equilibrium law were evaluated by the Chi-square test. Associations between genetic polymorphisms and the risk of GC were estimated by regression analysis. For genetic analysis, three genetic models (additive, dominant, and recessive) were used. Four significant associations were found. The SNPs rs1042522 of TP53 and rs1800896 of IL10 were risk factors for GC by the additive model. Two polymorphisms of IL10 were protective of GC, namely, rs1800872 by additive model and rs1800871 by recessive model. No significant associations were observed between the TNF and CD14 polymorphisms and GC. The polymorphisms TP53 rs1042522 and IL10 rs1800896 are associated with GC risk, while the polymorphisms IL10 rs1800872 and rs1800871 are protective of GC in the population of Kazakhs.

Non-Melanoma Skin Cancers at Sites of Previous Frostbite: Case Report and Review.

The association between ultraviolet radiation exposure and skin cancer is well established. Limited studies have reported an association between frostbite and the development of non-melanoma skin cancer but evidence for a proven link is insufficient and possible carcinogenic mechanisms have not been fully explored. In this report, 3 cases of non-melanoma skin cancer (1 case of basal cell carcinoma and 2 cases of squamous cell carcinoma of the skin) which developed at a site of previous frostbite caused by exposure to extremely cold temperatures in Astana, the capital city of Kazakhstan, are described.

Vitamin D Receptor Gene Polymorphisms and Breast Cancer Risk in Kazakhstan.

INTRODUCTION: The steroid hormone 1,25-dihydroxyvitamin D3 is thought to protect against breast cancer. The activity of 1,25-dihydroxyvitamin D3 is mediated via the vitamin D receptor (VDR), and a number of polymorphisms in the VDR gene have been identified. These result in distinct genotypes, some of which may alter susceptibility to breast cancer. Two common single nucleotide polymorphisms (SNP) in the VDR gene (VDR), rs1544410 (BsmI) and rs2228570 (FokI), have been inconsistently associated with breast cancer risk. Increased risk has been reported for the FokI ff genotype, which encodes a less transcriptionally active isoform of VDR. A reduced risk has been reported for the BsmI BB genotype which may influence VDR mRNA stability. AIM: We have investigated whether specific VDR gene polymorphisms are associated with breast cancer risk in Kazakhstan women. MATERIAL AND METHODS: In a case-control study, female breast cancer patients (315) and a female control group (n=604) were tested for two VDR polymorphisms. Statistical analysis was conducted using SPSS19.0. RESULTS: : The VDR rs2228570 (FokI) polymorphism was associated with an increased occurence of BC [rs2228570 (folk) ff vs. FF genotype: OR=1.71; 95% CI=1.21-2.43]. No association was noted between rs1544410 (BsmI) BB and breast cancer risk [OR=0.68; 95% CI=0.49-0.95]. CONCLUSION: : Although the factors that increase breast cancer susceptibility remain uncertain, future large studies should integrate genetic variation in VDR with biomarkers of vitamin D status. Additional testing on the effect of varying genotypes on the functional mechanisms of the VDR could help to improve future testing and treatment of woman at risk for breast cancer.

BRCA1 and BRCA2 Gene Mutations Screening In Sporadic Breast Cancer Patients In Kazakhstan.

BACKGROUND: A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but little is known regarding the role of these inherited susceptibility genes in breast cancer risk among Kazakhstan women. AIM: To evaluate the role of BRCA1/2 mutations in Kazakhstan women presenting with sporadic breast cancer. METHODS: We investigated the distribution and nature of polymorphisms in BRCA1 and BRCA2 entire coding regions in 156 Kazakhstan sporadic breast cancer cases and 112 age-matched controls using automatic direct sequencing. RESULTS: We identified 22 distinct variants, including 16 missense mutations and 6 polymorphisms in BRCA1/2 genes. In BRCA1, 9 missense mutations and 3 synonymous polymorphisms were observed. In BRCA2, 7 missense mutations and 3 polymorphisms were detected. There was a higher prevalence of observed mutations in Caucasian breast cancer cases compared to Asian cases (p<0.05); higher frequencies of sequence variants were observed in Asian controls. No recurrent or founder mutations were observed in BRCA1/2 genes. There were no statistically significant differences in age at diagnosis, tumor histology, size of tumor, and lymph node involvement between women with breast cancer with or without the BRCA sequence alterations. CONCLUSIONS: Considering the majority of breast cancer cases are sporadic, the present study will be helpful in the evaluation of the need for the genetic screening of BRCA1/2 mutations and reliable genetic counseling for Kazakhstan sporadic breast cancer patients. Evaluation of common polymorphisms and mutations and breast cancer risk in families with genetic predisposition to breast cancer is ongoing in another current investigation.