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Umeclidinium (UMEC), a long-acting muscarinic antagonist approved for chronic obstructive pulmonary disease (COPD), was investigated for primary hyperhidrosis as topical therapy. This study evaluated the pharmacokinetics, safety, and tolerability of a single dose of [14C]UMEC applied to either unoccluded axilla (UA), occluded axilla (OA), or occluded palm (OP) of healthy males. After 8 h the formulation was removed. [14C]UMEC plasma concentrations (Cp) were quantified by accelerator mass spectrometry. Occlusion increased systemic exposure by 3.8-fold. Due to UMEC absorption-limited pharmacokinetics, Cp data from the OA were combined with intravenous data from a phase I study. The data were described by a two-compartment population model with sequential zero and first-order absorption and linear elimination. Simulated systemic exposure following q.d. doses to axilla was similar to the exposure from the inhaled therapy, suggesting that systemic safety following dermal administration can be bridged to the inhaled program, and offering the potential for a reduced number of studies and/or subjects. [ABSTRACT FROM AUTHOR]

En Kañaris (Lambayeque) se encuentran grandes bosques relictos, probablemente los mayores de la vertiente occidental de los Andes peruanos. Actualmente están muy bien conservados, pero al mismo tiempo es la zona botánicamente menos estudiada de todos los bosques relictos de la zona. Estos bosques se ubican en las alturas de Upaypiteq y adyacentes a los flancos de la cordillera occidental de los Andes en la vertiente del Atlántico: Shin Shin, San Lorenzo, Huacapampa, Pandachí, Gramalote, Walte, Mollepampa; entre los 1500 a 3000 m sobre el nivel del mar, en el distrito de Kañaris (2300 m) y los bosques de Chiñama y Luto en la vertiente del Pacífico. La presente investigación se emprendió con el objeto de estudiar científicamente, mediante muestreos florísticos, la vida y estructura de los componentes de los bosques de Upaypiteq. Las muestras conducen a un avance de la investigación, determinando que los principales componentes arbóreos corresponden a las Lauráceas: Persea, Ocotea y Nectandra, Cunoniáceas: Weinmannia, Podocarpáceas: Podocarpus, Cecropiáceas: Cecropia, Mirtáceas: Myrcianthes, Moráceas: Ficus, Rubiáceas: Cinchona, Bignoniáceas: Tabebuia, Arecáceas: Ceroxylon y, helechos arborescentes del género Nephelea. Circundantes a la masa boscosa se encuentran varias especies de arbustos, de los géneros Miconia, Munnozia, Baccharis, Senna, Colignonia, Gaiadendron, Oreopanax, etc.; también en la estructura es muy frecuente las epífitas y lianas ascendentes: Bromeliáceas, Orquídeas, Heliconias, Aráceas, musgos. Los helechos herbáceos, hongos, líquenes gelatinosos, hepáticas, Balanoforáceas y Begonias, tapizan por completo el piso boscoso. La composición florística es similar al bosque de Cutervo y los bosques de la Vertiente Oriental de los Andes, que a los demás bosques relictos en la Vertiente Occidental. La presencia de estos bosques se debe preservar, por su importancia en los procesos ecológicos para la atracción de las lluvias, fijación del recurso hídrico, conservación del suelo y por sus recursos fitogenéticos.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive malignancies. Our previous work revealed Chitinase 3-like 1 (CHI3L1) involvement in PDAC resistance to gemcitabine, identifying it as a promising therapeutic target. Here, we aimed to identify putative CHI3L1 inhibitors and to investigate their chemosensitizing potential in PDAC., Methods: Docking analysis for CHI3L1 identified promising CHI3L1 inhibitors, including darifenacin (muscarinic receptor antagonist). PDAC cell lines (BxPC-3, PANC-1) and primary PDAC cells were used to evaluate darifenacin's effects on cell growth (Sulforhodamine B, SRB), alone or in combination with gemcitabine or gemcitabine plus paclitaxel. Cytotoxicity against normal immortalized pancreatic ductal cells (HPNE) was assessed. Recombinant protein was used to confirm the impact of darifenacin on CHI3L1-induced PDAC cellular resistance to therapy (SRB assay). Darifenacin's effect on Akt activation was analysed by ELISA. The association between cholinergic receptor muscarinic 3 (CHRM3) expression and therapeutic response was evaluated by immunohistochemistry of paraffin-embedded tissues from surgical resections of a 68 patients' cohort., Results: In silico screening revealed the ability of darifenacin to target CHI3L1 with high efficiency. Darifenacin inhibited PDAC cell growth, with a GI 50 of 26 and 13.6 µM in BxPC-3 and PANC-1 cells, respectively. These results were confirmed in primary PDAC-3 cells, while darifenacin showed no cytotoxicity against HPNE cells. Importantly, darifenacin sensitized PDAC cells to standard chemotherapies, reverted CHI3L1-induced PDAC cellular resistance to therapy, and decreased Akt phosphorylation. Additionally, high CHMR3 expression was associated with low therapeutic response to gemcitabine., Conclusion: This work highlights the potential of darifenacin as a chemosensitizer for PDAC treatment., (© 2024. The Author(s).)

The effectiveness of phytoremediation in Cd-contaminated soils is crucial for enhancing nutrient availability and plant tolerance to Cd. We simulated soil contamination with varying textures and fertilization conditions. Two experiments were conducted: one without liming and fertilization and another with soil fertilization for grasses. The soil types used were Oxisol and Entisol, and the grasses tested were Megathyrsus maximus and Urochloa brizantha at three Cd levels: 0 mg kg -1 (Control), 2 mg kg -1 (Low), and 12 mg kg -1 (High). Soil amendments and fertilization did not significantly change Cd availability. Soil chemical attributes were unaffected by Cd contamination but were influenced by fertilization, which kept the pH below optimal levels. Cd availability was higher in more contaminated soils, with Entisol showing greater concentrations than Oxisol. Dry matter production of the grasses decreased with higher contamination, with U. brizantha being more productive than M. maximus in fertilized soils. Cd accumulation was higher in highly contaminated soils, particularly for U. brizantha . The bioconcentration factor was higher in Entisol, while the translocation factor exceeded 1.0 only for M. maximus in low-contamination Oxisol. Fertilization can mitigate Cd contamination effects, with U. brizantha showing greater tolerance and accumulation capacity in fertilized soils.

