Endogenous Glucocorticoid Signaling Regulates CD8+ T Cell Differentiation and Development of Dysfunction in the Tumor Microenvironment.

Identifying signals in the tumor microenvironment (TME) that shape CD8+ T cell phenotype can inform novel therapeutic approaches for cancer. Here, we identified a gradient of increasing glucocorticoid receptor (GR) expression and signaling from naïve to dysfunctional CD8+ tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8+ TILs improved effector differentiation, reduced expression of the transcription factor TCF-1, and inhibited the dysfunctional phenotype, culminating in tumor growth inhibition. GR signaling transactivated the expression of multiple checkpoint receptors and promoted the induction of dysfunction-associated genes upon T cell activation. In the TME, monocyte-macrophage lineage cells produced glucocorticoids and genetic ablation of steroidogenesis in these cells as well as localized pharmacologic inhibition of glucocorticoid biosynthesis improved tumor growth control. Active glucocorticoid signaling associated with failure to respond to checkpoint blockade in both preclinical models and melanoma patients. Thus, endogenous steroid hormone signaling in CD8+ TILs promotes dysfunction, with important implications for cancer immunotherapy.

Association of Lipid Levels with Mefloquine and Carboxy-Mefloquine Concentrations in Patients with Uncomplicated Falciparum Malaria.

Mefloquine shows a high capacity to bind plasma proteins, which influences the amount of drug in erythrocytes. The study investigated the association of lipids levels with plasma concentrations of mefloquine and carboxy-mefloquine in 85 Brazilian patients with uncomplicated falciparum malaria. There were no significant associations between the total cholesterol or triglycerides with plasma concentrations of mefloquine and of carboxy-mefloquine. Lipoprotein levels explained 25.68% and 18.31% of mefloquine and carboxy-mefloquine plasma concentrations, respectively.

The extent of chloroquine underdosing in adult patients with malaria by Plasmodium vivax from an endemic area of the Brazilian Amazon basin.

OBJECTIVES: To evaluate the extent of chloroquine underdosing and to measure the concentrations of chloroquine and desethylchloroquine in adult patients with P. vivax malaria in the Brazilian Amazon basin. METHODS: Prospective study of cases in male adult patients with malaria by Plasmodium vivax treated with a total dose of 1500 mg chloroquine over three days and a short course of primaquine. Patients were weighed at admission, and the dose per mg/kg was determined. Blood samples were collected at 24 and 168 h after enrolment, and the concentrations of chloroquine and desethylchloroquine were measured in plasma by high-performance liquid chromatography with fluorescence detection. RESULTS: Of 61 patients were included in the study, and 60% received a total dose of chloroquine below 25 mg/kg. Plasma chloroquine concentrations ranged from 90 to 184 ng/ml and from 175 to 827 ng/ml at 24 and 168 hours. For desethylchloroquine, the values ranged from 32 to 144 ng/ml and from 90 to 440 ng/ml at 24 and 168 h. There were no significant correlations between the plasma levels of chloroquine and the doses administered (mg/kg) at 24 and 196 h. Similar results were found for desethylchloroquine. CONCLUSION: There is widespread suboptimal dosing of chloroquine that is probably due to the dosing regimen based on patient age, which reduces the drug exposure with a possible influence on parasite clearance.

