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Objective: beta-Cell response to glucose is characterized by mitochondrial membrane potential (Delta Psi) hyperpolarization and the production of metabolites that serve as insulin secretory signals. We have previously shown that glucose-induced mitochondrial hyperpolarization accompanies the concentration-dependent increase in insulin secretion within a wide range of glucose concentrations. This observation represents the integrated response of a large number of mitochondria within each individual cell. However, it is currently unclear whether all mitochondria within a single beta-cell represent a metabolically homogenous population and whether fuel or other stimuli can recruit or silence sizable subpopulations of mitochondria. This study offers insight into the different metabolic states of beta-cell mitochondria. Results: We show that mitochondria display a wide heterogeneity in Delta Psi and a millivolt range that is considerably larger than the change in millivolts induced by fuel challenge. Increasing glucose concentration recruits mitochondria into higher levels of homogeneity, while an in vitro diabetes model results in increased Delta Psi heterogeneity. Exploration of the mechanism behind heterogeneity revealed that temporary changes in Delta Psi of individual mitochondria, ATP-hydrolyzing mitochondria, and uncoupling protein 2 are not significant contributors to Delta Psi heterogeneity. We identified BAD, a proapoptotic BCL-2 family member previously implicated in mitochondrial recruitment of glucokinase, as a significant factor influencing the level of heterogeneity. Conclusions: We suggest that mitochondrial Delta Psi heterogeneity in beta-cells reflects a metabolic reservoir recruited by an increased level of fuels and therefore may serve as a therapeutic target. [ABSTRACT FROM AUTHOR]

Objective: Intestinal transplantation (ITx) has become an accepted option for children with serious complications from intestinal failure and parenteral nutrition (PN) dependence. We aimed to assess long-term growth and nutritional outcomes in these patients. We also assessed factors influencing nutritional status and ability to wean off tube feedings (TFs) after ITx., Methods: We looked retrospectively into post-ITx growth parameters, nutrition treatment, and micronutrient status for children who survived for 5 or more years after ITx. One hundred thirty-three children between 1993 and 2014 were involved. Descriptive data and growth parameters were collected over 15 years after ITx. We also analyzed influencing factors, including the presence of permanent stoma, prolonged use of steroids, partial gastrectomy at the time of ITx, developmental delay, concurrent visceral transplant, and graft rejection episodes., Results: There was an increase in the height z-scores over the 15-year period post-ITx (p < 0.001). There was a downward trend in body mass index (BMI) z-scores over the 15-year post-ITx period. Isolated intestinal transplant patients showed a better height z-score compared to multivisceral transplant (p = 0.04). The height and BMI z-scores for patients on steroids were not significantly different from the z-scores for steroid-free patients (p = 0.72, 0.99, respectively). There was no significant change in height and BMI z-scores based on prednisolone dose: ≤0.2 mg/kg (p = 0.76); >0.2 mg/kg (p = 0.52). Patients were more likely to require supplemental TF up to 15 years post-ITx when they had partial gastrectomy (p < 0.001), permanent ostomy (p = 0.009), or developmental delay (p < 0.001)., Conclusions: There was improved long-term linear growth post-ITx. Developmental delay, partial gastrectomy, and a permanent ostomy are likely to delay TF wean post-ITx., (© 2025 The Author(s). Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Cell-penetrating peptides (CPPs) are a diverse group of peptides, typically composed of 4 to 40 amino acids, known for their unique ability to transport a wide range of substances-such as small molecules, plasmid DNA, small interfering RNA, proteins, viruses, and nanoparticles-across cellular membranes while preserving the integrity of the cargo. CPPs exhibit passive and non-selective behavior, often requiring functionalization or chemical modification to enhance their specificity and efficacy. The precise mechanisms governing the cellular uptake of CPPs remain ambiguous; however, electrostatic interactions between positively charged amino acids and negatively charged glycosaminoglycans on the membrane, particularly heparan sulfate proteoglycans, are considered the initial crucial step for CPP uptake. Clinical trials have highlighted the potential of CPPs in diagnosing and treating various diseases, including cancer, central nervous system disorders, eye disorders, and diabetes. This review provides a comprehensive overview of CPP classifications, potential applications, transduction mechanisms, and the most relevant algorithms to improve the accuracy and reliability of predictions in CPP development.

Cell-penetrating peptides (CPPs) offer a unique and efficient mechanism for delivering therapeutic agents directly into cancer cells. These peptides can traverse cellular membranes, overcoming one of the critical barriers in drug delivery systems. In this review, we explore recent advancements in the application of CPPs for cancer treatment, focusing on mechanisms, delivery strategies, and clinical potential. The review highlights the use of CPP-drug conjugates, CPP-based vaccines, and their role in targeting and inhibiting tumor growth.

