BRCA 1/BRCA 2 Pathogenic/Likely Pathogenic Variant Patients with Breast, Ovarian, and Other Cancers.

The demographic and clinical characteristics of patients who have BRCA 1/BRCA 2 pathogenic/likely pathogenic variants may differ from their relatives who had BRCA-related cancer. In this study, we aimed to demonstrate the clinical and demographic findings of patients who had BRCA-related cancer and to assess the differences comparing their relatives who had BRCA-related cancer with breast, genital tract, prostate, and pancreas cancers as well. The results of sequencing analysis of 200 cancer patients (190 women, 10 men) who have been directed to genetic counseling with an indication of BRCA1/BRCA2 testing from different regions across 9 medical oncology centers were retrospectively analyzed. A total of 200 consecutive cancer patients who harbored the BRCA1/BRCA2 pathogenic/likely pathogenic variant (130 (65%) patients harbored BRCA 1 pathogenic/likely pathogenic variant, and 70 harbored BRCA 2 pathogenic/likely pathogenic variant) were included. Of these, 64.0% had breast cancer (43.8% of them had the triple-negative disease, and about 2.3% had only the HER-2 mutant), 31.5% had genital cancers (92.1% of them had ovarian cancer, 3.2% had endometrium, and 1.6% had peritoneum cancer as the primary site and mostly serous adenocarcinoma was the most common histopathology and 14.3% of the patients had endometrioid adenocarcinoma), 3.5% had prostate (median time from metastasis to castration-resistant status was 28 months) and 1.0% had pancreas cancer. Newly diagnosed cancer (breast and ovary) patients who had BRCA 1/BRCA 2 pathogenic/ likely pathogenic variant were younger than their previous cancer diagnosed (breast, ovary, and pancreas) parents who harbored BRCA pathogenic/likely pathogenic variant. We suggest that the genetic screening of BRCA 1/ BRCA 2 pathogenic/likely pathogenic variant is needed as a routine screening for those with a personal or family history of breast, ovarian, tubal, or peritoneal cancer. In addition, once BRCA 1 or BRCA 2 germline pathogenic variant has been identified in a family, testing of at-risk next-generation relatives earlier can identify those family members who also have the familial pathogenic variant, and thus need increased surveillance.

High crossreactivity of human T cell responses between Lassa virus lineages.

Lassa virus infects hundreds of thousands of people each year across rural West Africa, resulting in a high number of cases of Lassa fever (LF), a febrile disease associated with high morbidity and significant mortality. The lack of approved treatments or interventions underscores the need for an effective vaccine. At least four viral lineages circulate in defined regions throughout West Africa with substantial interlineage nucleotide and amino acid diversity. An effective vaccine should be designed to elicit Lassa virus specific humoral and cell mediated immunity across all lineages. Most current vaccine candidates use only lineage IV antigens encoded by Lassa viruses circulating around Sierra Leone, Liberia, and Guinea but not Nigeria where lineages I-III are found. As previous infection is known to protect against disease from subsequent exposure, we sought to determine whether LF survivors from Nigeria and Sierra Leone harbor memory T cells that respond to lineage IV antigens. Our results indicate a high degree of cross-reactivity of CD8+ T cells from Nigerian LF survivors to lineage IV antigens. In addition, we identified regions within the Lassa virus glycoprotein complex and nucleoprotein that contributed to these responses while T cell epitopes were not widely conserved across our study group. These data are important for current efforts to design effective and efficient vaccine candidates that can elicit protective immunity across all Lassa virus lineages.

Identification of Common CD8+ T Cell Epitopes from Lassa Fever Survivors in Nigeria and Sierra Leone.

