Effective suppression of Ih and INa caused by capsazepine, known to be a blocker of TRPV1 receptor.

A synthetic inhibitor of capsaicin-induced TRPV1 channel activation is called capsazepine (CPZ). In this study, we aimed to explore the effects of CPZ on hyperpolarization-activated cationic current (Ih) and voltage-gated Na + current (INa) in pituitary tumor (GH3) cells. Through patch-clamp recordings, we found that CPZ concentration-dependently inhibited Ih amplitude and slowed its activation time course. The IC50 and KD values were 3.1 and 3.16 µM, respectively. CPZ also shifted the steady-state activation curve of Ih towards a more hyperpolarized potential. However, there was no change in the gating charge of the curve. A modified Markovian model predicted the CPZ-induced decrease in the voltage-dependent hysteresis of Ih. CPZ suppressed INa in GH3 cells, without altering its activation or inactivation time course. Additionally, exposure to CPZ reduced spontaneous firing. These findings suggest that CPZ's inhibitory effects on Ih and INa are direct and not dependent on vanilloid receptor binding. This could provide light on an unidentified ionic mechanism influencing the membrane excitability of neurons and endocrine or neuroendocrine cells in vivo.

Chitosan/starch based unoxidized tannic acid modified microparticles for rapid hemostasis with broad spectrum antibacterial activity.

The development of a rapid hemostat through a facile method with co-existing antibacterial activity and minimum erythrocyte lysis property stands as a major requirement in the field of hemostasis. Herein, a series of novel microparticle hemostats were synthesized using chitosan, different hydrothermally-treated starches, and cross-linked with tannic acid (TA) simultaneously in an unoxidized environment via ionotropic gelation method. Hemostats' comparative functional properties, such as adjustable antibacterial and erythrocyte compatibility upon various starch additions were evaluated. The in vivo hemostatic study revealed that the developed hemostats for mouse liver laceration and rat tail amputation had clotting times (13 s and 38 s, respectively) and blood loss (51 mg and 62 mg, respectively) similar to those of Celox™. The erythrocyte adhesion test suggested that erythrocyte distortion can be lowered by modifying the antibacterial hemostats with different starches. The broad-spectrum antibacterial efficacy of the hemostats remained intact against S. aureus (>90 %), E. coli (>80 %), and P. mirabilis bacteria upon starch modification. They also demonstrated high hemocompatibility (<3 % hemolysis ratio), moderate cell viability (>81 %), in vivo biodegradation, and angiogenesis indicating adequate biocompatibility and wound healing. The developed hemostats hold significant promise to be employed as rapid hemostatic agents for preventing major bleeding and bacterial infection in emergencies.

Atrogin-1 promotes muscle homeostasis by regulating levels of endoplasmic reticulum chaperone BiP.

Skeletal muscle wasting results from numerous pathological conditions affecting both the musculoskeletal and nervous systems. A unifying feature of these pathologies is the upregulation of members of the E3 ubiquitin ligase family, resulting in increased proteolytic degradation of target proteins. Despite the critical role of E3 ubiquitin ligases in regulating muscle mass, the specific proteins they target for degradation and the mechanisms by which they regulate skeletal muscle homeostasis remain ill-defined. Here, using zebrafish loss-of-function models combined with in vivo cell biology and proteomic approaches, we reveal a role of atrogin-1 in regulating the levels of the endoplasmic reticulum chaperone BiP. Loss of atrogin-1 resulted in an accumulation of BiP, leading to impaired mitochondrial dynamics and a subsequent loss in muscle fiber integrity. We further implicated a disruption in atrogin-1-mediated BiP regulation in the pathogenesis of Duchenne muscular dystrophy. We revealed that BiP was not only upregulated in Duchenne muscular dystrophy, but its inhibition using pharmacological strategies, or by upregulating atrogin-1, significantly ameliorated pathology in a zebrafish model of Duchenne muscular dystrophy. Collectively, our data implicate atrogin-1 and BiP in the pathogenesis of Duchenne muscular dystrophy and highlight atrogin-1's essential role in maintaining muscle homeostasis.

Human cytokeratin 1 plays a role in the interaction of Pteropine orthoreovirus with Hek293 cells but not HeLa cells.