OBJECTIFS: Evaluer l'impact du sous-dosage de la chloroquine et mesurer les concentrations de chloroquine et de déséthylchloroquine chez les patients adultes atteints de paludisme à P. vivax dans le bassin de l'Amazonie brésilienne. MÉTHODES: Nous avons mené une étude prospective de cas chez des patients adultes de sexe masculin atteints de paludisme par Plasmodium vivax traités avec une dose totale de 1500 mg de chloroquine sur trois jours et une courte cure de primaquine. Les patients ont été pondérés à l'admission et la dose par mg/kg a été déterminée. Des échantillons de sang ont été prélevés 24 et 168 heures après l'enrôlement dans l'étude, et les concentrations de chloroquine et de déséthylchloroquine ont été mesurées dans le plasma par chromatographie liquide à haute performance avec détection par fluorescence. RÉSULTATS: Un total de 61 patients a été inclu dans l'étude et 60% ont reçu une dose totale de chloroquine en dessous de 25 mg/kg. Les concentrations plasmatiques de chloroquine variaient de 90 à 184 ng/ml et de 175 à 827 ng/ml à 24 et 168 heures. Pour la déséthylchloroquine, les valeurs variaient de 32 à 144 ng/ml et de 90 à 440 ng/ml à 24 et à 168 heures. Il n'y avait pas de corrélation significative entre les taux plasmatiques de chloroquine et les doses administrées (mg/kg) à 24 et à 168 heures. Des résultats similaires ont été trouvés pour la déséthylchloroquine. CONCLUSION: Il existe un dosage sous-optimal répandu de chloroquine qui est probablement dû au schéma posologique basé sur l'âge du patient, ce qui réduit l'exposition au médicament avec une influence possible sur la clairance des parasites.

Doses of chloroquine in the treatment of malaria by Plasmodium vivax in patients between 2 and 14 years of age from the Brazilian Amazon basin.

BACKGROUND: A total dose of chloroquine of 25 mg/kg is recommended by the World Health Organization (WHO) to treat malaria by Plasmodium vivax. In several endemic areas, including the Brazilian Amazon basin, anti-malarial drugs are dispensed in small plastic bags at a dosing regimen based on age. This practice can lead to suboptimal dosing of the drug, which can impact treatment outcomes. The aim of the present study was to estimate the extent of sub-dosing of chloroquine in children and adolescents with vivax malaria using an age-based dose regimen, in addition to investigating the influence of age on the plasma concentrations of chloroquine and desethylchloroquine. METHODS: A study of cases was conducted with male patients with a confirmed infection by P. vivax, ages 2 to 14 years, using a combined regimen of chloroquine and primaquine. Height, weight and body surface area were determined at admission on the study. The total dose of chloroquine administered was estimated based on the weight and on the body surface area of the study patients. Chloroquine and desethylchloroquine were measured on Day 7 in each patient included in the study by a high-performance liquid chromatographic method with fluorescence detection. RESULTS: A total of 81 patients were enrolled and completed the study. The median age was 9 years (2-14 years). All patients presented negative blood smears at 42 days follow-up. The total dose of chloroquine ranged from 13.1 to 38.1 mg/kg. The percentage of patients with a total dose of the drug below 25 mg/kg ranged from 29.4 to 63.6%. The total dose of chloroquine administered based on BSA ranged from 387 to 1079 mg/m2, increasing with age. Plasma chloroquine concentrations ranged from 107 to 420 ng/ml, increasing with age. For desethylchloroquine, the plasma concentrations ranged from 167 to 390 ng/ml, with similar values among age-groups. CONCLUSION: The data demonstrated the widespread exposure of children and adolescents to suboptimal doses of chloroquine in the endemic area investigated.

Pharmacokinetics of mefloquine administered with artesunate in patients with uncomplicated falciparum malaria from the Brazilian Amazon basin.

BACKGROUND: A fixed-dose combination of mefloquine with artesunate was evaluated in cases of falciparum malaria in the Brazilian Amazon basin with acceptable efficacy, safety and tolerability. However, there are no data on the pharmacokinetics of mefloquine in this coformulation in Brazil, which is valuable to evaluate whether Plasmodium is exposed to an effective concentration of the drug. METHODS: A prospective, single-arm study was conducted in male patients with slide-confirmed infection by Plasmodium falciparum using two tablets of a fixed-dose combination of artesunate (100 mg) and mefloquine base (200 mg) once daily and over 3 consecutive days. Serial blood samples were collected at admission and throughout 672 h post-administration of the drugs. Mefloquine was measured in each blood sample by high-performance liquid chromatography. The pharmacokinetic parameters were determined by non-compartmental analysis. RESULTS: A total of 61 patients were enrolled in the study and 450 whole blood samples were collected for mefloquine measurement. The mefloquine half-life was 10.25 days, the maximum concentration (Cmax) was 2.53 µg/ml, the area-under-the-curve (AUC0-∞) was 359 µg/ml h, the observed clearance (Cl/f) was 0.045 l/kg/h and the volume of distribution (V/f) was 14.6 l/kg. Mefloquine concentrations above 0.5 µg/ml were sustained for a mean time of 9.2 days. CONCLUSION: The pharmacokinetic parameters of mefloquine determined in the study suggest an adequate exposure of parasite to mefloquine in the multiple oral dose regimen of the fixed dose combination of mefloquine and artesunate.

