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Triple-negative breast cancer (TNBC) is the most aggressive subtype with high metastasis and mortality rates. Given the lack of actionable targets such as ER and HER2, TNBC still remains an unmet therapeutic challenge. Despite harboring high CDK4/6 expression levels, the efficacy of CDK4/6 inhibition in TNBC has been limited due to the emergence of resistance. The resistance to CDK4/6 inhibition is mainly mediated by RB1 inactivation. Since our aim is to overcome resistance to CDK4/6 inhibition, in this study, we primarily used the cell lines that do not express RB1 . Following a screening for activated receptor tyrosine kinases (RTKs) upon CDK4/6 inhibition, we identified the TAM (Tyro3, Axl, and MerTK) RTKs as a crucial therapeutic vulnerability in TNBC. We show that targeting the TAM receptors with a novel inhibitor, sitravatinib, significantly sensitizes TNBC to CDK4/6 inhibitors. Upon prolonged HER2 inhibitor treatment, HER2+ breast cancers suppress HER2 expression, physiologically transforming into TNBC-like cells. We further show that the combined treatment is highly effective against drug-resistant HER2+ breast cancer as well. Following quantitative proteomics and RNA-seq data analysis, we extended our study into the immunophenotyping of TNBC. Given the roles of the TAM receptors in promoting the creation of an immunosuppressive tumor microenvironment (TME), we further demonstrate that the combination of CDK4/6 inhibitor abemaciclib and sitravatinib modifies the immune landscape of TNBC to favor immune checkpoint blockade. Overall, our study offers a novel and highly effective combination therapy against TNBC and potentially treatment-resistant HER2+ breast cancer that can be rapidly moved to the clinic.

Acute pulmonary embolism (PE) and coronavirus disease -2019 (COVID-19) are life-threatening diseases associated with significant morbidity and mortality. Yet little is known about their co-existence.This study explored clinical and laboratory differences between PE patients who tested positive with real-time reverse-transcription polymerase chain reaction (PCR+) and those who tested negative (PCR-) for SARS-CoV-2. Also, to determine whether ferritin D-dimer ratio (FDR) and platelet D-dimer ratio (PDR) can be used to predict COVID-19 in patients with PE. Files of 556 patients who underwent a computed tomography pulmonary angography (CTPA) examination were retrospectively investigated. Out of them, 197 were tested positive and 188 negative for SARS-CoV-2. One hundred thirteen patients (57.36%) in the PCR+ group and 113 (60.11%) in the PCR- group had a diagnosis of PE. Complaints, respiratory rate, and oxygen saturation level in the blood (SpO 2 ) were recorded at the first admission. Monocyte and eosinophil levels remained low, whereas FDR and PDR were higher in the PCR+ group. No difference was detected in ferritin, D-dimer levels, comorbidities, SpO 2 , and death rates between the two groups. Cough, fever, joint pain, and higher respiratory rate were more common in the PCR+ group. A decrease in white blood cell, monocyte, and eosinophil levels, whereas an increase in FDR and PDR levels may predict COVID-19 in patients with PE. PE patients complaining of cough, fever, and fatigue should undergo PCR testing as common symptoms. COVID-19 does not seem to increase the risk of mortality in patients with PE.

Extracellular vesicles (EVs) play important roles in diabetes mellitus (DM) via connecting the immune cell response to tissue injury, besides stimulation to muscle insulin resistance, while DM is associated with increased risks for major cardiovascular complications. Under DM, chronic hyperglycemia, and subsequent increase in the production of reactive oxygen species (ROS) further lead to cardiac growth remodeling and dysfunction. The purinergic drug ticagrelor is a P 2 Y 12 receptor antagonist. Although it is widely used in cardioprotection, the underlying molecular mechanism of its inhibitory effect on diabetic cardiomyopathy is poorly elucidated. Here, we aimed to understand how ticagrelor exerts its cardio-regulatory effects. For this purpose, we investigated the anti-oxidative and cardioprotective effect of EVs derived from ticagrelor-pretreated cardiomyocytes under DM conditions. To mimic DM in cardiomyocytes, we used high glucose incubated H9c2-cells (HG). HG cells were treated with EVs, which were derived from either ticagrelor-pretreated or untreated H9c2-cells. Our results demonstrated that ticagrelor-pretreated H9c2-derived EVs significantly decreased the hyperglycemia-induced aberrant ROS production, prevented the development of apoptosis and ER stress, and alleviated oxidative stress associated miRNA-expression profile. Importantly, EVs derived from ticagrelor-pretreated H9c2-cells enhanced endothelial cell migration and tube formation, suggesting a modulation of the EV profile in cardiomyocytes. Our data, for the first time, indicate that ticagrelor can exert an important regulatory effect on diabetic cardiomyopathy through extracellular vesicular modulation behind its receptor-inhibition-related effects., (© 2022. The Author(s).)

