Chordoma cancer stem cell subpopulation characterization may guide targeted immunotherapy approaches to reduce disease recurrence.

Introduction: Cancer stem cells (CSCs), a group of tumor-initiating and tumor-maintaining cells, may be major players in the treatment resistance and recurrence distinctive of chordoma. Characterizing CSCs is crucial to better targeting this subpopulation. Methods: Using flow cytometry, six chordoma cell lines were evaluated for CSC composition. In vitro, cell lines were stained for B7H6, HER2, MICA-B, ULBP1, EGFR, and PD-L1 surface markers. Eighteen resected chordomas were stained using a multispectral immunofluorescence (mIF) antibody panel to identify CSCs in vivo. HALO software was used for quantitative CSC density and spatial analysis. Results: In vitro, chordoma CSCs express more B7H6, MICA-B, and ULBP1, assessed by percent positivity and mean fluorescence intensity (MFI), as compared to non-CSCs in all cell lines. PD- L1 percent positivity is increased by >20% in CSCs compared to non-CSCs in all cell lines except CH22. In vivo, CSCs comprise 1.39% of chordoma cells and most are PD-L1+ (75.18%). A spatial analysis suggests that chordoma CSCs cluster at an average distance of 71.51 mm (SD 73.40 mm) from stroma. Discussion: To our knowledge, this study is the first to identify individual chordoma CSCs and describe their surface phenotypes using in vitro and in vivo methods. PD-L1 is overexpressed on CSCs in chordoma human cell lines and operative tumor samples. Similarly, potential immunotherapeutic targets on CSCs, including B7H6, MICA-B, ULBP1, EGFR, and HER2 are overexpressed across cell lines. Targeting these markers may have a preferential role in combating CSCs, an aggressive subpopulation likely consequential to chordoma's high recurrence rate.

Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation.

Primary mitochondrial diseases result from mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) genes, encoding proteins crucial for mitochondrial structure or function. Given that few disease-specific therapies are available for mitochondrial diseases, novel treatments to reverse mitochondrial dysfunction are necessary. In this work, we explored new therapeutic options in mitochondrial diseases using fibroblasts and induced neurons derived from patients with mutations in the GFM1 gene. This gene encodes the essential mitochondrial translation elongation factor G1 involved in mitochondrial protein synthesis. Due to the severe mitochondrial defect, mutant GFM1 fibroblasts cannot survive in galactose medium, making them an ideal screening model to test the effectiveness of pharmacological compounds. We found that the combination of polydatin and nicotinamide enabled the survival of mutant GFM1 fibroblasts in stress medium. We also demonstrated that polydatin and nicotinamide upregulated the mitochondrial Unfolded Protein Response (mtUPR), especially the SIRT3 pathway. Activation of mtUPR partially restored mitochondrial protein synthesis and expression, as well as improved cellular bioenergetics. Furthermore, we confirmed the positive effect of the treatment in GFM1 mutant induced neurons obtained by direct reprogramming from patient fibroblasts. Overall, we provide compelling evidence that mtUPR activation is a promising therapeutic strategy for GFM1 mutations.

Assessment, distribution, and ecological risk of contaminants of emerging concern in a surface water-sediment-fish system impacted by wastewater.

The presence of contaminants of emerging concern in aquatic ecosystems represents an ever-increasing environmental problem. Aquatic biota is exposed to these contaminants, which can be absorbed and distributed to their organs. This study focused on the assessment, distribution, and ecological risk of 32 CECs in a Spanish river impacted by effluents from a wastewater treatment plant, analyzing the organs and plasma of common carp. Environmental concentrations in water and sediment were examined at sites upstream and downstream of the wastewater treatment plant. The two downstream sites showed 15 times higher total concentrations (12.4 µg L-1 and 30.1 µg L-1) than the two upstream sites (2.08 µg L-1 and 1.66 µg L-1). Half of the CECs were detected in fish organs, with amantadine having the highest concentrations in the kidney (158 ng g-1 w.w.) and liver (93 ng g-1 w.w.), followed by terbutryn, diazepam, and bisphenol F in the brain (50.2, 3.82 and 1.18 ng g-1 w.w.). The experimental bioaccumulation factors per organ were compared with the bioconcentration factors predicted by a physiologically based pharmacokinetic model, obtaining differences of one to two logarithmic units for most compounds. Risk quotients indicated a low risk for 38 % of the contaminants. However, caffeine and terbutryn showed an elevated risk for fish. The mixed risk quotient revealed a medium risk for most of the samples in the three environmental compartments: surface water, sediment, and fish.

