Ursolic acid interaction with transcription factors BRAF, V600E, and V600K: a computational approach towards new potential melanoma treatments.

CONTEXT: Melanoma is one of the cancers with the highest mortality rate for its ability to metastasize. Several targets have undergone investigation for the development of drugs against this pathology. One of the main targets is the kinase BRAF (RAF, rapidly accelerated fibrosarcoma). The most common mutation in melanoma is BRAFV600E and has been reported in 50-90% of patients with melanoma. Due to the relevance of the BRAFV600E mutation, inhibitors to this kinase have been developed, vemurafenib-OMe and dabrafenib. Ursolic acid (UA) is a pentacyclic triterpene with a privileged structure, the pentacycle scaffold, which allows to have a broad variety of biological activity; the most studied is its anticancer capacity. In this work, we reported the interaction profile of vemurafenib-OMe, dabrafenib, and UA, to define whether UA has binding capacity to BRAFWT, BRAFV600E, and BRAFV600K. Homology modeling of BRAFWT, V600E, and V600K; molecular docking; and molecular dynamics simulations were carried out and interactions and residues relevant to the binding of the inhibitors were obtained. We found that UA, like the inhibitors, presents hydrogen bond interactions, and hydrophobic interactions of van der Waals, and π-stacking with I463, Q530, C532, and F583. The ΔG of ursolic acid in complex with BRAFV600K (- 63.31 kcal/mol) is comparable to the ΔG of the selective inhibitor dabrafenib (- 63.32 kcal/mol) in complex to BRAFV600K and presents a ΔG like vemurafenib-OMe with BRAFWT and V600E. With this information, ursolic acid could be considered as a lead compound for design cycles and to optimize the binding profile and the selectivity towards mutations for the development of new selective inhibitors for BRAFV600E and V600K to new potential melanoma treatments. METHODS: The homology modeling calculations were executed on the public servers I-TASSER and ROBETTA, followed by molecular docking calculations using AutoGrid 4.2.6, AutoDockGPU 1.5.3, and AutoDockTools 1.5.6. Molecular dynamics and metadynamics simulations were performed in the Desmond module of the academic version of the Schrödinger-Maestro 2020-4 program, utilizing the OPLS-2005 force field. Ligand-protein interactions were evaluated using Schrödinger-Maestro program, LigPlot + , and PLIP (protein-ligand interaction profiler). Finally, all of the protein figures presented in this article were made in the PyMOL program.

Tooth loss in breast cancer patients: A comparison between tamoxifen-treated and non-treated patients.

BACKGROUND: Tooth loss (TL) affects quality of life and general health. The literature suggesting that tamoxifen treatment in patients with breast cancer (BC) could be associated with alterations in oral health, increasing the risk of TL, is still scarce. This work aimed to determine the relationship between TL and tamoxifen consumption in patients with BC. MATERIAL AND METHODS: This cross-sectional observational study was carried out from July to September 2023 in the medical oncology services of the "Virgen de la Puerta" - ESSALUD High Complexity Hospital and "Dr. Luis Pinillos Ganoza" - IREN Norte - Regional Institute of Neoplastic Diseases, in Trujillo - Peru. Overall, 200 adult patients diagnosed with BC were evaluated, of which 100 consumed tamoxifen and 100 did not. Inter- and intra-rater reliability was determined with respect to TL, resulting in intra-class correlation values RHO = 0.971 and interclass RHO = 0.938. The oncologist of the corresponding service performed BC diagnosis and stage. Poisson regression was used to analyze results with a significance level of p<0.05. RESULTS: No relationship was found between TL and tamoxifen consumption in patients with breast cancer (p= 0.221); however, greater TL was observed in women who consumed tamoxifen for more than one year compared to those who did not use it (p=0.025) and in older adult women compared to young women (p=0.030). CONCLUSIONS: There is a relationship between TL and time of use of tamoxifen in patients with BC, concluding that patients who consumed tamoxifen for more than one year had greater TL than those who did not. Furthermore, no relationship was found between TL and cancer stages, but there was greater TL in older adult patients and also in those who consumed tamoxifen and did not receive chemotherapy or radiotherapy.

