Differential sensitivity of renal carcinoma cells to doxorubicin and epigenetic therapeutics depends on the genetic background.

Differential sensitivity to chemotherapeutics is a limitation in chemotherapy of kidney cancer patients. Role of genetic background in chemotherapy is not fully understood. Therefore, this study evaluated the influence of genetic/epigenetic background of renal cancer cells on the sensitivity to chemotherapeutics. Two renal cell carcinoma (RCC) cell lines, Caki-1 and 786-0, with different genetic makeup of p53 and VHL were treated with doxorubicin either alone or in combination with epigenetic therapeutics 5-aza-2-dc and TSA. Sensitivity of RCC cells to these drugs was evaluated by cell viability and cell cycle analysis and was further confirmed by analysis of selected genes expression. Cell viability data revealed that 786-0 cells were more sensitive than Caki-1 to doxorubicin. Combination of doxorubicin with 5-aza-2-dc or TSA was more effective to inhibit growth of Caki-1 cells but not the 786-0. Data of cell cycle analysis and expression of representative genes for tumor suppressor, cell cycle and survival, drug transporter and DNA repair further provided the molecular basis for differential sensitivity of Caki-1 and 786-0 cell lines to doxorubicin. Important findings of this study suggest that doxorubicin is more cytotoxic to primary renal cancer 786-0 cells with mutant VHL and p53 than the metastatic Caki-1 cells with wild-type VHL and p53, and this differential response was independent of p53 expression level. This study suggests that combination of doxorubicin with epigenetic therapeutics could potentially be beneficial in clinical treatment of renal cancer patients with wild-type VHL and p53 but not in patients with mutant VHL and p53.

Selective Catalytic Chemistry at Rhodium(II) Nodes in Bimetallic Metal-Organic Frameworks.

We report the first study of a gas-phase reaction catalyzed by highly dispersed sites at the metal nodes of a crystalline metal-organic framework (MOF). Specifically, CuRhBTC (BTC3- =benzenetricarboxylate) exhibited hydrogenation activity, while other isostructural monometallic and bimetallic MOFs did not. Our multi-technique characterization identifies the oxidation state of Rh in CuRhBTC as +2, which is a Rh oxidation state that has not previously been observed for crystalline MOF metal nodes. These Rh2+ sites are active for the catalytic hydrogenation of propylene to propane at room temperature, and the MOF structure stabilizes the Rh2+ oxidation state under reaction conditions. Density functional theory calculations suggest a mechanism in which hydrogen dissociation and propylene adsorption occur at the Rh2+ sites. The ability to tailor the geometry and ensemble size of the metal nodes in MOFs allows for unprecedented control of the active sites and could lead to significant advances in rational catalyst design.

Recent advances in the molecular basis of chemotherapy resistance and potential application of epigenetic therapeutics in chemorefractory renal cell carcinoma.

Among various types of cancers, kidney cancer is unique with respect to a low frequency of mutations and a relatively higher level of chemotherapy resistance. Resistance to chemotherapy is a major challenge in kidney cancer treatment in the clinic. Tremendous progress has been made in identifying the molecular changes associated with chemotherapy resistance in RCC. However, the exact contribution of these molecular changes to the acquisition of chemotherapy resistance is not fully understood. In addition to genetic changes, epigenetic alterations have been shown to contribute to various pathways associated with chemotherapy resistance, such as increased cell proliferation and survival, regulation of drug influx and efflux transporters, increased DNA repair, loss of DNA-damage-dependent apoptotic potential, cellular dedifferentiation to cancer stem cell, and epithelial-mesenchymal transitions (EMT). Moreover, recent studies suggest that epigenetic aberrations that can be reversed by epigenetic therapeutics can potentially be targeted to restore chemosensitivity in chemorefractory kidney cancer. This review article highlights current knowledge of the role of genetic and epigenetic aberrations as well as the physiological and metabolic changes associated with chemotherapeutic resistance. Additionally, current approaches and future directions for overcoming chemotherapeutic resistance including the potential of epigenetic therapeutic in chemorefractory kidney cancer have also been discussed. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics.

PPR control program in Nepal: What next?