Background: We explored the impact of prior yellow fever (YF) or Japanese encephalitis (JE) vaccination on the efficacy of Takeda's dengue vaccine candidate, TAK-003., Methods: Children 4-16 years of age were randomized 2:1 to receive TAK-003 or placebo and were under active febrile surveillance. Symptomatic dengue was confirmed by serotype-specific reverse-transcription polymerase chain reaction. YF and JE vaccination history was recorded., Results: Of the 20 071 children who received TAK-003 or placebo, 21.1% had a YF and 23.9% had a JE vaccination history at randomization. Fifty-seven months after vaccination, vaccine efficacy (95% confidence interval) was 55.7% (39.7%-67.5%) in those with YF vaccination, 77.8% (70.8%-83.1%) for JE vaccination, and 53.5% (45.4%-60.4%) for no prior YF/JE vaccination. Regional differences in serotype distribution confound these results. The apparent higher vaccine efficacy in the JE vaccination subgroup could be largely explained by serotype-specific efficacy of TAK-003. Within 28 days of any vaccination, the proportions of participants with serious adverse events in the YF/JE prior vaccination population were comparable between the TAK-003 and placebo groups., Conclusions: The available data do not suggest a clinically relevant impact of prior JE or YF vaccination on TAK-003 performance. Overall, TAK-003 was well-tolerated and efficacious in different epidemiological settings. Clinical Trials Registration.  NCT02747927., Competing Interests: Potential conflicts of interest. S. B., M. R., I. E., S. T., E. L., V. T., N. F., and D. W. are permanent employees of the Takeda group of companies and may hold Takeda stock/stock options. A. B. and I. L. were permanent employees of Takeda and held Takeda stock/stock options at the time of the trial. H. F. was a consultant for Takeda Vaccines and previous employee of Takeda Vaccines, Inc. D. W. is an inventor of the international patent applications WO2017179017, WO2021/034349, and WO2020/051334 currently pending in several jurisdictions worldwide and being the basis of various granted patents. The institutions of principal investigators received a research grant from Takeda to conduct this study. X. S.-L., P. K., and L. B. have served as advisory board members for Takeda. P. K. has received funding for attending meetings. E. D. M. has participated in an advisory board for Takeda. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: Clinical practice guidelines (CPG) worldwide help steer the management of early-onset neonatal sepsis (EONS). These documents typically discourage the use of risk assessment tools. However, prior work has shown that the Kaiser Permanente calculator (Early-Onset Sepsis Calculator [EOScalc]) could be a useful tool in EONS risk assessment. This study aimed to determine the agreement between the recommendations of the Colombian EONS CPG and those of the EOSCalc tool in a cohort of newborns in Bogotá, Colombia., Study Design: Multicenter retrospective observational cohort study. We included newborns with a gestational age ≥ 34 weeks who were admitted to the neonatal care unit with a suspected diagnosis of EONS between 2017 and 2019. Agreement between the two tools was examined using Cohen's kappa under two scenarios (unequivocal and cautious)., Results: Of the 23.490 live births, 470 (1.71%) were admitted to the neonatal care unit with a presumptive diagnosis of EONS. This diagnosis was confirmed in seven patients by means of blood cultures, with group B streptococcus the most common organism (57%; 95% confidence interval [CI]: 18.4-90.1). A single death occurred among the patients with confirmed EONS (lethality: 14.3%). The overall incidence of EONS was 0.298 per 1,000 live births. After splitting the recommendations into two scenarios regarding antibiotic use, unequivocal and cautious, the agreement between EOSCalc and the CPG was below 15% (6 and 14%, respectively)., Conclusion: Recommendations from the Colombian EONS CPG show poor agreement with the EOSCalc, with the latter detecting all newborns with EONS. Although the use of EOSCalc is clinically and administratively advantageous, further prospective studies are warranted to determine the safety of its implementation., Key Points: · Colombian EONS CPGs recommend that an outsized number of newborns be given antibiotics.. · The KP EOSCalc risk assessment calculator shows poor agreement with CPG recommendations.. · The Colombian CPGs should be updated to include the use of risk assessment calculators.., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: About half of the world's population lives in dengue-endemic areas. We aimed to evaluate the long-term efficacy and safety of two doses of the tetravalent dengue vaccine TAK-003 in preventing symptomatic dengue disease of any severity and due to any dengue virus (DENV) serotypes in children and adolescents., Methods: In this ongoing double-blind, randomised, placebo-controlled trial, we enrolled healthy participants aged 4-16 years at 26 medical and research centres across eight dengue-endemic countries (Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). The main exclusion criteria were febrile illness (body temperature ≥38°C) at the time of randomisation, hypersensitivity or allergy to any of the vaccine components, pregnancy or breastfeeding, serious chronic or progressive disease, impaired or altered immune function, and previous receipt of a dengue vaccine. Participants were randomly assigned 2:1 (stratified by age and region) using an interactive web response system and dynamic block assignment to receive two subcutaneous doses of TAK-003 or placebo 3 months apart. Investigators, participants, and their parents or legal guardians were blinded to group assignments. Active febrile illness surveillance and RT-PCR testing of febrile illness episodes were performed for identification of virologically confirmed dengue. Efficacy outcomes were assessed in the safety analysis set (all randomly assigned participants who received ≥1 dose) and the per protocol set (all participants who had no major protocol violations), and included cumulative vaccine efficacy from first vaccination to approximately 4·5 years after the second vaccination. Serious adverse events were monitored throughout. This study is registered with ClinicalTrials.gov, NCT02747927., Findings: Between Sept 7, 2016, and March 31, 2017, 20 099 participants were randomly assigned (TAK-003, n=13 401; placebo, n=6698). 20 071 participants (10 142 [50·5%] males; 9929 [49·5%] females; safety set) received TAK-003 or placebo, with 18 257 (91·0%) completing approximately 4·5 years of follow-up after the second vaccination (TAK-003, 12 177/13 380; placebo, 6080/6687). Overall, 1007 (placebo: 560; TAK-003: 447) of 27 684 febrile illnesses reported were virologically confirmed dengue, with 188 cases (placebo: 142; TAK-003: 46) requiring hospitalisation. Cumulative vaccine efficacy was 61·2% (95% CI 56·0-65·8) against virologically confirmed dengue and 84·1% (77·8-88·6) against hospitalised virologically confirmed dengue; corresponding efficacies were 53·5% (41·6-62·9) and 79·3% (63·5-88·2) in baseline seronegative participants (safety set). In an exploratory analysis, vaccine efficacy was shown against all four serotypes in baseline seropositive participants. In baseline seronegative participants, vaccine efficacy was shown against DENV-1 and DENV-2 but was not observed against DENV-3 and low incidence precluded evaluation against DENV-4. During part 3 of the trial (approximately 22-57 months after the first vaccination), serious adverse events were reported for 664 (5·0%) of 13 380 TAK-003 recipients and 396 (5·9%) of 6687 placebo recipients; 17 deaths (6 in the placebo group and 11 in the TAK-003 group) were reported, none were considered study-vaccine related., Interpretation: TAK-003 demonstrated long-term efficacy and safety against all four DENV serotypes in previously exposed individuals and against DENV-1 and DENV-2 in dengue-naive individuals., Funding: Takeda Vaccines., Translations: For the Portuguese, Spanish translations and plain language summary of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests VT, SB, ST, IE, YH, EL, MR, OZ, NF, IL, and DW are, or were, employees of Takeda and hold, or held, stock or stock options in Takeda. PK, CB-T, and XS-L report receiving research grants from Takeda. PK reports receiving research grants from Takeda and funding from Takeda for attending meetings. EDM Jr reports participating in an advisory board for Takeda. DY, HR, CS, PL, LB, MTA, VW, RD, LKF, LR, LMV, VPW, ADF, DG, KL, ALO, and FE declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Opitz GBBB syndrome (GBBB) is an X-linked disease characterized by midline defects, including congenital heart defects. We present our diagnostic approach to the identification of GBBB in a consanguineous family in which two males siblings were concordant for a total anomalous connection of pulmonary veins and minor facial dysmorphias., Methods: Targeted exome sequencing analysis of a 380-gene panel associated with cardiovascular disease was performed on the propositus. Interpretative analysis of the exome results was conducted, and 3D models of the protein changes were generated., Results: We identified a NM&#95;000381.4:c.608G>A;p.(Arg203Gln) change in MID1, affecting the conformation of the B-box 2 domain of the protein, with a zinc finger structure and associated protein interactions. This clinical phenotype is consistent with GBBB; however, the type of congenital heart disease observed in this case has not been previously reported., Conclusion: A new likely pathogenic variant on MID1 c.608G>A was found to be associated with Opitz GBBB syndrome., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Spirituality and religiosity are complex cognitive phenomena; however, the relationship between spiritual experiences and epilepsy continues to be debated. Methods . Data from the daily spiritual experience scale (DSES) were related to EEG data and clinical variables of 100 adult people with epilepsy (PWEs). DSES scores were compared to 51 normal individuals (control group [CG]), with a significance level of P  < .05. Results . The total score in the DSES was 36.1 ± 14 and 37.6 ± 13.2, respectively, in the PWEs and in the CG. In the PWEs, there was a correlation between DSES and age (Pearson's correlation; -0.22; P  = .027) and educational level (0.207; P  = .039). PWEs with ≥one seizure/month have a lower frequency of daily spiritual experiences than those with better controlled seizures ( T -test; 39.2 ± 16.2 vs 31.7 ± 7.6; P  = .038). EEG epileptiform activity (EA) in the right hemisphere was associated with a higher frequency of spiritual experiences than those with left-hemisphere EA (29.8 ± 9.0 vs 38.5 ± 17.5; P  = .010). Conclusion . Demographic aspects, EA in the right hemisphere, and lower seizure frequency are associated with daily spiritual experiences in epilepsy, suggesting an association between aspects of spirituality, epilepsy, and neurobiological correlates.

Background: Previous cholecystectomy is common in patients with short bowel syndrome (SBS). An intact gallbladder is beneficial in preventing cirrhosis in SBS patients, but the nutritional consequences of cholecystectomy are largely unknown. Our aim was to evaluate the effect of pre-SBS cholecystectomy on need for chronic parenteral nutrition (PN)., Methods: We reviewed 485 adults with SBS: 267 underwent cholecystectomy prior to SBS and 218 patients had an intact gallbladder. Demographic data, intestinal anatomy, and nutritional outcome were compared., Results: Pre-SBS cholecystectomy patients were more likely to have had postoperative SBS and BMI >35. Intestinal remnant length and anatomy type and performance of surgical rehabilitation procedures within the first year were similar. Overall, there was no significant difference in the need for PN > 1year between the two groups. There was also no significant difference in the need for PN > 1year in any specific subgroup of intestinal remnant length or intestinal anatomy., Conclusions: Cholecystectomy performed prior to the development of SBS does not influence the nutritional prognosis of SBS, regardless of the intestinal remnant length and anatomy type., Competing Interests: Declaration of competing interest The authors have no relevant conflicts of interest related to this work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Despite the widespread emergence of memory effects in solid systems, understanding the basic microscopic mechanisms that trigger them is still puzzling. We report how ingredients of solid state transport in polycrystalline systems, such as semiconductor oxides, become sufficient conditions for a memristive response that points to the natural emergence of memory, discernible under an adequate set of driving inputs. The experimental confirmation of these trends will be presented along with a compact analytical theoretical picture that allows discerning the relative contribution of the main building blocks of memory and the effect of temperature, in particular. These findings can be extended to a vast universe of materials and devices, providing a unified physical explanation for a wide class of resistive memories and pinpointing the optimal driving configurations for their operation.