Coxiella and Bartonella spp. in bats (Chiroptera) captured in the Brazilian Atlantic Forest biome.

BACKGROUND: The role of bats as reservoirs of zoonotic agents, especially pathogenic bacteria such as Bartonella and Coxiella, has been discussed around the world. Recent studies have identified bats as potential hosts of species from the proteobacteria phylum. In Brazil, however, the role of bats in the natural cycle of these agents is poorly investigated and generally neglected. In order to analyze the participation of bats in the epidemiology of diseases caused by Bartonella, Coxiella, Rickettsia, Anaplasma and Ehrlichia, we conducted a descriptive epidemiological study in three biogeographic regions of the Brazilian Atlantic Forest. RESULTS: Tissues of 119 bats captured in preserved areas in the states of Rio de Janeiro, Bahia and Santa Catarina from 2014 to 2015 were submitted to molecular analysis using specific primers. Bartonella spp. was detected in 22 spleen samples (18.5%, 95% CI: 11.9-26.6), whose phylogenetic analysis revealed the generation of at least two independent clusters, suggesting that these may be new unique genotypes of Bartonella species. In addition, four samples (3.4%, 95% CI: 0.9-8.3) were positive for the htpAB gene of C. burnetii [spleen (2), liver (1) and heart (1)]. Rickettsia spp., Anaplasma and Ehrlichia were not identified. This is the first study reporting C. burnetii and Bartonella spp. infections in bats from the Atlantic Forest biome. CONCLUSIONS: These findings shed light on potential host range for these bacteria, which are characterized as important zoonotic pathogens.

Dapsone and body mass index in subjects with multibacillary leprosy.

BACKGROUND: The physiological changes in obese subjects can modify the pharmacokinetic profiles of drugs influencing the therapeutic efficacy. METHODS: In this study, the authors compare plasma dapsone trough levels of multibacillary leprosy subjects stratified by body mass index (BMI) to evaluate if obesity plays a significant role on drug levels. The relationship between drug levels and BMI was also determined. Dapsone was measured by high-performance liquid chromatography and BMI based on World Health Organization criteria. RESULTS: At steady state, the median plasma dapsone trough level was significantly lower in obesity class 2 group, when compared with other groups, but they were similar between normal weight and preobesity groups. A weak association between drug levels and BMI was observed. CONCLUSIONS: Obesity promotes a significant reduction in plasma dapsone trough levels of subjects with multibacillary leprosy with a weak association between drug levels and BMI.

[Maternal morbidity and mortality in Brazil and the urgency of a national surveillance system for maternal near miss]. / Morbimortalidade materna no Brasil e a urgência de um sistema nacional de vigilância do near miss materno.

The World Health Organization (WHO) recommends the analysis of severe maternal morbidity/maternal near miss cases as complementary to the analysis of maternal deaths since the incidence is higher and the predictive factors of the two outcomes are similar. Considering that the reasons for maternal mortality in Brazil have remained constant despite the commitment made during the General Assembly of the United Nations in 2015, this article aims to propose a nationwide maternal near miss surveillance system. We propose the inclusion of maternal near miss events in the National List of Compulsory Notification of Diseases, Injuries, and Public Health Events, via the compatibility of the diagnostic criteria of maternal near miss, informed by the WHO, with the codes of the International Classification of Diseases for the identification of cases. Considering that health surveillance is based on several sources of information, notification could be made by health service professionals as soon as a confirmed or suspected case is identified. With the study of the factors associated with the outcomes, we expect a qualified evaluation of the services focused on obstetric care and consequent implementation of more efficient policies to prevent not only maternal death but also events that can both cause irreversible sequelae to women's health and increase the risk of fetal and neonatal death.