Early and robust T cell responses have been associated with survival from Lassa fever (LF), but the Lassa virus-specific memory responses have not been well characterized. Regions within the virus surface glycoprotein (GPC) and nucleoprotein (NP) are the main targets of the Lassa virus-specific T cell responses, but, to date, only a few T cell epitopes within these proteins have been identified. We identified GPC and NP regions containing T cell epitopes and HLA haplotypes from LF survivors and used predictive HLA-binding algorithms to identify putative epitopes, which were then experimentally tested using autologous survivor samples. We identified 12 CD8-positive (CD8+) T cell epitopes, including epitopes common to both Nigerian and Sierra Leonean survivors. These data should be useful for the identification of dominant Lassa virus-specific T cell responses in Lassa fever survivors and vaccinated individuals as well as for designing vaccines that elicit cell-mediated immunity.IMPORTANCE The high morbidity and mortality associated with clinical cases of Lassa fever, together with the lack of licensed vaccines and limited and partially effective interventions, make Lassa virus (LASV) an important health concern in its regions of endemicity in West Africa. Previous infection with LASV protects from disease after subsequent exposure, providing a framework for designing vaccines to elicit similar protective immunity. Multiple major lineages of LASV circulate in West Africa, and therefore, ideal vaccine candidates should elicit immunity to all lineages. We therefore sought to identify common T cell epitopes between Lassa fever survivors from Sierra Leone and Nigeria, where distinct lineages circulate. We identified three such epitopes derived from highly conserved regions within LASV proteins. In this process, we also identified nine other T cell epitopes. These data should help in the design of an effective pan-LASV vaccine.

Recent and rapid reef recovery around Koh Phangan Island, Gulf of Thailand, driven by plate-like hard corals.

Mass bleaching events and local anthropogenic influences have changed the benthic communities of many coral reefs with pronounced spatial differences that are linked to resilience patterns. The Gulf of Thailand is an under-investigated region with only few existing datasets containing long-term developments of coral reef communities using the same method at fixed sites. We thus analyzed benthic community data from seven reefs surrounding the island of Koh Phangan collected between 2014 and 2022. Findings revealed that the average live hard coral cover around Koh Phangan increased from 37% to 55% over the observation period, while turf algae cover decreased from 52% to 29%, indicating some recovery of local reefs. This corresponds to a mean increased rate of coral cover by 2.2% per year. The increase in live hard coral cover was mainly driven by plate-like corals, which quadrupled in proportion over the last decade from 7% to 28% while branching corals decreased in proportion from 9% to 2%. Furthermore, the hard coral genus richness increased, indicating an increased hard coral diversity. While in other reefs, increasing live hard coral cover is often attributed to fast-growing, branching coral species, considered more susceptible to bleaching and other disturbances, the reefs around Koh Phangan recovered mainly via growth of plate-like corals, particularly of the genus Montipora. Although plate-like morphologies are not necessarily more bleaching tolerant, they are important for supporting reef fish abundance and structural complexity on reefs, aiding reef recovery and sturdiness. Hence, our findings indicate that the intensity of local stressors around Kho Phangan allows reef recovery driven by some hard coral species.

Short-term ocean acidification decreases pulsation and growth of the widespread soft coral Xenia umbellata.

Coral reefs may experience lower pH values as a result of ocean acidification (OA), which has negative consequences, particularly for calcifying organisms. Thus far, the effects of this global factor have been mainly investigated on hard corals, while the effects on soft corals remain relatively understudied. We therefore carried out a manipulative aquarium experiment for 21 days to study the response of the widespread pulsating soft coral Xenia umbellata to simulated OA conditions. We gradually decreased the pH from ambient (~8.3) to three consecutive 7-day long pH treatments of 8.0, 7.8, and 7.6, using a CO2 dosing system. Monitored response variables included pulsation rate, specific growth rate, visual coloration, survival, Symbiodiniaceae cell densities and chlorophyll a content, photosynthesis and respiration, and finally stable isotopes of carbon (C) and nitrogen (N) as well as CN content. Pulsation decreased compared to controls with each consecutive lowering of the pH, i.e., 17% at pH 8.0, 26% at pH 7.8 and 32% at pH 7.6, accompanied by an initial decrease in growth rates of ~60% at pH 8.0, not decreasing further at lower pH. An 8.3 ‰ decrease of δ13C confirmed that OA exposed colonies had a higher uptake and availability of atmospheric CO2. Coral productivity, i.e., photosynthesis, was not affected by higher dissolved inorganic C availability and none of the remaining response variables showed any significant differences. Our findings suggest that pulsation is a phenotypically plastic mechanism for X. umbellata to adjust to different pH values, resulting in reduced growth rates only, while maintaining high productivity. Consequently, pulsation may allow X. umbellata to inhabit a broad pH range with minimal effects on its overall health. This resilience may contribute to the competitive advantage that soft corals, particularly X. umbellata, have over hard corals.

