Possible prognostic impact of PKCι genetic variants in prostate cancer.

BACKGROUND: Single nucleotide polymorphisms (SNPs) have been linked with prostate cancer (PCa) and have shown potential as prognostic markers for advanced stages. Loss of function mutations in PKCι have been linked with increased risk of malignancy by enhancing tumor cell motility and invasion. We have evaluated the impact of two coding region SNPs on the PKCι gene (PRKCI) and their prognostic potential. METHODS: Genotypic association of non-synonymous PKCι SNPs rs1197750201 and rs1199520604 with PCa was determined through tetra-ARMS PCR. PKCι was docked with interacting partner Par-6 to determine the effect of these variants on PKCι binding capabilities. Molecular dynamic simulations of PKCι docked with Par-6 were performed to determine variant effects on PKCι protein interactions. The possible impact of changes in PKCι protein interactions on epithelial cell polarity was hypothesized. RESULTS: PKCι rs1199520604 mutant genotype TT showed association with PCa (p = 0.0055), while rs1197750201 mutant genotype AA also showed significant association with PCa (P = 0.0006). The binding interaction of PKCι with Par-6 was altered for both variants, with changes in Van der Waals energy and electrostatic energy of docked structures. CONCLUSION: Genotypic analysis of two non-synonymous PKCι variants in association with PCa prognosis was performed. Both variants in the PB1 domain showed potential as a prognostic marker for PCa. In silico analysis of the effect of the variants on PKCι protein interactions indicated they may be involved in PCa progression through aberration of epithelial cell polarity pathways.

Exploring the prognostic significance of PKCε variants in cervical cancer.

BACKGROUND: Protein Kinase C-epsilon (PKCε) is a member of the novel subfamily of PKCs (nPKCs) that plays a role in cancer development. Studies have revealed that its elevated expression levels are associated with cervical cancer. Previously, we identified pathogenic variations in its different domains through various bioinformatics tools and molecular dynamic simulation. In the present study, the aim was to find the association of its variants rs1553369874 and rs1345511001 with cervical cancer and to determine the influence of these variants on the protein-protein interactions of PKCε, which can lead towards cancer development and poor survival rates. METHODS: The association of the variants with cervical cancer and its clinicopathological features was determined through genotyping analysis. Odds ratio and relative risk along with Fisher exact test were calculated to evaluate variants significance and disease risk. Protein-protein docking was performed and docked complexes were subjected to molecular dynamics simulation to gauge the variants impact on PKCε's molecular interactions. RESULTS: This study revealed that genetic variants rs1553369874 and rs1345511001 were associated with cervical cancer. Smad3 interacts with PKCε and this interaction promotes cervical cancer angiogenesis; therefore, Smad3 was selected for protein-protein docking. The analysis revealed PKCε variants promoted aberrant interactions with Smad3 that might lead to the activation of oncogenic pathways. The data obtained from this study suggested the prognostic significance of PRKCE gene variants rs1553369874 and rs1345511001. CONCLUSION: Through further in vitro and in vivo validation, these variants can be used at the clinical level as novel prognostic markers and therapeutic targets against cervical cancer.

Ursolic acid: a natural modulator of signaling networks in different cancers.

Incidence rate of cancer is estimated to increase by 40% in 2030. Furthermore, the development of resistance against currently available treatment strategies has contributed to the cancer-associated mortality. Scientists are now looking for the solutions that could help prevent the disease occurrence and could provide a pain-free treatment alternative for cancers. Therefore, efforts are now put to find a potent natural compound that could sever this purpose. Ursolic acid (UA), a triterpene acid, has potential to inhibit the tumor progression and induce sensitization to conventional treatment drugs has been documented. Though, UA is a hydrophobic compound therefore it is usually chemically modified to increase its bioavailability prior to administration. However, a thorough literature indicating its mechanism of action and limitations for its use at clinical level was not reviewed. Therefore, the current study was designed to highlight the potential mechanism of UA, its anti-cancer properties, and potential applications as therapeutic compound. This endeavour is a valuable contribution in understanding the hurdles preventing the translation of its potential at clinical level and provides foundations to design new studies that could help enhance its bioavailability and anti-cancer potential for various cancers.

PRKCE non-coding variants influence on transcription as well as translation of its gene.