Background: Obesity causes significant difficulties in successful extracorporeal membrane oxygenation (ECMO) support and may interfere with patient outcomes. During the COVID-19 pandemic, we experienced an increased number of obese patients supported with ECMO in our intensive care unit due to severe illness in this population., Methods: We designed a single-center retrospective study to identify prognostic factors for 180-day survival in obese critical COVID-19 patients receiving venovenous ECMO (VV-ECMO). We included adult critical COVID-19 patients on VV-ECMO, who were obese and overweight (according to the World Health Organization) and admitted to a tertiary hospital's intensive care unit from April 1, 2020, to May 31, 2022. Univariate logistic regression analysis was performed to assess differences in 180-day mortality., Results: Forty-one patients were included. The median age was 55 (IQR 45-60) years, and 70.7% of the patients were male. The median body mass index (BMI) was 36 (IQR 31-42.5) kg/m 2 ; 39% of patients had a BMI ≥ 40 kg/m 2 . The participants had 3 (IQR 1.5-4) days of mechanical ventilation prior to ECMO, and 63.4% were weaned from VV-ECMO support after a median of 19 (IQR 10-34) days. The median ICU length of stay was 31.9 (IQR 17.5-44.5) days. The duration of mechanical ventilation was 30 (IQR 19-49.5) days. The 180-day mortality rate was 41.5%. Univariate logistic regression analysis revealed that a higher BMI was associated with greater 180-day survival (OR 1.157 [1.038-1.291], p = 0.009). Younger age, female sex, less invasive ventilation time before ECMO, and fewer complications at the time of ECMO cannulation were associated with greater 180-day survival [OR 0.858 (0.774-0.953), p 0.004; OR 0.074 (0.008-0.650), p 0.019; OR 0.612 (0.401-0.933), p 0.022; OR 0.13 (0.03-0.740), p 0.022), respectively]., Conclusion: In this retrospective cohort of critical COVID-19 obese adult patients supported by VV-ECMO, a higher BMI, younger age, and female sex were associated with greater 180-day survival. A shorter invasive ventilation time before ECMO and fewer complications at ECMO cannulation were also associated with increased survival., (© 2024. The Author(s).)

Introduction: Cognitive decline is prevalent in maintenance hemodialysis patients. The blood-brain barrier has been implicated in cognitive decline. In this prospective cohort study, we investigated the associations between endothelium-related biomarkers and steeper cognitive decline in this population., Methods: Cognitive function was assessed using the Portuguese-adapted Cambridge Cognitive Examination (CAMCOG) with items of the Mini-Mental State Examination (MMSE). Endothelium-related biomarkers included syndecan-1, ICAM-1, VCAM-1 and angiopoietin-2 (AGPT2). Patients were followed up for 4 years, and cognitive assessments were repeated. Multinomial regression analyses were performed to evaluate associations between biomarkers and cognitive decline., Results: A total of 216 patients completed the test battery at baseline. After 4 years, 102 patients had follow-up data. There was a significant decrease in cognitive function according to the CAMCOG and MMSE scores: a change of -0.39 (95% CI -0.27 to -0.51) and -0.51 (95% CI -0.27 to -0.76) standard deviation (SD) of the baseline scores. Additionally, executive function but not memory significantly decreased. Syndecan-1 level was independently associated with steeper cognitive decline; each increase in the SD of the syndecan-1 level was associated with a decrease in the CAMCOG of 0.20 (95% CI 0.07-0.33) SD from baseline. Syndecan-1 was associated with a steeper decline in MMSE score (β 0.54, 95% CI 0.28-0.81) and executive function (β 0.17, 95% CI 0.02-0.32). Syndecan-1 predicted severe cognitive impairment with an area under the curve for receiver operating characteristic curves of 0.75 (95% CI 0.64-0.83)., Conclusion: Our findings highlight the potential of syndecan-1, a biomarker of endothelium glycocalyx derangement, as a predictor of steeper cognitive decline in prevalent hemodialysis patients., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: The current definition of acute kidney injury (AKI) includes increased serum creatinine (sCr) concentration and decreased urinary output (UO). Recent studies suggest that the standard UO threshold of 0.5 ml/kg/h may be suboptimal. This study aimed to develop and validate a novel UO-based AKI classification system that improves mortality prediction and patient stratification., Methods: Data were obtained from the MIMIC-IV and eICU databases. The development process included (1) evaluating UO as a continuous variable over 3-, 6-, 12-, and 24-h periods; (2) identifying 3 optimal UO cutoff points for each time window (stages 1, 2, and 3); (3) comparing sensitivity and specificity to develop a unified staging system; (4) assessing average versus persistent reduced UO hourly; (5) comparing the new UO-AKI system to the KDIGO UO-AKI system; (6) integrating sCr criteria with both systems and comparing them; and (7) validating the new classification with an independent cohort. In all these steps, the outcome was hospital mortality. Another analyzed outcome was 90-day mortality. The analyses included ROC curve analysis, net reclassification improvement (NRI), integrated discrimination improvement (IDI), and logistic and Cox regression analyses., Results: From the MIMIC-IV database, 35,845 patients were included in the development cohort. After comparing the sensitivity and specificity of 12 different lowest UO thresholds across four time frames, 3 cutoff points were selected to compose the proposed UO-AKI classification: stage 1 (0.2-0.3 mL/kg/h), stage 2 (0.1-0.2 mL/kg/h), and stage 3 (< 0.1 mL/kg/h) over 6 h. The proposed classification had better discrimination when the average was used than when the persistent method was used. The adjusted odds ratio demonstrated a significant stepwise increase in hospital mortality with advancing UO-AKI stage. The proposed classification combined or not with the sCr criterion outperformed the KDIGO criteria in terms of predictive accuracy-AUC-ROC 0.75 (0.74-0.76) vs. 0.69 (0.68-0.70); NRI: 25.4% (95% CI: 23.3-27.6); and IDI: 4.0% (95% CI: 3.6-4.5). External validation with the eICU database confirmed the superior performance of the new classification system., Conclusion: The proposed UO-AKI classification enhances mortality prediction and patient stratification in critically ill patients, offering a more accurate and practical approach than the current KDIGO criteria., (© 2024. The Author(s).)

