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Despite the significant improvements made in breast cancer therapy during the last decades, this disease still has increasing incidence and mortality rates. Different targets involved ...in general processes, like cell proliferation and survival, have become alternative therapeutic options for this disease, with some of them already used in clinic, like the CDK4/6 inhibitors for luminal A tumors treatment. Nevertheless, there is a demand for novel therapeutic strategies focused not only on tumor cells, but also on their microenvironment.
Tumor microenvironment (TME) is a very complex and dynamic system that, more than surrounding and supporting tumor cells, actively participates in tumor development and progression. During the last decades, it has become clear that the cellular and acellular components of TME differ between the various breast cancer subtypes and shape the differences regarding their severity and prognosis. The pivotal role of the TME in controlling tumor growth and influencing responses to therapy represents a potential source for novel targets and therapeutic strategies.
In this review, we present a description of the multiple therapeutic options used for different breast cancer subtypes, as well as the influence that the TME may exert on the development of the disease and on the response to the distinct therapies, which in some cases may explain their failure by the occurrence of relapses and resistance. Furthermore, the ongoing studies focused on the use of TME components for developing potential cancer treatments are described.
The third-generation of aromatase inhibitors (AIs)-Exemestane (Exe), Letrozole (Let), and Anastrozole (Ana)-is the main therapeutic approach applied for estrogen receptor-positive (ER+) breast cancer ...(BC), the most common neoplasm in women worldwide. Despite their success, the development of resistance limits their efficacy. Genistein (G), a phytoestrogen present in soybean, has promising anticancer properties in ER+ BC cells, even when combined with anticancer drugs. Thus, the potential beneficial effects of combining G with AIs were investigated in sensitive (MCF7-aro) and resistant (LTEDaro) BC cells.
The effects on cell proliferation and expression of aromatase, ERα/ERβ, and AR receptors were evaluated.
Unlike the combination of G with Ana or Let, which negatively affects the Ais' therapeutic efficacy, G enhanced the anticancer properties of the steroidal AI Exe, increasing the antiproliferative effect and apoptosis relative to Exe. The hormone targets studied were not affected by this combination when compared with Exe.
This is the first
study that highlights the potential benefit of G as an adjuvant therapy with Exe, emphasizing, however, that soy derivatives widely used in the diet or applied as auxiliary medicines may increase the risk of adverse interactions with nonsteroidal AIs used in therapy.
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► eeRo has antioxidant, vasodilator, anti-inflammatory activity as anti-ulcerogenic mechanisms. ► Ethanol induced macroscopic, microscopic and biochemical alterations. ► eeRo showed ...effective gastric protection against the ulcerative action of ethanol.
The pathology of a gastric ulcer is complex and multifactorial. Gastric ulcers affect many people around the world and its development is a result of the imbalance between aggressive and protective factors in the gastric mucosa. In this study, we evaluated the ethanolic extract of Rosmarinus officinalis L. (eeRo); this plant, more commonly known as rosemary, has attracted the interest of the scientific community due to its numerous pharmacological properties and their potential therapeutic applications. Here, we tested the preventive effects of eeRo against gastric ulcer induced by 70% ethanol in male Wistar rats. In addition, we aimed to clarify the mechanism involved in the preventive action of the eeRo in gastric ulcers. Based on the analysis of markers of oxidative damage and enzymatic antioxidant defense systems, the measurement of nitrite and nitrate levels and the assessment of the inflammatory response, the eeRo exhibited significant antioxidant, vasodilator and antiinflammatory properties.
Estrogen receptor-positive (ER+) breast carcinomas are the most common subtype, corresponding to 60% of the cases in premenopausal and 75% in postmenopausal women. The third-generation of aromatase ...inhibitors (AIs), the non-steroidal Anastrozole (Ana) and Letrozole (Let) and the steroidal Exemestane (Exe), are considered a first-line endocrine therapy for postmenopausal women. Despite their clinical success, the development of resistance is the major setback in clinical practice. Nevertheless, the lack of cross-resistance between AIs hints that these drugs may act through distinct mechanisms. Therefore, this work studied the different effects induced by AIs on biological processes, such as cell proliferation, death, autophagy and senescence. Moreover, their effects on the regulation of the hormonal environment were also explored. The non-steroidal AIs induce senescence, through increased YPEL3 expression, on aromatase-overexpressing breast cancer cells (MCF-7aro), whereas Exe promotes a cytoprotective autophagy, thus blocking senescence induction. In addition, in a hormone-enriched environment, the non-steroidal AIs prevent estrogen signaling, despite up-regulating the estrogen receptor alpha (ERα), while Exe down-regulates ERα and maintains its activation. In these conditions, all AIs up-regulate the androgen receptor (AR) which blocks EGR3 transcription in Exe-treated cells. On the other hand, in hormone-depleted conditions, a crosstalk between AR and ERα occurs, enhancing the estrogenic effects of Exe. This indicates that Exe modulates both ERα and AR, while Ana and Let act as pure AIs. Thus, this study highlights the potential clinical benefit of combining AR antagonists with Exe and discourages the sequential use of Exe as second-line therapy in postmenopausal breast cancer.