The widely distributed soft coral Xenia umbellata exhibits high resistance against phosphate enrichment and temperature increase.

Both global and local factors affect coral reefs worldwide, sometimes simultaneously. An interplay of these factors can lead to phase shifts from hard coral dominance to algae or other invertebrates, particularly soft corals. However, most studies have targeted the effects of single factors, leaving pronounced knowledge gaps regarding the effects of combined factors on soft corals. Here, we investigated the single and combined effects of phosphate enrichment (1, 2, and 8 µM) and seawater temperature increase (26 to 32 °C) on the soft coral Xenia umbellata by quantifying oxygen fluxes, protein content, and stable isotope signatures in a 5-week laboratory experiment. Findings revealed no significant effects of temperature increase, phosphate enrichment, and the combination of both factors on oxygen fluxes. However, regardless of the phosphate treatment, total protein content and carbon stable isotope ratios decreased significantly by 62% and 7% under temperature increase, respectively, suggesting an increased assimilation of their energy reserves. Therefore, we hypothesize that heterotrophic feeding may be important for X. umbellata to sustain their energy reserves under temperature increase, highlighting the advantages of a mixotrophic strategy. Overall, X. umbellata shows a high tolerance towards changes in global and local factors, which may explain their competitive advantage observed at many Indo-Pacific reef locations.

Late-Onset Calorie Restriction Worsens Cognitive Performances and Increases Frailty Level in Female Wistar Rats.

The current study aims to determine the potential benefits of calorie restriction (CR), one of the most promising paradigms for life span and healthspan extension, on cognitive performances in female Wistar rats during aging. As a measure of a healthspan, we evaluated the effects of different onset and duration of CR on frailty level. Female Wistar rats were exposed to either ad libitum (AL) or CR (60% of AL daily intake) food intake during aging. Two different CR protocols were used, life-long CR with an early-onset that started at the adult stage (6 months) and 3-month-long CR, started at the middle (15 months) and late-middle (21 months) age, thus defined as a late-onset CR. The effects of CR were evaluated using open-field, Y-maze, and novel object recognition tests. We broadened 2 tools for frailty assessment currently in use for experimental animals, and in alignment with our previous study, we created a physical-cognitive frailty tool that combines both physical and cognitive performances. Our results clearly showed that CR effects are highly dependent on CR duration and onset. While a life-long restriction with an early-onset has been proven as protective and beneficial, short-term restriction introduced at late age significantly worsens an animal's behavior and frailty. These results complement our previous study conducted in males and contribute to the understanding of sex differences in a response to CR during aging.

Nerve sparing-distally based sural flap.

The management of soft-tissue defects in the ankle and foot area is a challenging task. Distally based sural flap is widely used, however it leaves donor area paresthesia. For this purpose, the sural nerve was dissected and preserved in the distally based sural flap in five cases of ankle and foot soft tissue reconstruction. This modification did not cause any compromise in flap circulation. All flaps survived with one partial distal necrosis. We suggest that, the distally based nerve sparing sural flap can be securely elevated with only a 3-4 cm wide subcutaneous pedicle without any compromise in flap circulation.

A food-responsive switch modulates TFEB and autophagy, and determines susceptibility to coxsackievirus infection and pancreatitis.