Background: Takeda's dengue vaccine is under evaluation in an ongoing phase 3 efficacy study; we present a 2-year update., Methods: Children (20 099, 4-16 years old) were randomized to receive 2 doses of TAK-003 or placebo 3 months apart and are under surveillance to detect dengue by serotype-specific RT-PCR., Results: Cumulative efficacy against dengue approximately 27 months since first dose was 72.7% (95% confidence interval [CI], 67.1%-77.3%), including 67.0% (95% CI, 53.6%-76.5%) in dengue-naive and 89.2% (95% CI, 82.4%-93.3%) against hospitalized dengue. In the second year, decline in efficacy was observed (56.2%; 95% CI, 42.3%-66.8%) with the largest decline in 4-5 year olds (24.5%; 95% CI, -34.2% to 57.5%); efficacy was 60.6% (95% CI, 43.8%-72.4%) in 6-11 year and 71.2% (95% CI, 41.0%-85.9%) in 12-16 year age groups. As TAK-003 efficacy varies by serotype, changes in serotype dominance partially contributed to efficacy differences in year-by-year analysis. No related serious adverse events occurred during the second year., Conclusions: TAK-003 demonstrated continued benefit independent of baseline serostatus in reducing dengue with some decline in efficacy during the second year. Three-year data will be important to see if efficacy stabilizes or declines further.Clinical Trials Registration. NCT02747927.Takeda's tetravalent dengue vaccine (TAK-003) continued to demonstrate benefit in reducing dengue independent of baseline serostatus up to 2 years after completing vaccination with some decline in efficacy during the second year in 4-16 year olds in dengue-endemic countries., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

In recent years, immune therapy, notably immune checkpoint inhibitors (ICI), in conjunction with chemotherapy and surgery has demonstrated therapeutic activity for some tumor types. However, little is known about the optimal combination of immune therapy with standard of care therapies and approaches. In patients with gastrointestinal (GI) cancers, especially pancreatic ductal adenocarcinoma (PDAC), preoperative (neoadjuvant) chemotherapy has increased the number of patients who can undergo surgery and improved their responses. However, most chemotherapy is immunosuppressive, and few studies have examined the impact of neoadjuvant chemotherapy (NCT) on patient immunity and/or the optimal combination of chemotherapy with immune therapy. Furthermore, the majority of chemo/immunotherapy studies focused on immune regulation in cancer patients have focused on postoperative (adjuvant) chemotherapy and are limited to peripheral blood (PB) and occasionally tumor infiltrating lymphocytes (TILs); representing a minority of immune cells in the host. Our previous studies examined the phenotype and frequencies of myeloid and lymphoid cells in the PB and spleens of GI cancer patients, independent of chemotherapy regimen. These results led us to question the impact of NCT on host immunity. We report herein, unique studies examining the splenic and PB phenotypes, frequencies, and numbers of myeloid and lymphoid cell populations in NCT treated GI cancer patients, as compared to treatment naïve cancer patients and patients with benign GI tumors at surgery. Overall, we noted limited immunological differences in patients 6 weeks following NCT (at surgery), as compared to treatment naive patients, supporting rapid immune normalization. We observed that NCT patients had a lower myeloid derived suppressor cells (MDSCs) frequency in the spleen, but not the PB, as compared to treatment naive cancer patients and patients with benign GI tumors. Further, NCT patients had a higher splenic and PB frequency of CD4 + T-cells, and checkpoint protein expression, as compared to untreated, cancer patients and patients with benign GI tumors. Interestingly, in NCT treated cancer patients the frequency of mature (CD45RO + ) CD4 + and CD8 + T-cells in the PB and spleens was higher than in treatment naive patients. These differences may also be associated, in part with patient stage, tumor grade, and/or NCT treatment regimen. In summary, the phenotypic profile of leukocytes at the time of surgery, approximately 6 weeks following NCT treatment in GI cancer patients, are similar to treatment naive GI cancer patients (i.e., patients who receive adjuvant therapy); suggesting that NCT may not limit the response to immune intervention and may improve tumor responses due to the lower splenic frequency of MDSCs and higher frequency of mature T-cells., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The purpose of this study was to verify the influence of physical activity level on the length of hospital stay in older men recovered from COVID-19. In total, 126 older men diagnosed with COVID-19 were admitted to the hospital between September and December 2020. Among them, 70 survived, of which 39 older men were included in the study. Within 30 days after discharge, patients answered the International Physical Activity Questionnaire to measure their physical activity level through phone contact, with questions corresponding to the week before symptom onset. Clinical and laboratorial data from admission, days between onset of symptoms and admission, length of stay, computed tomography abnormalities, and the need for the intensive care unit were collected. The groups (active × sedentary) were compared using the Student t test or Mann-Whitney test for quantitative data and chi-square test was used for categorical data. There is no difference between the groups in characteristics of admission ( p  > 0.05), except by potassium level. Active older men had a shorter length of stay (6.50 ± 3.46 vs 11.48 ± 7.63 days; p  = 0.03), disease duration (15.71 ± 4.84 vs 21.09 ± 7.69 days; p  = 0.02), and lower frequency of lung damage when compared to their sedentary counterparts. In conclusion, being physically active prior to infection can attenuate length of hospital stay in older men with COVID-19., Competing Interests: Conflict of interestThe authors report no conflict of interest., (© The Author(s), under exclusive licence to Springer-Verlag Italia S.r.l., part of Springer Nature 2022.)