Comprehensive comparative analysis of the periodontal pathogen Porphyromonas gingivalis: exploring the pan-genome, the reconstruction of the gene regulatory network and genome-scale metabolic network.

Porphyromonas gingivalis is a nonmotile, obligate anaerobic, Gram-negative bacterium known for its association with periodontal disease and its involvement in systemic diseases such as atherosclerosis, cardiovascular disease, colon cancer and Alzheimer's disease. This bacterium produces several virulence factors, including capsules, fimbriae, lipopolysaccharides, proteolytic enzymes and hemagglutinins. A comparative genomic analysis revealed the open pangenome of P. gingivalis and identified complete type IV secretion systems (T4SS) in strain KCOM2805 and almost complete type VI secretion systems (T6SS) in strains KCOM2798 and ATCC49417, which is a new discovery as previous studies did not find the proteins involved in secretion systems IV and VI. Conservation of some virulence factors between different strains was observed, regardless of their genetic diversity and origin. In addition, we performed for the first time a reconstruction analysis of the gene regulatory network (GRN), identifying transcription factors and proteins involved in the regulatory mechanisms of bacterial pathogenesis. In particular, QseB regulates the expression of hemagglutinin and arginine deaminase, while Rex may suppress the release of gingipain through interactions with PorV and the formatum/nitrate transporter. Our study highlights the central role of conserved virulence factors and regulatory pathways, particularly QseB and Rex, in P. gingivalis and provides insights into potential therapeutic targets.

Prognostic value of myocardial flow reserve vs corrected myocardial flow reserve in patients without obstructive coronary artery disease.

BACKGROUND: Myocardial flow reserve (MFR) by positron emission tomography (PET) is a validated measure of cardiovascular risk. Elevated resting rate pressure product (RPP = heart rate x systolic blood pressure) can cause high resting myocardial blood flow (MBF), resulting in reduced MFR despite normal/near-normal peak stress MBF. When resting MBF is high, it is not known if RPP-corrected MFR (MFRcorrected) helps reclassify CV risk. We aimed to study this question in patients without obstructive coronary artery disease (CAD). METHODS: We retrospectively studied patients referred for rest/stress cardiac PET at our center from 2006 to 2020. Patients with abnormal perfusion (summed stress score >3) or prior coronary artery bypass grafting (CABG) were excluded. MFRcorrected was defined as stress MBF/corrected rest MBF where corrected rest MBF = rest MBF x 10,000/RPP. The primary outcome was major cardiovascular events (MACE): cardiovascular death or myocardial infarction. Associations of MFR and MFRcorrected with MACE were assessed using unadjusted and adjusted Cox regression. RESULTS: 3276 patients were followed for a median of 7 (IQR 3-12) years. 1685 patients (51%) had MFR <2.0, and of those 366 (22%) had an MFR ≥2.0 after RPP correction. MFR <2.0 was associated with an increased absolute risk of MACE (HR 2.24 [1.79-2.81], P < 0.0001). Among patients with MFR <2.0, the risk of MACE was not statistically different between patients with an MFRcorrected ≥2.0 compared with those with MFRcorrected <2.0 (1.9% vs 2.3% MACE/year, HR 0.84 [0.63-1.13], P = 0.26) even after adjustment for confounders (P = 0.66). CONCLUSIONS: In patients without overt obstructive CAD and MFR< 2.0, there was no significant difference in cardiovascular risk between patients with discordant (≥2.0) and concordant (<2) MFR following RPP correction. This suggests that RPP-corrected MFR may not consistently provide accurate risk stratification in patients with normal perfusion and MFR <2.0. Stress MBF and uncorrected MFR should be reported to more reliably convey cardiovascular risk beyond perfusion results.