PPR is an economically important trans-boundary disease of sheep and goats. Nepal had experienced several episodes of PPR outbreaks in the past. Although severity and frequency of outbreaks have decreased due to strenuous effort of Government of Nepal, it has been rather endemic. National PPR Control Program 2001, and PPR Control Program Implementation Working Guidelines, 2013, the legal documents guiding PPR control activities, have not been effective as expected due to multifactorial reasons. Thus, a critical analysis of the program with emphasis on impeding factors is must. In this review, we attempted to analyse and suggest more effective strategies considering geopolitical, social and cultural context of Nepal.

Correction to: Human infection with Avian Influenza A virus in Nepal: requisite for timely management and preparedness.

[This corrects the article DOI: 10.1007/s13337-020-00593-z.].

Human infection with Avian influenza A virus in Nepal: requisite for timely management and preparedness.

Avian influenza virus infection in humans is an emerging zoonotic disease having high economic and public health impacts. Due to its capability for genetic re-assortment, this virus can emerge as novel influenza strains with pandemic potential. Even though the first Avian influenza incidence in humans in Nepal was reported in April 2019, the threat of the disease remains unmitigated. Limited resources for surveillance, disease tracking, and weak health care facilities in low and middle-income countries will increase the possibility of the outbreak. Therefore, timely management and preparedness by strengthening veterinary and medical services, operational capabilities of laboratories, and surveillance programs through the "One-Health" approach could be crucial for the control of possible outbreaks in Nepal.

One-health approach: A best possible way to control rabies.

More than 75% of emerging infectious diseases and 60% of known human infectious diseases are transmitted from animals. Among these zoonoses, rabies is of utmost public health significance due to its lethality. The multi-faceted nature of zoonotic disease complicates control and prevention and thus, a multi-sectoral One Health Approach could be a better strategy to cope with rabies. Up until now, rabies prevention and control programs are conducted utilizing mass vaccination of domestic and community dogs and cats, and mass awareness programs. However, the burden of rabies has not been reduced as these approaches have failed to include all stakeholders (human, animal, and environmental health sectors) in disease management programs. The aim of this review is to highlight why and how One Health Approach would be the most effective way to control rabies in low- and middle-income countries (LMICs) like Nepal.

Obesogenic Toxicants in Breast Milk of Lactating Women: Investigation of a Risk Factor for Childhood Obesity.

BACKGROUND: Persistent organic pollutants (POPs), dispersed in all environmental compartments, are associated with increased adipogenesis and body weight. These lipophilic toxicants bioaccumulate in the human body and get transferred from mothers to their offspring via the placental circulation and breast milk. The current study was designed to compare polychlorinated biphenyl (PCB) and hexachlorobenzene (HCB) concentrations between obese and normal-weight lactating women. METHODS: A cross-sectional correlation design was used to compare POP concentrations in breast milk samples of 24 obese and 21 normal-weight adult lactating women at their 2- to 8-week postpartum clinic visit. Concentrations of 12 specific PCB congeners and HCB were analyzed using high-resolution gas chromatography coupled with mass spectroscopy. RESULTS: Of 12 targeted PCB congeners, 6 were detected in the breast milk samples of obese women compared to 3 in normal-weight lactating women. PCB presence was not significantly different between the obese and normal-weight groups. HCB was not detected in any of the breast milk samples for either group. CONCLUSIONS: This exploratory study revealed no statistically significant difference in the presence of PCBs in breast milk of obese mothers compared to that of normal-weight women. Therefore, fear of increased risk of transmission of these toxicants may not be a good reason to avoid breastfeeding. Results point to the need for a large-scale multicenter study that examines the effect of PCBs on breastfeeding, considering possible geographic variations of the examined phenomenon.

Animal Welfare in Nepal.

The small densely populated country of Nepal rises from just above sea level to more than 8800 m and encompasses many agro-ecological zones. Rich in both nature and culture, livestock are integral to household and national economies. Most Nepalese consider the cow sacred, and slaughter is forbidden. Other nonhuman animals are less esteemed, slaughter is not proscribed, and many are sacrificed during religious festivals. Limited financial and material resources, inadequate feed supplies, poor access to veterinary services, absence of appropriate legislation, and ignoring the needs of livestock as sentient beings can compromise welfare and lead to inhumane treatment. This article reviews the welfare status of various groups (food-producing stock, work animals, street dogs, experimental animals, and elephants in captivity). Several animal welfare charities are represented. Suggestions for improved welfare are discussed, but the prognosis is not encouraging especially in view of the widespread struggle and people's own struggle for survival.