The depletion of visceral and subcutaneous adipose tissue (AT) during chemotherapy significantly correlates with diminished overall survival and progression-free survival. Despite its clinical significance, the intricate molecular mechanisms governing this AT loss and its chemotherapy-triggered initiation remain poorly understood. Notably, the evaluation of AT remodeling in most clinical trials has predominantly relied on computerized tomography scans or bioimpedance, with molecular studies often conducted using animal or in vitro models. To address this knowledge gap, a comprehensive narrative review was conducted. The findings underscore that chemotherapy serves as a key factor in inducing AT loss, exacerbating cachexia, a paraneoplastic syndrome that significantly compromises patient quality of life and survival. The mechanism driving AT loss appears intricately linked to alterations in AT metabolic remodeling, marked by heightened lipolysis and fatty acid oxidation, coupled with diminished lipogenesis. However, adipocyte stem cells' lost ability to divide due to chemotherapy also appears to be at the root of the loss of AT. Notably, chemotherapy seems to deactivate the mitochondrial antioxidant system by reducing key regulatory enzymes responsible for neutralizing reactive oxygen species (ROS), thereby impeding lipogenesis. Despite FDG-PET evidence of AT browning, no molecular evidence of thermogenesis was reported. Prospective investigations unraveling the molecular mechanisms modulated in AT by chemotherapy, along with therapeutic strategies aimed at preventing AT loss, promise to refine treatment paradigms and enhance patient outcomes., Competing Interests: Declaration of competing interest Declaration of interest: none., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The aims of this study were to determine anti-müllerian hormone (AMH) cutoff values for selecting Gir (Bos taurus indicus) oocyte donors and estimate the impact of using AMH concentrations as a selection criterion. In Exp. 1, Gir heifers (n=120) were sampled for AMH analysis and submitted to ovum pick-up and in vitro embryo production (OPU-IVEP). AMH cutoff values were calculated using ROC analysis or, alternatively, by the successive exclusion of heifers with the lowest AMH values. The correlations between AMH and OPU-IVEP outcomes were significant (P<0.001), though low or moderate (r= 0.34-0.52). We estimated an improvement (P<0.05) after the use of AMH cutoff values to select donors of +15.3% for total oocyes, +19.4% for viable COC, and +23.4% for blastocysts. This selection pressure, however, led to the exclusion of 32.8%, 37.9%, and 50.0% of the initial potential donors, respectively. In Exp. 2, we analyzed data from OPU-IVEP sessions of 658 Gir donors with known genomic values for predicted transmitting ability for milk (GPTAm) and age at first calving (GPTAafc). The selection based on the number of oocytes recovered had no effect (P>0.05) on the average GPTAm nor GPTAafc values of the remaining donors. In summary, plasma AMH ≥700 pg/mL is a cutoff value that can be used to select Gir heifers with a greater potential as oocyte donors. Nevertheless, this selection leads to the exclusion of up to 50% of potential donors. Finally, exclusion of poor responders had no effect on mean genomic estimates for milk production or age at first calving in the selected subset of donors., Competing Interests: Declaration of Competing Interest None Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Physical exercise can take on a multivariate form, including combat sports, specifically Taekwondo, a Korean sport characterized by strikes involving the hands and feet. This sport has been gaining popularity worldwide in recent years and is being practiced by diverse populations, including the older women., Objective: This study aimed to investigate the effects of Taekwondo training on self-esteem and body image in older women with low bone mineral density (BMD)., Methods: This is an experimental research with a two-group design, where assessments were conducted pre- and post during a 12-week intervention period. The sample consisted of 27 inexperienced older women in taekwondo practice, aged between 60 and 70 years, randomly distributed into the experimental group (n=14) and Control Group (n=13). BMD, self-esteem, and body image were assessed. For the evaluation of self-esteem, the Rosenberg Self-Esteem Scale (RSES) was utilized. For the evaluation of body images, the body image questionnaire was administered., Results: The results showed that the practice of taekwondo improved (p<0.001) body image in the variables, including physical condition, body skills, and health, while the variable appearance showed no difference (p=0.581)., Conclusion: The results of this experimental study indicate an improvement in the self-esteem and body image of older individuals practicing Taekwondo., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Premise: Increasingly complete phylogenies underpin studies in systematics, ecology, and evolution. Myrteae (Myrtaceae), with ~2700 species, is a key component of the exceptionally diverse Neotropical flora, but given its complicated taxonomy, automated assembling of molecular supermatrices from public databases often lead to unreliable topologies due to poor species identification., Methods: Here, we build a taxonomically verified molecular supermatrix of Neotropical Myrteae by assembling 3909 published and 1004 unpublished sequences from two nuclear and seven plastid molecular markers. We infer a time-calibrated phylogenetic tree that covers 712 species of Myrteae (~28% of the total diversity in the clade) and evaluate geographic and taxonomic gaps in sampling., Results: The tree inferred from the fully concatenated matrix mostly reflects the topology of the plastid data set and there is a moderate to strong incongruence between trees inferred from nuclear and plastid partitions. Large, species-rich genera are still the poorest sampled within the group. Eastern South America is the best-represented area in proportion to its species diversity, while Western Amazon, Mesoamerica, and the Caribbean are the least represented., Conclusions: We provide a time-calibrated tree that can be more reliably used to address finer-scale eco-evolutionary questions that involve this group in the Neotropics. Gaps to be filled by future studies include improving representation of taxa and areas that remain poorly sampled, investigating causes of conflict between nuclear and plastid partitions, and the role of hybridization and incomplete lineage sorting in relationships that are poorly supported., (© 2024 The Authors. American Journal of Botany published by Wiley Periodicals LLC on behalf of Botanical Society of America.)

Background: Colorectal cancer (CRC) is a significant global health concern, ranking as the third most common cancer and the second leading cause of cancer-related deaths. However, in Africa, CRC is the fifth most common invasive malignancy. Limited data hinder our understanding of the evolving burden of CRC in sub-Saharan Africa. This study explores CRC trends in Mozambique, utilising data from population-based oncological registries., Methods: CRC data were gathered from Beira and Maputo population-based cancer registries, along with supplementary information from pathology-based and hospital-based registries. Comparative analyses were performed across different time periods, focusing on trends and epidemiological characteristics., Results: Incidence rates of CRC in Maputo and Beira were relatively low historically. However, data from recent years showed an increase, especially in age groups above 50. Analyses from pathology-based and hospital-based registries affirmed the rising trend. The age-standardised incidence rate in Maputo (2015-2017) was 3.17 for males and 2.55 for females. Beira exhibited increasing rates between 2009 and 2020, particularly in individuals aged 50 and above., Conclusion: The study reveals an emerging burden of CRC in Mozambique, challenging the perception of low incidence. The rising trend underscores the necessity for tailored interventions, emphasizing early diagnosis, preventive strategies, and investments in healthcare infrastructure to address the increasing CRC burden in the region., Competing Interests: The authors declared that they have no competing interests., (© the authors; licensee ecancermedicalscience.)

Advanced-stage solid primary tumors and metastases often express mucin 16 (MUC16), carrying immature glycans such as the Tn antigen, resulting in specific glycoproteoforms not found in healthy human tissues. This presents a valuable approach for designing targeted therapeutics, including cancer glycovaccines, which could potentially promote antigen recognition and foster the immune response to control disease spread and prevent relapse. In this study, we describe an adjuvant-free poly(lactic- co -glycolic acid) (PLGA)-based nanoglycoantigen delivery approach that outperforms conventional methods by eliminating the need for protein carriers while exhibiting targeted and adjuvant properties. To achieve this, we synthesized a library of MUC16-Tn glycoepitopes through single-pot enzymatic glycosylation, which were then stably engrafted onto the surface of PLGA nanoparticles, generating multivalent constructs that better represent cancer molecular heterogeneity. These glycoconstructs demonstrated affinity for Macrophage Galactose-type Lectin (MGL) receptor, known to be highly expressed by immature antigen-presenting cells, enabling precise targeting of immune cells. Moreover, the glycopeptide-grafted nanovaccine candidate displayed minimal cytotoxicity and induced the activation of dendritic cells in vitro , even in the absence of an adjuvant. In vivo , the formulated nanovaccine candidate was also nontoxic and elicited the production of IgG specifically targeting MUC16 and MUC16-Tn glycoproteoforms in cancer cells and tumors, offering potential for precise cancer targeting, including targeted immunotherapies.

Colorectal cancer (CRC) screening relies primarily on stool analysis to identify occult blood. However, its sensitivity for detecting precancerous lesions is limited, requiring the development of new tools to improve CRC screening. Carcinogenesis involves significant alterations in mucosal epithelium glycocalyx that decisively contribute to disease progression. Building on this knowledge, we examined patient series comprehending premalignant lesions, colorectal tumors, and healthy controls for the T-antigen-a short-chain O -glycosylation of proteins considered a surrogate marker of malignancy in multiple solid cancers. We found the T-antigen in the secretions of dysplastic lesions as well as in cancer. In CRC, T-antigen expression was associated with the presence of distant metastases. In parallel, we analyzed a broad number of stools from individuals who underwent colonoscopy, which showed high T expressions in high-grade dysplasia and carcinomas. Employing mass spectrometry-based lectin-affinity enrichment, we identified a total of 262 proteins, 67% of which potentially exhibited altered glycosylation patterns associated with cancer and advanced pre-cancerous lesions. Also, we found that the stool (glyco)proteome of pre-cancerous lesions is enriched for protein species involved in key biological processes linked to humoral and innate immune responses. This study offers a thorough analysis of the stool glycoproteome, laying the groundwork for harnessing glycosylation alterations to improve non-invasive cancer detection.

