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1.
Immunol Invest ; : 1-16, 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33557640

RESUMO

Background: Myocardial toxicity is a common side effect of doxorubicin (DOXO) therapy in breast cancer patients. We hypothesized that DOXO-induced cardiotoxicity may be related to the release of inflammatory cytokines in response to the treatment. This study aimed to assess changes in plasma levels of interleukin (IL)-1ß, IL-6, IL-10 and tumor necrosis factor (TNF) after chemotherapy and to correlate these levels with cardiac biomarkers and clinical data. Methods: Sixty-four patients with breast cancer treated with DOXO were included. Twenty-two subjects (cases) developed cardiotoxicity until one year after the end of DOXO treatment. Cytokines and cardiac markers were evaluated before starting chemotherapy (T0), up to 7 days after the last infusion (T1) and 12 months after the last infusion (T2). Results: Higher IL-10 levels were observed in the case group compared to controls at T1 (p = .006) and T2 (p = .046). The IL-1ß, IL-6 and TNF levels did not change during treatment in each group (p > .05), nor between the case and control groups. The IL-10 levels were higher at T1 than at T0 and T2 (p < .05 for both) in the cardiotoxicity group. A correlation between IL-10 and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at T0 and T2 in the cardiotoxicity group was observed (p = .048 and p = .004, respectively). Conclusion: Our study demonstrated that DOXO induced an increase in plasma IL-10 levels in patients who presented cardiotoxicity after treatment, which correlated with NT-proBNP levels.

2.
Cancer Cell ; 39(2): 240-256.e11, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33417832

RESUMO

Treatment-persistent residual tumors impede curative cancer therapy. To understand this cancer cell state we generated models of treatment persistence that simulate the residual tumors. We observe that treatment-persistent tumor cells in organoids, xenografts, and cancer patients adopt a distinct and reversible transcriptional program resembling that of embryonic diapause, a dormant stage of suspended development triggered by stress and associated with suppressed Myc activity and overall biosynthesis. In cancer cells, depleting Myc or inhibiting Brd4, a Myc transcriptional co-activator, attenuates drug cytotoxicity through a dormant diapause-like adaptation with reduced apoptotic priming. Conversely, inducible Myc upregulation enhances acute chemotherapeutic activity. Maintaining residual cells in dormancy after chemotherapy by inhibiting Myc activity or interfering with the diapause-like adaptation by inhibiting cyclin-dependent kinase 9 represent potential therapeutic strategies against chemotherapy-persistent tumor cells. Our study demonstrates that cancer co-opts a mechanism similar to diapause with adaptive inactivation of Myc to persist during treatment.

3.
Cell Rep ; 34(1): 108532, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33406420

RESUMO

Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation of target oncoproteins and exhibit potent preclinical antitumor activity. To dissect the mechanisms regulating tumor cell sensitivity to different classes of pharmacological "degraders" of oncoproteins, we performed genome-scale CRISPR-Cas9-based gene editing studies. We observed that myeloma cell resistance to degraders of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; and this involves loss of function of the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (CRL) complex. The substantial gene-level differences for resistance mechanisms to CRBN- versus VHL-based degraders explains mechanistically the lack of cross-resistance with sequential administration of these two degrader classes. Development of degraders leveraging more diverse E3 ligases/CRLs may facilitate sequential/alternating versus combined uses of these agents toward potentially delaying or preventing resistance.

5.
Rev Assoc Med Bras (1992) ; 66(11): 1589-1594, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33295415

RESUMO

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by muscle weakness, atrophy, fasciculations, and decreased reflexes due to upper and lower motor neurons death. It can be present in both sexes (55-65 years), but with predominance in males. However, in female patients, ALS presents its first symptoms when they are already postmenopausal, when then the incidence ratio of the disease is practically equal between the sexes, which leads to a probable involvement of sex hormones in the development and protection against ALS. The aim of this systematic review, which used the PRISMA consensus and NOS (New Castle-Ottawa Scale) score, was to evaluate the evidence of the action of hormone therapy in women with ALS. The Medline and Cochrane databases were accessed from March 2019 to June 2019, and only full-text articles in Spanish, English, and Portuguese were included. Only four articles matched our inclusion criteria. Postmenopausal women who used exogenous estrogen did not have the same protective factor as women still under the action of endogenous estrogen in the same age group. There was also no increase in the survival of these women.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33260245