Polycyclic aromatic hydrocarbons in breast milk of obese vs normal women: Infant exposure and risk assessment.

Biomonitoring of human breast milk is one of the best ways to identify body burdens of contaminants and associated risk estimation. The objectives of the current study were to evaluate milk concentrations of persistent organic pollutants (POPs), mainly polycyclic aromatic hydrocarbons (PAHs), associated exposure estimation, and the role of body mass index (BMI) in their bioaccumulation. A total of 45 breast milk samples were collected from 24 women with BMI > 30 (obese) and 21 women with BMI < 25 (18.5-24.9, normal) from 14 different counties surrounding Lubbock in west Texas/New Mexico (age range: 18-34 years). Samples were analyzed using high resolution gas chromatography coupled with mass spectrometry. A total of 31/45 (69%) of samples tested positive for PAHs. Phenanthrene was the most frequently detected PAH followed by pyrene and fluoranthene. The mean of individual PAH concentration for all samples ranged from 0 to 25.1 ng/g milk fat; the sum of all means of individual PAHs was 146.9 ng/g milk fat. The mean concentration of total PAHs in the BMI > 30 group was 224.8 ng/g milk fat, which was approximately 4 times the mean concentration of total PAHs in the BMI 18.5-24.9 group (57.9 ng/g milk fat). None of the samples from the BMI 18.5-24.9 group contained higher molecular weight (5-6 rings) PAHs, while in the BMI >30 group, a total of 11 PAHs including listed EPA priority pollutants were observed. In this study, benzo(b)fluoranthene was found to contribute the highest percentage of carcinogenic PAHs (32.08%), yet it was not detected in any samples from the BMI 18.5-24.9 group. The estimated total PAHs intakes by infants via obese and normal mothers' milk were 1.26 and 0.32 (µg/kg/day), which are 0.049 and 0.003 (µg/kg/day) B[a]P equivalent, respectively. These findings suggest that breastfed babies from obese mothers are potentially at higher risk of exposure to carcinogenic PAHs.

Effectiveness of health education-based conventional intervention method to reduce noncommunicable diseases risk factors among rural population.

BACKGROUND: Noncommunicable diseases (NCDs) are the major public health challenges that can be averted through prevention and control of behavioral risk factors. The study aimed to assess the effectiveness of health education-based conventional intervention method to reduce NCD risk factors among a selected rural population of Bangladesh. METHODS: A quasi-experimental study was conducted among 80 adults of Basulia village. Cluster sampling technique was used to grasp the participants. A baseline pre-test was done, followed by health education intervention in terms of awareness creating and warning messages containing leaflets on NCD risk factors. A weekly leaflet was provided to the participants throughout 3 months followed by post-test. World Health Organization STEPS instrument was used for data collection. Paired t-test was done to see the significance of the intervention. RESULTS: Men were dominator (60%), and the mean age of the participants was 37.1±13.8 years. Significant pre- and post-test differences were found for decreasing the number of smoking tobacco sticks daily (11.1±5.9 and 7.4±2.9; P=0.016) along with the frequency of smokeless tobacco use daily (6.7±3.6 and 4.3±1.7; P=0.005), increasing the servings of fruit and vegetables intake daily (3.3±0.8 and 4.9±1.1; P=0.046), decreasing the amount of added salt intake daily (1.2±0.5 and 0.8±0.5 teaspoon; P<0.001), and also increasing the total weekly metabolic equivalent (MET) of physical activity (3,756±4,094 and 4,002±4,249; P=0.046). In terms of percentage of the risk factors, all were reduced except tobacco use. CONCLUSIONS: A fair positive interventional effect of health education messages using conventional method has been evinced for all NCD risk factors.

Cross-sectional sero-prevalence study of Peste des Petits Ruminants (PPR) in goats of Syangja and Kaski districts of Nepal.