A Organização Mundial da Saúde (OMS) recomenda a análise dos casos de morbidade materna severa/near miss materno como complemento às análises das mortes de mães, dado que a incidência é mais elevada e os fatores preditivos dos dois desfechos são semelhantes. Tendo em vista que as razões de mortalidade materna, no Brasil, têm se mantido constantes apesar do compromisso firmado durante a Assembleia Geral da Organização das Nações Unidas (ONU), em 2015, o objetivo deste artigo é propor um sistema nacional de vigilância de near miss materno. Propõe-se a inclusão dos eventos near miss materno na Lista Nacional de Notificação Compulsória de Doenças, Agravos e Eventos de Saúde Pública, por meio da compatibilização dos critérios diagnósticos de near miss materno, informados pela OMS, com os códigos da Classificação Internacional de Doenças (CID) para identificação dos casos. Tendo em vista que a vigilância em saúde se faz baseada em diversas fontes de informações, a notificação poderia ser feita pelos profissionais dos serviços de saúde tão logo fosse identificado um caso confirmado ou suspeito. A partir do estudo dos fatores associados aos desfechos, espera-se a avaliação mais qualificada dos serviços voltados à assistência obstétrica e consequente implementação de políticas mais eficientes de prevenção não apenas do óbito materno, mas de eventos que podem tanto causar sequelas irreversíveis à saúde da mulher quanto aumento do risco de óbito fetal e neonatal.

La Organización Mundial de la Salud (OMS) recomienda el análisis de los casos de morbilidad materna grave/near miss materno como complemento a los análisis de las muertes maternas, dado que la incidencia es más elevada y los factores predictivos de los dos resultados son similares. Teniendo en vista que las razones de mortalidad materna, en Brasil, se han mantenido constantes a pesar del compromiso firmado durante la Asamblea General de la Organización de las Naciones Unidas, en el año 2015, el objetivo de este artículo es proponer un sistema de vigilancia de near miss materno de alcance nacional. Se propone la inclusión de los eventos de near miss materno en la Lista Nacional de Notificación Obligatoria de Enfermedades, Agravios y Eventos de Salud Pública, por medio de la compatibilización de los criterios diagnósticos de near miss materno; informados por la OMS, con los códigos de la Clasificación Internacional de Enfermedades para identificación de los casos. Teniendo en vista que la vigilancia en salud se basa en diversas fuentes de Informaciones, la notificación podría ser hecha por los profesionales de los servicios de salud, tan pronto fuese identificado un caso confirmado o sospechoso. Se espera que el estudio de los factores asociados a los resultados conduzca a una evaluación más calificada de los servicios de atención obstétrica y a la consecuente implementación de políticas más eficientes de prevención no solo de la muerte materna; sino de eventos que pueden tanto causar secuelas irreversibles a la salud de la mujer como aumento del riesgo de muerte fetal y neonatal.

Aberrant N-glycosylation in cancer: MGAT5 and ß1,6-GlcNAc branched N-glycans as critical regulators of tumor development and progression.

BACKGROUND: Changes in protein glycosylation are widely observed in tumor cells. N-glycan branching through adding ß1,6-linked N-acetylglucosamine (ß1,6-GlcNAc) to an α1,6-linked mannose, which is catalyzed by the N-acetylglucosaminyltransferase V (MGAT5 or GnT-V), is one of the most frequently observed tumor-associated glycan structure formed. Increased levels of this branching structure play a pro-tumoral role in various ways, for example, through the stabilization of growth factor receptors, the destabilization of intercellular adhesion, or the acquisition of a migratory phenotype. CONCLUSION: In this review, we provide an updated and comprehensive summary of the physiological and pathophysiological roles of MGAT5 and ß1,6-GlcNAc branched N-glycans, including their regulatory mechanisms. Specific emphasis is given to the role of MGAT5 and ß1,6-GlcNAc branched N-glycans in cellular mechanisms that contribute to the development and progression of solid tumors. We also provide insight into possible future clinical implications, such as the use of MGAT5 as a prognostic biomarker.