The physicochemical properties, including nutrient and bioactive compound compositions, in fruit of four creole avocados (CA) from Mexico were determined and compared with those of 'Hass' fruit. 'Hass' pulp and some CA pulps contained similar concentrations of lutein, chlorophyll a, β-sitosterol and α-tocopherol. CA pulp contained 3.91-9.55% more oil than 'Hass'. Oil from CA pulp contained 10.10-26.79% more oleic acid than 'Hass' pulp. However, CA were small (CA = 81.40-137.15 g, 'Hass' = 188.59 g) and their pulp contents were low (CA = 39.83-84.82 g, 'Hass' = 144.14 g). CA peels were very thin, making these avocado peels edible but prone to mechanical damage. CA peels also contained higher concentrations and greater diversity of anthocyanins and glycosylated quercetin compounds than 'Hass' peels. Some CA were particularly rich in mannoheptulose and perseitol. Consumption of CA, including their peel, might result in higher intakes of some nutrients and bioactive compounds compared with 'Hass' avocados., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Myeloid derived suppressor cells (MDSCs) can be subset into monocytic (M-), granulocytic (G-) or polymorphonuclear (PMN-), and immature (i-) or early MDSCs and have a role in many disease states. In cancer patients, the frequencies of MDSCs can positively correlate with stage, grade, and survival. Most clinical studies into MDSCs have been undertaken with peripheral blood (PB); however, in the present studies, we uniquely examined MDSCs in the spleens and PB from patients with gastrointestinal cancers. In our studies, MDSCs were rigorously subset using the following markers: Lineage (LIN) (CD3, CD19 and CD56), human leukocyte antigen (HLA)-DR, CD11b, CD14, CD15, CD33, CD34, CD45, and CD16. We observed a significantly higher frequency of PMN- and M-MDSCs in the PB of cancer patients as compared to their spleens. Expression of the T-cell suppressive enzymes arginase (ARG1) and inducible nitric oxide synthase (i-NOS) were higher on all MDSC subsets for both cancer patients PB and spleen cells as compared to MDSCs from the PB of normal donors. Similar findings for the activation markers lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), program death ligand 1 (PD-L1) and program cell death protein 1 (PD-1) were observed. Interestingly, the total MDSC cell number exported to clustering analyses was similar between all sample types; however, clustering analyses of these MDSCs, using these markers, uniquely documented novel subsets of PMN-, M- and i-MDSCs. In summary, we report a comparison of splenic MDSC frequency, subtypes, and functionality in cancer patients to their PB by clustering and cytometric analyses., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The peels of ripe fruit of 'Hass' and 'Hass' type (HT) avocado cultivars were evaluated for phytochemical composition and other attributes. Peels represented from 8.78 to 14.11% of fruit weight. Their color ranged from homogeneous black to black with very small greenish spots. The oil content in the peels was low. Twelve fatty acids were identified in peel oil and the ratio of unsaturated to saturated fatty acids suggested that peel oil might contribute to human health. The phytochemical composition varied significantly with cultivar. However, many HT peels were superior than 'Hass' peel in their content of α-tocopherol, β-sitosterol, perseitol, and cyanidin-3-glucoside, which was up to 211.67, 45.92, 337.17, and 519.27% higher in HT peels, respectively. The content of some phenolic compounds, especially procyanidin B2 and epicatechin, was significantly lower in 'Hass' than in many HT peels. Few HT peels showed a higher content of carotenoids and chlorophyll than 'Hass' peels. Lutein was the most abundant carotenoid. Chlorophyll a and b were also abundant in peels and low concentrations of chlorophyll derivatives were observed. Avocado peels are an important source of bioactive compounds, including some carotenoids, acids, sterols, and volemitol, which were observed for the first time., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Hematologic malignancies such as leukemias and lymphomas are among the leading causes of pediatric cancer death worldwide, and although survival rates have improved with conventional treatments, the development of drug-resistant cancer cells may lead to patient relapse and limited possibilities of a cure. Drug-resistant cancer cells in these hematologic neoplasms are induced by overexpression of the antiapoptotic B-cell lymphoma 2 (Bcl-2) protein families, such as Bcl- XL , Bcl-2, and Mcl-1. We have previously shown that peptides from the BH3 domain of the proapoptotic Bax protein that also belongs to the Bcl-2 family may antagonize the antiapoptotic activity of the Bcl-2 family proteins, restore apoptosis, and induce chemosensitization of tumor cells. Furthermore, cell-permeable Bax BH3 peptides also elicit antitumor activity and extend survival in a murine xenograft model of human B non-Hodgkin's lymphoma. However, the activity of the BH3 peptides of the proapoptotic Bak protein of the Bcl-2 family against these hematologic malignant cells requires further characterization. In this study, we report the ability of the cell-permeable Bak BH3 peptide to restore apoptosis and induce chemosensitization of acute lymphoblastic leukemia and non-Hodgkin's lymphoma cell lines, and this event is enhanced with the coadministration of cell-permeable Bax BH3 peptide and represents an attractive approach to improve the patient outcomes with relapsed or refractory hematological malignant cells., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Omar Ugarte-Alvarez et al.)

In this work, we studied the mechanisms of classical activation and inactivation of signal transduction by the histamine H3 receptor, a 7-helix transmembrane bundle G-Protein Coupled Receptor through long-time-scale atomistic molecular dynamics simulations of the receptor embedded in a hydrated double layer of dipalmitoyl phosphatidyl choline, a zwitterionic polysaturated ordered lipid. Three systems were prepared: the apo receptor, representing the constitutively active receptor; and two holo-receptors-the receptor coupled to the antagonist/inverse agonist ciproxifan, representing the inactive state of the receptor, and the receptor coupled to the endogenous agonist histamine and representing the active state of the receptor. An extensive analysis of the simulation showed that the three states of H3R present significant structural and dynamical differences as well as a complex behavior given that the measured properties interact in multiple and interdependent ways. In addition, the simulations described an unexpected escape of histamine from the orthosteric binding site, in agreement with the experimental modest affinities and rapid off-rates of agonists.

Patients with resectable tumor, either in the body or the tail of the pancreas, and cancer patients with a primary tumor adjacent to the splenic vasculature frequently undergo a splenectomy as standard of care during resection. The spleen provides an unutilized source of lymphocytes with potential utility for adoptive cellular therapy (ACT). In this report, spleen and peripheral blood (PB) cells from cancer patients were compared to one another and normal PB by flow cytometry with a focus on CD8 + T-cells, memory phenotype, and their relative expression of checkpoint proteins including program death ligand-1 (PD1). PD1 is both an activation marker for T-cells including antigen (Ag) specific responses, as well as a marker of T-cell exhaustion associated with co-expression of other checkpoint molecules such as lymphocyte activating gene-3 (LAG-3) and T-cell immunoglobulin and mucin domain containing-3 (TIM-3). In summary, the spleen is a rich source of CD8 + PD1 + T-cells, with an 8-fold higher frequency compared to the PB. These CD8+ T-cells are predominantly central and transitional memory T-cells with associated effector phenotypes and low expression of TIM-3 and LAG-3 with potential utility for ACT"., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cognitive deficits often occur in people with epilepsy (PWE). However, in Brazil, PWE might not undergo neurocognitive evaluation due to the low number of validated tests available and lack of multidisciplinary teams in general epilepsy outpatient clinics., Objective: To correlate Brief Cognitive Battery-Edu (BCB-Edu) scores with epilepsy characteristics of 371 PWE., Methods: Clinical and cognitive assessment (MMSE, BCB-Edu) of 371 PWE aged >18 years was performed. The clinical aspects of epilepsy were correlated with BCB-Edu data. Cognitive data of PWE were compared against those of 95 healthy individuals (NC), with p-<0.05., Results: People with epilepsy had lower cognitive performance than individuals in the NC group. Cognitive aspects also differed according to epilepsy characteristics. Predictive factors for impairment in multiple cognitive domains were age and use of more than one antiepileptic drug (logistic regression; R 2 Nagelkerke=0.135)., Conclusion: Worse cognitive performance was found in PWE on different domains. There was a relationship between cognitive impairment and the aspects of epilepsy. BCB-Edu proved to be effective as a cognitive assessment screening test for epilepsy in adults., Competing Interests: Disclosure: The authors report no conflicts of interest.

Intestinal transplant recipients (ITR) are at high risk for infections due to the high level of immunosuppression required to prevent rejection. There are limited data regarding viral enteritis post-intestinal transplantation. We retrospectively reviewed ITR transplanted between January 2008 and December 2016. Descriptive statistics, including mean (standard deviation) and median (range), were performed. Sixty-one (43.9%) of the 139 transplanted patients had viral enteritis: 26% norovirus, 25% adenovirus, and 9% each rotavirus and sapovirus. The median age of pediatric patients was 1.6 years (0.4-16.9) and for adults 36.3 years (27.1-48.2). Fifty-seven (58%) of 99 pediatric ITR had viral enteritis compared to 4 (10%) of 40 adult ITR. Median time-to-clinical resolution of enteritis for all patients was 5 days (1-92). Standard of care therapies administered: anti-motility agents (10%), anti-emetics agents (14%), and intravenous fluids (42%). There was a higher incidence of viral enteritis in pediatric compared to adults ITR. The majority of viral enteritis episodes resolved within 1 week and were treated with supportive therapy., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Spine pathology has been implicated in the early onset of Alzheimer's disease (AD), where Aβ-Oligomers (AβOs) cause synaptic dysfunction and loss. Previously, we described that pharmacological inhibition of c-Abl prevents AβOs-induced synaptic alterations. Hence, this kinase seems to be a key element in AD progression. Here, we studied the role of c-Abl on dendritic spine morphological changes induced by AβOs using c-Abl null neurons (c-Abl-KO). First, we characterized the effect of c-Abl deficiency on dendritic spine density and found that its absence increases dendritic spine density. While AβOs-treatment reduces the spine number in both wild-type (WT) and c-Abl-KO neurons, AβOs-driven spine density loss was not affected by c-Abl. We then characterized AβOs-induced morphological changes in dendritic spines of c-Abl-KO neurons. AβOs induced a decrease in the number of mushroom spines in c-Abl-KO neurons while preserving the populations of immature stubby, thin, and filopodia spines. Furthermore, synaptic contacts evaluated by PSD95/Piccolo clustering and cell viability were preserved in AβOs-exposed c-Abl-KO neurons. In conclusion, our results indicate that in the presence of AβOs c-Abl participates in synaptic contact removal, increasing susceptibility to AβOs damage. Its deficiency increases the immature spine population reducing AβOs-induced synapse elimination. Therefore, c-Abl signaling could be a relevant actor in the early stages of AD., (Copyright © 2019 Gutierrez, Vargas, Chandia-Cristi, de la Fuente, Leal and Alvarez.)