A cross-sectional study was conducted to determine sero-prevalence of Peste des Petits Ruminants (PPR) among goat population of outbreak suspected areas; Kaski and Syangja districts of Nepal. A total of 460 goat serum samples were tested by using c-ELISA for the presence of antibodies against PPR. Out of the 460 samples tested, 380 samples were found positive, giving overall sero-positivity of 82.60%. Significantly higher sero-prevalence was found (*P < 0.05) in females (87.50%) compared to males (70.45%) and crossbreed goats were found highly susceptible than the pure breed goats (*P < 0.05). Likewise, higher sero-prevalence of PPR was observed in adults and cross breed goats compared to their counterparts and significantly higher sero-prevalence was observed in Syangja district compared to Kaski. Thus, adults, females and cross-breeds populations of goats are at higher risk of PPR whereas geographically, goat population of Syangja district were found significantly prone to PPR. Appropriate control measures, such as ring vaccination can be followed to prevent the potential outbreak situation.

Enhanced anticancer effects of Scutellaria barbata D. Don in combination with traditional Chinese medicine components on non-small cell lung cancer cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Experience-based herbal medicine as a complementary to modern western medicine has triggered an array of studies in quest of novel anticancer drugs. Scutellaria barbata D. Don (SB) is commonly used to treat different types of cancers, but its molecular mechanism of action is not clearly understood. In this study, we attempted to elucidate the mode of action of a traditional Chinese medicine prescription with a total of 14 components, named Lian-Jia-San-Jie-Fang (LJSJF, in Chinese), where SB works as the "principle" against non-small cell lung cancer (NSCLC) cells. MATERIALS AND METHODS: Four different NSCLC cell lines (A549, H460, H1650, and H1975) were used. Cytotoxicity, in vitro tumorigenicity, gene expression, and protein expression were analyzed by MTT assay, soft agar assay, real-time PCR, and Western blots, respectively. RESULTS: Among the 14 components in LJSJF, SB was the only one to possess cytotoxic effects at its pharmacologically relevant doses. Additionally, we observed synergistically dose-dependent cytotoxic effects of SB in combination with other LJSJF components. After SB or LJSJF treatment, significant reductions in colony number and/or size were observed in A549 and H460; a notable dose-dependent decrease in EGFR was observed in A549, H460, and H1650; significant downregulation in EGFR and its downstream signaling targets mTOR and p38MAPK were also observed in A549 and H460; and p53 and p21 were significantly increased while survivin, cyclin D1, and MDM2 were significantly decreased in A549. Additionally, p53, p21, and Mettl7b were decreased, but p73 was increased in H460. Neither EGFR nor p53 was changed in H1975. Therefore, SB or LJSJF may induce cytotoxic effects by regulating multiple and/or distinct apoptotic pathways in different NSCLC cells. CONCLUSION: LJSJF exerts more pronounced cytotoxic effects against NSCLC cells than SB does by synergistically regulating the underlining molecular mechanisms including EGFR and/or p53 signaling pathways.

Positive reinforcement training for a trunk wash in Nepal's working elephants: demonstrating alternatives to traditional elephant training techniques.

Many trainers of animals in the zoo now rely on positive reinforcement training to teach animals to voluntarily participate in husbandry and veterinary procedures in an effort to improve behavioral reliability, captive management, and welfare. However, captive elephant handlers in Nepal still rely heavily on punishment- and aversion-based methods. The aim of this project was to determine the effectiveness of secondary positive reinforcement (SPR) in training free-contact elephants in Nepal to voluntarily participate in a trunk wash for the purpose of tuberculosis testing. Five female elephants, 4 juveniles and 1 adult, were enrolled in the project. Data were collected in the form of minutes of training, number of offers made for each training task, and success rate for each task in performance tests. Four out of 5 elephants, all juveniles, successfully learned the trunk wash in 35 sessions or fewer, with each session lasting a mean duration of 12 min. The elephants' performance improved from a mean success rate of 39.0% to 89.3% during the course of the training. This study proves that it is feasible to efficiently train juvenile, free-contact, traditionally trained elephants in Nepal to voluntarily and reliably participate in a trunk wash using only SPR techniques.