Pteropine orthoreovirus (PRV) causes respiratory tract infections in humans. Despite its emergence as a zoonotic and respiratory virus, little is known about its cell tropism, which hampers progress in fully understanding its pathogenesis in humans. Hek293 cells are most susceptible to PRV infection, while HeLa cells are the least. Human cytokeratin 1 (CK1) was identified as the protein that interacts with PRV. The immunofluorescence assay and qPCR results revealed prior treatment with anti-CK1 may provide Hek293 cells protection against PRV. The KRT1-knockout Hek293 cells were less susceptible to PRV infection. Further study into the pathogenesis of PRV in humans is needed.

Self-assembled sodium alginate polymannuronate nanoparticles for synergistic treatment of ophthalmic infection and inflammation: Preparation optimization and in vitro/vivo evaluation.

Frequent administrations are often needed during the treatment of ocular diseases due to the low bioavailability of the existing eye drops owing to inadequate corneal penetration and rapid drug washout. Herein, sodium alginate polymannuronate (SA) nanocarriers were developed using ionic gelation method that can provide better bioavailability through mucoadhesivity and sustained drug release by binding to the ocular mucus layer. This study disproves the common belief that only the G block of SA participates in the crosslinking reaction during ionic gelation. Self-assembly capability due to the linear flexible structure of the M block, better biocompatibility than G block along with the feasibility of controlling physicochemical characteristics postulate a high potential for designing efficient ocular drug delivery systems. Initially, four crosslinkers of varied concentrations were investigated. Taguchi design of experiment revealed the statistically significant effect of the crosslinker type and concentration on the particle size and stability. The best combination was detected by analyzing the particle size and zeta potential values that showed the desired microstructural properties for ocular barrier penetration. The desired combination was SA-Ca-1 that had particle size within the optimal corneal penetration range, that is 10-200 nm (135 nm). The drug carriers demonstrated excellent entrapment efficiency (∼89 % for Ciprofloxacin and ∼96 % for Dexamethasone) along with a sustained and simultaneous release of dual drug for at least 2 days. The nanoparticles also showed biocompatibility (4 ± 0.6 % hemolysis) and high mucoadhesivity (73 ± 2 % for 0.25 g) which was validated by molecular docking analysis. The prepared formulation was able to reduce the scleral inflammation of the rabbit uveitis models significantly within 3 days. Thus, the eye drop showed remarkable potential for efficient drug delivery leading to faster recovery.

Association of vitamin D-binding protein polymorphisms and serum 25(OH)D concentration varies among Chinese healthy infants of different VDR-FokI genotypes: A multi-centre cross-sectional study.

Hypovitaminosis D during infancy is associated with the development of chronic diseases and poor health later in life. While the effect of environmental factors on vitamin D concentration has been extensively explored, this study aimed to explore the effect of genetic factors on vitamin D concentration among Chinese infants. We conducted a multi-centre cross-sectional study in Hong Kong from July 2019 to May 2021. A candidate genetic approach was adopted to study four selected genetic variants of the vitamin D-binding protein (DBP) and vitamin D receptor (VDR) (rs4588, rs7041, rs2282679 and rs2228570) to examine their associations with measured serum 25(OH)D concentration. A total of 378 Chinese infants aged 2-12 months were recruited in this study. Peripheral blood samples were collected from the infants to measure serum 25(OH)D concentration and extract DNA. Results showed that rs7041T and rs2282679C were significantly associated with lower serum 25(OH)D concentration. Further analysis of the DBP variants revealed that the GC1F allele was significantly associated with lower 25(OH)D concentration and identified as the risk DBP isoform in infants. While our results revealed that there is no direct association between VDR-FokI genotype and serum 25(OH)D concentration, a VDR-FokI genotype-specific pattern was observed in the association between DBP isoforms and serum 25(OH)D concentration. Specifically, significant associations were observed in the DBP genotypes GC1F/F, GC1F/2 and GC1S/2 among VDR-FokI TT/TC carriers, but not in VDR-FokI CC carriers. Our findings lay down the basis for the potential of genetic screening to identify high risk of hypovitaminosis D in Chinese infants.

Prevalence of zoonotic (brugian) filariasis in Asia: A proportional meta-analysis.