Untranslated regions of the gene play a crucial role in gene expression regulation at mRNA and protein levels. Mutations at UTRs impact expression by altering transcription factor binding, transcriptional/translational efficacy, miRNA-mediated gene regulation, mRNA secondary structure, ribosomal translocation, and stability. PKCε, a serine/threonine kinase, is aberrantly expressed in numerous diseases such as cardiovascular disorders, neurological disorders, and cancers; its probable cause is unknown. Therefore, in the current study, the influence of PRKCE 5'-and 3'UTR variants was explored for their potential impact on its transcription and translation through several bioinformatics approaches. UTR variants data was obtained through different databases and initially evaluated for their regulatory function. Variants with regulatory function were then studied for their effect on PRKCE binding with transcription factors (TF) and miRNAs, as well as their impact on mRNA secondary structure. Study outcomes indicated the regulatory function of 73 5'UTR and 17 3'UTR variants out of 376. 5'UTR variants introduced AP1 binding sites and promoted the PRKCE transcription. Four 3'UTR variants introduced a circular secondary structure, increasing PRKCE translational efficacy. A region in 5'UTR position 45,651,564 to 45,651,644 was found where variants readily influenced the miRNA-PRKCE mRNA binding. The study further highlighted a PKCε-regulated feedback loop mechanism that induces the activity of TFs, promoting its gene transcription. The study provides foundations for experimentation to understand these variants' role in diseases. These variants can also serve as the genetic markers for different diseases' diagnoses after validation at the cell and population levels.

Nutritional inequalities among under-five children: a geospatial analysis of hotspots and cold spots in 73 low- and middle-income countries.

BACKGROUND: Child undernutrition is a severe health problem in the developing world, which affects children's development in the long term. This study analyses the extent and patterns of under-five child undernutrition using Demographic and Health Surveys (DHS) for 73 low- and middle-income countries (LMICs). METHODS: First, we mapped the prevalence of undernutrition in the developing world. Second, using the LISA (a local indicator of spatial association) technique, we analyzed the geographical patterns in undernutrition to highlight the localized hotspots (regions with high undernutrition prevalence surrounded by similar other regions), cold spots (regions with low undernutrition prevalence surrounded by similar other regions), and outliers (regions with high undernutrition surrounded by low undernutrition and vice versa). Third, we used Moran's I to find global patterns in child undernutrition. RESULTS: We find that South Asia has the highest under-five child undernutrition rates. The intra-country nutritional inequalities are highest in Burundi (stunting), Kenya (wasting), and Madagascar (underweight). The local indicator of spatial association (LISA) analysis suggests that South Asia, Middle East and North Africa (MENA) region, and Sub-Saharan Africa are undernutrition hotspots and Europe and Central Asia and Latin America, and the Caribbean are undernutrition cold spots (regions with low undernutrition surrounded by similar other regions). Getis Ord-Gi* estimates generally support LISA analysis. Moran's I and Geary's C gave similar results about the global patterns of undernutrition. Geographically weighted regressions suggest that several socioeconomic indicators significantly explain child undernutrition. CONCLUSIONS: We found a significant within and across country variation in stunting, wasting and underweight rates among the under-five children's population. The geospatial analysis also suggested that stunting, wasting, and underweight patterns exhibit clear regional patterns, underscoring the need for coordinated interventions at the regional level.

Assessing the determinants of crash propensity using structural equation modeling: Role of distractions caused by fellow drivers.

INTRODUCTION: Aggressive behavior of drivers is a source of crashes and high injury severity. Aggressive drivers are part of the driving environment, however, excessive aggressive driving by fellow drivers may take the attention of the recipient drivers away from the road resulting in distracted driving. Such external distractions caused by the aggressive and discourteous behavior of other road users have received limited attention. These distractions caused by fellow drivers (DFDs) may agitate recipient drivers and ultimately increase crash propensity. Aggressive driving behaviors are quite common in South Asia and, thus, it is necessary to determine their contribution to distractions and crash propensity. METHOD: Our study aimed to evaluate the effects of DFDs using primary data collected through a survey conducted in Lahore, Pakistan. A total of 801 complete responses were obtained. Various hypotheses were defined to explore the associations between the latent factors such as DFDs, anxiety/stress (AS), anxiety-based performance deficits (APD), hostile behavior (HB), acceptability of vehicle-related distractions (AVRD), and crash propensity (CP). Structural Equation Modeling (SEM) was employed as a multivariate statistical technique to test these hypotheses. RESULTS: The results supported the hypothesis that DFDs lead to AS among recipient drivers. DFDs and AS were further found to have positive associations with APDs. Whereas, there was a significant negative association between DFD, AS, and AVRD. As hypothesized, DFD and AS had positive associations with CP, indicating that distractions caused by aggressive behaviors leads to stress and consequently enhances crash propensity. PRACTICAL APPLICATIONS: The results of this study provide a statistically sound foundation for further exploration of the distractions caused by the aggressive behaviors of fellow drivers. Further, the results of this study can be utilized by the relevant authorities to alter aggressive driving behaviors and reduce DFDs.