Diagnosing low-mode (ℓ < 6) and mid-mode (6 ≤ ℓ ≤ 60) asymmetries in the post-stagnation phase of laser-direct-drive deuterium-tritium cryogenic implosions on OMEGA.

Low- and mid-mode perturbations are possible candidates for performance limitations in cryogenic direct-drive implosions on the OMEGA laser at the Laboratory of Laser Energetics. Simulations with a 3D hydrocode demonstrated that hotspot imagers do not show evidence of the shell breakup in the dense fuel. However, these same simulations revealed that the low- and mid-mode perturbations in the dense fuel could be diagnosed more easily in the post-stagnation phase of the implosion by analyzing the peak in the x-ray emission limb at the coronal-fuel interface than before or at the stagnation phase. In experiments, the asymmetries are inferred from gated images of the x-ray emission of the implosion by using a 16-pinhole array imager filtered to record x-ray energies >800 eV and an x-ray framing camera with 40-ps time integration and 20-µm spatial resolution. A modal analysis is applied to the spatial distribution of the x-ray emission from deuterium and tritium cryogenic implosions on OMEGA recorded after the bang time to diagnose the low- and mid-mode asymmetries, and to study the effect that the beam-to-target ratio (Rb/Rt) has on the shell integrity.

Diagnosis of the imploding shell asymmetry in polar-direct-drive deuterium-tritium cryogenic target implosions on OMEGA.

We discuss the analyses of gated, x-ray imaging data from polar-direct-drive experiments with cryogenically layered deuterium-tritium targets on the OMEGA laser. The in-flight shell asymmetries were diagnosed at various times during the implosion, which was caused by the beam pointing geometry and preimposed variations in the energy partition between the different groups of laser beams. The shape of the ablation surface during the acceleration phase of the implosion was measured along two different lines of sight, and a Legendre mode (ℓ-mode) decomposition was applied for modes of up to ten to investigate shell asymmetries. A clear causal relationship between the imposed beam imbalance and the shape of the in-flight shell asymmetries was observed. The imploded shell with a balanced energy ratio shows smaller values of the amplitudes of ℓ-mode 2 compared to that from implosions with an imbalanced ring energy ratio. The amplitudes of ℓ-modes 4 and 6 are the same within the measurement uncertainty with respect to the change in beam energy ratio.

Plant-Rich Field Margins Influence Natural Predators of Aphids More Than Intercropping in Common Bean.

Field margins support important ecosystem services including natural pest regulation. We investigated the influence of field margins on the spatial and temporal distribution of natural enemies (NEs) of bean pests in smallholder farming systems. We sampled NEs from high and low plant diversity bean fields using sweep netting and coloured sticky traps, comparing monocropped and intercropped farms. NEs collected from within crops included predatory bugs, lacewings, predatory flies, parasitic flies, parasitic wasps, lady beetles, and a range of other predatory beetles; with the most dominant group being parasitic wasps. Overall, high plant diversity fields had a higher number of NEs than low-diversity fields, regardless of sampling methods. The field margin had a significantly higher number of lacewings, parasitic wasps, predatory bugs, syrphid flies, and other predatory beetles relative to the crop, but beneficial insects were collected throughout the fields. However, we observed marginally higher populations of NEs in intercropping than in monocropping although the effect was not significant in both low and high plant diversity fields. We recommend smallholder farmers protect the field margins for the added benefit of natural pest regulation in their fields.

Field Margin Plants Support Natural Enemies in Sub-Saharan Africa Smallholder Common Bean Farming Systems.

Flower-rich field margins provide habitats and food resources for natural enemies of pests (NEs), but their potential, particularly in the tropics and on smallholder farms, is poorly understood. We surveyed field margins for plant-NE interactions in bean fields. NEs most often interacted with Bidens pilosa (15.4% of all interactions) and Euphorbia heterophylla (11.3% of all interactions). In cage trials with an aphid-infested bean plant and a single flowering margin plant, the survival of Aphidius colemani, the most abundant parasitoid NE in bean fields, was greater in the presence of Euphorbia heterophylla than Bidens pilosa, Tagetes minuta, and Hyptis suaveolens. UV-fluorescent dye was applied to flowers of specific field margin plant species and NE sampled from within the bean crop and field margins using sweep-netting and pan-traps respectively. Captured insects were examined for the presence of the dye, indicative of a prior visit to the margin. Lady beetles and assassin bugs were most abundant in plots with B. pilosa margins; hoverflies with T. minuta and Parthenium hysterophorus margins; and lacewings with T. minuta and B. pilosa margins. Overall, NE benefitted from field margin plants, and those possessing extra floral nectaries had an added advantage. Field margin plants need careful selection to ensure benefits to different NE groups.