Lymphatic filariasis is a public health problem and targeted for global elimination. WHO recommends mass drug administration to interrupt transmission of the parasites involved. There are concerns that transmission interruption may be difficult in areas of zoonotic filarial infections. This study aimed to estimate the pooled prevalence of zoonotic brugian filariasis, and to compare the pooled prevalence of brugian filariasis in human and animal populations in the same area based on available studies. A comprehensive literature search was conducted in health-related electronic databases (PubMed, Ovid MEDLINE, Index Medicus, google scholar). A random-effect meta-analysis of the pooled overall prevalence of filariasis in animal populations was conducted. Sixteen studies from four different Asian countries were identified. Studies were conducted most frequently in Thailand (n = 7), followed by Malaysia (n = 5), India (n = 3), and Sri Lanka (n = 1). Regardless of animal group, the pooled overall prevalence of animal Brugia infections was 13% (95%CI: 7-21%, I2:98%, 16 studies). On stratification, the pooled overall prevalence in the animal population was 19% (95%CI: 1-50%, I2: 99%, 3 studies) in India, 8% (95%CI: 2-7%, I2: 97%, 5 studies) in Malaysia, and 13% (95%CI: 7-20%, I2: 94%, 7 studies) in Thailand. The prevalence in the animal population was 17% (95%CI: 13-21%, 1 study) in Sri Lanka. The pooled overall prevalence of Brugia malayi was 13% (95%CI: 7-21%, I2:98%, 12 studies), while for Brugia pahangi this was 12% (95%CI: 7-19%, I2:86%, 7 studies). Regardless of animal group, geographic area, or diagnostic test, the prevalence of B. malayi was consistently high. On stratification by animal category, the pooled overall prevalence was 10% (95%CI: 6-14%, I2:92%, 13 studies) in cats, 12% (95%CI: 2-28%, I2: 99%, 6 studies) in dogs, and 55% (95%CI: 47-63%, 1 study) in leaf-eating monkeys. The findings show the extent of zoonotic Brugiainfections in domestic cats and dogs, suggesting that these animals are potential reservoirs for human brugian filariasis in the study countries. To substantiate this with more accuracy, future well designed whole genomic sequencing of individual mf collected from humans and B. malayi infected animals in the same area are needed.

Toll-like receptor 9 (-1237 T/C, -1486 T/C) and the risk of gastric cancer: a meta-analysis of genetic association studies.

BACKGROUND: Gastric cancer has a complex aetiology including genetic factors. Individual case-control studies of toll like receptor (TLR) 9 (-1237 T/C, -1486 T/C) polymorphisms in the gastric cancer risk were available, and they showed variation in the findings. Therefore, we performed a meta-analysis to synthesize the evidence on the association between polymorphisms of TLR 9 (-1237 T/C, -1486 T/C) and the risk of gastric cancer using data from eligible studies. METHODS: This study followed the PRISMA 2020 Checklist. Studies were searched in health-related databases. The methodological quality of studies was evaluated with the use of Newcastle-Ottawa Scale criteria. The summary odds ratio (OR) and its 95% confidence interval (CI) were used to determine the strength of association between each polymorphism and the risk of gastric cancer using five genetic models. Stratification was done by ethnic groups. For the robustness of the analysis, a leave-one-out meta-analysis was performed. RESULTS: Eight case-control studies with 3,644 participants (1914 cases, 1730 controls) were conducted across six countries. Half of the studies were conducted in China. In the NOS methodological quality assessment, only three studies received a high-quality rating (i.e., a score of ≥ 7). TLR 9 (-1486 T/C) polymorphism and the risk of gastric cancer were assessed in six studies, four of Asian ethnicity and two of non-Asian. Under the dominant model, only in the Asian ethnic group showed a marginally and significantly increased risk of gastric cancer (overall: OR = 1.22, 95%CI = 0.90-1.67, I2 = 56%; Asian: OR = 1.24, 95%CI = 1.00-1.54, I2 = 0%, non-Asian: OR = 1.25, 95%CI = 0.38-4.09, I2 = 89%). Under the recessive model in the absence of heterogeneity, only the Asian group had a significantly higher risk of developing gastric cancer (overall: OR = 1.4, 95% CI = 0.74-2.64, I2 = 85%; Asian: OR: 1.41, 95% CI = 1.07-1.86, I2 = 0%, non-Asian: OR = 1.18, 95% CI = 0.12-11.76, I2 = 97%). Under the heterozygous model, there was no significant association with the risk of gastric cancer overall or among any ethnic subgroup. Under the homozygous model in the absence of heterogeneity, only the Asian group had a significantly higher risk of gastric cancer (overall, OR = 1.47, 95% CI = 0.76-2.86, I2 = 82%; Asian: OR = 1.54, 95% CI = 1.13-2.1, I2 = 0%; non-Asian: OR = 1.19, 95% CI = 0.1-14.33, I2 = 96%). Under the allele model, a significantly increased risk of gastric cancer was observed only in the Asian group (overall: OR = 1.23, 95% CI = 0.89-1.71, I2 = 84%; Asian: OR = 1.22, 95% CI = 1.05-1.41, I2 = 0%; non-Asian: OR = 1.24, 95% CI = 0.34-4.59, I2 = 97%). Four studies investigated the association between TLR 9 (-1237 T/C) polymorphism and the risk of developing gastric cancer. Under any of the five genetic models, there was no association between TLR 9 (-1237 T/C) and the development of gastric cancer in overall or in any ethnic subgroup. Sensitivity analysis revealed that the effect was unstable. With a small number of studies with a small number of participants, we addressed the issue of insufficient power for drawing conclusions. CONCLUSIONS: The findings suggested that TLR9 (-1486 T/C) may play a role in the risk of gastric cancer specific to the Asian ethnic group. To substantiate the findings on the association between these two polymorphisms (TLR9 -1237 T/C, -1486 T/C) and the risk of gastric cancer, future well-designed case-control studies with a sufficient number of participants in multi-ethnic groups are recommended.