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•AIs act through distinct mechanisms at the cellular and molecular levels.•Anastrazole and Letrozole induce cell senescence.•Exemestane-induced autophagy blocks senescence.•ERα and AR cooperate to promote the survival of Exemestane-treated cells.
The paper expands the finite difference method to the complex plane, and thus obtains an improvement in the resolution of differential equations with an increase in numerical precision and a ...generalization in the mathematical modeling of problems. The article begins with a selection of the best techniques for obtaining finite difference coefficients for approximating derivatives in the real domain. Then, the calculation is expanded to the complex domain. The research expands forward, backward, and central difference approximations of the real case by a quadrant approximation in the complex plane, which facilitates the use in boundary conditions of differential equations. The article shows many real and complex finite difference equations with their respective order of error, intended to serve as a basis and reference, which have been tested in practical examples of solving differential equations used in engineering. Finally, a comparison is made between the real and complex techniques of finite difference methods applied in the Theory of Elasticity. As a surprising result, the article shows that the finite difference method has great advantages in numerical precision, diversity of formulas, and modeling generalities in the complex domain when compared to the real domain.
Step initiation involves anticipatory postural adjustments (APAs) that can be measured using inertial measurement units (IMUs) such as accelerometers. However, previous research has shown ...heterogeneity in terms of the population studied, sensors used, and methods employed. Validity against gold standard measurements was only found in some studies, and the weight of the sensors varied from 10 to 110 g. The weight of the device is a crucial factor to consider when assessing APAs, as APAs exhibit significantly lower magnitudes and are characterized by discrete oscillations in acceleration paths.
This study aims to validate the performance of a commercially available ultra-light sensor weighing only 5.6 g compared to a 168-g smartphone for measuring APAs during step initiation, using a video capture kinematics system as the gold standard. The hypothesis is that APA oscillation measurements obtained with the ultra-light sensor will exhibit greater similarity to those acquired using video capture than those obtained using a smartphone.
Twenty subjects were evaluated using a commercial lightweight MetaMotionC accelerometer, a smartphone and a system of cameras-kinematics with a reflective marker on lumbar vertebrae. The subjects initiated 10 trials of gait after a randomized command from the experimenter and APA variables were extracted: APAonset, APAamp, PEAKtime. A repeated measures ANOVA with
test analyzed the effect of device on APA measurements. Bland-Altman plots were used to evaluate agreement between MetaMotionC, smartphone, and kinematics measurements. Pearson's correlation coefficients were used to assess device correlation. Percentage error was calculated for each inertial sensor against kinematics. A paired Student's t-test compared th devices percentage error.
The study found no significant difference in temporal variables APAonset and PEAKtime between MetaMotionC, smartphone, and kinematic instruments, but a significant difference for variable APAamp, with MetaMotionC yielding smaller measurements. The MetaMotionC had a near-perfect correlation with kinematic data in APAonset and APAamp, while the smartphone had a very large correlation in APAamp and a near-perfect correlation in APAonset and PEAKtime. Bland-Altman plots showed non-significant bias between smartphone and kinematics for all variables, while there was a significant bias between MetaMotionC and kinematics for APAamp. The percentage of relative error was not significantly different between the smartphone and MetaMotionC.
The temporal analysis can be assessed using ultralight sensors and smartphones, as MetaMotionC and smartphone-based measurements have been found to be valid compared to kinematics. However, caution should be exercised when using ultralight sensors for amplitude measurements, as additional research is necessary to determine their effectiveness in this regard.
Chronic low back pain (CLBP) is associated with postural control impairments and is highly prevalent in elderly people. The objective of this study is to verify whether anticipatory postural ...adjustments (APAs) and compensatory postural adjustments (CPAs) are affected by CLBP in elderly people by assessing their postural control during a self-initiated perturbation paradigm induced by rapid upper arm movement when pointing to a target. The participants' lower limb muscle onset and center of pressure (COP) displacements were assessed prior to perturbation and throughout the entire movement. T
moment (i.e., the beginning of the movement) was defined as the anterior deltoid (DEL) onset, and all parameters were calculated with respect to it. The rectus femoris (RT), semitendinosus (ST), and soleous (SOL) showed delayed onset in the CLBP group compared with the control group: RF (control: - 0.094 ± 0.017 s; CLBP: - 0.026 ± 0.012 s, t = 12, p < 0.0001); ST (control: - 0.093 ± 0.013 s; CLBP: - 0.018 ± 0.019 s, t = 12, p < 0.0001); and SOL (control: - 0.086 ± 0.018 s; CLBP: - 0.029 ± 0.015 s, t = 8.98, p < 0.0001). In addition, COP displacement was delayed in the CLBP group (control: - 0.035 ± 0.021 s; CLBP: - 0.015 ± 0.009 s, t = 3; p = 0.003) and presented a smaller amplitude during APA COP
control: 0.444 cm (0.187; 0.648); CLBP: 0.228 cm (0.096; 0.310), U = 53, p = 0.012. The CLBP group required a longer time to reach the maximum displacement after the perturbation (control: 0.211 ± 0.047 s; CLBP 0.296 ± 0.078 s, t = 3.582, p = 0.0013). This indicates that CLBP elderly patients have impairments to recover their postural control and less efficient anticipatory adjustments during the compensatory phase. Our results suggest that people with CLBP have altered feedforward hip and ankle muscle control, as shown from the SOL, ST, and RT muscle onset. This study is the first study in the field of aging that investigates the postural adjustments of an elderly population with CLBP. Clinical assessment of this population should consider postural stability as part of a rehabilitation program.