RESUMO

BACKGROUND AND OBJECTIVE: Learning a new technique in neurosurgery is a big challenge especially for trainees. In recent years, simulations and simulators got into the focus as a teaching tool. Our objective is to propose a simulator for placement of cortical bone trajectory (CBT) screws to improve results and reduce complications. METHODS: We have created a platform consisting of a sawbone navigated with a 3D fluoroscope to familiarize our trainees and consultants with CBT technique and later implement it in our department. Objective Structured Assessment of Technical Skills (OSATS) and Physician Performance Diagnostic Inventory Scale (PPDI) were obtained before and after the use of the simulator by the five participants in the study. Patients who were operated on after the implementation of the technique were retrospectively reviewed. RESULTS: During the simulation, there were 4 cases of pedicle breach out of 24 screws inserted (16.6%). After having completed simulation, participants demonstrated an improvement in OSATS and PPDI (p = 0.039 and 0.042, respectively). Analyzing the answers to the different items of the tests, participants mainly improved in the knowledge (p = 0.038), the performance (p = 0.041), and understanding of the procedure (p = 0.034). In our retrospective series, eight patients with L4-L5 instability were operated on using CBT, improving their Oswestry Disability Index (ODI) score (preoperative ODI 58.5 [SD 16.7] vs. postoperative ODI 31 [SD 13.4]; p = 0.028). One intraoperative complication due to a dural tear was observed. In the follow-up, we found a case of pseudoarthrosis and a facet joint violation, but no other complications related to misplacement, pedicle fracture, or hardware failure. CONCLUSION: The simulation we have created is useful for the implementation of CBT. In our study, consultants and trainees have valued very positively the learning obtained using the system. Moreover, simulation facilitated the learning of the technique and the understanding of surgical anatomy. We hope that simulation helps reducing complications in the future.

7.
Gynecol Endocrinol ; : 1-4, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33146055

RESUMO

OBJECTIVE: To evaluate the histomorphometric and immunohistochemical changes in interstitial cells and ovarian follicles of rats treated with clomiphene citrate during and after induction of permanent estrus. METHODS: Twenty four adult-female rats with regular estrous cycle were equally divided into three groups: (1) GCtrl-at estrous phase. (2) GPCOS-at permanent-estrous phase. (3) GCC-PCOS rats, which remained exposed to 60 days of continuous illumination and treated with Clomiphene Citrate. After that, the animals were euthanized, and the ovaries were removed and processed for paraffin embedding. Sections were stained with H.E. for histomorphometry or subjected to immunohistochemistry for Ki-67 and cleaved caspase-3 detections. RESULTS: The GPCOS showed lack of corpus luteum and several ovarian cysts, as well as interstitial-like cells. The presence of corpus luteum and a significant increase in primary and antral follicles were observed in GCC, which also showed a decrease in the number of ovarian cysts and in the area occupied by interstitial-like cells, as well as a decrease in nuclear volume of interstitial cells. The percentage of cell proliferation was significantly higher in granulosa cells of the GCC. On the other hand, the percentage of apoptosis was significantly higher in the granulosa cells of GPCOS than the GCC. CONCLUSION: The ovaries of rats treated with clomiphene citrate showed a decrease in the number of cysts, an increase in the number of ovarian follicles, the presence of corpus luteum along with a decrease in the nuclear volume in the area occupied by interstitial cells.

8.
Rev Assoc Med Bras (1992) ; 66(10): 1323-1326, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33174919

RESUMO

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.

9.
Rev. Assoc. Med. Bras. (1992) ; 66(11): 1589-1594, Nov. 2020. graf
Artigo em Inglês | LILACS-Express | LILACS, Sec. Est. Saúde SP | ID: biblio-1143649

RESUMO

SUMMARY Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by muscle weakness, atrophy, fasciculations, and decreased reflexes due to upper and lower motor neurons death. It can be present in both sexes (55-65 years), but with predominance in males. However, in female patients, ALS presents its first symptoms when they are already postmenopausal, when then the incidence ratio of the disease is practically equal between the sexes, which leads to a probable involvement of sex hormones in the development and protection against ALS. The aim of this systematic review, which used the PRISMA consensus and NOS (New Castle-Ottawa Scale) score, was to evaluate the evidence of the action of hormone therapy in women with ALS. The Medline and Cochrane databases were accessed from March 2019 to June 2019, and only full-text articles in Spanish, English, and Portuguese were included. Only four articles matched our inclusion criteria. Postmenopausal women who used exogenous estrogen did not have the same protective factor as women still under the action of endogenous estrogen in the same age group. There was also no increase in the survival of these women.