Facilitators and barriers to engaging communities in health service research on dengue control in Indo-Pacific region: a systematic review.

BACKGROUND: Dengue is a public health problem in the Indo-Pacific countries. There are concerns over the facilitators and barriers to community engagement in health service research aimed at dengue control. The objective of his study was to identify and synthesize facilitators and barriers to community engagement in health service research aimed at dengue control. METHODOLOGY: The Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) checklist was used to perform this review. Health-related databases including PubMed, Ovid, and Google Scholar were searched for relevant studies. A consolidated framework with five domains was developed after undertaking a six-phase reflective thematic assessment of the data. RESULTS: Thirteen studies were identified, spanning eight low-and middle-income countries of the Indo-Pacific region including Cambodia, India, Indonesia, Myanmar, Philippines, Sri Lanka, Thailand, and Vietnam. The studies in this review covered the period from 2002 to 2021. A broad range of study designs and objectives were revealed across these 13 studies. An array of communities such as the local government, project-related health staff, local health services staff, community leaders, local communities/residences/general public, heads of households, community health volunteers, school teachers, and schoolchildren participated in these dengue related studies. The five Consolidated Framework for Implementation Research (CFIR) domains of 'intervention characteristics', 'inner setting', 'outer setting',' individual characteristics', and 'program implementations' were used to identify and describe barriers and facilitators. CONCLUSIONS: The findings indicate a range of barriers and facilitators to community engagement in dengue control in the selected LMIC in the Indo-Pacific countries. Future health services research on dengue control approaches should be carefully planned, methodologically constructed, aligned with community engagement principles, and involve considerable community participation at all stages of the research.

Association between IL-10 gene polymorphisms (- 1082 A/G, -819 T/C, -592 A/C) and hepatocellular carcinoma: a meta-analysis and trial sequential analysis.

BACKGROUND: The carcinogenesis of hepatocellular carcinoma is complicated, and genetic factor may have the role in the malignant transformation of liver cells. IL-10 gene polymorphisms have been investigated for their potential roles in hepatocellular carcinoma This study aimed to investigate the relationship between polymorphisms of IL-10 (-1082 A/G, -819 T/C, -592 A/C), and hepatocellular carcinoma by performing a meta-analysis with eligible individual studies. METHODS: This study followed the PRISMA 2020 Checklist. Relevant studies were searched in health-related databases. The Newcastle-Ottawa Scale criteria were used to evaluate the studies quality. Pooled odds ratio (OR) and its 95% confidence interval (CI) were used to determine the strength of association between each polymorphism and hepatocellular carcinoma using five genetic models. Stratification was done by ethnic groups. Trial sequential analysis (TSA) was performed to determine the required information size. RESULTS: Fifteen case-control studies (n = 8182) were identified. Overall, the heterozygous model showed a marginal significant association only between IL-10 (-1082 A/G) and hepatocellular carcinoma risk (OR: 0.82, 95% CI: 0.67-1.00, 9 studies). On stratification, IL-10 (-1082 A/G) was significantly associated with hepatocellular carcinoma risk in the non-Asian population under dominant (OR: 0.62, 95% CI: 0.45-0.86, 4 studies), heterozygous (OR: 0.60, 95% CI: 0.43-0.85) and allelic models (OR: 0.79, 95% CI: 0.64-0.99). IL-10 (-819 T/C) was significantly associated with hepatocellular carcinoma risk only among non-Asians under the dominant (OR: 1.47, 95% CI: 1.02-2.13, 8 studies), recessive (OR: 1.99, 95% CI: 1.03-3.86, and homozygous models (OR: 2.18, 95% CI: 1.13-4.23). For IL-10 (-592 A/C) with 11 studies, there was no significant association with hepatocellular carcinoma in all five genetic models (P values > 0.5). TSA plots indicated that the information size for firm evidence of effect was sufficient only for the analysis of IL-10 (-592 A/C), but not for the - 1082 A/G or -819 T/C. CONCLUSIONS: Findings suggest that IL-10 (-1082 A/G and - 819 T/C) polymorphisms are associated with hepatocellular carcinoma in ethnic-specific manner. However, this evidence is not conclusive because the sample size was insufficient. IL-10 (-592 A/C) polymorphism was not associated with hepatocellular carcinoma albeit with sufficient information size. Future well-designed large case-control studies on IL-10 (-1082 A/G and - 819 T/C) with different ethnicities are recommended.