Interactions of ruthenium(II) polypyridyl complexes with human telomeric DNA.

Eight [Ru(bpy)2L]2+ and three [Ru(phen)2L]2+complexes (where bpy = 2,2'-bipyridine and phen = 1,10-phenanthroline are ancillary ligands, and L = a polypyridyl experimental ligand) were investigated for their G-quadruplex binding abilities. Fluorescence resonance energy transfer melting assays were used to screen these complexes for their ability to selectively stabilize human telomeric DNA variant, Tel22. The best G-quadruplex stabilizers were further characterized for their binding properties (binding constant and stoichiometry) using UV-vis, fluorescence spectroscopy, and mass spectrometry. The ligands' ability to alter the structure of Tel22 was determined via circular dichroism and PAGE studies. We identified me2allox as the experimental ligand capable of conferring excellent stabilizing ability and good selectivity to polypyridyl Ru(II) complexes. Replacing bpy by phen did not significantly impact interactions with Tel22, suggesting that binding involves mostly the experimental ligand. However, using a particular ancillary ligand can help fine-tune G-quadruplex-binding properties of Ru(II) complexes. Finally, the fluorescence "light switch" behavior of all Ru(II) complexes in the presence of Tel22 G-quadruplex was explored. All Ru(II) complexes displayed "light switch" properties, especially [Ru(bpy)2(diamino)]2+, [Ru(bpy)2(dppz)]2+, and [Ru(bpy)2(aap)]2+. Current work sheds light on how Ru(II) polypyridyl complexes interact with human telomeric DNA with possible application in cancer therapy or G-quadruplex sensing.

Production of galactan phthalates derivatives extracted from Gracilaria birdie: Characterization, cytotoxic and antioxidant profile.

The present work explores the esterification reaction in the polysaccharide extracted from the seaweed Gracilaria birdiae and investigates its antioxidant potential. The reaction process was conducted with phthalic anhydride at different reaction times (10, 20 and 30 min), using a molar ratio of 1:2 (polymer: phthalic anhydride). Derivatives were characterized by FTIR, TGA, DSC and XRD. The biological properties of derivatives were investigated by assays of cytotoxicity and antioxidant activity (2,2-diphenyl-1-picrylhydroxyl - DPPH and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt - ABTS). The results obtained by FT-IR confirmed the chemical modification, there was a reduction related to the presence of carbonyl and hydroxyl groups when compared to the in nature polysaccharide spectrum. TGA analysis showed a change in the thermal behavior of the modified materials. X-ray diffraction, it was shown that the in nature polysaccharide appeared as an amorphous material, while the material obtained after the chemical modification process had increased crystallinity, due to the introduction of phthalate groups. For the biological assays, it was observed that the phthalate derivative was more selective than the unmodified material for the murine metastatic melanoma tumor cell line (B16F10), revealing a good antioxidant profile for DPPH and ABTS radicals.

Top Ten Tips Palliative Care Clinicians Should Know About Managing Immune-Mediated Endocrine Toxicities in Cancer.

Immune checkpoint inhibitors (ICI), such as PD-1/PDL-1 and CTLA-4, have become widely used in the treatment of solid and hematological malignancies; their use and side effects are increasingly seen in the palliative care (PC) population. These drugs can result in immune-mediated endocrinopathies; the thyroid is the most common endocrine gland affected, but the pituitary, adrenals, and pancreas may be affected as well. Symptoms may be insidious and nonspecific. A high index of suspicion and routine laboratory monitoring allows for prompt diagnosis and treatment, which can significantly improve symptoms and increase quality of life. In this study, we present an approach to monitoring and initial management of ICI-induced endocrinopathies in the PC patient population.

Photodynamic therapy for treatment of bacterial keratitis.