Natural Pest Regulation and Its Compatibility with Other Crop Protection Practices in Smallholder Bean Farming Systems.

Common bean (Phaseolus vulgaris) production and storage are limited by numerous constraints. Insect pests are often the most destructive. However, resource-constrained smallholders in sub-Saharan Africa (SSA) often do little to manage pests. Where farmers do use a control strategy, it typically relies on chemical pesticides, which have adverse effects on the wildlife, crop pollinators, natural enemies, mammals, and the development of resistance by pests. Nature-based solutions -in particular, using biological control agents with sustainable approaches that include biopesticides, resistant varieties, and cultural tools-are alternatives to chemical control. However, significant barriers to their adoption in SSA include a lack of field data and knowledge on the natural enemies of pests, safety, efficacy, the spectrum of activities, the availability and costs of biopesticides, the lack of sources of resistance for different cultivars, and spatial and temporal inconsistencies for cultural methods. Here, we critically review the control options for bean pests, particularly the black bean aphid (Aphis fabae) and pod borers (Maruca vitrata). We identified natural pest regulation as the option with the greatest potential for this farming system. We recommend that farmers adapt to using biological control due to its compatibility with other sustainable approaches, such as cultural tools, resistant varieties, and biopesticides for effective management, especially in SSA.

Observations of anomalous x-ray emission at early stages of hot-spot formation in deuterium-tritium cryogenic implosions.

In deuterium-tritium cryogenic implosions, hot-spot x-ray self-emission is observed to begin at a larger shell radius than is predicted by a one-dimensional radiation-hydrodynamic implosion model. Laser-imprint is shown to explain the observation for a low-adiabat implosion. For more-stable implosions the data are not described by the imprint model and suggest there are additional sources of decompression of the dense fuel.

Global transcriptome analysis provides new insights in Thellungiella salsuginea stress response.

Thellungiella salsuginea is highly tolerant to abiotic stress, while its a close relative Arabidopsis thaliana is sensitive to stress. This characteristic makes T. salsuginea an excellent model for uncovering the mechanisms of abiotic stress tolerance. Abscisic acid (ABA) plays essential roles in plant abiotic and biotic stress tolerance. To test the changes in gene expression of T. salsuginea under ABA treatment, in this study, the transcriptomes of T. salsuginea roots and leaves were compared in response to exogenously application of ABA. The results showed that ABA treatment caused different expression of 2,200 and 3,305 genes in leaves and roots, respectively, compared with the untreated control. In particular, genes encoding transcription factors such as WRKY, MYB, NAC, GATA, ethylene-responsive factors (ERFs), heat stress transcription factors, basic helix-loop-helix, PLATZ and B3 domain-containing family members were enriched. In addition, 49 and 114 differentially expressed genes were identified as ABA-regulated genes, separately in leaves and roots, respectively, which were related to biotic and abiotic stresses. The expression levels of some genes were validated by qRT-PCR. Different responses of genes to ABA treatment were discovered in T. salsuginea and A. thaliana. This transcriptome analysis expands our understanding of the role of ABA in stress tolerance in T. salsuginea. Our study provides a wealth of information for improving stress tolerance in crop plants.

Cloning and characterization of SPL-family genes in the peanut (Arachis hypogaea L.).