Xanthan and gum acacia modified olive oil based nanoemulsion as a controlled delivery vehicle for topical formulations.

In this study, olive oil nanoemulsion modified with xanthan gum and gum acacia was explored as a potential controlled topical delivery vehicle. Oil-in-water nanoemulsion formulated with optimized composition of olive oil, tween 80, and water was used as the drug carrier and further modified with gum. Effect of gum on nanoemulsion different physiochemical characteristics, stability, rheology, drug release and encapsulation efficiency were investigated. Results showed that developed nanoemulsion behaved as low viscosity Newtonian fluid and released 100 % drug within 6 h. Modification with xanthan and gum acacia had significantly improved formulation viscosity, drug encapsulation efficiency (>85 %) and controlled drug release up to 40 % with release pattern following Korsmeyer-Peppas model. Additionally, xanthan gum modified formulation exhibited shear thinning rheology by forming an extended network in the continuous phase, whereas gum acacia modified formulation behaved as Newtonian fluid at high shear rate (>200 s-1). Furthermore, xanthan gum modified formulations had improved zeta potential, stability, monodispersity, and hemocompatibility and showed high antibacterial activity against S. aureus than gum acacia modified formulations. These results indicate the higher potential of xanthan gum modified formulation as a topical delivery vehicle. Moreover, skin irritation test demonstrated the safety of developed formulations for topical application.

Adolescent Independent Eating Occasions, Dietary Intake, and Parenting Practices During the COVID-19 Pandemic: A Qualitative Study of Parents and Adolescents From Households With Low Income.

OBJECTIVE: Examine how experiencing the coronavirus disease 2019 (COVID-19) pandemic influenced adolescent independent eating occasions (iEOs) and iEO-related parenting practices from the perspective of parents and adolescents METHODS: Cross-sectional remote interviews were conducted for this basic qualitative research study. Participants were a purposive sample of multiracial/ethnic adolescents aged 11-14 years and their parents from households with low income (n = 12 dyads) representing 9 US states. The main outcome measures were iEOs and iEO-related parenting practices. Data were analyzed using directed content analysis. RESULTS: About half of the parents indicated that their adolescents had more iEOs during the COVID-19 pandemic and that there were changes in the types of foods consumed during iEOs. In contrast, most adolescents indicated their iEOs had not changed remarkably in frequency or foods consumed since the onset of the pandemic. Most parents reported no change in how they taught their adolescents about healthy food, the rules for foods/beverages permitted during iEOs, or how they monitored what their adolescents ate during iEOs; adolescent reports were in general agreement. Most parents indicated that family members were home together more often during the pandemic, which increased cooking frequency. CONCLUSIONS AND IMPLICATIONS: The effect of the COVID-19 pandemic on adolescents' iEOs varied, and the parenting practices used to influence iEOs remained stable during the pandemic. Families experienced having more time together and cooking at home more often.

Parenting Practices Are Associated With Adolescent Food Choices During Independent Eating Occasions.