Almost a billion people worldwide are chronically undernourished. Herein, using a mouse model of coxsackievirus B3 (CVB3) infection, we report that a single day of food restriction (FR) markedly increases susceptibility to attenuated enterovirus infection, replication, and disease. These "pro-viral" effects, which are rapidly-reversed by the restoration of food, are mediated by several genes whose expression is altered by FR, and which support CVB3 replication. Central to this is TFEB, a protein whose expression and activation status are rapidly increased by FR. TFEB, which regulates the transcription of >100 genes involved in macroautophagy/autophagy and lysosomal biogenesis, responds similarly to both FR and CVB3 infection and plays a pivotal role in determining host susceptibility to CVB3. We propose that, by upregulating TFEB, FR generates an intracellular environment that is more hospitable to the incoming virus, facilitating its replication. This interplay between nutritional status and enterovirus replication has implications for human health and, perhaps, for the evolution of these viruses.Abbreviations: Atg/ATG: autophagy-related; CAR: Coxsackievirus and adenovirus receptor; Cas9: CRISPR associated protein 9; Cre: recombinase that causes recombination; CRISPR: clustered regularly interspaced short palindromic repeats; Ctsb/CTSB: cathepsin B; CVB3: coxsackievirus B3; DsRedCVB3: a recombinant CVB3 that encodes the Discosoma red fluorescent protein; EL: elastase; FR: food restriction; GFP: green fluorescent protein; gRNA: guide RNA; HBSS: Hanks Buffered Salt Solution; LYNUS: lysosomal nutrient sensing machinery; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; Nluc: nanoluciferase; NlucCVB3: a recombinant CVB3 encoding nanoluciferase; pfu: plaque-forming unit(s); p.i.: post infection; rCVB: recombinant coxsackievirus B3; RPS6KB/p70S6K: ribosomal protein S6 kinase; RT: room temperature; siRNA: small interfering RNA; TFEB: transcription factor EB; tg: transgenic; TUBB: ß-tubulin; UNINF: uninfected; wrt: with respect to; WT: wild type.

Cumulative burden of clinically significant aortic stenosis in community-dwelling older adults.

OBJECTIVES: Current estimates of aortic stenosis (AS) frequency have mostly relied on cross-sectional echocardiographic or longitudinal administrative data, making understanding of AS burden incomplete. We performed case adjudications to evaluate the frequency of AS and assess differences by age, sex and race in an older cohort with long-term follow-up. METHODS: We developed case-capture methods using study echocardiograms, procedure and diagnosis codes, heart failure events and deaths for targeted review of medical records in the Cardiovascular Health Study to identify moderate or severe AS and related procedures or hospitalisations. The primary outcome was clinically significant AS (severe AS or procedure). Assessment of incident AS burden was based on subdistribution survival methods, while associations with age, sex and race relied on cause-specific survival methods. RESULTS: The cohort comprised 5795 participants (age 73±6, 42.2% male, 14.3% Black). Cumulative frequency of clinically significant AS at maximal 25-year follow-up was 3.69% (probable/definite) to 4.67% (possible/probable/definite), while the corresponding 20-year cumulative incidence was 2.88% to 3.71%. Of incident cases, about 85% had a hospitalisation for severe AS, but roughly half did not undergo valve intervention. The adjusted incidence of clinically significant AS was higher in men (HR 1.62 [95% CI 1.21 to 2.17]) and increased with age (HR 1.08 [95% CI 1.04 to 1.11]), but was lower in Blacks (HR 0.43 [95% CI 0.23 to 0.81]). CONCLUSIONS: In this community-based study, we identified a higher burden of clinically significant AS than reported previously, with differences by age, sex and race. These findings have important implications for public health resource planning, although the lower burden in Blacks merits further study.

Effects of Different Dietary Protocols on General Activity and Frailty of Male Wistar Rats During Aging.

Dietary restriction (DR) is an important experimental paradigm for lifespan and healthspan extension, but its specific contribution regarding the type, onset, and duration are still debatable. This study was designed to examine the impact of different dietary protocols by assessing the behavioral changes during aging. We exposed male Wistar rats of various age to ad libitum (AL) or DR (60 per cent of AL daily intake) feeding regimens with different onsets. The impact of DR on locomotor activity, memory, and learning was examined in 12-, 18-, and 24-month-old treated animals and controls using open field and Y-maze tests. We have also evaluated the effects of different DR's through the quantification of animal frailty, using behavioral data to create the frailty score. Our results indicated that DR improves general animal activity and spatial memory and decreases frailty with the effect being highly dependent on DR duration and onset. Notably, life-long restriction started at young age had the most profound effect. In contrast, shorter duration and later onset of restricted diet had significantly lower or no impact on animal's behavior and frailty. This study signifies the importance of DR starting point and duration as critical determinants of DR effects on healthspan.