Malignant hyperthermia (MH) is a rare, hereditary disease with a hypermetabolic response to volatile anesthetics/succinylcholine. Susceptible patients face difficulties due to a lack of knowledge ...about MH. As informational materials could increase knowledge and adherence to prevention/therapy, digital information about rare diseases validated for patients is needed. Our objective was to evaluate the following: (1) the impact of digital manuals on the knowledge/quality of life of MH patients and (2) access to MH services. Fifty MH-susceptible patients filled out a virtual questionnaire twice (demographic/economic/clinical data, MH knowledge and impact on daily life, and SF-36 quality of life). Test groups 1 (n = 17) and 2 (n = 16) were evaluated 30 and 180 days after receiving a digital manual, and the control group (n = 17; without manual) was evaluated after 180 days. We collected the MH service data about the number of contacts. Twenty-four (48%) patients reported problems in personal/professional life, sports, clinical/surgical/dental treatments, and military service, in addition to concerns about emergency care and complaints of sequelae. The percentage of correct answers in the second MH knowledge questionnaire increased for test group 2 (62% vs. 74.1%; unpaired t test, p < 0.01), was significantly greater in test groups 1 (68.1%) and 2 (74.1%) than in the control group (56.5%; Kruskal-Wallis, p < 0.05), and correlated with more time studying the manual and reports of MH-related problems (multiple regression, p < 0.05). The digital manual improved patients' MH knowledge. Online contacts with the MH service increased, allowing greater information dissemination. As informational materials could increase knowledge/adherence to prevention/therapy, digital information about MH validated for patients should be implemented.
Although cannabinoids have been used for centuries for diverse pathological conditions, recently, their clinical interest and application have emerged due to their diverse pharmacological properties. ...Indeed, it is well established that cannabinoids exert important actions on multiple sclerosis, epilepsy and pain relief. Regarding cancer, cannabinoids were first introduced to manage chemotherapy-related side effects, though several studies demonstrated that they could modulate the proliferation and death of different cancer cells, as well as angiogenesis, making them attractive agents for cancer treatment. In relation to breast cancer, it has been suggested that estrogen receptor-negative (ER
) cells are more sensitive to cannabinoids than estrogen receptor-positive (ER
) cells. In fact, most of the studies regarding their effects on breast tumors have been conducted on triple-negative breast cancer (TNBC). Nonetheless, the number of studies on human epidermal growth factor receptor 2-positive (HER2
) and ER
breast tumors has been rising in recent years. However, besides the optimistic results obtained thus far, there is still a long way to go to fully understand the role of these molecules. This review intends to help clarify the clinical potential of cannabinoids for each breast cancer subtype.
ABSTRACT
Background:
Obstructive Sleep Apnea Syndrome (OSAS) is a public health problem of high prevalence and impacts on quality of life, anesthetic complications and cardiovascular diseases. In ...view of the difficulty in accessing the polysomnography, it is necessary to validate other methods for OSAS diagnostic screening in clinical practice in our country, such as the STOP-Bang questionnaire.
Objective:
To validate the STOP-Bang questionnaire in Brazilians and evaluate optimal cutoff points.
Methods:
After translation and back-translation, STOP-Bang questionnaire was applied to 71 individuals previously submitted to polysomnography and classified into control, mild, moderate or severe OSAS.
Results:
The majority of patients was male (59.2%), white (79%), aged 48.9±13.9 years, and with neck circumference >40 centimeters (73.8%). STOP-Bang score was higher in OSAS mild (median/inter-quartis 25-75%: 5/3.5-6), moderate (4.5/4-5) and severe (5/4-6), versus control (2.5/1-4). The receiver operating characteristic (ROC) curve indicate that scores 3, 4 and 6, present the best specificity values (100, 80 and 92.9%) with acceptable sensitivity (60, 66.7 and 50%) in the mild, moderate and severe OSAS subgroups, respectively. In OSAS group analysis (Apnea Hypopnea Index AHI ≥5, <15, ≥15 - <30, ≥30), STOP-Bang cutoff point of 6 was optimal to detect OSAS.
Conclusion:
STOP-Bang Brazilian version identified OSAS patients with lower sensitivity and higher specificity compared to previous studies. Different cutoff points would improve the performance to detect patients with more severe OSAS.
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