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BACKGROUND: Breast cancer (BC) is associated with a continuous increase in incidence, with high mortality rates in several countries. CD44, STAT3, and SOX2 are related to regulating of somatic cell division, tumorigenesis, and metastasis in BC. METHODS: A cross-sectional study was carried out at the Hospital de Cancer de Pernambuco (HCP) between 2017 and 2018. Fifty-one women with locally advanced (LA) and 14 with metastatic BC were included in the study. RESULTS: High CD44+/CD24neg and CD44+/CD24neg/SOX2+ levels in Luminal B (LB), HER2+, and triple-negative breast cancer (TNBC) compared with controls (p < 0.05). Low CD44+/CD24negSTAT3+ levels in LB, HER2+, and TNBC compared with controls (p < 0.05). High T lymphocytes, and low STAT3 + T, and SOX2 + T levels in BC patients (p < 0.05). High SOX2 + T levels in patients with axillary lymph node-negative (N0) compared with the axillary lymph node-positives (N1 and N2 groups; p < 0.05). High SOX2 + T levels in N1 compared to N2 (p < 0.05). High T lymphocytes and low SOX2 + T levels in the LA tumor compared to metastatic disease (p = 0.0007 and p = 0.02, respectively). High CD44 + /CD24negSTAT3+, and T lymphocyte levels in TNBC patients with LA tumor compared to metastatic (p < 0.05). Low STAT3 + T levels in TBNC patients with LA tumor compared to metastatic (p = 0.0266). CONCLUSION: SOX2 and STAT3 expression on circulating T lymphocytes and CD44 + /CD24neg cells in peripheral blood have prognostic roles in breast cancer. SOX2 and STAT3 expression are potential predictive biomarkers of disease progression in breast cancer regardless of tumor subtype.

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Alzheimer's disease (AD) is a neurodegenerative disorder caused by accumulation of amyloid-ß oligomers (AßO) in the brain, neuroinflammation, oxidative stress, and cognitive decline. Grandisin, a tetrahydrofuran neolignan, exhibits relevant anti-inflammatory and antioxidant properties. Interestingly, grandisin-based compounds were shown to prevent AßO-induced neuronal death in vitro. However, no study has assessed the effect of these compounds on the AD animal model. This study focuses on a triazole grandisin analogue (TGA) synthesized using simplification and bioisosteric drug design, which resulted in improved potency and solubility compared with the parent compound. This study aimed to investigate the possible in vivo effects of TGA against AßO-induced AD. Male C57/Bl6 mice underwent stereotaxic intracerebroventricular AßO (90 µM) or vehicle injections. 24 h after surgery, animals received intraperitoneal treatment with TGA (1 mg/kg) or vehicle, administered on a 14 day schedule. One day after treatment completion, a novel object recognition task (NORT) was performed. Memantine (10 mg/kg) was administered as a positive control. NORT retention sessions were performed on days 8 and 16 after AßO injection. Immediately after retention sessions, animals were euthanized for cortex and hippocampus collection. Specimens were subjected to oxidative stress and cytokine analyses. TGA reduced the level of cortex/hippocampus lipoperoxidation and prevented cognitive impairment in AßO-injected mice. Additionally, TGA reduced tumor necrosis factor (TNF) and interferon-γ (IFN-γ) levels in the hippocampus. By contrast, memantine failed to prevent cortex/hippocampus lipid peroxidation, recognition memory decline, and AßO-induced increases in TNF and IFN-γ levels in the hippocampus. Thus, memantine was unable to avoid the AßO-induced persistent cognitive impairment. The results showed that TGA may prevent memory impairment by exerting antioxidant and anti-inflammatory effects in AßO-injected mice. Moreover, TGA exhibited a persistent neuroprotective effect compared to memantine, reflecting an innovative profile of this promising agent against neurodegenerative diseases, such as AD.