Background: A detailed understanding of the genetic basis of cancer is of great interest to public health monitoring programs. Although many studies have been conducted in Brazil, a global view on the molecular profile related to hereditary breast and ovarian cancer (HBOC) in this large and heterogeneous population is lacking., Methods: A systematic review following the PRISMA guidelines was conducted in three electronic databases (PubMed, BIREME and SciELO). Brazilian studies covering molecular analysis of genes related to HBOC, published until December 2023, were considered., Results: We identified 35 original studies that met all the inclusion criteria. A total of 137 distinct mutations were found in the BRCA1 gene, but four of them corresponded to 44.5% of all mutations found in this gene. The c.5266dupC BRCA1 mutation was responsible for 26.8% of all pathogenic mutations found in the BRCA1 gene in patients with clinical criteria for HBOC from the Brazilian population. Considering all studies that track this mutation in the BRCA1 gene, we found a frequency of 2% (120/6008) for this mutation in Brazilian patients. In the BRCA2 gene, the four most frequent mutations corresponded to 29.2% of pathogenic mutations. Even though it was tracked by few studies, the c.156&#95;157insAlu mutation was responsible for 9.6% of all pathogenic mutations reported in the BRCA2 gene. Seventeen studies found pathogenic mutations in other non-BRCA genes, the c.1010G > A mutation in the TP53 gene being the most frequent one. Considering all studies that screened for this specific mutation in patients with the clinical criteria for HBOC, the frequency of c.1010G > A was estimated at 1.83% (61/3336)., Conclusions: Despite significant molecular heterogeneity among mutations in HBOC patients from Brazil, three mutations deserve to be highlighted, c.5266dupC, c.156&#95;157insAlu and c.1010G > A in the BRCA1, BRCA2 and TP53 genes, respectively. With more than 200 records, these three mutations play a vital role in the pathology of breast and ovarian cancer in Brazil. The data collected shed light on the subject, but there is still not enough data from certain subpopulations., (© 2024. The Author(s).)

Muscle-invasive bladder cancer (MIBC) remains a pressing health concern due to conventional treatment failure and significant molecular heterogeneity, hampering the development of novel targeted therapeutics. In our quest for novel targetable markers, recent glycoproteomics and bioinformatics data have pinpointed (glucose transporter 1) GLUT1 as a potential biomarker due to its increased expression in tumours compared to healthy tissues. This study explores this hypothesis in more detail, with emphasis on GLUT1 glycosylation patterns and cancer specificity. Immunohistochemistry analysis across a diverse set of human bladder tumours representing all disease stages revealed increasing GLUT1 expression with lesion severity, extending to metastasis, while remaining undetectable in healthy urothelium. In line with this, GLUT1 emerged as a marker of reduced overall survival. Revisiting nanoLC-EThcD-MS/MS data targeting immature O -glycosylation on muscle-invasive tumours identified GLUT1 as a carrier of short glycosylation associated with invasive disease. Precise glycosite mapping uncovered significant heterogeneity between patient samples, but also common glycopatterns that could provide the molecular basis for targeted solutions. Immature O -glycosylation conferred cancer specificity to GLUT1, laying the molecular groundwork for enhanced targeted therapeutics in bladder cancer. Future studies should focus on a comprehensive mapping of GLUT1 glycosites for highly specific cancer-targeted therapy development for bladder cancer.

Bladder cancer (BCa) research relying on Omics approaches has increased over the last few decades, improving the understanding of BCa pathology and contributing to a better molecular classification of BCa subtypes. To gain further insight into the molecular profile underlying the development of BCa, a systematic literature search was performed in PubMed until November 2023, following the PRISMA guidelines. This search enabled the identification of 25 experimental studies using mass spectrometry or nuclear magnetic resonance-based approaches to characterize the metabolite signature associated with BCa. A total of 1562 metabolites were identified to be altered by BCa in different types of samples. Urine samples displayed a higher likelihood of containing metabolites that are also present in bladder tumor tissue and cell line cultures. The data from these comparisons suggest that increased concentrations of L-isoleucine, L-carnitine, oleamide, palmitamide, arachidonic acid and glycoursodeoxycholic acid and decreased content of deoxycytidine, 5-aminolevulinic acid and pantothenic acid should be considered components of a BCa metabolome signature. Overall, molecular profiling of biological samples by metabolomics is a promising approach to identifying potential biomarkers for early diagnosis of different BCa subtypes. However, future studies are needed to understand its biological significance in the context of BCa and to validate its clinical application.