Influence of thermal aging on the marginal integrity of computer aided design/computer aided manufacturing fabricated crowns.

Background/purpose: The adaptation and marginal integrity of computer-aided designed and computer-aided manufactured (CAD/CAM) crowns after exposure to thermal aging need to be investigated. The present in-vitro study was designed to investigate the marginal integrity of CAD/CAM fabricated crowns cemented on extracted teeth after thermocycling aging. Materials and methods: Twenty-six newly extracted human premolars were prepared for full-coverage CAD/CAM crowns and were divided into two groups (leucite-reinforced glass-ceramics and lithium disilicate glass-ceramics). Both crowns' groups were cemented using dual curing resin cement. All specimen margins were measured for marginal integrity using an imaging system 24 h post cementation; then after 1, 3, and 5 estimated clinical years (10,000, 30,000, and 50,000 thermocycles). Two-way ANOVA analysis were used to determine whether the mean value difference is significantly different (ɑ = 0.05). Results: The average margin gaps recorded for leucite-reinforced glass-ceramic crowns were: 82.61 µm initial, and 91.02 µm after 5 estimated clinical year). For the lithium disilicate glass-ceramic crowns, the average margin gaps recorded were: 100.01 µm initial, and 120.21 µm after 5 estimated clinical year. During all measuring intervals, the leucite-reinforced glass-ceramic crown group had a lower marginal discrepancy. No statistically significant difference between the two groups was recorded. Conclusion: After being subjected to thermocycling, both CAD/CAM ceramic crowns, exhibited an increase in their marginal discrepancy; the difference was within the accepted clinical range.

[Consenso del grupo de trabajo de los trastornos de la conducta alimentaria de SENPE (GTTCA-SENPE). Evaluación y tratamiento médico-nutricional en la anorexia nerviosa. Actualización 2023]. / Consenso del grupo de trabajo de los trastornos de la conducta alimentaria de SENPE (GTTCA-SENPE). Evaluación y tratamiento médico-nutricional en la anorexia nerviosa. Actualización 2023.

Anorexia nervosa (AN) is a multifactorial disorder. A possible role of the social network and the gut microbiota in pathogenesis has been added. Exogenous shocks such as the COVID19 pandemic have had a negative impact on patients with AN. The potential medical and nutritional impact of malnutrition and/or compensatory behaviors gives rise to a complex disease with a wide range of severity, the management of which requires a multidisciplinary team with a high level of subject matter expertise. Coordination between levels of care is necessary as well as understanding how to transition the patient from pediatric to adult care is essential. A proper clinical evaluation can detect possible complications, as well as establish the organic risk of the patient. This allows caregivers to tailor the medical-nutritional treatment for each patient. Reestablishing adequate nutritional behaviors is a fundamental pillar of treatment in AN. The design of a personalized nutritional treatment and education program is necessary for this purpose. Depending on the clinical severity, artificial nutrition may be necessary. Although the decision regarding the level of care necessary at diagnosis or during follow-up depends on a number of factors (awareness of the disease, medical stability, complications, suicidal risk, outpatient treatment failure, psychosocial context, etc.), outpatient treatment is the most frequent and most preferred choice. However, more intensive care (total or partial hospitalization) may be necessary in certain cases. In severely malnourished patients, the appearance of refeeding syndrome should be prevented during renourishment. The presence of AN in certain situations (pregnancy, vegetarianism, type 1 diabetes mellitus) requires specific care. Physical activity in these patients must also be addressed correctly.

Speed and degree of functional and compositional recovery varies with latitude and community age.