The ingrained capacity of melanoma cells to rapidly evolve toward an aggressive phenotype is manifested by their increased ability to develop drug-resistance, evident in the case of vemurafenib, a therapeutic-agent targeting BRAF V600E . Previous studies indicated a tight correlation between heightened melanoma-associated macroautophagy/autophagy and acquired Vemurafenib resistance. However, how this vesicular trafficking pathway supports Vemurafenib resistance remains unclear. Here, using isogenic human and murine melanoma cell lines of Vemurafenib-resistant and patient-derived melanoma cells with primary resistance to the BRAF V600E inhibitor, we found that the enhanced migration and invasion of the resistant melanoma cells correlated with an enhanced autophagic capacity and autophagosome-mediated secretion of ATP. Extracellular ATP (eATP) was instrumental for the invasive phenotype and the expansion of a subset of Vemurafenib-resistant melanoma cells. Compromising the heightened autophagy in these BRAF V600E inhibitor-resistant melanoma cells through the knockdown of different autophagy genes (ATG5, ATG7, ULK1), reduced their invasive and eATP-secreting capacity. Furthermore, eATP promoted the aggressive nature of the BRAF V600E inhibitor-resistant melanoma cells by signaling through the purinergic receptor P2RX7. This autophagy-propelled eATP-dependent autocrine-paracrine pathway supported the maintenance and expansion of a drug-resistant melanoma phenotype. In conclusion, we have identified an autophagy-driven response that relies on the secretion of ATP to drive P2RX7-based migration and expansion of the Vemurafenib-resistant phenotype. This emphasizes the potential of targeting autophagy in the treatment and management of metastatic melanoma.

Background/aim: We investigated the role of body flora and chronic inflammatory infections in the etiology of allergic disorders in Turkish children., Materials and Methods: Forty pediatric asthma patients with positive skin prick tests and 40 age-matched healthy subjects with negative skin prick tests were enrolled in this cross-sectional study. Serum H. pylori IgG, viral hepatitis serology, IL-10, and TGF-beta levels were measured. Stool and throat cultures were taken and tested for occurrence of microorganisms., Results: A significantly higher percentage of nonatopic subjects tested positive for anti-H. pylori antibodies compared to atopic subjects (60% vs. 20%). Serum IL-10 levels were also significantly higher in nonatopic subjects. No significant differences in direct microscopy and culture specimens of stools were observed. Examination of throat flora showed significantly higher occurrences of Neisseria and beta-hemolytic Streptococcus in nonatopic subjects, but higher occurrences of gram-positive bacilli in atopic subjects., Conclusion: Higher prevalence of anti-H. pylori antibody and higher serum levels of IL-10 in nonatopic subjects suggest that chronic infection and inflammation may protect against atopic disease. Higher occurrences of Neisseria and beta-hemolytic Streptococcus in throat cultures from nonatopic subjects are novel findings that lend further support to the hygiene hypothesis.

We argue that the field of extracellular vesicle (EV) biology needs more transparent reporting to facilitate interpretation and replication of experiments. To achieve this, we describe EV-TRACK, a crowdsourcing knowledgebase (http://evtrack.org) that centralizes EV biology and methodology with the goal of stimulating authors, reviewers, editors and funders to put experimental guidelines into practice.