Cancer presents a high mortality rate due to ineffective treatments and tumour relapse with progression. Cancer vaccines hold tremendous potential due to their capability to eradicate tumour and prevent relapse. In this study, we present a novel glycovaccine for precise targeting and immunotherapy of aggressive solid tumours that overexpress CD44 standard isoform (CD44s) carrying immature Tn and sialyl-Tn (sTn) O-glycans. We describe an enzymatic method and an enrichment strategy to generate libraries of well-characterized cancer-specific CD44s-Tn and/or sTn glycoproteoforms, which mimic the heterogeneity found in tumours. We conjugated CD44-Tn-derived glycopeptides with carrier proteins making them more immunogenic, with further demonstration of the importance of this conjugation to overcome the glycopeptides' intrinsic toxicity. We have optimized the glycopeptide-protein maleimide-thiol conjugation chemistry to avoid undesirable cross-linking between carrier proteins and CD44s glycopeptides. The resulting glycovaccines candidates were well-tolerated in vivo, inducing both humoral and cellular immunity, including immunological memory. The generated antibodies exhibited specific reactivity against synthetic CD44s-Tn glycopeptides, CD44s-Tn glycoengineered cells, and human tumours. In summary, we present a promising prototype of a cancer glycovaccine for future therapeutical pre-clinical efficacy validation., Competing Interests: Declaration of competing interest José Alexandre Ferreira is the CEO of GlycoMatters Biotech and Lucio Lara Santos and André M. N. Silva are founders of the company. The authors have issued a patent on CD44 glycoepitopes and chimeric vaccine glycoconjugates for cancer therapy and synthesis methods thereof (PCT/PT2021/050025)., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Janus kinase 1 inhibition may alleviate hidradenitis suppurativa (HS)-associated inflammation and improve symptoms., Objective: To assess efficacy and safety of povorcitinib (selective oral Janus kinase 1 inhibitor) in HS., Methods: This placebo-controlled phase 2 study randomized patients with HS 1:1:1:1 to receive povorcitinib 15, 45, or 75 mg or placebo for 16 weeks. Primary and key secondary end points were mean change from baseline in abscess and inflammatory nodule count and percentage of patients achieving HS Clinical Response at week 16., Results: Of 209 patients randomized (15 mg, n = 52; 45 mg, n = 52; 75 mg, n = 53; placebo, n = 52), 83.3% completed the 16-week treatment. At week 16, povorcitinib significantly reduced abscess and inflammatory nodule count from baseline (least squares mean [SE] change: 15 mg, -5.2 [0.9], P = .0277; 45 mg, -6.9 [0.9], P = .0006; 75 mg, -6.3 [0.9], P = .0021) versus placebo (-2.5 [0.9]). More povorcitinib-treated patients achieved HS Clinical Response at week 16 (15 mg, 48.1%, P = .0445; 45 mg, 44.2%, P = .0998; 75 mg, 45.3%, P = .0829) versus placebo (28.8%). A total of 60.0% and 65.4% of povorcitinib- and placebo-treated patients had adverse events., Limitations: Baseline lesion counts were mildly imbalanced between groups., Conclusion: Povorcitinib demonstrated efficacy in HS, with no evidence of increased incidence of adverse events among doses., Competing Interests: Conflicts of interest Dr Kirby has served as a speaker for AbbVie and as a consultant for AbbVie, Bayer, ChemoCentryx, Incyte Corporation, InflaRx, Janssen, Novartis, Pfizer, and UCB. Dr Okun is a consultant for AbbVie, Azora, Bluefin, Boehringer Ingelheim, ChemoCentryx, Incyte, InflaRx, Innovaderm, Novartis, Pfizer, and Vyne. Dr Alavi received honoraria as a consultant or advisory board participant from AbbVie, InflaRx, Incyte, Novartis, Boehringer Ingelheim, and UCB and received honoraria as an investigator for Boehringer Ingelheim and Processa. Dr Bechara has received honoraria for participation in advisory boards, in clinical trials, and/or as a speaker from AbbVie, AbbVie Deutschland, Boehringer Ingelheim, Incyte, Janssen-Cilag, MoonLake, Novartis, and UCB. Dr Zouboulis declares that none of the mentioned conflicts of interest had any influence on this manuscript. He reports consultancy/advisory board disease-relevant honoraria from Boehringer Ingelheim, Incyte, InflaRx, Janssen-Cilag, Novartis, Regeneron, Sanofi, UCB, and Viatris. He has received speaker fees from Almirall, Novartis, and UCB; is President of the EHSF eV, coordinator of the ALLOCATE Skin group of the ERN Skin and chair of the ARHS Task Force group of the EADV. He is Editor of the EADV News; is cocopyright holder of IHS4 on behalf of the EHSF eV. His employer has received disease-relevant grants from Boehringer Ingelheim, InflaRx, Novartis, and UCB for his participation as clinical investigator. Dr Bibeau was an employee of Incyte at the time of the study. Drs Brown, Santos, and Wang are employees and shareholders of Incyte. Dr Kimball’s institution has received grants from AbbVie, Admirx, AnaptysBio, Aristea, Bristol Myers Squibb, Eli Lilly, Incyte, Janssen, MoonLake, Novartis, Pfizer, Prometheus, UCB, and Sonoma Bio, fellowship funding from Janssen and AbbVie. She received consulting fees from AbbVie, Alumis, Bayer, Boehringer Ingelheim, Eli Lilly, Evommune, Janssen, MoonLake, Novartis, Pfizer, Priovant, Sonoma Bio, Sanofi, UCB, and Target RWE, and serves on the board of directors of Almirall. Dr Porter is a consultant and/or investigator for AbbVie, Acelyrin, Alumis, AnaptysBio, Aristea, Bayer, Bristol Myers Squibb, Eli Lilly, Incyte, Janssen, MoonLake, Novartis, Pfizer, Prometheus Laboratories, Regeneron, Sanofi, Trifecta Clinical, Sonoma Bio, and UCB., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Oxygen atom transfer (OAT) from N 2 O to the Ni-H bond of proton-responsive picoline-derived CNP nickel complexes has been investigated both experimentally and theoretically. These Ni-CNP complexes efficiently catalyse the reduction of N 2 O with pinacolborane (HBpin) under mild conditions.

Background: Cancer is a leading cause of death worldwide, with metastasis playing a significant role. Circulating Tumour Cells (CTCs) can provide important real-time insights into tumour heterogeneity and clonal evolution, making them an important tool for early diagnosis and patient monitoring. Isolated CTCs are typically identified by immunocytochemistry using positive biomarkers (cytokeratin) and exclusion biomarkers (CD45). However, some white blood cell (WBC) populations can express low levels of CD45 and stain non-specifically for cytokeratin, increasing their risk of misclassification as CTCs. There is a clear need to improve CTC detection and enumeration criteria to unequivocally eliminate interfering WBC populations., Results: This study showed that, indeed, some granulocyte subpopulations expressed low levels of CD45 and stained non-specifically for cytokeratin, misidentifying them as CTCs. These same cells, however, strongly expressed CD15, allowing them to be identified as WBCs and excluded from CTC classification. Flow cytometry confirmed the specificity of the CD15 antibody for the granulocyte subpopulation. False positives were considerably reduced from 25 % to 0.2 % by double exclusion, combining a CD15 antibody with a highly specific CD45 antibody. Furthermore, complete elimination of potential false positives was achieved using double exclusion in combination with improved selection of cytokeratin antibody. The study emphasises the importance of a robust exclusion criteria and high antibody specificity in CTC immuno-assays for accurate identification of CTC candidates and thorough exclusion of interfering WBC subpopulations., Significance: This study demonstrated how misidentifying a granulocyte subpopulation can lead to inaccurate CTC evaluation. However, sensitivity and specificity of CTC identification may be improved by using high-performing antibodies and by including a second exclusion biomarker, in turn, allowing for a more comprehensive clinical application of CTCs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The RUBYchip™ is based on the patent (PCT/EP2016/078406), for which Lorena Diéguez is an author. Moreover, the exploitation rights of the RUBYchip™ technology have been licensed to the spin-off company RUBYnanomed Lda., incorporated by Lorena Diéguez, Paulina Piairo and co-workers., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Cancer incidence rates are increasing worldwide including in Portuguese speaking African countries. We present the results of the fellowship in surgical oncology promoted by the Portuguese Institute of Oncology in Porto (IPO), Fernando Pessoa University, Portugal, and the Calouste Gulbenkian Foundation, which involved the training of residents and surgeons from Portuguese-speaking African countries in Portugal. The program's structure and content was the same of UMES/ESSO. The hands-on activity took place at the IPO. After the fellowship, a theoretical and practical assessment was held, and all fellows scored above the threshold to pass. The surgical performance of the fellows was assessed in their workplaces in Africa. The impact of the training was evaluated by a questionnaire completed by all the fellows. It was reported an increase in knowledge, skills and organizational skills that fellows are committed to implement. As the fellowship is certified by a Portuguese University, it may be recognized by the Local Health and University Authorities, impacting on the professional progression of fellows., Competing Interests: Declaration of competing interest The authors declare no financial interests. There was no funding for this article., (© 2023 Published by Elsevier Ltd.)