Exertional dyspnoea in a 28-year-old woman.

CLINICAL INTRODUCTION: A 28-year-old woman with a history of critical pulmonic stenosis, status postsurgical valvotomy and subsequent pulmonary valve replacement, presented to the cardiology clinic with 1 year of progressive exertional dyspnoea. She has a heart rate of 75 bpm and blood pressure of 110/55 mm Hg. Cardiac auscultation reveals a 1/6 systolic ejection murmur along the left sternum and an early 3/6 diastolic decrescendo murmur. A transthoracic echocardiogram is obtained (figure 1). QUESTIONS: Which of the following would be most likely found during right heart catheterisation?Ratio of pulmonary to systemic blood flow (Qp:Qs) >1.5Pulmonary vascular resistance >3 Wood unitsRight atrial pressure >10mm HgPulmonary artery systolic pressure >45mm Hg E. Pulmonary artery diastolic pressure <10mm Hg.

Discrimination and Latino psychological distress: the moderating role of ethnic identity exploration and commitment.

This study sought to examine the moderating effect of ethnic identity exploration and ethnic identity commitment on the various types of discrimination and psychological distress within a sample of Latino adults (N = 397). The results revealed that ethnic identity exploration was associated with increased psychological distress within the context of discrimination in work, academic, and public settings. Ethnic identity commitment, on the other hand, served as a buffer between covert discrimination and mental health. These findings highlight the circumstances in which ethnic identity functioned as a protective and as a risk factor in the psychological distress of Latinos. The implications are discussed within a stress and coping framework and outline directions for future research.

[Influence of current smoking on adherence and responses to pulmonary rehabilitation in patients with COPD]. / Influência do tabagismo atual na aderência e nas respostas à reabilitação pulmonar em pacientes com DPOC.

OBJECTIVE: To investigate the modulating effects of current smoking on adherence and responses to pulmonary rehabilitation (PR) in patients with chronic obstructive pulmonary disease (COPD). METHODS: In a prospective study, 18 ex-smokers and 23 current smokers (GOLD stages II-III) were enrolled in a 12-week multidisciplinary, supervised PR program. The patients were assessed clinically and as to subjective variables (dyspnea and health-related quality of life) and objective variables (body composition, pulmonary function and 6-min walking distance). The degree of nicotine dependence in current smokers was assessed by the Fagerström test. Program completion defined PR 'adherence'. RESULTS: There was a significant association between current smoking and non-adherence to PR with 30.4% vs. 11.1% and odds ratio=2.9 (1.6-4.1; p<0.01). However, the current smokers who completed the program (n=16) had a similar absentee rate to the ex-smokers, as well as similar gains in the subjective (quality of life) and objective (walked distance) items. Additionally, there was a significant reduction in daily cigarette consumption and in the degree of nicotine dependence in current smokers (p<0.05). CONCLUSIONS: Although current smoking is negatively related to PR adherence, COPD smokers who complete the PR can have similar gains in functionality and quality of life compared to ex-smokers. Moreover, PR may be related to decreased nicotine dependence, even without a formal smoking withdrawal program.

Sulfated polysaccharide extracted of the green algae Caulerpa racemosa increase the enzymatic activity and paw edema induced by sPLA2 from Crotalus durissus terrificus venom