Men's perspectives on public-space sexual harassment of women in South Asia.

The ubiquity of public-space sexual harassment (PSH) of women in the global South, particularly in South Asia, is both a public health and gender equity issue. This study examined men's experiences with and perspectives on PSH of women in three countries with shared cultural norms and considerable gender inequalities - Bangladesh, India, and Pakistan. The three-country survey in 2021-2022 was completed by 237 men who were generally young, urban, single, well-educated, and middle-/high-income. Among the 53.3% who witnessed PSH, 80% reported intervening to stop it or help the victim. A substantial share of men worried about PSH, and bore emotional, time, and financial costs as they took precautionary or restorative measures to help women in their families avoid PSH or deal with its consequences. Most respondents articulated potential gains for men, women, and society if PSH no longer existed. However, a non-negligible share of participants held patriarchal gender attitudes that are often used to justify harassment, and a small share did not favour legal and community sanctions. Many called for stricter legal sanctions and enforcement, culture change, and education. Men's perspectives offer insights for prevention of harassment and mitigation of its consequences.

Koetjapic acid: unveiling its potential as a saviour in the realm of biological and medicinal properties, with a focus on anticancer mechanism of action.

Scientists have been compelled to search for alternative treatments due to the increasing prevalence of chemoresistance as well as the agonising and distressing side effects of both chemotherapy and radiation. Plant extracts have been exploited to treat various medical conditions for ages. Considering this fact, the main focus of various recent studies that are being conducted to find new and potent anticancer drugs involves the identification and utilisation of potential therapeutic chemicals present in plant extracts. Koetjapic acid (KJA), which belongs to the family of triterpenes, is primarily isolated from Sandoricum koetjape. Ongoing investigations into its therapeutic applications have revealed its tendency to impede the growth and proliferation of cancer cells. Koetjapic acid activates the intrinsic apoptotic pathway and promotes the death of cancer cells. Moreover, it inhibits angiogenesis and the dissemination of tumour (metastasis) by targeting the VEGF signalling cascade. Therefore, this study aims to elucidate the underlying mechanism of anticancer activity of koetjapic acid, providing significant insight into the compound's potential as an anticancer agent.

Does Childhood Experience of Interparental Abuse Shape Women's Attitude Toward Intimate Partner Violence in Their Adult Life? Evidence From 31 Developing Countries.

A significant amount of literature exists on the lasting effects of interparental abuse on children's psychological health as adults. However, evidence on how children's childhood experience of interparental violence shapes their attitude toward partner violence in adult intimate relationships is limited. Given the existing evidence that women's acceptance of partner violence as a social norm increases the risk of partner violence, we analyzed the effect of girls' witnessing interparental abuse (where a father is a perpetrator) on their attitude toward partner violence in their intimate relationships as adults. We used data from the Demographic and Health Surveys for 31 low and middle-income countries in Asia and Africa. Aggregating information about women's attitudes toward partner violence into a binary "intimate partner violence acceptance" variable, we found that a woman who witnessed her father beat her mother was 1.62 times more likely to justify partner violence than a woman who did not experience such interparental abuse (adjusted odds ratio [AOR] = 1.62, 95% CI [1.57, 1.66], p < .001). Additionally, using individual components of acceptance as response variables, we found that a woman who witnessed interparental abuse was significantly more likely to justify partner violence if she went out without telling her husband (OR = 1.49, 95% CI [1.45, 1.54], p < .001), neglected children (OR = 1.53, 95% CI [1.49, 1.58], p < .001), argued with the husband (OR = 1.49, 95% CI [1.45, 1.53], p < .001), refused sex with the husband (OR = 1.35, 95% CI [1.31, 1.39], p < .001), or burned food (OR = 1.36, 95% CI [1.31, 1.41], p < .001). This study highlights the need to put in place children-specific social policies to limit the intergenerational transmission of the adverse effects of intimate partner violence.

Cross talk of tumor protein D52 (TPD52) with KLF9, PKCε, and MicroRNA 223 in ovarian cancer.