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According to the WHO, antimicrobial resistance is among the top 10 threats to global health. Due to increased resistance rates, an increase in the mortality and morbidity of patients has been observed, with projections of more than 10 million deaths associated with infections caused by antibacterial resistant microorganisms. Our research group has developed a new family of pyrimido-isoquinolin-quinones showing antibacterial activities against multidrug-resistant Staphylococcus aureus. We have developed 3D-QSAR CoMFA and CoMSIA studies (r2 = 0.938; 0.895), from which 13 new derivatives were designed and synthesized. The compounds were tested in antibacterial assays against methicillin-resistant Staphylococcus aureus and other bacterial pathogens. There were 12 synthesized compounds active against Gram-positive pathogens in concentrations ranging from 2 to 32 µg/mL. The antibacterial activity of the derivatives is explained by the steric, electronic, and hydrogen-bond acceptor properties of the compounds.

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Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder without a cure, despite the enormous number of investigations and therapeutic approaches. AD is a consequence of microglial responses to "damage signals", such as aggregated tau oligomers, which trigger a neuro-inflammatory reaction, promoting the misfolding of cytoskeleton structure. Since AD is the most prevalent cause of dementia in the elderly (>60 years old), new treatments are essential to improve the well-being of affected subjects. The pharmaceutical industry has not developed new drugs with efficacy for controlling AD. In this context, major attention has been given to nutraceuticals and novel bioactive compounds, such as molecules from the Andean Shilajit (AnSh), obtained from the Andes of Chile. Primary cultures of rat hippocampal neurons and mouse neuroblastoma cells were evaluated to examine the functional and neuroprotective role of different AnSh fractions. Our findings show that AnSh fractions increase the number and length of neuronal processes at a differential dose. All fractions were viable in neurons. The AnSh fractions inhibit tau self-aggregation after 10 days of treatment. Finally, we identified two candidate molecules in M3 fractions assayed by UPLC/MS. Our research points to a novel AnSh-derived fraction that is helpful in AD. Intensive work toward elucidation of the molecular mechanisms is being carried out. AnSh is an alternative for AD treatment or as a coadjuvant for an effective treatment.

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INTRODUCTION: Menopause and post-menopause are characterized by low levels of estrogen that can be associated with the emergence of metabolic diseases. While hormone replacement therapy can alleviate many symptoms, it can also exacerbate other diseases such as breast cancer. In the search for natural alternatives, Ilex paraguariensis (Yerba Mate) has been identified as a potential therapy for the onset of obesity. Here, the effect of MATE consumption on white adipose tissue (WAT) was studied in ovariectomized rats, an animal model for post-menopause hormone loss. METHODS: Four groups of animals were used: ovariectomy with MATE (OVX MATE) and without MATE (OVX), as well as sham surgery with MATE (Sham MATE) and without MATE (Sham). MATE was provided by gavage at 1 g/kg of body weight for eight weeks before measuring biochemical parameters in plasma and characterizing WAT morphology. RESULTS: The consumption of Yerba MATE significantly decreased weight gain in ovariectomized rats and presented near control levels of triglycerides, total cholesterol, and LDL. A morphometric analysis of WAT showed a significant decrease in the area occupied by adipocytes in the group that consumed MATE. Finally, MATE consumption increased the UCP1 content in the WAT of the ovariectomized group. Yerba MATE treatment was also associated with higher levels of SIRT1 protein. CONCLUSION: MATE consumption has a preventive effect on the weight gain observed in ovariectomized rats and potential benefits in naturally avoiding the onset of obesity post menopause.

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Annexin A1 (AnxA1) is a pleiotropic protein that exerts essential roles in breast cancer (BC) growth and aggressiveness. In our previous work, we described the autocrine signaling of AnxA1 through formyl peptide receptor 1 (FPR1) in the triple-negative (TN) BC cell line, MDA-MB-231. Here, we aimed to describe the interaction between the AnxA1/FPR1 and the Interleukin-6 (IL-6) signaling pathways and their role in the tumor microenvironment (TME). First, we demonstrated that AnxA1 and IL-6 expression levels are correlated in BC tissue samples. In three TNBC cell lines, overexpression of both AnxA1 and IL-6 was also identified. Next, we inhibited FPR1, the IL-6 receptor and STAT3 in both MDA-MB-231 and MDA-MB-157 cells. The FPR1 inhibition led to increased levels of IL-6 and secreted AnxA1 in both cell lines. On the other side, inhibition of the IL-6 receptor or STAT3 led to the impairment of AnxA1 secretion, suggesting the essential role of the IL-6 signaling cascade in the activation of the AnxA1/FPR1 autocrine axis. Finally, we described the interaction between IL-6 and the AnxA1/FPR1 pathways and their role on the TME by analyzing the effect of supernatants derived from MDA-MB-231 and MDA-MB-157 cells under the inhibition of FPR1 or IL-6 signaling on fibroblast cell motility.