The survival of patients with non-Hodgkin's lymphoma (NHL) has substantially improved with current treatments. Nevertheless, the appearance of drug-resistant cancer cells leads to patient relapse. It is therefore necessary to find new antitumor therapies that can completely eradicate transformed cells. Chemotherapy-resistant cancer cells are characterized by the overexpression of members of the anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein family, such as Bcl- XL , Bcl-2, and Mcl-1. We have recently shown that peptides derived from the BH3 domain of the pro-apoptotic Bax protein may antagonize the anti-apoptotic activity of the Bcl-2 family proteins, restore apoptosis, and induce chemosensitization of tumor cells. In this study, we investigated the feasibility of releasing this peptide into the tumor microenvironment using live attenuated Salmonella enterica , which has proven to be an ally in cancer therapy due to its high affinity for tumor tissue, its ability to activate the innate and adaptive antitumor immune responses, and its potential use as a delivery system of heterologous molecules. Thus, we expressed and released the cell-permeable Bax BH3 peptide from the surface of Salmonella enterica serovar Typhimurium SL3261 through the MisL autotransporter system. We demonstrated that this recombinant bacterium significantly decreased the viability and increased the apoptosis of Ramos cells, a human B NHL cell line. Indeed, the intravenous administration of this recombinant Salmonella enterica elicited antitumor activity and extended survival in a xenograft NHL murine model. This antitumor activity was mediated by apoptosis and an inflammatory response. Our approach may represent an eventual alternative to treat relapsing or refractory NHL., (Copyright © 2019 Mateos-Chávez, Muñoz-López, Becerra-Báez, Flores-Martínez, Prada-Gracia, Moreno-Vargas, Baay-Guzmán, Juárez-Hernández, Chávez-Munguía, Cabrera-Muñóz and Luria-Pérez.)

Open abdomen and fascial dehiscence after intestinal transplantation increase morbidity. This study aims to identify recipient and donor factors associated with failure to achieve sustained primary closure (failed-SPC) of the abdomen after intestinal transplant. We conducted a single-center retrospective study of 96 intestinal transplants between 2013 and 2018. Thirty-eight (40%) were adult patients, and 58 were pediatric patients. Median age at transplantation was 36.0 and 5.8 years, respectively. Failed-SPC occurred in 31 (32%) patients. Identified risk factors of failed-SPC included preexisting enterocutaneous fistula (OR: 6.8, CI: 2.4-19.6, P = .0003), isolated intestinal graft (OR: 3.4, CI: 1.24-9.47, P = .02), male sex in adults (OR: 3.93, CI: 1.43-10.8, P = .009), and age over four years (OR: 6.22, CI: 1.7-22.7, P = .004). There was no association with primary diagnosis and prior transplant with failed-SPC. Donor-to-recipient size ratios did not predict failed-SPC. There was an association between failed-SPC and extended median hospital stay (100 vs 57 days, P = .007) and increased time to enteral autonomy in pediatric patients. There is a relationship between failed-SPC and a higher rate of laparotomy (OR: 21.4, CI: 2.78-178.2, P = .0003) and fistula formation posttransplant (OR: 11.4, CI: 2.83-45.84, P = .0005) in pediatric patients. Given inferior outcomes with failed-SPC, high-risk recipients require careful evaluation., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Biliary cancer is a highly aggressive malignancy arising from the biliary tree, with its incidence increasing steadily on a global level. Most biliary cancers are diagnosed in the advanced and metastatic stages due to the paucity of signs and symptoms in the early presentation. Only about one-third of the patients can be treated with curative intent with an overall median survival of less than 24 months for all-comers from the time of diagnosis. This fact and the poor results of the currently available local and systemic therapies, are responsible for the disappointing outcome of biliary cancer patients. There is an unmet need for novel therapeutic approaches. Surgery, the backbone of curative treatments for biliary cancer, is effective in early, completely-resectable stages or in combination with neoadjuvant or adjuvant chemotherapy and/or radiation therapy for locally advanced stages. Systemic therapies in unresectable and recurrent cases are associated with poor outcomes. The introduction of next-generation sequencing technologies has opened new horizons for a better understanding of the molecular basis of this cancer with potential identification and evaluation of new treatment options.

Aims: To describe the methodology of the EPISER 2016 (study of the prevalence of rheumatic diseases in adult population in Spain), as well its strengths and limitations. The aim of this study is to estimate the prevalence of rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), osteoarthritis (knee, hip, hands, and cervical and lumbar spine), fibromyalgia, gout and clinical osteoporotic fracture., Material and Method: Population-based, multicenter, cross-sectional study, with the participation of 45 municipalities in the 17 Spanish autonomous communities. The reference population will consist of adults aged 20 years and over residing in Spain. A computer-assisted telephone interview (CATI) system will be used for data collection. Diagnostic suspicions and diagnoses received by the participants will be studied by rheumatologists in the referral hospitals in the selected municipalities., Statistical Analysis: the prevalence of the rheumatic diseases will be calculated using estimators and their 95% confidence intervals. Weights will be calculated in each of the sampling stages in accordance with the probability of selection. The distribution of the population in Spain will be obtained from the Spanish Statistics Institute., Conclusions: Sociodemographic and lifestyle changes over the last 16 years justify EPISER 2016. This study will provide current data about the prevalences of RA, AS, PsA, SLE, SS, osteoarthritis, fibromyalgia, gout and clinical osteoporotic fracture. The results will allow comparisons with studies from other countries and EPISER 2000., (Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

The deficiency of glucose‑6‑phosphate dehydrogenase (G6PD) is one of the most common inborn errors of metabolism worldwide. This congenital disorder generally results from mutations that are spread throughout the entire gene of G6PD. Three single-point mutations for G6PD have been reported in the Mexican population and named Veracruz (Arg365His), G6PD Seattle (Asp282His), and G6PD Mexico DF (Thr65Ala), whose biochemical characterization have not yet been studied. For this reason, in this work we analyzed the putative role of the three mutations to uncover the functional consequences on G6PD activity. To this end, was developed a method to clone, overexpress, and purify recombinant human G6PD. The results obtained from all variants showed a loss of catalysis by 80 to 97% and had a decrease in affinity for both physiological substrates with respect to the wild type (WT) G6PD. Our results also showed that the three mutations affected three-dimensional structure and protein stability, suggesting an unstable structure with low conformational stability that affected its G6PD functionality. Finally, based on the biochemical characterization of the unclassified G6PD Mexico DF, we suggest that this variant could be grouped as a Class I variant, because biochemical data are similar with other Class I G6PDs., (Copyright © 2018. Published by Elsevier B.V.)