11.
Gynecol Endocrinol ; : 1-8, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33043731

RESUMO

AIM: Although soy isoflavones (ISO) have been shown to relief postmenopausal symptoms, it remains inconclusive whether ISO can improve lipid-profile without uterotrophic effects under estrogen-deficiency. Thus, we investigated the effects of ISO on lipid-profile and uterus of ovariectomized (Ovx) rats. MATERIALS AND METHODS: Twenty-five adult rats were Ovx or Sham-operated (Sham) and assigned into five groups: Sham and Ovx groups, administered with vehicle solutions; Ovx-E, treated with 10 µg/kg of 17ß-Estradiol; Ovx-ISO, treated with 200 mg/kg of ISO; Ovx-E + ISO, treated with estradiol + ISO combined. After fifty days of treatments, rats were euthanized and uterine horns were processed for histomorphometry or to collagen fibers and glycosaminoglycans evaluations. Blood samples were collected to evaluate levels of triglycerides, total cholesterol (TC) and its fractions (HDL/VLDL). Data were subjected to statistical analysis (p < .05). RESULTS: Uterus weight was lower in Ovx group than the Sham and Ovx-E groups, whereas it was similar between Ovx and Ovx-ISO groups. Histomorphometry showed atrophic uterus in Ovx and Ovx-ISO groups, whereas uterotrophic effects were noticed in Ovx-E and Ovx-E + ISO groups. Collagen fibers-birefringence was higher in Sham, Ovx, and Ovx-ISO groups than in Ovx-E and Ovx-E + ISO groups. Sulfated glycosaminoglycans content was similar among Sham, Ovx, and Ovx-ISO groups, while it was higher in estrogen-treated groups; total glycosaminoglycans content was similar among groups. TC and HDL was higher in Ovx-ISO group, whereas VLDL and triglycerides levels was higher in Ovx-E + ISO group and similar among other groups. CONCLUSION: Soy isoflavones at 200 mg/kg have slight beneficial effects on lipid-profile without uterotrophic effects in Ovx rats.

12.
Rev. Assoc. Med. Bras. (1992) ; 66(10): 1323-1326, Oct. 2020. tab
Artigo em Inglês | LILACS-Express | LILACS, Sec. Est. Saúde SP | ID: biblio-1136147

RESUMO

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.

13.
Arq. bras. cardiol ; 115(4): 720-775, out. 2020. tab, graf
Artigo em Português | LILACS, Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1131346
14.
Gynecol Endocrinol ; 36(12): 1047-1050, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32960105

RESUMO

Polycystic Ovary Syndrome (PCOS) is a complex endocrine disorder, which affects 5-17% of reproductive age women and is often associated with obesity and metabolic impairment. Common treatment strategies are based on exercise, diet and nutrient supplementation since PCOS is often linked with obesity and metabolic impairment. Studies have recommended that nutrition is a key factor in the health maintenance of women with PCOS, however, little is known about the subject in the context of such a disease. This narrative review aims to identify dietary and nutritional aspects of PCOS and discuss the role of nutrients in management of polycystic ovary syndrome in view of clinical trials.