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OBJECTIVE: the recommendations of the decisions made by the Tumor Board (TB) should be followed to identify barriers that may interfere with the execution of the previously decided, best care for the patient. The aim of this study is to assess whether the TB conduct decision was performed in patients with pancreatic tumors, their life status 90 days after the TB decision, and to analyze the reasons why the conduct was not performed. METHODS: we conducted a retrospective study with patients with pancreas tumors, evaluated between 2017 and 2019. We collected data on epidemiological status, whether the TB procedure was performed, the reason for not performing it, life status 90 days after the TB decision, and how many times each patient was discussed at a meeting. We compared categorical variables using the chi square test, numerical variables were presented as means and standard deviation. RESULTS: we studied 111 session cases, in 95 patients, 86 (90.5%) diagnosed with cancer. After 90 days of TB, 83 patients (87.37%) remained alive, 9 had (9.47%) died, and 3 (3.16%) were lost to follow-up. The TB decision was not observed in 12 (10.8%) cases and the reasons were: 25% (3) for loss of follow-up, 8.33% (1) for patient refusal, and 66.67% (8) due to clinical worsening. The cases of patients with metastases had a lower rate of TB conduct compliance (p=0.006). CONCLUSIONS: the TB conduct was performed in most cases and the most evident reason for non-compliance with the conducts is the patient's clinical worsening.

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PURPOSE: Breast cancer (BC) is considered a heterogeneous disease composed of distinct subtypes with diverse clinical outcomes. Luminal subtype tumors have the best prognosis, and patients benefit from endocrine therapy. However, resistance to endocrine therapies in BC is an obstacle to successful treatment, and novel biomarkers are needed to understand and overcome this mechanism. The RET, BCAR1, and BCAR3 genes may be associated with BC progression and endocrine resistance. METHODS: Aiming to evaluate the expression profile and prognostic value of RET, BCAR1, and BCAR3, we performed immunohistochemistry on tissue microarrays (TMAs) containing a cohort of 361 Luminal subtype BC. RESULTS: Low expression levels of these three proteins were predominantly observed. BCAR1 expression was correlated with nuclear grade (p = 0.057), and BCAR3 expression was correlated with lymph node status (p = 0.011) and response to hormonal therapy (p = 0.021). Further, low expression of either BCAR1 or BCAR3 was significantly associated with poor prognosis (p = 0.005; p = 0.042). Pairwise analysis showed that patients with tumors with low BCAR1/low BCAR3 expression had a poorer overall survival (p = 0.013), and the low BCAR3 expression had the worst prognosis with RET high expression stratifying these patients into two different groups. Regarding the response to hormonal therapy, non-responder patients presented lower expression of RET in comparison to the responder group (p = 0.035). Additionally, the low BCAR1 expression patients had poorer outcomes than BCAR1 high (p = 0.015). CONCLUSION: Our findings suggest RET, BCAR1, and BCAR3 as potential candidate markers for endocrine therapy resistance in Luminal BC.