BACKGROUND: Gynecologic cancers comprise malignancies in the female reproductive organs. Ovarian cancer ranks sixth in terms of incidence rates while seventh in terms of mortality rates. The stage at which ovarian cancer is diagnosed mainly determines the survival outcomes of patients. Various screening approaches are presently employed for diagnosing ovarian cancer; however, these techniques have low accuracy and are non-specific, resulting in high mortality rates of patients due to this disease. Hence, it is crucial to identify improved screening and diagnostic markers to overcome this cancer. This study aimed to find new biomarkers to facilitate the prognosis and diagnosis of ovarian cancer. METHODS: Bioinformatics approaches were used to predict the tertiary structure and cellular localization along with phylogenetic analysis of TPD52. Its molecular interactions were determined through KEGG analysis, and real-time PCR-based expression analysis was performed to assess its co-expression with another oncogenic cellular pathway (miR-223, KLF9, and PKCε) proteins in ovarian cancer. RESULTS: Bioinformatics analysis depicted the cytoplasmic localization of TPD52 and the high conservation of its coiled-coil domains. Further study revealed that TPD52 mRNA and miRNA-223 expression was elevated, while the expression of KLF 9 and PKCε was reduced in the blood of ovarian cancer patients. Furthermore, TPD52 and miR-223 expression were upregulated in the early stages of cancer and non-metastatic cancers. CONCLUSION: TPD52, miR-223, PKCε, and KLF9, can be used as a blood based markers for disease prognosis, metastasis, and treatment response. The study outcomes hold great potential to be translated at the clinical level after further validation on larger cohorts.

New insights into the anticancer therapeutic potential of maytansine and its derivatives.

Maytansine is a pharmacologically active 19-membered ansamacrolide derived from various medicinal plants and microorganisms. Among the most studied pharmacological activities of maytansine over the past few decades are anticancer and anti-bacterial effects. The anticancer mechanism of action is primarily mediated through interaction with the tubulin thereby inhibiting the assembly of microtubules. This ultimately leads to decreased stability of microtubule dynamics and cause cell cycle arrest, resulting in apoptosis. Despite its potent pharmacological effects, the therapeutic applications of maytansine in clinical medicine are quite limited due to its non-selective cytotoxicity. To overcome these limitations, several derivatives have been designed and developed mostly by modifying the parent structural skeleton of maytansine. These structural derivatives exhibit improved pharmacological activities as compared to maytansine. The present review provides a valuable insight into maytansine and its synthetic derivatives as anticancer agents.

Troubling Trade-offs Between Women's Work and Intimate Partner Violence: Evidence From 19 Developing Countries.

The empirical link between women's employment status and their experience of different types of intimate partner violence (IPV) is not very apparent. Using Demographic and Health Surveys (DHS) data from 19 developing countries in South Asia, Sub-Saharan Africa, and the Middle East, we found that working women were significantly more likely to experience IPV than their stay-at-home counterparts. Given the great diversity in women's employment with respect to economic returns and working conditions, we disaggregated women's employment into three categories vis-à-vis agriculture jobs (AJ), blue-collar jobs (BJ), and white-collar jobs (WJ). The disaggregated analysis revealed that women engaged in all three job categories were significantly more likely to experience IPV. After controlling for potential endogeneity of women's employment, we found that women's work increased the risk of less severe physical violence (LSPV) and emotional violence (EV) but reduced the risk of sexual violence (SV). Endogeneity-adjusted disaggregated analysis showed that women engaged in BJ and WJ faced an increased risk of LSPV but reduced risk of SV. In contrast, women undertaking AJ faced a smaller risk of severe physical violence (SPV) and SV. This study contradicts some long-held beliefs that women's work is a sufficient condition for protecting them from IPV. The public policy should not assume that women's earnings automatically protect them against the risk of IPV. While encouraging a greater female labor force participation rate is important in its own right, women's risk of IPV is context-specific.

Maternal Correlates of Poliomyelitis Vaccination Uptake: Evidence from Afghanistan, Pakistan, and Nigeria.

Poliomyelitis (polio) is a communicable viral disease that mainly affects under-5 children. This study focuses on the impact of women's empowerment and women's working status on the uptake of polio vaccination of children in polio-endemic countries, including Pakistan and Afghanistan, and Nigeria, the latter of which has recently been declared polio-free. The polio vaccination status can be divided into no vaccination (NV), incomplete vaccination (IV), and complete vaccination. We used data from the most recent Demographic and Health Surveys (DHS) rounds for this manuscript. Multinomial logistic regression-based estimates suggest that mothers' working status, empowerment, age, education, father's education, and household wealth status reduce the risk of NV and IV in the polio-endemic countries (Afghanistan and Pakistan) and Nigeria. In addition, the mothers' working status, empowerment, age, education, and father's education increase the child's healthcare information that helps complete polio vaccination of the child. On the other hand, the children whose mothers work in the agriculture sector or are engaged in a blue-collar job are more likely to remain unvaccinated than women in white-collar jobs. Similarly, mothers engaged in government jobs are more likely to get their children fully vaccinated than unemployed mothers. Thus, as a child's polio vaccination is strongly dependent on a mother's working status and empowerment, the focus of public policy on empowering women and promoting their labor force participation may increase polio vaccination uptake, besides adopting other measures to increase immunization.