Melanoma has emerged as a paradigm of a highly aggressive and plastic cancer, capable to co-opt the tumor stroma in order to adapt to the hostile microenvironment, suppress immunosurveillance mechanisms, and disseminate. In particular, oncogene- and aneuploidy-driven dysregulations of proteostasis in melanoma cells impose a rewiring of central proteostatic processes, such as the heat shock and unfolded protein responses, autophagy, and the endo-lysosomal system, to avoid proteotoxicity. Research over the past decade has indicated that alterations in key nodes of these proteostasis pathways act in conjunction with crucial oncogenic drivers to increase intrinsic adaptations of melanoma cells against proteotoxic stress, modulate the high metabolic demand of these cancer cells and the interface with other stromal cells, through the heightened release of soluble factors or exosomes. Here, we overview and discuss how key proteostasis pathways and vesicular trafficking mechanisms are turned into vital conduits of melanoma progression, by supporting cancer cell's adaptation to the microenvironment, limiting or modulating the ability to respond to therapy and fueling melanoma dissemination.

The late endo-/lysosomal P-type ATPase ATP13A2 (PARK9) is implicated in Parkinson's disease (PD) and Kufor-Rakeb syndrome, early-onset atypical Parkinsonism. ATP13A2 interacts at the N-terminus with the signaling lipids phosphatidic acid (PA) and phosphatidylinositol (3,5) bisphosphate (PI(3,5)P2), which modulate ATP13A2 activity under cellular stress conditions. Here, we analyzed stable human SHSY5Y cell lines overexpressing wild-type (WT) or ATP13A2 mutants in which three N-terminal lipid binding sites (LBS1-3) were mutated. We explored the regulatory role of LBS1-3 in the cellular protection by ATP13A2 against mitochondrial stress induced by rotenone and found that the LBS2-3 mutants displayed an abrogated protective effect. Moreover, in contrast to WT, the LBS2 and LBS3 mutants responded poorly to pharmacological inhibition of, respectively, PI(3,5)P2 and PA formation. We further demonstrate that PA and PI(3,5)P2 are also required for the ATP13A2-mediated protection against the toxic metals Mn(2+), Zn(2+), and Fe(3+), suggesting a general lipid-dependent activation mechanism of ATP13A2 in various PD-related stress conditions. Our results indicate that the ATP13A2-mediated protection requires binding of PI(3,5)P2 to LBS2 and PA to LBS3. Thus, targeting the N-terminal lipid binding sites of ATP13A2 might offer a therapeutic approach to reduce cellular toxicity of various PD insults including mitochondrial stress.

Background: Previous studies on school-based education programs have reported that asthmatic and nonasthmatic adolescents, teachers and school personnel do not have enough information on asthma. However, the number of education programs including adolescents without asthma is not sufficient. The aim of the present study was to determine the knowledge of school children about asthma and to investigate whether their knowledge of asthma can be increased by an education program through a booklet distributed as a handout., Methods: This cross-sectional prospective questionnaire survey was carried out in a private school in Ankara, Turkey, between February and April 2006. 720 adolescents in grades 6, 7 and 8 were included. Knowledge about asthma was evaluated by a scoring system before and after the education offered by means of a booklet., Results: The final analysis was conducted on 642 students in total. The number of right answers in 5 categories, percentage of right answers and total questionnaire score improved significantly after the education received (p < 0.001). The total questionnaire scores of the girls (p = 0.002), those students with a university graduate mother (p = 0.006) and those with a physician parent (p = 0.041) were higher than those of the other pupils., Conclusion: Theoretical material in the form of a booklet can be used in a school-based asthma education program in order to improve the knowledge of adolescents about asthma., (Copyright © 2011 S. Karger AG, Basel.)

The study involved 1342 primary school students aged 7-14 years who applied to Ankara, a primary care center for general health check-up between 2006 and 2007. Forty-three students, 35 of whom had PE and 8 of whom had PC, were subjected to thorax measurement. All 43 students underwent pulmonary function tests (PFT).The prevalence rate of PC was 0.6%, and of PE, 2.6%. The thorax widths of the groups were similar (P = 0.273). The thorax circumference and depth of PE group were lower than those of the controls (P < 0.05). The probability rate of abnormality in PFT scores of PE group was statistically significantly higher than that of the controls (P = 0.022) whereas absence of normal PFT scores the difference between PC group and the controls was not statistically significant (p = 0.095). The results indicate that more than half of the individuals with pectus deformity do not have any physical complaints and do not have statistically significant differences in their PFT parameters.