Introduction: Cholelithiasis is common in patients with short bowel syndrome (SBS). Prophylactic cholecystectomy (PC) of the non-diseased gallbladder has been recommended in SBS patients when laparotomy is being undertaken for other reasons. Our aim was to determine if PC is being utilized., Methods: 500 adults with SBS were seen over a 25 year period. 215 undergoing cholecystectomy prior to SBS were excluded, leaving 285 patients for evaluation., Results: 151 (53%) SBS patients underwent a subsequent laparotomy. 77 underwent cholecystectomy for cholelithiasis at the 1st opportunity. 27 patients underwent a PC at the 1st opportunity. 47 patients did not undergo PC at the 1st opportunity. 17 (36%) of these 47 patients subsequently developed cholelithiasis with 7 undergoing cholecystectomy. Age, gender, diagnosis and initial BMI and need for longterm parenteral nutrition were similar in patients who had PC or did not. PC patients were more likely to have intestinal remnant length <60 cm (59% vs 21%, p < .05)., Conclusions: Overall 10% of SBS patients underwent PC. However, only 36% of eligible patients undergoing laparotomy had a PC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Children undergoing LSBPTx are at increased risk of IPI due to splenectomy. We aimed to describe the clinical features and outcomes of IPI in pediatric LSBPTx recipients. Between 2008 and 2016, 122 LSBPTx children at our center were retrospectively reviewed. Nine patients had 12 episodes of IPI; the median age at first infection was 3.5 years (range: 1.5-7.1 years). The median time from transplant to first infection was 3 years (range: 0.8-5.8 years). Clinical presentation included as follows: pneumonia (n = 1), bacteremia/sepsis (n = 7), pneumonia with sepsis (n = 1), meningitis with sepsis (n = 2), pneumonia and meningitis with sepsis (n = 1). The overall risk for IPI was 7.4% or 0.9% per year. The mortality rate was 22%. Seven (78%) children had received at least one dose of PCV13, four (44%) patients had received 23-valent pneumococcal polysaccharide vaccine prior to IPI. All patients were on oral penicillin prophylaxis. In conclusion, despite partial or complete pneumococcal immunization and reported antimicrobial prophylaxis, IPI in LSBPTx children can have a fatal outcome. Routine monitoring of pneumococcal serotype antibodies to determine the timing for revaccination might be warranted to ensure protective immunity in these transplant recipients., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Alzheimer's disease (AD) is characterized by progressive memory loss and dementia. The strong correlation between cognitive decline and the loss of synapses supports the idea that synaptic damage is a relevant pathogenic mechanism underlying AD progression. It has been shown that amyloid beta oligomers (AβOs) induce synaptotoxicity ultimately leading to the reduction of dendritic spine density, which underlies cognitive damage. However, the signaling pathways connecting AβOs to synaptic dysfunction have not been completely elucidated. In this review, we have gathered evidence on AβOs receptors and the signaling pathways involved in synaptic damage. We make special emphasis on a new AβOs induced axis that involves the tyrosine kinase ephrin receptor A4 (EphA4) and c-Abl tyrosine kinase activation. EphA4 is a key player in homeostatic plasticity, mediating dendritic spine remodeling and retraction. AβOs aberrantly activate EphA4 leading to dendritic spine elimination. c-Abl is activated in AβOs exposed neurons and in AD patient's brain, and the inhibition of activated c-Abl ameliorates cognitive deficits in AD mouse model. The EphA4 receptor activates c-Abl intracellular signaling. Therefore EphA4 is an emerging AβOs receptor and the activation of the EphA4/c-Abl axis would explain the synaptic spine alterations found in AD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Splenic artery aneurysm is the most common visceral arterial aneurysm. Rupture of aneurysm is a rare event but associated with a high mortality. Endovascular coil embolization of bleeding splenic artery aneurysm has emerged as a promising minimal invasive treatment and considered safer than open surgery in selected patients. Nevertheless, several complications related to coils have been reported, the rarest being coil migration and erosion. We report a case of splenic artery coil migration into the stomach and its successful removal by laparoscopic endoscopy combined surgery.

Aims: The purpose of this study was to evaluate the effect of warehouse storage conditions on the composition of the fungal community of green coffee beans (GCB) that were stored in jute sacks for 1 year., Methods and Results: Molecular characterization of the fungal community composition and population dynamics obtained by Q-PCR, CE-SSCP (Simpson's diversity index D) and Illumina MiSeq sequencing indicated that Saccharomycetales dominated during the first 6 months of storage period with species as Meyerozyma guilliermondii and Pichia kluyveri. However, after 6 months of storage, the filamentous genus Wallemia became dominant. Principal components analysis correlated this fungal dynamic with storage conditions and other variables as chromaticity (colour), water activity, moisture content, reducing sugars concentration, fungal infection and ochratoxin A production., Conclusions: This study demonstrated that GCB stored in jute sacks after 6 months of storage lead to fungal population dynamics, decreased chromaticity in GCB by bleaching and, then, affected overall quality., Significance and Impact of the Study: Storage plays an important role in the quality evolution during the handling of the GCB. In this context, the composition of the microbial community could be considered a marker to assess the trade value of the coffee beans., (© 2017 The Society for Applied Microbiology.)

The design of new drugs that target vasopressin 2 receptor (V2R) is of vital importance to develop new therapeutic alternatives to treat diseases such as heart failure, polycystic kidney disease. To get structural insights related to V2R-ligand recognition, we have used a combined approach of docking, molecular dynamics simulations (MD) and quantitative structure-activity relationship (QSAR) to elucidate the detailed interaction of the V2R with 119 of its antagonists. The three-dimensional model of V2R was built by threading methods refining its structure through MD simulations upon which the 119 ligands were subjected to docking studies. The theoretical results show that binding recognition of these ligands on V2R is diverse, but the main pharmacophore (electronic and π-π interactions) is maintained; thus, this information was validated under QSAR results. QSAR studies were performed using MLR analysis followed by ANN analysis to increase the model quality. The final equation was developed by choosing the optimal combination of descriptors after removing the outliers. The applicability domains of the constructed QSAR models were defined using the leverage and standardization approaches. The results suggest that the proposed QSAR models can reliably predict the reproductive toxicity potential of diverse chemicals, and they can be useful tools for screening new chemicals for safety assessment., (© 2017 John Wiley & Sons A/S.)

Background: Postresection intestinal adaptation is an augmented self-renewal process that might increase the risk of malignant transformation in the intestine. Furthermore, patients with short bowel syndrome (SBS) have other characteristics that might increase this risk. Our aim was to determine the incidence of new intestinal malignancy in SBS patients., Methods: We reviewed the records of 500 adult SBS patients identified from 1982-2013. There were 199 men and 301 women ranging in age from 19-91 years. Follow-up from the time of diagnosis of SBS ranged from 12-484 months. A total of 186 (37%) patients were followed >5 years., Results: The cause of SBS was postoperative in 35% of patients, malignancy/radiation in 19%, mesenteric vascular disease in 17%, Crohn's disease in 16%, and other in 13%. Twenty-eight (6%) patients received growth stimulatory medications. Fifteen percent of patients had a prior total colectomy. Twenty-eight (6%) patients underwent intestinal transplantation, and 115 (23%) patients had a previous abdominal malignancy, including colorectal cancer in 43 patients. Thirty-six (7%) received radiation therapy. Recurrent colon cancer was found in 2 patients, one at a stoma and the other with lung metastases. New colon cancer was found in 1 patient (0.2%), a 62-year-old woman with long-standing Crohn's disease., Conclusion: The incidence of colon cancer in this heterogenous group of patients with SBS was similar to that of the normal population. This suggests that the risk of developing a new colon cancer in patients with SBS is not increased.

Females are born with a finite number of oocyte-containing follicles and ovary damage results in reduced fertility. Cadmium accumulates in the reproductive system, damaging it, and the cigarette smoke is a potential exposure route. Natural therapies are relevant to health benefits and disease prevention. This study verified the effect of cadmium exposure on the ovaries of mice and the blueberry extract as a potential therapy. Blueberry therapy was effective in restoring reactive species levels and δ-aminolevulinate dehydratase activity, and partially improved the viability of cadmium-disrupted follicles. This therapy was not able to restore the 17 β-hydroxysteroid dehydrogenase activity. Extract HPLC evaluation indicated the presence of quercetin, quercitrin, isoquercetin, and ascorbic acid. Ascorbic acid was the major substance and its concentration was 620.24 µg/mL. Thus, cadmium accumulates in the ovaries of mice after subchronic exposure, inducing cellular damage, and the blueberry extract possesses antioxidant properties that could protect, at least in part, the ovarian tissue from cadmium toxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 188-196, 2017., (© 2015 Wiley Periodicals, Inc.)