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ABSTRACT Objective: the recommendations of the decisions made by the Tumor Board (TB) should be followed to identify barriers that may interfere with the execution of the previously decided, best care for the patient. The aim of this study is to assess whether the TB conduct decision was performed in patients with pancreatic tumors, their life status 90 days after the TB decision, and to analyze the reasons why the conduct was not performed. Methods: we conducted a retrospective study with patients with pancreas tumors, evaluated between 2017 and 2019. We collected data on epidemiological status, whether the TB procedure was performed, the reason for not performing it, life status 90 days after the TB decision, and how many times each patient was discussed at a meeting. We compared categorical variables using the chi square test, numerical variables were presented as means and standard deviation. Results: we studied 111 session cases, in 95 patients, 86 (90.5%) diagnosed with cancer. After 90 days of TB, 83 patients (87.37%) remained alive, 9 had (9.47%) died, and 3 (3.16%) were lost to follow-up. The TB decision was not observed in 12 (10.8%) cases and the reasons were: 25% (3) for loss of follow-up, 8.33% (1) for patient refusal, and 66.67% (8) due to clinical worsening. The cases of patients with metastases had a lower rate of TB conduct compliance (p=0.006). Conclusions: the TB conduct was performed in most cases and the most evident reason for non-compliance with the conducts is the patient's clinical worsening.

RESUMO Objetivo: as recomendações das decisões em Tumor Board (TB) deveriam ser acompanhadas para identificar barreiras que possam interferir na execução do melhor cuidado para o paciente decidido previamente. O objetivo do estudo é avaliar se a decisão de conduta em TB foi realizada em pacientes com tumores pancreáticos, o status de vida 90 dias após TB e analisar os motivos pelos quais a conduta não foi realizada. Métodos: estudo retrospectivo com pacientes com tumores de pâncreas, avaliados entre 2017 a 2019. Dados epidemiológicos, se a conduta de TB foi realizada, o motivo da não realização, o status de vida em 90 dias após decisão de TB e quantas vezes cada paciente foi discutido em reunião foram coletados. As variáveis categóricas foram comparadas pelo teste de qui-quadrado; variáveis numéricas foram apresentadas como médias e desvio padrão. Resultados: 111 casos, 95 pacientes, 86 (90,5%) com diagnóstico de câncer. Após 90 dias de TB, 83 pacientes (87,37%) permaneceram vivos, 9 pacientes (9,47%) faleceram e 3 (3,16%) perderam o seguimento. A conduta do TB não foi realizada em 12 (10,8%) dos casos e os motivos foram: 25% (3) por perda de seguimento, 8,33% (1) por recusa do paciente e 66,67% (8) devido à piora clínica. Os casos de pacientes com metástases tiveram menor execução de conduta de TB (p=0,006). Conclusões: a conduta do TB é realizada na maior parte dos casos e o motivo mais evidente para o não cumprimento das condutas é a piora clínica do paciente.

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Abstract Histoid leprosy is a rare form of multibacillary leprosy, characterized by the presence of papules, plaques, or nodules whose appearance is keloid-like, skin colored, or erythematous. Fusiform cells are the main histopathological feature. Due to the fact that it can simulate other dermatological lesions, for example, dermatofibroma and neurofibroma, it constitutes a diagnostic challenge for clinicians and pathologists. It is a bacilliferous form of leprosy, and it plays an important role in disease transmission. A case of a patient with histoid leprosy living in the Northeast Region of Brazil is reported.

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Histoid leprosy is a rare form of multibacillary leprosy, characterized by the presence of papules, plaques, or nodules whose appearance is keloid-like, skin colored, or erythematous. Fusiform cells are the main histopathological feature. Due to the fact that it can simulate other dermatological lesions, for example, dermatofibroma and neurofibroma, it constitutes a diagnostic challenge for clinicians and pathologists. It is a bacilliferous form of leprosy, and it plays an important role in disease transmission. A case of a patient with histoid leprosy living in the Northeast Region of Brazil is reported.