Rates at which a community recovers after disturbance, or its resilience, can be accelerated by increased net primary productivity and recolonization dynamics such as recruitment. These mechanisms can vary across biogeographic gradients, such as latitude, suggesting that biogeography is likely important to predicting resilience. To test whether community resilience, informed by functional and compositional recovery, hinges on geographic location, we employed a standardized replicated experiment on marine invertebrate communities across four regions from the tropics to the subarctic zone. Communities assembled naturally on standardized substrate while experiencing distinct levels of biomass removal (no removal, low disturbance, and high disturbance), which opened space for new colonizers, thereby providing a pulse of limited resource to these communities. We then quantified functional (space occupancy and biomass) and compositional recovery from these repeated pulse disturbances across two community assembly timescales (early and late at 3 and 12 months, respectively). We documented latitudinal variation in resilience across 47° latitude, where speed of functional recovery was higher toward lower latitudes yet incomplete at late assembly in the tropics and subtropics. The degree of functional recovery did not coincide with compositional recovery, and regional differences in recruitment and growth likely contributed to functional recovery in these communities. While biogeographic variation in community resilience has been predicted, our results are among the first to examine functional and compositional recovery from disturbance in a single large-scale standardized experiment.

[A consensus report by the Working Group on Eating Disorders of Sociedad Española de Nutrición Clínica y Metabolismo (GTTCA-SENPE). Evaluation, medical and nutritional management of anorexia nervosa. Update 2023]. / Consenso del grupo de trabajo de los trastornos de la conducta alimentaria de SENPE (GTTCA-SENPE). Evaluación y tratamiento médico-nutricional en la anorexia nerviosa. Actualización 2023.

Introduction: Anorexia nervosa (AN) is a multifactorial disorder. A possible role of the social network and the gut microbiota in pathogenesis has been added. Exogenous shocks such as the COVID19 pandemic have had a negative impact on patients with AN. The potential medical and nutritional impact of malnutrition and/or compensatory behaviors gives rise to a complex disease with a wide range of severity, the management of which requires a multidisciplinary team with a high level of subject matter expertise. Coordination between levels of care is necessary as well as understanding how to transition the patient from pediatric to adult care is essential. A proper clinical evaluation can detect possible complications, as well as establish the organic risk of the patient. This allows caregivers to tailor the medical-nutritional treatment for each patient. Reestablishing adequate nutritional behaviors is a fundamental pillar of treatment in AN. The design of a personalized nutritional treatment and education program is necessary for this purpose. Depending on the clinical severity, artificial nutrition may be necessary. Although the decision regarding the level of care necessary at diagnosis or during follow-up depends on a number of factors (awareness of the disease, medical stability, complications, suicidal risk, outpatient treatment failure, psychosocial context, etc.), outpatient treatment is the most frequent and most preferred choice. However, more intensive care (total or partial hospitalization) may be necessary in certain cases. In severely malnourished patients, the appearance of refeeding syndrome should be prevented during renourishment. The presence of AN in certain situations (pregnancy, vegetarianism, type 1 diabetes mellitus) requires specific care. Physical activity in these patients must also be addressed correctly.

Introducción: La anorexia nerviosa (AN) es una enfermedad de origen multifactorial. Recientemente se ha sumado el papel de las redes sociales y la microbiota intestinal en la patogenia. La pandemia por COVID-19 ha tenido un impacto negativo en los pacientes con AN. La potencial afectación médica y nutricional derivada de la desnutrición o las conductas compensatorias dan lugar a una compleja enfermedad de gravedad variable, cuyo manejo precisa un equipo multidisciplinar con elevado nivel de conocimientos en la materia. Es fundamental la coordinación entre niveles asistenciales y en la transición de pediatría a adultos. Una adecuada valoración clínica permite detectar eventuales complicaciones, así como establecer el riesgo orgánico del paciente y, por tanto, adecuar el tratamiento médico-nutricional de forma individualizada. El restablecimiento de un apropiado estado nutricional es un pilar fundamental del tratamiento en la AN. Para ello es necesario diseñar una intervención de renutrición individualizada que incluya un programa de educación nutricional. Según el escenario clínico puede ser necesaria la nutrición artificial. Aunque la decisión de qué nivel de atención escoger al diagnóstico o durante el seguimiento depende de numerosas variables (conciencia de enfermedad, estabilidad médica, complicaciones, riesgo autolítico, fracaso del tratamiento ambulatorio o contexto psicosocial, entre otros), el tratamiento ambulatorio es de elección en la mayoría de las ocasiones. No obstante, puede ser necesario un escenario más intensivo (hospitalización total o parcial) en casos seleccionados. En pacientes gravemente desnutridos debe prevenirse la aparición de un síndrome de alimentación cuando se inicia la renutrición. La presencia de una AN en determinadas situaciones (gestación, vegetarianismo, diabetes mellitus de tipo 1, etc.) exige un manejo particular. En estos pacientes también debe abordarse de forma correcta el ejercicio físico.