Sulfated polysaccharides derived from seaweed have shown great potential for use in the development of new drugs. In this study, we observed that a low-molecular-weight sulfated polysaccharide from Caulerpa racemosa, termed CrSP, could interact with secretory phospholipase A2 (sPLA2) isolated from Crotalus durissus terrificus venom. When native sPLA2 (14 kDa) was incubated with CrSP, they formed a molecular complex (sPLA2:CrSP) with a molecular mass of 32 kDa, approximately. Size exclusion chromatography experiments suggested that CrSP formed a stable complex with sPLA2. We belived that sPLA2 and SPCr are involved an ionic interaction between negatively charged CrSP and the positively charged basic amino acid residues of sPLA2, because this interaction induced significant changes in sPLA2 enzymatic and pharmacological activities. CrSP caused a significant increase in sPLA2 enzymatic and bactericidal activity and increased its edematogenic effect. A pharmacological assay showed that the myotoxic activity of sPLA2:CrSP is unrelated to its enzymatic activity and that sPLA2:CrSP may have a practical application as a natural antibacterial agent for use in humans and commercially raised animals.

Influência do tabagismo atual na aderência e nas respostas à reabilitação pulmonar em pacientes com DPOC / Influence of current smoking on adherence and responses to pulmonary rehabilitation in patients with COPD

OBJETIVO: Investigar o possível efeito modulador do tabagismo atual na aderência e nos efeitos da reabilitação pulmonar (RP) em pacientes com doença pulmonar obstrutiva crônica (DPOC). MÉTODOS: Em um estudo prospectivo, 18 pacientes ex-tabagistas e 23 tabagistas atuais (GOLD estádios II-IV) foram incluídos num programa multidisciplinar de RP com duração de 12 semanas. Os pacientes foram submetidos à avaliação clínica e à de variáveis subjetivas (dispneia e qualidade de vida) e objetivas (composição corporal, função pulmonar e teste da caminhada de 6 minutos). Nos pacientes tabagistas, obteve-se o nível de dependência da nicotina pela escala de Fagerstrõm. A interrupção da RP antes do término previsto foi considerada indicativa de não aderência ao programa. RESULTADOS: A proporção de pacientes não-aderentes à RP foi maior nos tabagistas do que nos ex-tabagistas (30,4 por cento vs 11,1 por cento, respectivamente; razão de chance=2,9 (1,6-4,1); p<0,01). Entretanto, os tabagistas atuais que completaram o programa (n=16) apresentaram taxa de absenteísmo à RP similar ao observado nos ex-tabagistas, assim como ganhos equivalentes nas respostas subjetivas (qualidade de vida) e objetivas (distância caminhada). Adicionalmente, houve redução significante no número de cigarros consumidos diariamente e no grau de dependência da nicotina nos tabagistas atuais (p<0,05). CONCLUSÕES: Embora o tabagismo atual reduza a aderência à RP, pacientes tabagistas com DPOC que completam tais programas apresentam ganhos funcionais e na qualidade de vida equivalentes aos observados nos ex-tabagistas. A RP, mesmo sem um programa estruturado de cessação do tabagismo, pode associar-se com redução, ao menos a curto prazo, da dependência da nicotina.

OBJECTIVE: To investigate the modulating effects of current smoking on adherence and responses to pulmonary rehabilitation (PR) in patients with chronic obstructive pulmonary disease (COPD). METHODS: In a prospective study, 18 ex-smokers and 23 current smokers (GOLD stages II-III) were enrolled in a 12-week multidisciplinary, supervised PR program. The patients were assessed clinically and as to subjective variables (dyspnea and health-related quality of life) and objective variables (body composition, pulmonary function and 6-min walking distance). The degree of nicotine dependence in current smokers was assessed by the Fagerstrõm test. Program completion defined PR "adherence". RESULTS: There was a significant association between current smoking and non-adherence to PR with 30.4 percent vs. 11.1 percent and odds ratio=2.9 (1.6-4.1; p<0.01). However, the current smokers who completed the program (n=16) had a similar absentee rate to the ex-smokers, as well as similar gains in the subjective (quality of life) and objective (walked distance) items. Additionally, there was a significant reduction in daily cigarette consumption and in the degree of nicotine dependence in current smokers (p<0.05). CONCLUSIONS: Although current smoking is negatively related to PR adherence, COPD smokers who complete the PR can have similar gains in functionality and quality of life compared to ex-smokers. Moreover, PR may be related to decreased nicotine dependence, even without a formal smoking withdrawal program.