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BACKGROUND: Triple-negative mammary carcinoma (TNBC) is an aggressive breast cancer subtype associated with dismal prognosis. The interaction between the immune system and the cancer cells plays a crucial role in tumor development and progression. However, it is still unclear how each diverse cell of the immune system contributes to the prognosis of patients with breast cancer. In this study, we investigated how the cell composition of the immune cell infiltrated modifies the survival of patients with resected TNBC. METHODS: Retrospectively, we collected data from 76 patients diagnosed with non-metastatic TNBC with available tissue blocks for tissue micro-array (TMA) construction. The TMA was constructed using two cores from each tumor block. The expression of CD4, CD8, FOXP3, CD20, CD68, CD163, PD-1, PD-L1, PTEN and phospho-STAT1 was determined by immunohistochemistry. RESULTS: We observed that the inflammatory infiltrate in TNBC is enriched for M2 macrophages and T lymphocytes (CD4+, CD8+). PD-L1 expression in the stroma was associated with the percentage of TILs (p = 0.018) as, PD-L1 expression in the tumor was associated with the percentage of TILs (p = 0.049). We found a correlation between TILs and PD-L1 expression in stroma cells (p = 0.020) and in tumor cells (p = 0.027). In our cohort, we observed a trend for improved survival associated with higher CD8+ (p = 0.054) and CD4 + (p = 0.082) cell counts, but the results were not statistically significant. Conversely, the expression of PTEN in tumor cells and a low number of FOXP3+ cells in tumor stroma were both associated with improved OS. The CD8 to FOXP3 ratio and the CD4 to FOXP3 ratio were associated with better OS as well, however, only the CD8 to FOXP3 ratio had its prognostic impact confirmed in the METABRIC TNBC cohort. There was no association between PD-L1 expression and OS. CONCLUSION: TNBC tumor microenvironment is enriched for lymphocytes and macrophages. FOXP3 expression and the CD8 to FOXP3 ratio in the tumor stroma as well as the loss of PTEN expression in tumor cells are prognostic factors in non-metastatic TNBC.

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Breast cancer is the most diagnosed malignancy in women. Increasing evidence has highlighted the importance of chronic inflammation at the local and/or systemic level in breast cancer pathobiology, influencing its progression, metastatic potential and therapeutic outcome by altering the tumor immune microenvironment. These processes are mediated by a variety of cytokines, chemokines and growth factors that exert their biological functions either locally or distantly. Inflammasomes are protein signaling complexes that form in response to damage- and pathogen-associated molecular patterns (DAMPS and PAMPS), triggering the release of pro-inflammatory cytokines. The dysregulation of inflammasome activation can lead to the development of inflammatory diseases, neurodegeneration, and cancer. A crucial signaling pathway leading to acute and chronic inflammation occurs through the activation of NLRP3 inflammasome followed by caspase 1-dependent release of IL-1ß and IL-18 pro-inflammatory cytokines, as well as, by gasdermin D-mediated pyroptotic cell death. In this review we focus on the role of NLRP3 inflammasome and its components in breast cancer signaling, highlighting that a more detailed understanding of the clinical relevance of these pathways could significantly contribute to the development of novel therapeutic strategies for breast cancer.

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Non-Hodgkin's lymphoma (NHL) is a cancer of the lymphatic system where the lymphoid and hematopoietic tissues are infiltrated by malignant neoplasms of B, T, and natural killer lymphocytes. Effective and less invasive methods for NHL screening are urgently needed. Herein, we report an untargeted gas chromatography-mass spectrometry (GC-MS) method to investigate metabolic changes in non-volatile derivatized compounds from urine samples of NHL patients (N = 15) and compare them to healthy controls (N = 34). Uni- and multivariate data analysis showed 18 endogenous metabolites, including amino acids and their metabolites, sugars, small organic acids, and vitamins, as statistically significant for group differentiation. A receiver operating characteristic curve (ROC) generated from a support vector machine (SVM) algorithm-based model achieved 0.998 of predictive accuracy, displaying the potential and relevance of GC-MS-detected urinary non-volatile compounds for predictive purposes. Furthermore, a specific panel of key metabolites was also evaluated, showing similar results. All in all, our results indicate that this robust GC-MS method is an effective screening tool for NHL diagnosis and it is able to highlight different pathways of the disease. Graphical Abstract.