Fragile X syndrome in the largest world clustering. I. Genetic epidemiology and founder effect outline.

The FMR1 5' regulation gene region harbors a CGG trinucleotide repeat expansion (CGG-TRE) that causes Fragile X syndrome (FXS) when it expands to more than 200 repetitions. Ricaurte is a small village in southwestern Colombia, with an FXS prevalence of 1 in 38 men and 1 in 100 women (~100 times higher than the worldwide reported prevalence), defining Ricaurte as the largest FXS cluster in the world. In the present study, using next-generation sequencing of whole exome capture, we genotype 55 individuals from Ricaurte (49 with either full mutation or with premutation), four individuals from neighboring villages (with either the full mutation or with the premutation), and one unaffected woman, native of Ricaurte, who did not belong to any of the affected families. With advanced clustering and haplotype reconstruction, we modeled a common haplotype of 33 SNPs spanning 83,567,899 bp and harboring the FMR1 gene. This reconstructed haplotype was found in all the men from Ricaurte who carried the expansion, demonstrating that the genetic conglomerate of FXS in this population is due to a founder effect. The definition of this founder effect and its population outlining will allow a better prediction, follow-up, precise and personalized characterization of epidemiological parameters, better knowledge of the disease's natural history, and confident improvement of the clinical attention, life quality, and health interventions for this community.

Pharmaceutical and pesticide mixtures in a Mediterranean coastal wetland: comparison of sampling methods, ecological risks, and removal by a constructed wetland.

Pharmaceuticals and pesticides can be considered hazardous compounds for Mediterranean coastal wetland ecosystems. Although many of these compounds co-occur in environmental samples, only a few studies have been dedicated to assessing the ecotoxicological risks of complex contaminant mixtures. We evaluated the occurrence of 133 pharmaceuticals and pesticides in 12 sites in a protected Mediterranean wetland, the Albufera Natural Park (ANP), based on conventional grab sampling and polar organic chemical integrative samplers (POCIS). We assessed acute and chronic ecological risks posed by these contaminant mixtures using the multi-substance Potentially Affected Fraction (msPAF) approach and investigated the capacity of a constructed wetland to reduce chemical exposure and risks. This study shows that pharmaceuticals and pesticides are widespread contaminants in the ANP, with samples containing up to 75 different compounds. POCIS samplers were found to be useful for the determination of less predictable exposure profiles of pesticides occurring at the end of the rice cultivation cycle, while POCIS and grab samples provide an accurate method to determine (semi-)continuous pharmaceutical exposure. Acute risks were identified in one sample, while chronic risks were determined in most of the collected samples, with 5-25% of aquatic species being potentially affected. The compounds that contributed to the chronic risks were azoxystrobin, ibuprofen, furosemide, caffeine, and some insecticides (diazinon, imidacloprid, and acetamiprid). The evaluated constructed wetland reduced contaminant loads by 45-73% and reduced the faction of species affected from 25 to 6%. Our study highlights the need of addressing contaminant mixture effects in Mediterranean wetlands and supports the use of constructed wetlands to reduce contaminant loads and risks in areas with high anthropogenic pressure.

Clinical predictors of right ventricular dysfunction and association with adverse outcomes in peripartum cardiomyopathy.