BACKGROUND: Frequency of independent eating occasions (iEOs) has been linked to intake of unhealthy foods and overweight or obesity among adolescents. Parenting practices involving modeling healthy food intake and making healthy foods available have been associated with healthy food intake among adolescents; however, little is known about these associations during iEOs. OBJECTIVE: To determine whether parenting practices involving structure (monitoring, availability, modeling, and expectations), lack of structure (indulgence), and autonomy support reported by adolescents or parents were associated with adolescent iEO intake of junk foods, sugar-sweetened beverages (SSBs), sugary foods, and fruit and vegetables. DESIGN: Cross-sectional study measuring parenting practices and adolescent iEO food choices via an online survey and adapted food frequency questionnaire. PARTICIPANTS/SETTING: Parent/adolescent dyads (n = 622) completed surveys (November-December 2021) using a national Qualtrics panel database. Adolescents were 11 to 14 years of age and had iEOs at least weekly. MAIN OUTCOME MEASURES: Primary measures included parent- and adolescent-reported frequency of food parenting practices and adolescent-reported iEO intake of junk foods, sugary foods, SSBs, and fruits and vegetables. STATISTICAL ANALYSES PERFORMED: Multivariable linear regression models were used to examine associations between parenting practices and iEO intake of foods/beverages, adjusting for adolescent's age, sex, race and ethnicity, iEO frequency, parent's education and marital status, and household food security status. Bonferroni multiple comparison corrections were conducted. RESULTS: More than half of parents were female (66%) and 35 to 64 years of age (58%). Adolescents/parents identified as White/Caucasian (44%/42%), Black/African American (28%/27%), Asian (21%/23%), and Hispanic ethnicity (42%/42%). Positive associations were observed among adolescent-reported and parent-reported autonomy support, monitoring, indulgence and expectations parenting practices, and adolescent-reported daily iEO intake frequencies of junk foods, sugary foods, and fruits and vegetables (P < 0.001). CONCLUSIONS: Structural and autonomy support parenting practices were positively associated with both healthy and unhealthy iEO food intake by adolescents. Interventions to improve adolescent iEO intake could promote positive practices associated with healthy food consumption.

KRAS-specific antibody binds to KRAS protein inside colorectal adenocarcinoma cells and inhibits its localization to the plasma membrane.

Colorectal cancer (CRC) is the third highest incidence cancer and a leading cause of cancer mortality worldwide. To date, chemotherapeutic treatment of advanced CRC that has metastasized has a dismayed success rate of less than 30%. Further, most (80%) sporadic CRCs are microsatellite-stable and are refractory to immune checkpoint blockade therapy. KRAS is a gatekeeper gene in colorectal tumorigenesis. Nevertheless, KRAS is 'undruggable' due to its structure. Thus, focus has been diverted to develop small molecule inhibitors for its downstream effector such as ERK/MAPK. Despite intense research efforts for the past few decades, no small molecule inhibitor has been in clinical use for CRC. Antibody targeting KRAS itself is an attractive alternative. We developed a transient ex vivo patient-derived matched mucosa-tumor primary culture to assess whether anti-KRAS antibody can be internalized to bind and inactivate KRAS. We showed that anti-KRAS antibody can enter live mucosa-tumor cells and specifically aggregate KRAS in the cytoplasm, thus hindering its translocation to the inner plasma membrane. The mis-localization of KRAS reduces KRAS dwelling time at the site where it tethers to activate downstream effectors. We previously showed that expression of SOX9 was KRAS-mutation-dependent and possibly a better effector than ERK in CRC. Herein, we showed that anti-KRAS antibody treated tumor cells have less intense SOX9 cytoplasmic and nuclear staining compared to untreated cells. Our results demonstrated that internalized anti-KRAS antibody inhibits KRAS function in tumor. With an efficient intracellular antibody delivery system, this can be further developed as combinatorial therapeutics for CRC and other KRAS-driven cancers.

Community engagement in health services research on soil-transmitted helminthiasis in Asia Pacific region: Systematic review.