15.
Biomed Pharmacother ; 131: 110709, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32937248

RESUMO

BACKGROUND: Cardiotoxicity is a common and serious adverse effect of anthracycline therapy in breast cancer patients. The current criteria for cardiotoxicity are based on imaging and cardiac biomarkers. However, there is a need for new biomarkers to help with early diagnosis. MicroRNAs (miRNAs) are small non-coding RNA molecules that play an important role in the regulation of gene expression. Several miRNAs have been associated with cardiovascular diseases and are biomarkers under investigation for cancer treatment-related cardiotoxicity. METHODS: We performed a systematic literature search of Medline/PubMed, Cochrane Central Register of Controlled Trials, Scopus, Lilacs, Web of Science and Embase, until April 2020. Cohort studies that reported miRNA biomarkers in breast cancer patients with anthracycline-induced cardiotoxicity and non-cardiotoxicity patients were included. Moreover, we searched the miRTarBase for experimentally validated miRNA-target interactions. RESULTS: Among the 209 studies retrieved, five fulfilled the inclusion criteria. Let-7f, miR-1, miR-20a, miR-126 and miR-210 were validated in two population-based cohorts. The pro-angiogenic miRNAs let-7f, miR-20a, miR-126 and miR-210 were significantly down-regulated in epirubicin-cardiotoxicity when compared to the non-cardiotoxicity group. miR-1 has been shown to provide diagnostic and prognostic information in the setting of myocardial infarction, but changes in its levels are controversial in doxorubicin-treated breast cancer patients with cardiotoxicity. Reactome pathways relevant to cardiotoxicity were found from the target genes for let-7f, miR-1, miR-20a, miR-126 and miR-210 at miRTarBase. CONCLUSION: The data suggest that let-7f, miR-1, miR-20a, miR-126 and miR-210 are associated with anthracycline-based cardiotoxicity during chemotherapy in breast cancer patients.

16.
Cardiovasc Toxicol ; 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32844368

RESUMO

Cardiovascular adverse events in patients with breast cancer undergoing chemotherapy (CT) are frequent due to the high cardiotoxic potential of treatments, especially doxorubicin (DOXO). This study aimed to evaluate the association of plasma levels of various biomarkers with cardiotoxicity in women with breast cancer on DOXO-based chemotherapy. In this single center prospective cohort, 80 breast cancer patients who used DOXO as a first-line treatment for cancer were evaluated. Patients were assessed at three time points: before CT (T0), 1 week after (T1) and 12 months after DOXO treatment (T2). The predominant histological classification was ductal carcinoma, n = 72 (90.0%); the most frequent molecular classification was Human epidermal growth factor receptor-type 2 positive (HER2+), n = 34 (43.0%). In patients submitted to complementary treatment with trastuzumab (n = 23), there was no association with cardio-specific biomarkers. Evaluating the clinical variables and the laboratory parameters in T1 and T2 in relation to T0, the reduction any time of N-terminal-pro hormone B-type natriuretic peptide (NT-proBNP), triglycerides and hematocrit levels showed an association with higher cardiotoxicity risk. In addition, increased levels of troponin I (cTnI) and glycated hemoglobin (HbA1c) showed an independent association with the occurrence of cardiotoxicity. These results suggest that the evaluation of these laboratory tests should be included routinely to identify breast cancer patients under DOXO treatment at cardiotoxicity risk.

17.
Braz J Psychiatry ; 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32756805

RESUMO

OBJECTIVE: Understanding the distal (≤ 6 years of age) and proximal (between 6 years of age and early adolescence) factors in adolescent risk behavior is important for preventing and reducing morbidity and mortality in this population. This study sought to investigate the factors associated with the following adolescent risk behaviors: i) aggressiveness and violence, ii) tobacco, alcohol, and illicit substance use, iii) depressive behavior and self-harm (including suicidal ideation and attempts), iv) sexual risk behavior, and v) multiple risk behavior. METHODS: A systematic review was conducted to identify longitudinal studies that examined factors associated with adolescent risk behaviors. The PubMed, PsycINFO, and LILACS databases were searched. RESULTS: Of the 249 included studies, 23% reported distal risk factors, while the remaining reported proximal risk factors. Risk factors were related to sociodemographic characteristics (neighborhood, school, and peers), family patterns, and the presence of other adolescent risk behaviors. CONCLUSION: Distal and proximal factors in adolescent risk behavior that are not exclusively socioeconomic, familial, environmental, or social should be explored more thoroughly.