AIMS: We sought to identify factors associated with right ventricular (RV) dysfunction and elevated pulmonary artery systolic pressure (PASP) and association with adverse outcomes in peripartum cardiomyopathy (PPCM). METHODS AND RESULTS: We conducted a multi-centre cohort study to identify subjects with PPCM with the following criteria: left ventricular ejection fraction (LVEF) < 40%, development of heart failure within the last month of pregnancy or 5 months of delivery, and no other identifiable cause of heart failure with reduced ejection fraction. Outcomes included a composite of (i) major adverse events (need for extracorporeal membrane oxygenation, ventricular assist device, orthotopic heart transplantation, or death) or (ii) recurrent heart failure hospitalization. RV function was obtained from echocardiogram reports. In total, 229 women (1993-2017) met criteria for PPCM. Mean age was 32.4 ± 6.8 years, 28% were of African descent, 50 (22%) had RV dysfunction, and 38 (17%) had PASP ≥ 30 mmHg. After a median follow-up of 3.4 years (interquartile range 1.0-8.8), 58 (25%) experienced the composite outcome of adverse events. African descent, family history of cardiomyopathy, LVEF, and PASP were significant predictors of RV dysfunction. Using Cox proportional hazards models, we found that women with RV dysfunction were three times more likely to experience the adverse composite outcome: hazard ratio 3.21 (95% confidence interval: 1.11-9.28), P = 0.03, in a multivariable model adjusting for age, race, body mass index, preeclampsia, hypertension, diabetes, kidney disease, and LVEF. Women with PASP ≥ 30 mmHg had a lower probability of survival free from adverse events (log-rank P = 0.04). CONCLUSIONS: African descent and family history of cardiomyopathy were significant predictors of RV dysfunction. RV dysfunction and elevated PASP were significantly associated with a composite of major adverse cardiac events. This at-risk group may prompt closer monitoring or early referral for advanced therapies.

Factors associated with prior completion of colorectal cancer and hepatitis C virus screenings among community health center patients: a cross-sectional study to inform a multi-behavioral educational intervention.

BACKGROUND: Colorectal cancer (CRC) and liver cancer are two of the leading causes of cancer death in the United States and persistent disparities in CRC and liver cancer incidence and outcomes exist. Chronic hepatitis C virus (HCV) infection is one of the main contributors to liver cancer. Effective screening for both CRC and HCV exist and are recommended for individuals based upon age, regardless of gender or sex assigned at birth. Recommendations for both screening behaviors have been recently updated. However, screening rates for both CRC and HCV are suboptimal. Targeting adoption of multiple screening behaviors has the potential to reduce cancer mortality and disparities. OBJECTIVE: To examine psychosocial factors associated with completion of CRC and HCV screenings in order to inform a multi-behavioral educational intervention that pairs CRC and HCV screening information. METHODS: A cross-sectional survey was conducted with participants (N = 50) recruited at two community health centers in Florida (United States). Kruskal-Wallis and Fisher's exact tests were used to examine associations between completion of both CRC and HCV screening, CRC and HCV knowledge, Preventive Health Model constructs (e.g., salience and coherence, response efficacy, social influence), and sociodemographic variables. RESULTS: Most participants were White (84%), female (56%), insured (80%), and reported a household income of $25,000 or less (53%). 30% reported ever previously completing both CRC and HCV screenings. Prior completion of both screening behaviors was associated with higher educational attainment (p = .014), having health insurance (p = .022), being U.S.-born (p = .043), and higher salience and coherence scores for CRC (p = .040) and HCV (p = .004). CONCLUSIONS: Findings demonstrate limited uptake of both CRC and HCV screenings among adults born between 1945 and 1965. Uptake was associated with multiple sociodemographic factors and health beliefs related to salience and coherence. Salience and coherence are modifiable factors associated with completion of both screening tests, suggesting the importance of incorporating these health beliefs in a multi-behavioral cancer education intervention. Additionally, health providers could simultaneously recommend and order CRC and HCV screening to improve uptake among this age cohort.

Role of disruptions in O RhD negative donations in Colombia on increasing maternal mortality ratio from haemorrhage.