Background: Salmeterol is a new long-acting beta 2 selective adrenoreceptor agonist. There are some reports about the cardiac side-effects of salmeterol in asthmatic adults. The aim of this study was to determine the cardiac side effects of salmeterol in children., Methods: Seventeen children with moderate asthma (aged between 6 and 13 years, mean 8.76 years) received salmeterol with a spacer device (Volumatic 200 micrograms daily, b.i.d.) for 3 weeks. All the children were evaluated by 24 h ambulatory electrocardiography monitoring and echocardiography before, on the second and on the 21st day of treatment., Results: In minimum heart rate measurements, there were significant differences between the baseline (mean +/- SD 54.29 +/- 7.13), second (59.24 +/- 6.86) and 21st day (60.65 +/- 8.23) results. Also, the mean heart rate before the treatment (89.59 +/- 6.78) was significantly different from that on the second (94.76 +/- 6.51) and 21st day (92.65 +/- 8.90) of treatment. Although all the values were within normal limits and there were no significant differences between the control group's values, a trend of increase in mean and the minimum heart rates was seen. There were no significant differences in blood pressure, serum K+, maximum heart rate, supraventricular and ventricular ectopic beats, ejection fraction, stroke volume, cardiac output and corrected QT interval at any time. No complaints of tremors or palpitations were reported., Conclusions: As no cardiac side effects were detected, it could be concluded that salmeterol is quite a safe drug for use in childhood asthma treatment.

Background: An increased frequency of autoimmune thyroiditis is seen in patients with chronic urticaria and angioedema (CUA) and it has been hypothesized that autoimmunity may be playing a role in the pathogenesis of CUA. The aim of this study was to learn the extent of autoimmune thyroid disease in a series of patients who presented with CUA., Methods: Thyroid function tests and thyroid autoantibodies were measured by radioimmunoassay and immunoradiometric assay respectively in 94 CUA patients and 80 age- and sex-matched healthy volunteers., Results: Eleven patients (11.7%) were found to have thyroglobulin antibodies (TGA) and nine patients (9.57%) thyroid microsomal (TMA) titers ranging from 150 to 1340.37 and from 165.73 to 8000 IU/mL respectively. Both antibodies were detected in three control cases (3.7%). The association was statistically significant (P < 0.01). Six of 11 patients had thyroid dysfunction and the other five cases were euthyroid., Conclusions: Our results justified the use of TMA and TGA for the early diagnosis of autoimmune thyroiditis in combination with CUA. The higher frequency of these antibodies in our patients, along with results from previously published data, suggest that this entity may reflect an autoimmune basis in some CUA patients. Thyroid function tests are not enough to rule out thyroid disease, and thyroid antibody tests should be carried out in all patients with CUA.

The case of a 1-year-old cyanotic boy diagnosed with asplenia syndrome has been reported. By physical and laboratory examinations, levocardia, atrial inversion, primum ASD, single atrioventricular valve, single ventricle (left-hand morphology), rudimentary right ventricle (anterior, left-sided), pulmonary stenosis, left-sided vena cava, single vena cava superior were established and the case was diagnosed with asplenia syndrome. The patient has concordance between tracheo-bronchial situs and lung anatomy and inverted atrial and visceral situs, but without atrial isomerism that makes his case an unusual variation of asplenia syndrome.

Epidermal growth factor is a potent stimulator of the growth of epithelial and mesenchymal cells. In this study the effect of epidermal growth factor on the cells of developing mice intestine and on the serum zinc concentrations were assessed. Higher serum zinc concentrations (840.21 +/- 187.82 mg/dl) were found in the mice given epidermal growth factor (n: 10) as compared to the values obtained in the controls (347.55 +/- 108.88 mg/dl), (n: 12) (p less than 0.05).

We report a case of mucopolysaccharidoses I with severe cardiac involvement, which was diagnosed on the basis of clinical and laboratory findings even though, symptoms begin to occur in mucopolysaccharidoses after the first year of life. In our case cardiac failure occurred in the third month of life, which resulted in the patient's death after one month.