The efficiency and the propensity of a drug to be bound to its target protein have been inseparable concepts for decades now. The correlation between the pharmacological activity and the binding affinity has been the first rule to design and optimize a new drug rationally. However, this argument does not prove to be infallible when the results of in vivo assays have to be confronted. Only recently, we understand that other magnitudes as the kinetic rates of binding and unbinding, or the mean residence time of the complex drug-protein, are equally relevant to draw a more accurate model of the mechanism of action of a drug. It is in this scenario where new computational techniques to simulate the all-atom dynamics of the biomolecular system find its valuable place on the challenge of designing new molecules for more effective and less toxic therapies., (Copyright © 2016 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.)

Developing a novel drug is a complex, risky, expensive and time-consuming venture. It is estimated that the conventional drug discovery process ending with a new medicine ready for the market can take up to 15 years and more than a billion USD. Fortunately, this scenario has recently changed with the arrival of new approaches. Many novel technologies and methodologies have been developed to increase the efficiency of the drug discovery process, and computational methodologies have become a crucial component of many drug discovery programs. From hit identification to lead optimization, techniques such as ligand- or structure-based virtual screening are widely used in many discovery efforts. It is the case for designing potential anticancer drugs and drug candidates, where these computational approaches have had a major impact over the years and have provided fruitful insights into the field of cancer. In this paper, we review the concept of rational design presenting some of the most representative examples of molecules identified by means of it. Key principles are illustrated through case studies including specifically successful achievements in the field of anticancer drug design to demonstrate that research advances, with the aid of in silico drug design, have the potential to create novel anticancer drugs., (Copyright © 2016 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.)

Background: Recently, an association has been proposed between cholecystectomy and various liver diseases. Our aim was to determine whether cholecystectomy in short bowel patients influences the risk of liver disease., Methods: We reviewed 422 adults: 182 underwent cholecystectomy prior to short bowel, 102 after developing short bowel, and 138 patients still had the gallbladder in place., Results: Compared to pre and post short bowel, gallbladder patients were significantly less likely to have obesity (18 % and 21 % vs 9 %), central line infections (59 % and 69 % vs 46 %), intestine <60 cm (30 % and 39 % vs 26 %), and require parenteral nutrition >1 year (72 % and 77 % vs 64 %). The incidence of fatty liver was similar (31, 26, and 25 %). Fibrosis/cirrhosis was less common in the gallbladder group (26 % and 36 % vs 16 %). Frequency of end-stage liver disease was similar (15, 22, and 11 %). On multivariate analysis, cholecystectomy, parenteral nutrition >1 year, line infection, and intestine <60 cm were predictors of fibrosis/cirrhosis. Parenteral nutrition >1 year, line infection, and intestine <60 cm were predictors of end-stage liver disease., Conclusions: Cholecystectomy does not appear to increase the incidence of liver disease in short bowel patients overall. Fibrosis/cirrhosis occurs significantly less frequently in patients with an intact gallbladder.

Aims: Hippocampus is the brain center for memory formation, a process that requires synaptogenesis. However, hippocampus is dramatically compromised in Alzheimer's disease due to the accumulation of amyloid β-peptide, whose production is initiated by β-site APP Cleaving Enzyme 1 (BACE1). It is known that pathological stressors activate BACE1 translation through the phosphorylation of the eukaryotic initiation factor-2α (eIF2α) by GCN2, PERK, or PKR kinases, leading to amyloidogenesis. However, BACE1 physiological regulation is still unclear. Since nitric oxide (NO) participates directly in hippocampal glutamatergic signaling, we investigated the neuronal role of the heme-regulated eukaryotic initiation factor eIF2α kinase (HRI), which can bind NO by a heme group, in BACE1 translation and its physiological consequences., Results: We found that BACE1 is expressed on glutamate activation with NO being the downstream effector by triggering eIF2α phosphorylation, as it was obtained by Western blot and luciferase assay. It is due to the activation of HRI by NO as assayed by Western blot and immunofluorescence with an HRI inhibitor and HRI siRNA. BACE1 expression was early detected at synaptic spines, contributing to spine growth and consolidating the hippocampal memory as assayed with mice treated with HRI or neuronal NO synthase inhibitors., Innovation: We provide the first description that HRI and eIF2α are working in physiological conditions in the brain under the control of nitric oxide and glutamate signaling, and also that BACE1 has a physiological role in hippocampal function., Conclusion: We conclude that BACE1 translation is controlled by NO through HRI in glutamatergic hippocampal synapses, where it plays physiological functions, allowing the spine growth and memory consolidation.

Background: In cattle, recent studies have shown positive associations between pre-ovulatory concentrations of estradiol (E2), progesterone (P4) at early diestrus and fertility. However, information on cellular and molecular mechanisms through which sex steroids regulate uterine function to support early pregnancy is lacking. Based on endometrial transcriptome data, objective was to compare function of the redox system in the bovine uterus in response to different periovulatory endocrine milieus., Methods: We employed an animal model to control growth of the pre-ovulatory follicle and subsequent corpus luteum (CL). The large follicle-large CL group (LF-LCL, N=42) presented greater levels of E2 on the day of GnRH treatment (D0; 2.94 vs. 1.27 pg/mL; P=0.0007) and P4 at slaughter on D7 (3.71 vs. 2.62 ng/mL, P=0.01), compared with the small follicle-small CL group (SF-SCL, N=41). Endometrium and uterine washings (N=9, per group) were collected for analyses of variables associated with the uterine redox system., Results: The SF-SCL group had lower endometrial catalase (0.5 vs. 0.79 U/mg protein, P<0.001) and glutathione peroxidase (GPx; 2.0 vs. 2.43 nmol β-nicotinamide adenine dinucleotide phosphate reduced/min/mg protein, P=0.04) activity, as well as higher lipid peroxidation (28.5 vs. 17.43 nmol malondialdehyde/mg of protein, P<0.001) and superoxide dismutase (SOD) activity (44.77 vs. 37.76 U; P=0.04). There were no differences in the endometrial reactive species (RS) or glutathione (GSH) concentrations between the groups. The uterine washing samples showed no differences in the concentrations of RS or GSH or in total SOD activity (P>0.1). Additionally, catalase, GPx4, SOD1 and SOD2 gene expression was lower in the SF-SCL group than in the LF-LCL group., Conclusions: We concluded that the intrauterine environment of cows from the LF-LCL group exhibited higher antioxidant activity than that of the cows from the SF-SCL group. We speculate that uterine receptivity and fertility are associated with an optimal redox environment, such as that present in the animals in the LF-LCL group.

Green tea presents catechins as its major components and it has a potential antioxidant activity. Cyclophosmamide (CP) is an antineoplastic and immunosuppressive agent, known to reduce fertility. In the present study, we evaluated the effect of green tea infusion on cyclophosphamide-induced damage in male mice reproductive system. Mice received green tea infusion (250 mg/kg) or vehicle by gavage for 14 days. Saline or CP were injected intraperitoneally at a single dose (100 mg/kg) at the 14th day. Animals were euthanized 24 h after CP administration and testes and epididymis were removed for biochemical analysis and sperm evaluation. Catechins concentration in green tea infusion was evaluated by HPLC. CP increased lipid peroxidation, DNA damage and superoxide dismutase activity whereas sperm concentration, glutathione peroxidase (GPx), glutathione S-transferase (GST) and 17β-hydroxysteroid (17β-HSD) dehydrogenase activities were reduced in both tissues tested. Catalase activity and protein carbonyl levels were changed only in testes, after CP administration. Green tea pre-treatment reduced significantly lipid peroxidation, protein carbonylation, DNA damage and restored GPx and GST activity in testes. In epididymis, therapy significantly increased sperm concentration and restored GPx and 17β-HSD activity. Green tea improves CP-induced damage on reproductive system, probably due to their high catechins content.