OBJECTIVE: The aim of this work was to evaluate the relationship of the maternal mortality ratio due to obstetric haemorrhage (MMROH) with the national blood donations, particularly O RhD negative (Oneg) before and during COVID-19 pandemic. BACKGROUND: The maternal mortality ratio is increasing in Colombia, yet little is known regarding the relationship between blood donations and maternal mortality due to obstetric haemorrhage. MATERIALS AND METHODS: A retrospective cross-sectional study between January 1, 2018, and December 31, 2021, was performed, to assess MMROH compared to the blood donations notified to the Colombian National Haemovigilance System, through non-parametric methods. Because a relationship between blood donations and MMROH was identified, the analysis was expanded from 2009 to 2017. RESULTS: In 2020, Colombia increased the MMROH by 32% compared to 2019 which coincided with the lockdown period to contain COVID-19. An inversed relationship (SumD2 = 631.0; rs = -0.7335; p 0.01) between blood donations, particularly Oneg (SumD2 = 652.0; rs = -0.7912; p 0.002) and MMROH was identified. For the years 2015-2019 and 2021, the annual mean MMROH was 8.5 ± 0.5 per 100 000 live births when the annual mean blood donations was 18.2 ± 0.4 donations per 1000 people and the Oneg was 1.0 ± 0.0 donations per 1000 people. In contrast, the years 2009-2014 and 2020 displayed an annual MMROH of 12.6 ± 0.8, when the annual collection of blood was 16.4 ± 0.8 donations and the Oneg was 0.9 ± 0.0, p < 0.001. CONCLUSION: There was an inverse relationship between blood donation, mainly Oneg, and maternal mortality from obstetric haemorrhage. However, we recognise these deaths could be related to other reasons, especially when they occurred in rural areas with limited access to medical services.

Ligand-Based Drug Design of Genipin Derivatives with Cytotoxic Activity against HeLa Cell Line: A Structural and Theoretical Study.

Cervical cancer is a malignant neoplastic disease, mainly associated to HPV infection, with high mortality rates. Among natural products, iridoids have shown different biological activities, including cytotoxic and antitumor effects, in different cancer cell types. Geniposide and its aglycone Genipin have been assessed against different types of cancer. In this work, both iridoids were evaluated against HeLa and three different cervical cancer cell lines. Furthermore, we performed a SAR analysis incorporating 13 iridoids with a high structural similarity to Geniposide and Genipin, also tested in the HeLa cell line and at the same treatment time. Derived from this analysis, we found that the dipole moment (magnitude and direction) is key for their cytotoxic activity in the HeLa cell line. Then, we proceeded to the ligand-based design of new Genipin derivatives through a QSAR model (R2 = 87.95 and Q2 = 62.33) that incorporates different quantum mechanic molecular descriptor types (ρ, ΔPSA, ∆Polarizability2, and logS). Derived from the ligand-based design, we observed that the presence of an aldehyde or a hydroxymethyl in C4, hydroxyls in C1, C6, and C8, and the lack of the double bond in C7-C8 increased the predicted biological activity of the iridoids. Finally, ten simple iridoids (D9, D107, D35, D36, D55, D56, D58, D60, D61, and D62) are proposed as potential cytotoxic agents against the HeLa cell line based on their predicted IC50 value and electrostatic features.

Actin Polymerization Defects Induce Mitochondrial Dysfunction in Cellular Models of Nemaline Myopathies.