Plasmodium berghei ANKA (PbA) infection in mice resembles several aspects of severe malaria in humans, such as cerebral malaria and acute respiratory distress syndrome. Herein, the effects of N -(coumarin-3-yl)cinnamamide (M220) against severe experimental malaria have been investigated. Treatment with M220 proved to protect cognitive abilities and lung function in PbA-infected mice, observed by an object recognition test and spirometry, respectively. In addition, treated mice demonstrated decreased levels of brain and lung inflammation. The production and accumulation of microglia, and immune cells that produce the inflammatory cytokines TNF and IFN-γ, decreased, while the production of the anti-inflammatory cytokine IL-10 by innate and adaptive immune cells was enhanced. Treatment with M220 promotes immunomodulatory, neuroprotective, and lung function-preserving effects during experimental severe malaria. Therefore, it may be an interesting therapeutic candidate to treat severe malaria effects.

Introduction: Student assistance policies in higher education, in their various modalities, seek to reduce the dropout of a new profile of students, non-traditional, with socioeconomic weaknesses, promoting quality of life (QoL) and mental health during the university journey. In this context, the Student Social Support Center (C.A.S.A) promotes assistance to students who need personal and/or economic support., Objectives: To evaluate the QoL and the presence of minor mental disorders (MMD) in students from the 1st to the 4th year of medicine at a public college in Brazil, comparing C.A.S.A beneficiaries and non-beneficiaries., Materials and Methods: Cross-sectional study with 283 students. SRQ-20 and WHOQOL-BREF questionnaires were used, in addition to a questionnaire addressing sociodemographic data., Results: The general average of QoL was regular in the four evaluated domains (physical, psychological, social relationships, environment) and 55.5% of the students have evidence of MMD, in which the QoL scores are lower in all domains. The environment domain, which discusses socioeconomic conditions, has the worst score among C.A.S.A beneficiaries and the best among C.A.S.A non-beneficiaries., Discussion: The data corroborate the fragile situation of mental health and QoL of medical students. The student assistance modality of the analyzed program possibly presents vulnerabilities in its performance since the environment domain, the one with the lowest score among the program beneficiaries, precisely encompasses financial resources, access to goods and leisure and the individual's physical environment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 dos Santos de Brito, Pereira, dos Santos, de Barros, Martinez, dos Santos, Brienze, de Abreu Lima, Bizotto and André.)

Objective: To assess the rate of textbook outcome (TO) and textbook oncological outcome (TOO) in the European population based on the GASTRODATA registry., Background: TO is a composite parameter assessing surgical quality and strongly correlates with improved overall survival. Following the standard of treatment for locally advanced gastric cancer, TOO was proposed as a quality and optimal multimodal treatment parameter., Methods: TO was achieved when all the following criteria were met: no intraoperative complications, radical resection according to the surgeon, pR0 resection, retrieval of at least 15 lymph nodes, no severe postoperative complications, no reintervention, no admission to the intensive care unit, no prolonged length of stay, no postoperative mortality and no hospital readmission. TOO was defined as TO with the addition of perioperative chemotherapy compliance., Results: Of the 2558 patients, 1700 were included in the analysis. TO was achieved in 1164 (68.5%) patients. The use of neoadjuvant chemotherapy [odds ratio (OR) = 1.33, 95% CI: 1.04-1.70] and D2 or D2+ lymphadenectomy (OR = 1.55, 95% CI: 1.15-2.10) had a positive impact on TO achievement. Older age (OR = 0.73, 95% CI: 0.54-0.94), pT3/4 (OR = 0.79, 95% CI: 0.63-0.99), ASA 3/4 (OR = 0.68, 95% CI: 0.54-0.86) and total gastrectomy (OR = 0.56, 95% CI: 0.45-0.70), had a negative impact on TO achievement. TOO was achieved in 388 (22.8%) patients. Older age (OR = 0.37, 95% CI: 0.27-0.53), pT3 or pT4 (OR = 0.52, 95% CI: 0.39-0.69), and ASA 3 or 4 (OR = 0.58, 95% CI: 0.43-0.79) had a negative impact on TOO achievement., Conclusions: Despite successively improved surgical outcomes, stage-appropriate chemotherapy in adherence to the current guidelines for multimodal treatment of gastric cancer remains poor. Further implementation of oncologic quality metrics should include greater emphasis on perioperative chemotherapy and adequate lymphadenectomy., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The causative agent of human Q fever, Coxiella burnetii, is highly adapted to infect alveolar macrophages by inhibiting a range of host responses to infection. Despite the clinical and biological importance of this pathogen, the challenges related to genetic manipulation of both C. burnetii and macrophages have limited our knowledge of the mechanisms by which C. burnetii subverts macrophages functions. Here, we used the related bacterium Legionella pneumophila to perform a comprehensive screen of C. burnetii effectors that interfere with innate immune responses and host death using the greater wax moth Galleria mellonella and mouse bone marrow-derived macrophages. We identified MceF (Mitochondrial Coxiella effector protein F), a C. burnetii effector protein that localizes to mitochondria and contributes to host cell survival. MceF was shown to enhance mitochondrial function, delay membrane damage, and decrease mitochondrial ROS production induced by rotenone. Mechanistically, MceF recruits the host antioxidant protein Glutathione Peroxidase 4 (GPX4) to the mitochondria. The protective functions of MceF were absent in primary macrophages lacking GPX4, while overexpression of MceF in human cells protected against oxidative stress-induced cell death. C. burnetii lacking MceF was replication competent in mammalian cells but induced higher mortality in G. mellonella, indicating that MceF modulates the host response to infection. This study reveals an important C. burnetii strategy to subvert macrophage cell death and host immunity and demonstrates that modulation of the host antioxidant system is a viable strategy to promote the success of intracellular bacteria.

Cancer remains a leading cause of death worldwide due to the lack of safer and more effective therapies. Cancer vaccines developed from neoantigens are an emerging strategy to promote protective and therapeutic anti-cancer immune responses. Advances in glycomics and glycoproteomics have unveiled several cancer-specific glycosignatures, holding tremendous potential to foster effective cancer glycovaccines. However, the immunosuppressive nature of tumours poses a major obstacle to vaccine-based immunotherapy. Chemical modification of tumour associated glycans, conjugation with immunogenic carriers and administration in combination with potent immune adjuvants constitute emerging strategies to address this bottleneck. Moreover, novel vaccine vehicles have been optimized to enhance immune responses against otherwise poorly immunogenic cancer epitopes. Nanovehicles have shown increased affinity for antigen presenting cells (APCs) in lymph nodes and tumours, while reducing treatment toxicity. Designs exploiting glycans recognized by APCs have further enhanced the delivery of antigenic payloads, improving glycovaccine's capacity to elicit innate and acquired immune responses. These solutions show potential to reduce tumour burden, while generating immunological memory. Building on this rationale, we provide a comprehensive overview on emerging cancer glycovaccines, emphasizing the potential of nanotechnology in this context. A roadmap towards clinical implementation is also delivered foreseeing advances in glycan-based immunomodulatory cancer medicine., Competing Interests: Declaration of Competing Interest I hereby declare, on behalf of all authors of the manuscript entitled “Immunomodulatory glycomedicine: introducing next generation cancer glycovaccines” by Freitas R and Peixoto A et al. submitted for consideration in Biotechnology Advances, that the disclosed information is correct and that no other situation of real, potential or apparent conflict of interest is known to me., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Preeclampsia is a life-threatening disorder of pregnancy unique to humans. Interleukin (IL)11 is elevated in serum from pregnancies that subsequently develop early-onset preeclampsia and pharmacological elevation of IL11 in pregnant mice causes the development of early-onset preeclampsia-like features (hypertension, proteinuria, and fetal growth restriction). However, the mechanism by which IL11 drives preeclampsia is unknown., Method: Pregnant mice were administered PEGylated (PEG)IL11 or control (PEG) from embryonic day (E)10-16 and the effect on inflammasome activation, systolic blood pressure (during gestation and at 50/90 days post-natal), placental development, and fetal/post-natal pup growth measured. RNAseq analysis was performed on E13 placenta. Human 1 st trimester placental villi were treated with IL11 and the effect on inflammasome activation and pyroptosis identified by immunohistochemistry and ELISA., Result: PEGIL11 activated the placental inflammasome causing inflammation, fibrosis, and acute and chronic hypertension in wild-type mice. Global and placental-specific loss of the inflammasome adaptor protein Asc and global loss of the Nlrp3 sensor protein prevented PEGIL11-induced fibrosis and hypertension in mice but did not prevent PEGIL11-induced fetal growth restriction or stillbirths. RNA-sequencing and histology identified that PEGIL11 inhibited trophoblast differentiation towards spongiotrophoblast and syncytiotrophoblast lineages in mice and extravillous trophoblast lineages in human placental villi., Discussion: Inhibition of ASC/NLRP3 inflammasome activity could prevent IL11-induced inflammation and fibrosis in various disease states including preeclampsia., Competing Interests: AM is an employee of and holds shares in Adiso Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Menkhorst, Santos, Zhou, Yang, Winship, Rainczuk, Nguyen, Zhang, Moore, Williams, Lê Cao, Mansell and Dimitriadis.)