The research question was what studies are available that have assessed community engagement in the health services research on soil-transmitted helminths? We aimed to synthesise evidence on how communities were engaged in health services research on soil-transmitted helminths in low-and-middle-income countries of the Asia-Pacific Region. We focused on this region because soil-transmitted helminths are endemic, and their burden is significant in this region. This review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) checklist. Relevant studies were searched in health-related databases including PubMed, Ovid, and Google Scholar. We selected studies based on the selection criteria set for this review. We collected textual information about the type of health services research, the degree of community engagement, the research phases involved, and the barriers/enablers affecting community engagement in research since they are pertinent to our review question and objective. Ten studies from seven countries in the Asia Pacific region were identified for this review. Albeit with variation in the extent of their involvement, various forms of communities/groups within communities were included such as Aboriginal communities, local communities, school children and their parents, school teachers and headmasters of schools, heads of villages, religious leaders, and so on. Overall, community engagement in health services research focused on of soil-transmitted helminths was limited. Six studies (60%) had collaboration at 'developing methodology', mainly through an explanation of the objectives of the study or study process to be conducted. Seven studies (70%) revealed community participation in soil-transmitted helminths at the "data collection" stage. Only one study (10%) documented that a community leader was involved as a co-author, reflecting an involvement in 'report writing' and further 'dissemination'. Findings suggest that there were various forms of community engagement in various aspects of the health services research context. Overall, there was moderate level of participation, but there was insufficient information on the partnership between various stakeholders, which prevented in-depth analysis of the engagement. Future health services research on soil-transmitted helminth interventions needs to be carefully planned, well designed, grounded in principles of community engagement, and designed methodologically to allow in-depth participation by communities in all stages of the research.

Targeting the 'Undruggable' Driver Protein, KRAS, in Epithelial Cancers: Current Perspective.

This review summarizes recent development in synthetic drugs and biologics targeting intracellular driver genes in epithelial cancers, focusing on KRAS, and provides a current perspective and potential leads for the field. Compared to biologics, small molecule inhibitors (SMIs) readily penetrate cells, thus being able to target intracellular proteins. However, SMIs frequently suffer from pleiotropic effects, off-target cytotoxicity and invariably elicit resistance. In contrast, biologics are much larger molecules limited by cellular entry, but if this is surmounted, they may have more specific effects and less therapy-induced resistance. Exciting breakthroughs in the past two years include engineering of non-covalent KRAS G12D-specific inhibitor, probody bispecific antibodies, drug-peptide conjugate as MHC-restricted neoantigen to prompt immune response by T-cells, and success in the adoptive cell therapy front in both breast and pancreatic cancers.

Effects of plastic-derived carbon dots on germination and growth of pea (Pisum sativum) via seed nano-priming.

Seed nano-priming is a promising technology employed in the agronomic field to promote seed germination and plant growth. However, the effects of carbon dots (CDs) on plant development via seed nano-priming remain unclear. In the present study, CDs synthesized from non-biodegradable plastic wastes were adopted as a nano-priming agent for pea (Pisum sativum) seed treatment. The results demonstrated positive effects of seed priming at all CD concentrations (0.25-2 mg/mL), including accelerated seed germination rate, increased shoot and root elongation, biomass accumulation, and root moisture level compared to the control groups. Surface erosion of seed coat was observed after CD priming, which effectively promoted seed imbibition capability. CD penetration, internalization, and translocation were confirmed using transmission electron microscopy. Furthermore, the CD-plant interaction significantly enhanced seed antioxidant enzyme activity, as well as augmented root vigor, chlorophyll content, and carbohydrate content. These findings exhibit great potential of waste-derived CDs as nano-priming agents for seed germination and seedling development in a cost-effective and sustainable manner.

Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma.

Large numbers of neutrophils infiltrate tumors and comprise a notable component of the inflammatory tumor microenvironment. While it is established that tumor cells exhibit the Warburg effect for energy production, the contribution of the neutrophil metabolic state to tumorigenesis is unknown. Here, we investigated whether neutrophil infiltration and metabolic status promotes tumor progression in an orthotopic mouse model of pancreatic ductal adenocarcinoma (PDAC). We observed a large increase in the proportion of neutrophils in the blood and tumor upon orthotopic transplantation. Intriguingly, these tumor-infiltrating neutrophils up-regulated glycolytic factors and hypoxia-inducible factor 1-alpha (HIF-1α) expression compared to neutrophils from the bone marrow and blood of the same mouse. This enhanced glycolytic signature was also observed in human PDAC tissue samples. Strikingly, neutrophil-specific deletion of HIF-1α (HIF-1αΔNφ) significantly reduced tumor burden and improved overall survival in orthotopic transplanted mice, by converting the pro-tumorigenic neutrophil phenotype to an anti-tumorigenic phenotype. This outcome was associated with elevated reactive oxygen species production and activated natural killer cells and CD8+ cytotoxic T cells compared to littermate control mice. These data suggest a role for HIF-1α in neutrophil metabolism, which could be exploited as a target for metabolic modulation in cancer.