Nemaline myopathy (NM) is one of the most common forms of congenital myopathy and it is identified by the presence of "nemaline bodies" (rods) in muscle fibers by histopathological examination. The most common forms of NM are caused by mutations in the Actin Alpha 1 (ACTA1) and Nebulin (NEB) genes. Clinical features include hypotonia and muscle weakness. Unfortunately, there is no curative treatment and the pathogenetic mechanisms remain unclear. In this manuscript, we examined the pathophysiological alterations in NM using dermal fibroblasts derived from patients with mutations in ACTA1 and NEB genes. Patients' fibroblasts were stained with rhodamine-phalloidin to analyze the polymerization of actin filaments by fluorescence microscopy. We found that patients' fibroblasts showed incorrect actin filament polymerization compared to control fibroblasts. Actin filament polymerization defects were associated with mitochondrial dysfunction. Furthermore, we identified two mitochondrial-boosting compounds, linoleic acid (LA) and L-carnitine (LCAR), that improved the formation of actin filaments in mutant fibroblasts and corrected mitochondrial bioenergetics. Our results indicate that cellular models can be useful to study the pathophysiological mechanisms involved in NM and to find new potential therapies. Furthermore, targeting mitochondrial dysfunction with LA and LCAR can revert the pathological alterations in NM cellular models.

Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.

Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.

TGF-ß/SMAD canonical pathway induces the expression of transcriptional cofactor TAZ in liver cancer cells.

The TGF-ß and Hippo pathways are critical for liver size control, regeneration, and cancer progression. The transcriptional cofactor TAZ, also named WWTR1, is a downstream effector of Hippo pathway and plays a key role in the maintenance of liver physiological functions. However, the up-regulation of TAZ expression has been associated with liver cancer progression. Recent evidence shows crosstalk of TGF-ß and Hippo pathways, since TGF-ß modulates TAZ expression through different mechanisms in a cellular context-dependent manner but supposedly independent of SMADs. Here, we evaluate the molecular interplay between TGF-ß pathway and TAZ expression and observe that TGF-ß induces TAZ expression through SMAD canonical pathway in liver cancer HepG2 cells. Therefore, TAZ cofactor is a primary target of TGF-ß/SMAD-signaling, one of the pathways altered in liver cancer.

Retooling the Remediation Process: An Overview of One School's Process Overhaul.

OBJECTIVE: This article describes the process of review and modification of a Doctor of Pharmacy didactic course remediation process. A highlight of the new process includes early intervention with a Learning Specialist, creating the opportunity for students to address learning issues earlier in the courses. METHODS: Review of past remediation processes, student success, and pertinent literature related to remediation processes to allow for a new remediation process that supports students' learning and success. RESULTS: Creation of a new 2-phase process, including an early intervention and remediation process. The process includes a Learning Specialist position to focus on learning and barriers to academics. Remediation opportunities focus on proficiency in specific areas for each course. CONCLUSION: The new remediation policy provides greater support to students through the Learning Specialist. The new policy helps students connect with resources earlier in the program and provides multiple opportunities for assisting students during the semester. Over the past 4 years, the Learning Specialist has met with an average of 73 individual students per semester, while only an average of 25 students in the didactic portion of the curriculum (year 1-3) require remediation each semester.

Antioxidants Prevent Iron Accumulation and Lipid Peroxidation, but Do Not Correct Autophagy Dysfunction or Mitochondrial Bioenergetics in Cellular Models of BPAN.

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic disorders frequently associated with iron accumulation in the basal nuclei of the brain. Among NBIA subtypes, ß-propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate the autophagic defects and secondary pathological consequences in cellular models derived from two patients harboring WDR45 mutations. Both protein and mRNA expression levels of WDR45 were decreased in patient-derived fibroblasts. In addition, the increase of LC3B upon treatments with autophagy inducers or inhibitors was lower in mutant cells compared to control cells, suggesting decreased autophagosome formation and impaired autophagic flux. A transmission electron microscopy (TEM) analysis showed mitochondrial vacuolization associated with the accumulation of lipofuscin-like aggregates containing undegraded material. Autophagy dysregulation was also associated with iron accumulation and lipid peroxidation. In addition, mutant fibroblasts showed altered mitochondrial bioenergetics. Antioxidants such as pantothenate, vitamin E and α-lipoic prevented lipid peroxidation and iron accumulation. However, antioxidants were not able to correct the expression levels of WDR45, neither the autophagy defect nor cell bioenergetics. Our study demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism and cell bioenergetics. Antioxidants partially improved cell physiopathology; however, autophagy and cell bioenergetics remained affected.