Gastric cancer is a dominating cause of cancer-associated mortality with limited therapeutic options. Here, we show that syndecan-4 (SDC4), a transmembrane proteoglycan, is highly expressed in intestinal subtype gastric tumors and that this signature associates with patient poor survival. Further, we mechanistically demonstrate that SDC4 is a master regulator of gastric cancer cell motility and invasion. We also find that SDC4 decorated with heparan sulfate is efficiently sorted in extracellular vesicles (EVs). Interestingly, SDC4 in EVs regulates gastric cancer cell-derived EV organ distribution, uptake, and functional effects in recipient cells. Specifically, we show that SDC4 knockout disrupts the tropism of EVs for the common gastric cancer metastatic sites. Our findings set the basis for the molecular implications of SDC4 expression in gastric cancer cells and provide broader perspectives on the development of therapeutic strategies targeting the glycan-EV axis to limit tumor progression.

(1) Background: Gastric cancer patients are known to be at a high risk of malnutrition, sarcopenia, and cachexia, and the latter impairs the patient's nutritional status during their clinical course and also treatment response. A clearer identification of nutrition-related critical points during neoadjuvant treatment for gastric cancer is relevant to managing patient care and predicting clinical outcomes. The aim of this systematic review was to identify and describe nutrition-related critical domains associated with clinical outcomes. (2) Methods: We performed a systematic review (PROSPERO ID:CRD42021266760); (3) Results: This review included 14 studies compiled into three critical domains: patient-related, clinical-related (disease and treatment), and healthcare-related. Body composition changes during neoadjuvant chemotherapy (NAC) accounted for the early termination of chemotherapy and reduced overall survival. Sarcopenia was confirmed to have an independent prognostic value. The role of nutritional interventions during NAC has not been fully explored. (4) Conclusions: Understanding critical domain exposures affecting nutritional status will enable better clinical approaches to optimize care plans. It may also provide an opportunity for the mitigation of poor nutritional status and sarcopenia and their deleterious clinical consequences.

Background: Habitual Physical activity (HPA) is a non-pharmacological strategy to prevent and control chronic diseases, and it plays an important role in minimizing healthcare costs., Objectives: This study aimed to investigate the relationship between HPA and healthcare costs from the perspective of the Brazilian National Healthcare System, and to establish the mediating role of comorbidities in this relationship among patients with cardiovascular diseases (CVD)., Design and Setting: This longitudinal study was conducted in a medium-sized Brazilian city and included 278 participants assisted by the Brazilian National Healthcare System., Methods: Information on healthcare costs were obtained from medical records and included primary, secondary, and tertiary levels. Comorbidities (diabetes, dyslipidemia, and arterial hypertension) were self-reported, and obesity was confirmed with the percentage of body fat. HPA was measured using a questionnaire (Baecke questionnaire). Face-to-face interviews provided information on sex, age, and education level. Statistical analysis included linear regression and Structural Equation Modeling, significance was set at 5 % and the Stata software (version 16.0) was used to perform the analysis., Results: The sample included 278 adults with a mean age of 54.49 (8.32) years. For each score of HPA, there was a reduction in healthcare costs of US$ 83.99/ 24 months (95 % CI: - 159.15; - 8.84), and the sum of comorbidities did not mediate this relationship., Conclusion: It is concluded that healthcare costs seem to be affected by HPA among patients with CVD, while this phenomenon seems not to be mediated by the sum of comorbidities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: Conflicts of interest L.L.S. and K.B. are employees and shareholders of Incyte Corporation. Z.Z. was an employee of Incyte Corporation at the time of the study. J.S.K. has served as a speaker for AbbVie and as a consultant for AbbVie, Bayer, ChemoCentryx, Incyte Corporation, InflaRX, Janssen, Novartis, Pfizer and UCB.

Janus kinase (JAK)/signal transducer and activator of transcription signaling (STAT) has been implicated in the pathophysiology of hidradenitis suppurativa (HS). This study evaluated treatment-related transcriptomic and proteomic changes in patients with moderate-to-severe HS treated with the investigational oral JAK1-selective inhibitor povorcitinib (INCB054707) in two phase 2 trials. Lesional skin punch biopsies (baseline and Week 8) were taken from active HS lesions of patients receiving povorcitinib (15 or 30 mg) once daily (QD) or a placebo. RNA-seq and gene set enrichment analyses were used to evaluate the effects of povorcitinib on differential gene expression among previously reported gene signatures from HS and wounded skin. The number of differentially expressed genes was the greatest in the 30 mg povorcitinib QD dose group, consistent with the published efficacy results. Notably, the genes impacted reflected JAK/STAT signaling transcripts downstream of TNF-α signaling, or those regulated by TGF-β. Proteomic analyses were conducted on blood samples obtained at baseline and Weeks 4 and 8 from patients receiving povorcitinib (15, 30, 60, or 90 mg) QD or placebo. Povorcitinib was associated with transcriptomic downregulation of multiple HS and inflammatory signaling markers as well as the reversal of gene expression previously associated with HS lesional and wounded skin. Povorcitinib also demonstrated dose-dependent modulation of several proteins implicated in HS pathophysiology, with changes observed by Week 4. The reversal of HS lesional gene signatures and rapid, dose-dependent protein regulation highlight the potential of JAK1 inhibition to modulate underlying disease pathology in HS.