Aplastic anemia (AA) has been observed in nearly a third of patients undergoing liver transplantation (LT) for non-A-E fulminant hepatic failure (FHF). Few of these patients have been successfully managed with sequential LT and bone marrow transplantation (BMT). No causative agent has been identified for the FHF or AA in these reported cases. At our center, two patients, aged 15 years and 7 years, respectively, underwent sequential living-related LT and living-unrelated BMT. These patients are 10/9 years and 5/4 years post-LT/BMT. Human parvovirus B19 (HPV-B19) was established as the causative agent for FHF in both these patients by polymerase chain reaction. This report presents the first two cases associating HPV-B19 with FHF and AA who underwent sequential LT and BMT with excellent outcomes., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Progesterone (P4) is the main steroid secreted by the corpora lutea (CL) and is required for successful implantation and maintenance of pregnancy. Although adequate circulating levels of thyroid hormone (TH) are needed to support formation and maintenance of CL during pregnancy, TH signaling had not been described in this gland. We determined luteal thyroid hormone receptor isoforms (TR) expression and regulation throughout pregnancy and under the influence of thyroid status, and in vitro effects of triiodothyronine (T3) exposure on luteal P4 synthesis., Methods: Euthyroid female Wistar rats were sacrificed by decapitation on gestational day (G) 5, G10, G15, G19, or G21 of pregnancy or on day 2 postpartum (L2). Hyperthyroidism and hypothyroidism were induced in female Wistar rats by daily administration of thyroxine (T4; 0.25 mg/kg subcutaneously) or 6-propyl-2-thiouracil (PTU; 0.1 g/L in drinking water), respectively. Luteal TR expression of mRNA was determined using real-time reverse-transcription quantitative polymerase chain reaction, and of protein using Western blot and immunohistochemistry. Primary cultures of luteal cells and of luteinized granulosa cells were used to study in vitro effects of T3 on P4 synthesis. In addition, the effect of T3 on P4 synthesis under basal conditions and under stimulation with luteinizing hormone (LH), prolactin (PRL), and prostaglandin E2 (PGE2) was evaluated., Results: TRα1, TRα2, and TRβ1 mRNA were present in CL, increasing during the first half and decreasing during the second half of pregnancy. At the protein level, TRβ1 was abundantly expressed during gestation reaching a peak at G19 and decreasing afterwards. TRα1 was barely expressed during early gestation, peaked at G19, and diminished thereafter. Expression of TRβ1 and TRα1 at the protein and mRNA level were not influenced by thyroid status. T3 neither modified P4 secretion from CL of pregnancy nor its synthesis in luteinized granulosa cells in culture., Conclusions: This study confirms for the first time the presence of TR isoforms in the CL during pregnancy and postpartum, identifying this gland as a TH target during gestation. TR expression is modulated in this tissue in accordance with the regulation of P4 metabolism, and the abrupt peripartum changes suggest a role of TH during luteolysis. However, TH actions on the CL do not seem to be related to a direct regulation of P4 synthesis.

The early stages of Alzheimer's disease are characterised by impaired synaptic plasticity and synapse loss. Here, we show that amyloid-β oligomers (AβOs) activate the c-Abl kinase in dendritic spines of cultured hippocampal neurons and that c-Abl kinase activity is required for AβOs-induced synaptic loss. We also show that the EphA4 receptor tyrosine kinase is upstream of c-Abl activation by AβOs. EphA4 tyrosine phosphorylation (activation) is increased in cultured neurons and synaptoneurosomes exposed to AβOs, and in Alzheimer-transgenic mice brain. We do not detect c-Abl activation in EphA4-knockout neurons exposed to AβOs. More interestingly, we demonstrate EphA4/c-Abl activation is a key-signalling event that mediates the synaptic damage induced by AβOs. According to this results, the EphA4 antagonistic peptide KYL and c-Abl inhibitor STI prevented i) dendritic spine reduction, ii) the blocking of LTP induction and iii) neuronal apoptosis caused by AβOs. Moreover, EphA4-/- neurons or sh-EphA4-transfected neurons showed reduced synaptotoxicity by AβOs. Our results are consistent with EphA4 being a novel receptor that mediates synaptic damage induced by AβOs. EphA4/c-Abl signalling could be a relevant pathway involved in the early cognitive decline observed in Alzheimer's disease patients.

Objective: To analyze the effects of serial transverse enteroplasty (STEP) on parenteral and enteral calories in children with short bowel syndrome, and examine short- and long-term complications., Study Design: A retrospective analysis of prospectively-collected data from a large single center cohort of patients undergoing STEP procedure was analyzed. Baseline demographic and clinical information, operative data, and short- and long-term complications were recorded. Detailed growth and nutritional data were obtained for 6 months prior and 12 months following STEP procedure., Results: Sixty-eight procedures were performed in 51 patients over a 68-month period. Median bowel length at first STEP was 51 cm with a median length gain of 54%. Repeat STEP patients had longer initial length (77 cm) and reduced length gain (20%). Operative times and blood loss were low, with few complications. Parenteral calorie requirement was stable or rising for 6 months prior to STEP, but decreased to median <20 kCal/kg/d at 1 year postop. Longer length gains were associated with higher risk of stricture formation. Seven children were transplanted, and 60% of nontransplanted children were enterally independent, with the remainder making ongoing progress; 48/51 children are alive at a median of 39 months follow-up., Conclusions: STEP is shown to be safe, well tolerated, and to have definitive benefit in reducing parenteral calorie requirements over the first year following the procedure. It has an important role in achieving enteral independence in children with short bowel syndrome., (Published by Mosby, Inc.)

Despite its vast potential, concerns about donor safety continue to limit the expansion of living-donor liver transplantation (LDLT) in Western countries. In light of the technical refinements, relatively lower risk of complications with left lobe (LL) LDLT with comparable outcomes, and the overriding concern for donor safety, there is renewed interest in using LL allograft as the first choice for LDLT; thereby, fundamentally shifting the risks of LDLT from the donor to the recipient. There is ample evidence that LL LDLT when performed with graft inflow modification where indicated, has long-term outcomes as good as cadaveric LT., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Cadmium (Cd) toxicity is a concern to the tobacco-smoking sub-population which includes millions of people worldwide. Although this metal may cause severe damage to embryos and the reproductive organs, the precise mechanisms underlying its toxicity remain unclear. In the present study, the Cd effect on ovary δ-aminolevulinate dehydratase (δ-ALA-D) activity was investigated in vitro and ex vivo. We observed that low concentrations of Cd inhibited cow ovary δ-ALA-D activity in vitro and the IC50 value obtained was 19.17 μM. Furthermore, the protective effect of a novel organic selenium compound (seleno-furanoside) in restoring enzyme activity was evaluated. Seleno-furanoside (10, 50, 100, 200, 400 and 1000 μM) did not reverse the Cd toxicity in bovine ovarian tissue in vitro. According to the in vitro reults, acute Cd exposure (2.5 and 5 mg kg(-1)) caused a significant inhibition in ovary δ-ALA-D activity in mice (around 27% and 34%, respectively). Therapy with seleno-furanoside (100 µmol kg(-1)) was able to restore enzyme activity. Thus, we demonstrated for the first time that δ-ALA-D activity from ovary is inhibited by Cd both in vitro and ex vivo. Additionally, seleno-furanoside therapy was effective in restoring ovarian enzyme activity inhibited by Cd exposure in mice, but it did not reverse the in vitro metal effect. This study detected a new toxicity marker of Cd toxicity on ovarian tissue as well as the beneficial effect of a new compound to manage the metal effect after acute exposure., (Copyright © 2012 John Wiley & Sons, Ltd.)