Microbial keratitis is the main cause of corneal opacification and the fourth leading cause of blindness worldwide, with bacteria the major infectious agent. Recently, bacterial keratitis has become a serious threat due to routine use of antibiotics leading to selection of resistant and multidrug-resistant bacteria strains. New approaches for treatment of bacterial keratitis are necessary to outcome the increasing antibiotic resistance. Antimicrobial photodynamic therapy is based on three agents: photosensitizer, oxygen, and light radiation. This therapy has been successful for treatment of infections in different tissues and organs as well as against different type of infectious agents and no resistance development. Also, new photosensitizers are being developed that has increased the spectrum of therapeutic protocols for treatment of a number of infectious diseases. Thus, antimicrobial photodynamic therapy has an extraordinary potential for treatment of those bacterial keratitis cases that actually are not solved by traditional antibiotic therapy.

Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti-PD-1 immunotherapy.

The tumor-intrinsic NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome-heat shock protein 70 (HSP70) signaling axis is triggered by CD8+ T cell cytotoxicity and contributes to the development of adaptive resistance to anti-programmed cell death protein 1 (PD-1) immunotherapy by recruiting granulocytic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Here, we demonstrate that the tumor NLRP3-HSP70 axis also drives the accumulation of PMN-MDSCs into distant lung tissues in a manner that depends on lung epithelial cell Toll-like receptor 4 (TLR4) signaling, establishing a premetastatic niche that supports disease hyperprogression in response to anti-PD-1 immunotherapy. Lung epithelial HSP70-TLR4 signaling induces the downstream Wnt5a-dependent release of granulocyte colony-stimulating factor (G-CSF) and C-X-C motif chemokine ligand 5 (CXCL5), thus promoting myeloid granulopoiesis and recruitment of PMN-MDSCs into pulmonary tissues. Treatment with anti-PD-1 immunotherapy enhanced the activation of this pathway through immunologic pressure and drove disease progression in the setting of Nlrp3 amplification. Genetic and pharmacologic inhibition of NLRP3 and HSP70 blocked PMN-MDSC accumulation in the lung in response to anti-PD-1 therapy and suppressed metastatic progression in preclinical models of melanoma and breast cancer. Elevated baseline concentrations of plasma HSP70 and evidence of NLRP3 signaling activity in tumor tissue specimens correlated with the development of disease hyperprogression and inferior survival in patients with stage IV melanoma undergoing anti-PD-1 immunotherapy. Together, this work describes a pathogenic mechanism underlying the phenomenon of disease hyperprogression in melanoma and offers candidate targets and markers capable of improving the management of patients with melanoma.

COVID-19 cross-sectional study in Maricá, Brazil: The impact of vaccination coverage on viral incidence.

Population surveillance in COVID-19 Pandemic is crucial to follow up the pace of disease and its related immunological status. Here we present a cross-sectional study done in Maricá, a seaside town close to the city of Rio de Janeiro, Brazil. Three rounds of study sampling, enrolling a total of 1134 subjects, were performed during May to August 2021. Here we show that the number of individuals carrying detectable IgG antibodies and the neutralizing antibody (NAb) levels were greater in vaccinated groups compared to unvaccinated ones, highlighting the importance of vaccination to attain noticeable levels of populational immunity against SARS-CoV-2. Moreover, we found a decreased incidence of COVID-19 throughout the study, clearly correlated with the level of vaccinated individuals as well as the proportion of individuals with detectable levels of IgG anti-SARS-CoV-2 and NAb. The observed drop occurred even during the introduction of the Delta variant in Maricá, what suggests that the vaccination slowed down the widespread transmission of this variant. Overall, our data clearly support the use of vaccines to drop the incidence associated to SARS-CoV-2.

Guiding immunotherapy combinations: Who gets what?