SQUAMOSA promoter-binding protein-like (SPL) proteins play crucial roles in plant growth, development, and responses to environmental stressors. The peanut (Arachis hypogaea L.) is a globally important oil crop. In this study, we cloned the full-length cDNA of 15 SPLs in the peanut by transcriptome sequencing and rapid amplification of cDNA ends, and analyzed their genomic DNA sequences. cDNA lengths varied significantly, from 369 to 3102 bp. The SBP domain of the peanut SPL proteins was highly conserved compared to SPLs in other plant species. Based on their sequence similarity to SPLs from other plant species, the peanut SPLs could be grouped into five subgroups. In each subgroup, lengths of individual genes, conserved motif numbers, and distribution patterns were similar. Seven of the SPLs were predicted to be targets of miR156. The SPLs were ubiquitously expressed in the roots, leaves, flowers, gynophores, and seeds, with different expression levels and accumulation patterns. Significant differences in the expression of most of the SPLs were observed between juvenile and adult leaves, suggesting that they are involved in developmental regulation. Dynamic changes occurred in transcript levels at stage 1 (aerial grown green gynophores), stage 2 (gynophores buried in soil for about three days), and stage 3 (gynophores buried in soil for about nine days with enlarged pods). Possible roles that these genes play in peanut pod initiation are discussed.

The effects of establishment practices, knowledge and attitudes on condom use among Filipina sex workers.

The findings for a baseline assessment for a community-based HIV/STD prevention intervention for commercial sex workers (CSWs) and managers of the establishments that employ them in the Philippines is presented in this study. CSW knowledge, attitudes, behaviours and establishment policies concerning HIV prevention were assessed. Baseline assessments are part of an iterative process that will be used to modify the planned intervention. The preliminary findings point to the importance of an intervention that stresses changes in establishment policies and expectations as a means of reducing risk behaviours associated with HIV/STD transmission.

PIP: As of May 1996, 1025 HIV-infected individuals had been identified in the Philippines, 260 of whom had AIDS. However, in the Philippines' total population of 65 million, approximately 18,000 adults are estimated to carry HIV. Unprotected sex and multiple partners place prostitutes at risk of contracting and transmitting HIV and other STDs. There are 65,000 registered prostitutes and 200,000 or more freelance sex workers in the Philippines. 1394 registered prostitutes, of whom 98.6% were female, were recruited from commercial sex work establishments in 4 sites about 400 miles from Manila for participation in a study assessing prostitutes' knowledge, attitudes, behaviors, and establishment policies concerning HIV prevention. The participants were aged 15-54 of mean age 23.5 years. Establishment policies and practices appear to be more important than prostitutes' knowledge of HIV transmission or their attitudes toward condoms. Any intervention to prevent HIV/STD among prostitutes in the Philippines should therefore consider and possibly target sex work establishments' policies.

Prenatal tetanus immunization and other practices associated with neonatal tetanus.

The relationship between neonatal tetanus (NT) on one hand, and maternal tetanus immunization and other prenatal and natal practices on the other hand, was examined in a case-control study done at San Lazaro Hospital (SLH) in Manila from late 1990 to mid 1991. Included as cases were 54 patients diagnosed as NT on the basis of WHO criteria, and 50 controls who were patients 0-4 months of age, hospitalized at SLH during the study period and with no past history of tetanus. The result showed that the following were statistically associated with the risk of NT: home delivery (OR = 30.5); delivered by a traditional birth attendant (OR = 5.2); use of instrument other than scissors to cut the cord (OR = 19.3); traditional birth attendant who dressed the cord (OR = 12.7); and having less than two doses of tetanus toxoid (OR = 15.3). The need to intensify prenatal tetanus immunization, health education of the mothers as well as the training of birth attendants is evident from this study if NT has to be prevented.

[The reproductive characteristics of adolescents and young adults in Mexico City]. / Características reproductivas de adolescentes y jóvenes en la Ciudad de México.