18.
Cancer Res ; 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859606

RESUMO

Although hormonal therapy (HT) inhibits the growth of hormone receptor-positive (HR+) breast (BrCa) and prostate (PrCa) cancers, HT resistance frequently develops within the complex metastatic microenvironment of the host organ (often the bone), a setting poorly recapitulated in 2D culture systems. To address this limitation, we cultured HR+ BrCa and PrCa spheroids and patient-derived organoids in 3D extracellular matrices (ECM) alone or together with bone marrow stromal cells (BMSC). In 3D monocultures, antiestrogens and antiandrogens induced anoikis by abrogating anchorage-independent growth of HR+ cancer cells but exhibited only modest effects against tumor cells residing in the ECM niche. In contrast, BMSC induced hormone-independent growth of BrCa and PrCa spheroids and restored lumen filling in the presence of HR-targeting agents. Molecular and functional characterization of BMSC-induced hormone independence and HT resistance in anchorage-independent cells revealed distinct context-dependent mechanisms. Cocultures of ZR75-1 and LNCaP with BMSC exhibited paracrine IL-6-induced HT resistance via attenuation of HR protein expression, which was reversed by inhibition of IL-6 or JAK signaling. Paracrine IL-6/JAK/STAT3-mediated HT resistance was confirmed in patient-derived organoids cocultured with BMSC. Distinctly, MCF7 and T47D spheroids retained ER protein expression in cocultures but acquired redundant compensatory signals enabling anchorage independence via ERK and PI3K bypass cascades activated in a non-IL-6-dependent manner. Collectively, these data characterize the pleiotropic hormone-independent mechanisms underlying acquisition and restoration of anchorage-independent growth in HR+ tumors. Combined analysis of tumor and microenvironmental biomarkers in metastatic biopsies of HT-resistant patients can help refine treatment approaches.

19.
Expert Rev Clin Pharmacol ; 13(6): 615-622, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32538185

RESUMO

INTRODUCTION: The coronavirus disease (COVID-19) is a global health emergency. Major disruption to healthcare services during the current COVID-19 pandemic will last even after its peak. Sexual and reproductive health (SRH), specially contraception, needs to be understood as an essential service. AREAS COVERED: This paper is a narrative review. Data from PubMed/MEDLINE, Scopus, and websites of scientific societies were screened during the months of April and May 2020. It addresses the main aspects related to contraception during the COVID-19 pandemic, with special emphasis on family planning services, extended use of long-acting reversible contraceptive (LARC) methods, drug interactions, and thromboembolism risk. We also specified some issues focused on the Brazilian reality. EXPERT OPINION: Ensuring proper contraception use in the COVID-19 time is very important. We encourage women, healthcare providers, policymakers, and the society to consider SRH services as priority.


Assuntos
Betacoronavirus , Anticoncepção , Infecções por Coronavirus/epidemiologia , Serviços de Planejamento Familiar , Pneumonia Viral/epidemiologia , Adulto , Infecções por Coronavirus/tratamento farmacológico , Interações Medicamentosas , Feminino , Humanos , Pandemias , Pneumonia Viral/tratamento farmacológico , Saúde Reprodutiva , Saúde Sexual , Tromboembolia Venosa/etiologia
20.
Acta Neurochir (Wien) ; 162(8): 1967-1975, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32556522

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most frequent intraaxial malignant brain tumour, in which recurrence management is a frequent and demanding issue. Recently, reintervention has emerged as a useful tool for treatment. However, some new evidence has shown that most of the articles published could have overestimated its effects. We aimed to analyse the effect on survival of reintervention considering it as a time-dependent variable and to compare it with classic statistical analysis. METHODS: We performed a retrospective study with GBM patients between 2007 and 2017. We compared the overall survival (OS) between reintervention and non-reintervention groups with time-dependent statistical methods (Simon-Makuch and landmarking methods and time-dependent multivariable Cox analysis) and compared them with those obtained with non-dependent time variable analysis. RESULTS: A total of 183 patients were included in the analysis and 44 of them were reoperated. The standard analysis with Kaplan-Meier and multivariable Cox regression of the cohort showed an OS of 22.2 months (95% CI 12.56-16.06) in the reintervention group and 11.8 months (95% CI 9.87-13.67) in the non-reintervention group (p < .001); and an HR 0.649 (95% CI 0.434-0.97 p = .035) for reintervention, demonstrating an increase in OS. However, time-dependent analysis with the Simon-Makuch test and the landmarking method showed that the relationship was not consistent, as this increase in OS was not significant. Moreover, time-dependent multivariable Cox analysis did not show that reintervention improved OS in our cohort (HR 0.997 95% CI 0.976-1.018 p = 0.75). CONCLUSIONS: There has been a temporal bias in the literature that has led to an overestimation of the positive effect of reintervention in recurrent GBM. However, reintervention could still be useful in some selected patients, who should be individualized according to prognostic factors related to the patient, biology of the tumour, and characteristics of surgical procedure.

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