Introduction: Breast cancer (BC) is a public health problem in developing countries, including Cape Verde. Immunohistochemistry (IHC) is the gold standard technique used for BC phenotypic characterisation to support efficient therapeutic decisions. However, IHC is a demanding technique that requires knowledge, trained technicians, expensive antibodies and reagents, controls, and results validation. The low number of cases in Cape Verde increases the risk of expiring the validity of the antibodies, and manual procedures often jeopardise the quality of the results. Thus, IHC is limited in Cape Verde, and an alternative technically easy solution is needed. A point-of-care messenger RNA (mRNA) STRAT4 BC assay to assess estrogen (ER), progesterone (PR), hormone growth factor 2 receptor (HER2), and Ki67, using the GeneXpert platform, has been recently validated on tissues from internationally accredited laboratories, showing excellent concordance with IHC results.To assess whether this technology can be implemented in Cape Verde to guide BC treatment we decided to study the level of agreement between the findings yielded by BC STRAT4 and the results are the same cases obtained by IHC., Methods: Formalin-fixed and paraffin-embedded (FFPE) tissue samples from 29 Cabo Verdean BC patients diagnosed in Agostinho Neto University Hospital were analysed by applying IHC and BC STRAT4 assay. The time between sample collection and pre-analytic procedures is unknown. All the samples were pre-processed in Cabo Verde (fixed in formalin and embedded in paraffin). IHC studies were performed in referenced laboratories in Portugal. STRAT4 and IHC result concordance was assessed by calculating the percentage of results agreement and Cohen's Kappa (K) statistics., Results: STRAT4 assay failed in 2 out of the 29 analysed samples. Of the 27 successfully analysed samples, STRAT4/IHC results for ER, PR, HER2, and Ki67 were concordant in 25, 24, 25, and 18 cases, respectively. Ki67 was indeterminate in three cases, and PR was indeterminate once.The percentage of agreement between STRAT4 and IHC results for ER, PR, HER2, and Ki67 was 92.59%, 92.31%, 92.59% and 81.82%, respectively. The Cohen's K statistic coefficients for each biomarker were 0.809, 0.845, 0.757 and 0.506, respectively., Conclusions: According to our preliminary results, a point-of-care mRNA STRAT4 BC assay may be an alternative in laboratories unable to provide quality and/or cost-efficient IHC services. However, more data and improvement on sample pre-analytic processes are required to implement this BC STRAT4 Assay in Cape Verde., Competing Interests: The authors declare that there is no conflict of interest., (© the authors; licensee ecancermedicalscience.)

Paraneoplastic conditions such as cancer cachexia are often exacerbated by chemotherapy, which affects the patient's quality of life as well as the response to therapy. The aim of this narrative review was to overview the body-composition-related changes and molecular effects of different chemotherapy agents used in cancer treatment on skeletal-muscle remodeling. A literature search was performed using the Web of Science, Scopus, and Science Direct databases and a total of 77 papers was retrieved. In general, the literature survey showed that the molecular changes induced by chemotherapy in skeletal muscle have been studied mainly in animal models and mostly in non-tumor-bearing rodents, whereas clinical studies have essentially assessed changes in body composition by computerized tomography. Data from preclinical studies showed that chemotherapy modulates several molecular pathways in skeletal muscle, including the ubiquitin-proteasome pathway, autophagy, IGF-1/PI3K/Akt/mTOR, IL-6/JAK/STAT, and NF-κB pathway; however, the newest chemotherapy agents are underexplored. In conclusion, chemotherapy exacerbates skeletal-muscle wasting in cancer patients; however, the incomplete characterization of the chemotherapy-related molecular effects on skeletal muscle makes the development of new preventive anti-wasting strategies difficult. Therefore, further investigation on molecular mechanisms and clinical studies are necessary.

In Brief: miR-23b-3p expression is increased in fertile endometrium during receptivity. This study investigates the function of miR-23b-3p on endometrial adhesion and its downstream targets., Abstract: The human endometrium undergoes dramatic remodeling throughout the menstrual cycle that is essential for successful blastocyst attachment and implantation in the mid-secretory (receptive) phase. microRNA (miR) plays a role in the preparation of endometrial receptivity. miR-23b-3p expression is increased in fertile endometrium during receptivity. Here, we aimed to investigate miR-23b-3p function during receptivity. qPCR and in situ hybridization were used to investigate the expression and localization of miR-23b-3p in human endometrium, respectively. Ishikawa cells (endometrial epithelial cell line) and endometrial organoid-derived epithelial cells were transfected with miR-23b-3p mimic, and trophoblast progenitor spheroid (blastocyst surrogate) adhesion assay was used to determine effects on blastocyst adhesion to endometrial cells. We demonstrated that miR-23b-3p was significantly upregulated in the fertile endometrium of the receptive phase compared to the non-receptive, proliferative phase. No difference was identified for the expression of miR-23b-3p between fertile and infertile mid-secretory phase endometrium. miR-23b-3p localized to the epithelium and stroma in the mid-secretory phase but was undetectable in the proliferative phase of fertile endometrium. Functionally, miR-23-3p overexpression in Ishikawa cells and fertile endometrial organoid-derived epithelial cells significantly improved their adhesive capacity to trophoblast progenitor spheroids. miR-23b-3p overexpression in infertile endometrial organoid-derived epithelial cells did not improve adhesion. Among 10 miR-predicted gene targets examined, miR-23b-3p overexpression in Ishikawa cells significantly reduced the expression of MET, secreted frizzled-related protein 4 (SFRP4) and acyl-CoA dehydrogenase short/branched chain (ACADSB) compared to control. The reduction of SFRP4 after miR23b-3p overexpression was confirmed by immunoblotting in fertile organoid-derived epithelial cells. SFRP4 expression in fertile endometrium exhibited an inverse expression pattern compared to miR-23b-3p and was higher in the proliferative phase compared to the mid-secretory phase. Overall, miR-23b-3p is likely a critical regulator of endometrial epithelial adhesion and receptivity.

Objective: To investigate the effects of different physical exercise programs and polymorphisms of the FTO (fat mass and obesity-associated gene) on body composition and cardiovascular risk factors in adolescents with overweight and obesity., Methods: A randomized, parallel, double-blind clinical trial consisting of the adolescent overweight from the state public network, in a simple representative random sample, who participated in an aerobic exercise or weight training intervention for 10 weeks. Anthropometry, body composition, biochemical markers, sexual maturation, and rs9939609 polymorphism in the FTO gene were assessed. 347 adolescents had their characterization of nutritional status. 72 individuals with overweight and obesity were invited to participate. 39 remained for the start of the program and were randomly allocated to both types of intervention. In the end, 26 subjects participated in the intervention programs, with 12 and 14 in the aerobic and weight training programs, respectively., Results: Heterozygous and homozygous bearers of risk allele A participating in the aerobic program showed improvements in glycemia (p = 0.002) and total cholesterol (p = 0.023) and a reduction in body fat mass (p = 0.041). The weight training program reduced glycemia in patients with the risk allele A (p = 0.027). Cameron's stage four sexual maturation participants were 2.1 times more likely to improve their body fat (CI = 1.31-3.39)., Conclusion: Aerobic exercises produced exclusively a significant decrease in fat mass and total cholesterol in patients with risk allele A. Distinct physical exercise programs may cause diverse changes in risk variables related to the health of adolescents., Competing Interests: Conflicts of interest The authors declare no conflicts of interest, (Copyright © 2022. Published by Elsevier Editora Ltda.)