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The long-lived tree species Eschweilera tenuifolia (O. Berg) Miers is characteristic of oligotrophic Amazonian black-water floodplain forests (igapó), seasonally inundated up to 10 months per year, often forming monodominant stands. We investigated E. tenuifolia' growth and mortality patterns in undisturbed (Jaú National Park - JNP) and disturbed igapós (Uatumã Sustainable Development Reserve - USDR, downstream of the Balbina hydroelectric dam). We analysed age-diameter relationships, basal area increment (BAI) through 5-cm diameter classes, growth changes and growth ratios preceding death, BAI clustering, BAI ratio, and dated the individual year of death (14 C). Growth and mortality patterns were then related to climatic or anthropogenic disturbances. Results were similar for both populations for estimated maximum ages (JNP, 466 yr; USDR, 498 yr, except for one USDR tree with an estimated age of 820 yr) and slightly different for mean diameter increment (JNP: 2.04 mm; USDR: 2.28 mm). Living trees from JNP showed altered growth post-1975 and sparse tree mortality occurred at various times, possibly induced by extreme hydroclimatic events. In contrast with the JNP, abrupt growth changes and massive mortality occurred in the USDR after the dam construction began (1983). Even more than 30 yr after dam construction, flood-pulse alteration continues to affect both growth and mortality of E. tenuifolia. Besides its vulnerability to anthropogenic disturbances, this species is also susceptible to long-lasting dry and wet periods induced by climatic events, the combination of both processes may cause its local and regional extinction.

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BACKGROUND: Alzheimer's disease (AD) is a multifactorial disease, that involves neuroinflammatory processes in which microglial cells respond to "damage signals". The latter includes oligomeric tau, iron, oxidative free radicals, and other molecules that promotes neuroinflammation in the brain, promoting neuronal death and cognitive impairment. Since AD is the first cause of dementia in the elderly, and its pharmacotherapy has limited efficacy, novel treatments are critical to improve the quality of life of AD patients. Multitarget therapy based on nutraceuticals has been proposed as a promising intervention based on evidence from clinical trials. Several studies have shown that epicatechin-derived polyphenols from tea improve cognitive performance; also, the polyphenol molecule N-acetylcysteine (NAC) promotes neuroprotection. OBJECTIVE: To develop an approach for a rational design of leading compounds against AD, based on specific semisynthetic epicatechin and catechin derivatives. METHODS: We evaluated tau aggregation in vitro and neuritogenesis by confocal microscopy in mouse neuroblastoma cells (N2a), after exposing cells to either epicatechin-pyrogallol (EPIC-PYR), catechin-pyrogallol (CAT-PYR), catechin-phloroglucinol (CAT-PhG), and NAC. RESULTS: We found that EPIC-PYR, CAT-PYR, and CAT-PhG inhibit human tau aggregation and significantly increase neuritogenesis in a dose-dependent manner. Interestingly, modification with a phloroglucinol group yielded the most potent molecule of those evaluated, suggesting that the phloroglucinol group may enhance neuroprotective activity of the catechin-derived compounds. Also, as observed with cathechins, NAC promotes neuritogenesis and inhibits tau self-aggregation, possibly through a different pathway. CONCLUSION: EPIC-PYR, CAT-PYR, CAT-PhG, and NAC increased the number of neurites in Na2 cell line and inhibits tau-self aggregation in vitro.

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BACKGROUND Retinoid-induced myositis is a rare condition encountered in clinical practice. Its occurrence implies a diagnostic challenge due to the multiple causes associated with myopathic syndromes. The most common clinical presentation is generalized affection. Focal myositis is even less frequent and easily misdiagnosed as muscular disease of other etiology. CASE REPORT We describe a case of 45-year-old male with a history of nephrolithiasis and rosacea diagnosed by dermatology, who was management with isotretinoin 1 mg/kg per day in 2 doses with clinical improvement. Later, he presents muscle pain in the upper limbs with marked functional limitation associated by choluria, without muscular pains in other location; he had no history of using another medication. At his physical examination, vital signs were normal, with edema and pain in the bilateral bicipital region associated with limitation for flexion-extension of shoulders and elbows and high levels of creatine phosphokinase (CPK). He was transferred to the intensive care unit where he received fluid therapy because of the high risk of deterioration of renal function, very high CPK levels, and a history of obstructive uropathy. One year after this hospitalization, the cutaneous symptoms worsened and the patient voluntarily restarted isotretinoin and 5 months later he presented again with the same symptoms of the first episode. CONCLUSIONS Drug-induced myositis should be taken into consideration in the differential diagnosis of myopathic syndromes. Retinoids have the potential to cause varying degrees of myositis and their rapid identification could prevent major complications.