This article presents the preliminary findings of the Survey on Teenagers and Youth Reproductive Behavior in the Metropolitan Area of Mexico City, which contains information on 1,010 teenagers and young adults from 10 to 25 years of age interviewed in 1987. The average age was 17 years; 51.7 per cent of those interviewed were male and 48.3 per cent were female. A total of 14.6 per cent were married, being the average age at marriage 19.2 years for males and 17.8 years for females. Menarche occurred at an average age of 12.4 years, and spermarche at 14. Of those interviewed, 32.7 per cent have had sexual intercourse at least once in their lives. The average age at which sexual activity had begun, in the case of males, was 16 years and for females, 17 years. Of this group, 33.8 per cent stated that they had used some form of contraception during the first sexual intercourse; the contraceptive methods used most often were rhythm and withdrawal. The main source of supply of other methods is the pharmacy, in 67 per cent. 18.4 per cent of women had been pregnant, and 20.4 per cent of men's partners had presented this same condition. The first pregnancy occurred at 17.8 years for women and 18.7 for men. Of those men and women with a pregnancy experience 66.1 per cent and 57.3 per cent, respectively, stated that their first pregnancy was an unplanned one. Also, first pregnancy was related to their first marriage in 48.1 per cent of women and 82.4 per cent of male. The data presented here will reinforce current knowledge and will enable us to obtain a profile of the reproductive behavior of teenagers and young adults in the metropolitan area of Mexico City.

Frequency of glucose-6-phosphate dehydrogenase (G6PD) mutations in Chinese, Filipinos, and Laotians from Hawaii.

In a Hawaii Hereditary Anemia Screening Project, 4,984 participants were tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency by a filter paper blood spot fluorescence test. Abnormal samples and suspected heterozygotes were checked by quantitative G6PD assay (normal 4.5 to 14 units/g Hb). G6PD was deficient (< 1.5 units/g Hb) in 188 of 2,155 males; 7 other males had low activity (1.5 to 2.8 units/g Hb). The gene frequency, estimated from males after excluding referred and related cases, was 0.037 for Chinese, 0.134 for Filipinos, and 0.203 for Laotians. Among 2,829 females tested, family data showed 111 females were obliged to be at least heterozygous, regardless of G6PD activity, and 43 others had low G6PD activity. Most heterozygotes probably remained undetected by G6PD screening. In 28 females, activity was under 10%; in another 9 females, activity was < 1.5 units/g Hb. Since only 25 homozygotes would be predicted, this apparent excess of females with deficient activity could be due to unequal X-inactivation in some heterozygotes. DNA analysis by polymerase chain reaction amplification and special analytic procedures revealed 10 different missense mutations in 75 males. The nucleotide 835 A-->T and 1360 C-->T transitions were first detected in this Hawaiian Project; we found that the nucleotide 1360 mutation was the most common cause of G6PD deficiency in Filipinos. This is the first report of G6PD screening and analysis of molecular G6PD mutations in Filipino and Laotian populations.

[An evaluation of the quality of medical care for hypertensive patients. A review of the record of explicit criteria and standards in the clinics of the District of Lisbon]. / Avaliação da qualidade dos cuidados médicos em hipertensos. Observação do registo de critérios explícitos e normativos em clínicos do distrito de Lisboa.

Cardiovascular and in particular cerebrovascular diseases are the most significant in mortality in Portugal, as well as in Lisbon. Arterial hypertension is the highest and most prevalent risk factor for cardiovascular diseases, the most important predictor of life span and apparently easy to control. A descriptive study has been made through observation of the clinical procedures, from the record of the explicit normative criteria used in identified hypertensive people aged between forty five and sixty four years. From the analysis of the results we may confirm that 28% of the studied hypertensive individuals had a complete diagnostical process, 48% has a complete following process and 41% had controlled arterial hypertension. The possible justifications for these values are the adherence of the ill individuals to vigilance, the undervalue of risk factors by health professionals or even the fact that the family doctor, due to his deep knowledge of the individual, neglects the records of the observations already made.

Hygiene behaviour and hospitalized severe childhood diarrhoea: a case-control study.

The relationship between personal and domestic hygiene behaviour and hospitalized childhood diarrhoea was examined in a case-control study of 356 cases and 357 controls from low-income families in metropolitan Manila. Indices of hygiene behaviour were defined for overall cleanliness, kitchen hygiene, and living conditions. Only the indices for overall cleanliness and kitchen hygiene were significantly associated with diarrhoea. An increasing excess risk of hospitalization with severe diarrhoea was noted as the ratings for standards of hygiene became lower, and this excess risk persisted even after controlling for confounding variables. The implications of our findings for the control of diarrhoeal disease are discussed.