Although PD-1 and CTLA-4 inhibitors have proven successful in a range of malignancies, there are subsets of patients that do not respond to these agents due to upregulation of adaptive and innate resistance mechanisms by the tumor and its surrounding microenvironment. As new immunotherapeutic strategies are developed, there is a need for rational implementation of novel immunotherapy combinations that target complementary mechanisms of immunotherapy resistance intrinsic to each patient and tumor type. In this short review, we cover mechanisms by which tumors evade the immune system, as well as summarize available clinical data on emerging therapeutic agents that target these defense mechanisms. Rational implementation of combination immunotherapy targeting patient- and malignancy-specific immune evasion mechanisms may thus lead to enhanced response rates and allow immunotherapy to be effective even in tumors that are historically considered poorly responsive to immunotherapy.

Dermatologic toxicities associated with radiation therapy in women with breast cancer.

Breast-conserving surgery with adjuvant radiation therapy has become the standard of care for women with early stage breast cancer, and as a result, a large number of patients are affected by the cutaneous sequelae of radiation therapy. These dermatologic toxicities may present during treatment or years later and can significantly impact patients' quality of life. In this review, we discuss the clinical presentation, prevention, and management of radiation-induced cutaneous toxicities in women with breast cancer, including radiation dermatitis, radiation recall, radiation-induced morphea, radiation-induced fibrosis, and cutaneous malignancies in irradiated skin.

N­glycosylation and receptor tyrosine kinase signaling affect claudin­3 levels in colorectal cancer cells.

Changes in protein levels in different components of the apical junctional complex occur in colorectal cancer (CRC). Claudin­3 is one of the main constituents of tight junctions, and its overexpression can increase the paracellular flux of macromolecules, as well as the malignant potential of CRC cells. The aim of this study was to investigate the molecular mechanisms involved in the regulation of claudin­3 and its prognostic value in CRC. In silico evaluation in each of the CRC consensus molecular subtypes (CMSs) revealed that high expression levels of CLDN3 (gene encoding claudin­3) in CMS2 and CMS3 worsened the patients' long­term survival, whereas a decrease in claudin­3 levels concomitant with a reduction in phosphorylation levels of epidermal growth factor receptor (EGFR) and insulin­like growth factor 1 receptor (IGF1R) could be achieved by inhibiting N­glycan biosynthesis in CRC cells. We also observed that specific inactivation of these receptor tyrosine kinases (RTKs) led to a decrease in claudin­3 levels, and this regulation seems to be mediated by phospholipase C (PLC) and signal transducer and activator of transcription 3 (STAT3) in CRC cells. RTKs are modulated by their N­linked glycans, and inhibition of N­glycan biosynthesis decreased the claudin­3 levels; therefore, we evaluated the correlation between N­glycogenes and CLDN3 expression levels in each of the CRC molecular subtypes. The CMS1 (MSI immune) subtype concomitantly exhibited low expression levels of CLDN3 and N­glycogenes (MGAT5, ST6GAL1, and B3GNT8), whereas CMS2 (canonical) exhibited high gene expression levels of CLDN3 and N­glycogenes (ST6GAL1 and B3GNT8). A robust positive correlation was also observed between CLDN3 and B3GNT8 expression levels in all CMSs. These results support the hypothesis of a mechanism integrating RTK signaling and N­glycosylation for the regulation of claudin­3 levels in CRC, and they suggest that CLDN3 expression can be used to predict the prognosis of patients identified as CMS2 or CMS3.

Dermatologic conditions in women receiving systemic cancer therapy.

As advances in cancer therapies have improved cancer-related survival, novel therapeutics have also introduced a variety of dermatologic toxicities, and an increased number of patients are living with these sequalae. Women with cancer in particular experience a spectrum of dermatologic conditions that affect their skin, hair, nail, and mucosal surfaces. Studies have shown that these toxic effects can significantly affect quality of life and alter a woman's self-image, cultural identity, femininity, sexuality, and mental health. In severe instances, dermatologic toxicities may even disrupt cancer therapy and can therefore affect overall survival and treatment response. In this article, we review the dermatologic adverse effects from traditional chemotherapy, targeted therapy, immune checkpoint inhibitors, and endocrine therapy that disproportionately affect women. The timely diagnosis and management of these dermatologic conditions is crucial in the multidisciplinary care of women with cancer.