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Clinically meaningful molecular subtypes for classification of breast cancers have been established, however, initiation and progression of these subtypes remain poorly understood. The recent development of desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) facilitates the convergence of analytical chemistry and traditional pathology, allowing chemical profiling with minimal tissue pretreatment in frozen samples. Here, we characterized the chemical composition of molecular subtypes of breast cancer with DESI-MSI. Regions of interest were identified, including invasive breast cancer (IBC), ductal carcinoma in situ (DCIS), and adjacent benign tissue (ABT), and metabolomic profiles at 200 µm elaborated using Biomap software and the Lasso method. Top ions identified in IBC regions included polyunsaturated fatty acids, deprotonated glycerophospholipids, and sphingolipids. Highly saturated lipids, as well as antioxidant molecules [taurine (m/z 124.0068), uric acid (m/z 167.0210), ascorbic acid (m/z 175.0241), and glutathione (m/z 306.0765)], were able to distinguish IBC from ABT. Moreover, luminal B and triple-negative subtypes showed more complex lipid profiles compared with luminal A and HER2 subtypes. DCIS and IBC were distinguished on the basis of cell signaling and apoptosis-related ions [fatty acids (341.2100 and 382.3736 m/z) and glycerophospholipids (PE (P-16:0/22:6, m/z 746.5099, and PS (38:3), m/z 812.5440)]. In summary, DESI-MSI identified distinct lipid composition between DCIS and IBC and across molecular subtypes of breast cancer, with potential implications for breast cancer pathogenesis. SIGNIFICANCE: These findings present the first in situ metabolomic findings of the four molecular subtypes of breast cancer, DCIS, and normal tissue, and add to the understanding of their pathogenesis.

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Breast cancer stromal compartment, may influence responsiveness to chemotherapy. Our aim was to detect a stromal cell signature (using a direct approach of microdissected stromal cells) associated with response to neoadjuvant chemotherapy (neoCT) in locally advanced breast cancer (LABC). The tumor samples were collected from 44 patients with LABC (29 estrogen receptor (ER) positive and 15 ER negative) before the start of any treatment. Neoadjuvant chemotherapy consisted of doxorubicin and cyclophosphamide, followed by paclitaxel. Response was defined as downstaging to maximum ypT1a-b/ypN0. The stromal cells, mainly composed of fibroblast and immune cells, were microdissected from fresh frozen tumor samples and gene expression profile was determined using Agilent SurePrint G3 Human Gene Expression microarrays. Expression levels were compared using MeV (MultiExperiment Viewer) software, applying SAM (significance analysis of microarrays). To classify samples according to tumor response, the order of median based on confidence statements (MedOr) was used, and to identify gene sets correlated with the phenotype downstaging, gene set enrichment analysis (GSEA). Nine patients presented disease downstaging. Eleven sequences (FDR 17) were differentially expressed, all of which (except H2AFJ) more expressed in responsive tumors, including PTCHD1 and genes involved in abnormal cytotoxic T cell physiology, TOX, LY75, and SH2D1A. The following four pairs of markers could correctly classify all tumor samples according to response: PTCHD1/PDXDC2P, LOC100506731/NEURL4, SH2D1A/ENST00000478672, and TOX/H2AFJ. Gene sets correlated with tumor downstaging (FDR < 0.01) were mainly involved in immune response or lymphocyte activation, including CD47, LCK, NCK1, CD24, CD3E, ZAP70, FOXP3, and CD74, among others. In locally advanced breast cancer, stromal cells may present specific features of immune response that may be associated with chemotherapy response.

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