PIP: Between April and October, 1989, professors from the College of Public Health at the University of the Philippines in Manila compared data on 356 5-year-old children living in Manila, who had been admitted to a government hospital with diarrhea of 7 days duration, with data on 357 age and neighborhood matched controls to study the relationship between personal and domestic hygiene behavior and hospitalized severe childhood diarrhea. To address selection bias, the researchers chose controls who could potentially use the hospital services. All the children were from low-income families. As standards of hygiene for overall cleanliness and kitchen hygiene fell, the risk of severe diarrhea increased. Specifically, children in the group with a middle score in overall cleanliness acquired severe diarrhea at 2 times the rate as those with a low score (i.e. better hygienic conditions). Those in the high score group acquired it at 3.9 times the rate as those in the low score group. For kitchen hygiene, the odds ratios were 2.7 and 5.3, respectively. Living conditions did not influence the rate of diarrhea. Living conditions included inside and outside sanitary conditions, number of rooms, and presence or lack of a dining table. These findings suggested that effective health education programs aimed to change hygiene behavior could prevent severe diarrhea. Therefore, public health programs should develop suitable interventions for the education of mothers and of the general public.

[Contraceptive practices among adolescents and youths of the metropolitan area of Mexico City]. / Práctica anticonceptiva en adolescentes y jóvenes del área metropolitana de la Ciudad de México.

The purpose of this article is to provide a brief description of the information that the adolescent and youth population of Mexico City has concerning the knowledge and use of contraceptive methods, as well as the reasons why they do not adopt some contraceptive method during their sexual relations. The data obtained from the Survey on Adolescent and Youth Reproductive Behavior in the Metropolitan Area of Mexico City serves as a basis for pointing out several behavior patterns of the male and female population from 10 to 25 years of age. Of those interviewed, 32.7 per cent had had at least one sexual contact; the average age at which sexual relations had begun was 16 years for males and 17 for females. A total of 33.8 per cent of those who had had sexual contact stated that they had used some form of contraception, the principal methods used during first sexual intercourse being rhythm (36.9%); withdrawal (23.6%), and condoms (12.3%). The reasons for not using any contraceptive method were as follows: lack of knowledge regarding the methods, how to use them or where to obtain them (39.4%), and unplanned sexual intercourse (28.9%). During the last sexual contact they had, 70.5 per cent had used a contraceptive. The methods most frequently used were hormonal contraceptives and IUD (40.9%); rhythm (23.8%), and withdrawal and condoms. The reasons why no contraceptive was used in the last sexual contact were: neither partner thought that pregnancy would occur (27.1%) and the sexual contact was unplanned.

The potential of the case-control method for rapid epidemiological assessment.

Over the past few decades, the case-control method has been mostly applied to risk-factor studies of chronic diseases. Recently, among its new applications is the use of the method to study the health effect of improvements in sanitation and water supply. The methodological considerations, prospects and constraints of the method for rapid assessment are reviewed.

PIP: It has been proposed that case-control studies be used to evaluate the health impact of sanitation and water supply improvement programs upon diarrheal disease. Experimental and still in need of field studies for further substantiation, methodological considerations, prospects, and constraints of this rapid assessment method are reviewed. Drawing from a clinic-based case-control study in Cebu, a peri-urban area of the Philippines, the paper discusses the issues of methodological approach, study site, study period, sample size, potential sources of bias, and comparing findings from field studies. Case-control studies have the advantages of requiring only a single round of data collection over a short period, while yielding better quality information on disease status. This approach also avoids some ethical problems associated with quasi-experimental designs. These studies do not, however, permit examination of the effect of exposure upon more than 1 outcome, and are inappropriate for situations in which exposure is rare. Case-control studies are also highly vulnerable to bias. In closing, the paper concludes that this method could save time and money over prospective designs in rapid assessment without sacrificing a study's integrity. Case-control studies are, nonetheless, complicated with heavy demands for trained manpower and logistical support. Accordingly, they are presently best suited for urban areas. Steps toward procedural and method design simplification are needed, with care taken to safeguard the method's quality and applicability.