Activity

BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in children and can frequently cause hypersensitivity reactions. Rates of confirmed NSAID hypersensitivity (NSAID-H) in children are low. OBJECTIVE The aim of this study was to evaluate the results of drug provocation tests with NSAID and to evaluate the difficulties encountered in the classification of NSAID-H in children. METHODS The study included patients with suspected NSAID-H who were evaluated in our clinic between January 1,2015 and December 31,2018. Oral provocation tests (OPT) with NSAIDs were performed and reactions were classified according to the European Academy of Allergy and Clinical Immunology position paper on NSAID-H. RESULTS A total of 243 patients (57.2% male) presented with suspected NSAID-H during the study period. Most of the patients (n=168, 69.1%) had a history of reaction to ibuprofen. Isolated skin involvement was the most frequent symptom (86%). A total of 238 DPTs were performed with the suspected agents and 34 had positive results. Twelve patients’ families refused provocation testing with the suspected agent or aspirin and these patients couldn’be diagnosed. NSAID-H was diagnosed in a total of 47 (20.3%) of the 231 patients. Twenty patients with NSAID hypersensitivity could not be classified because their guardians did not consent to further testing with aspirin. CONCLUSION Performing diagnostic tests is important in patients with no contraindications. Characterizing these reactions in children can be difficult due to the coexistence of indistinguishable symptoms in their history and DPT, as well as the need for multiple provocation tests. Therefore, further research is needed on this subject. Breast cancer is the most frequently occurring cancer in women. Chemotherapy in combination with immunotherapy has been used to treat breast cancer. Atezolizumab targeting the protein programmed cell death-ligand (PD-L1) in combination with paclitaxel was recently approved by the Food and Drug Administration (FDA) for Triple-Negative Breast Cancer (TNBC), the most incurable type of breast cancer. However, the use of such drugs is restricted by genotype and is effective only for those TNBC patients expressing PD-L1. In addition, resistance to chemotherapy with drugs such as lapatinib, geftinib, and tamoxifen can develop. In this review, we address chemoresistance in breast cancer and discuss Akt as the master regulator of drug resistance and several oncogenic mechanisms in breast cancer. Akt not only directly interacts with the mitogen-activated protein (MAP) kinase signaling pathway to affect PD-L1 expression, but also has crosstalk with Notch and Wnt/β-catenin signaling pathways involved in cell migration and breast cancer stem cell integrity. In this review, we discuss the effects of tyrosine kinase inhibitors on Akt activation as well as the mechanism of Akt signaling in drug resistance. Akt also has a crucial role in mitochondrial metabolism and migrates into mitochondria to remodel breast cancer cell metabolism while also functioning in responses to hypoxic conditions. The Akt inhibitors ipatasertib, capivasertib, uprosertib, and MK-2206 not only suppress cancer cell proliferation and metastasis, but may also inhibit cytokine regulation and PD-L1 expression. Ipatasertib and uprosertib are undergoing clinical investigation to treat TNBC. Inhibition of Akt and its regulators can be used to control breast cancer progression and also immunosuppression, while discovery of additional compounds that target Akt and its modulators could provide solutions to resistance to chemotherapy and immunotherapy. Cerebellar outputs originate from the dentate nucleus (DN), project to the primary motor cortex (M1) via the motor thalamus, control M1 activity, and play an essential role in coordinated movements. However, it is unclear when and how the cerebellar outputs contribute to M1 activity. To address this question, we examined the response of M1 neurons to electrical stimulation of the DN and M1 activity during performance of arm-reaching tasks. selleck chemicals llc Based on response patterns to DN stimulation, M1 neurons were classified into facilitation-, suppression-, and no-response-types. During tasks, not only facilitation- and suppression-type M1 neurons, but also no response-type M1 neurons increased or decreased their firing rates in relation to arm reaching movements. However, the firing rates of facilitation- and suppression-type neurons were higher than those of no-response-type neurons during both inter-trial intervals and arm reaching movements. These results imply that cerebellar outputs contribute to both spontaneous and movement-related activity in the M1, which help to maintain muscle tones and execute coordinated movements, although other inputs also contribute to movement-related activity. Pharmacological inactivation of the DN supports this notion, in that DN inactivation reduced both spontaneous firing rates and movement-related activity in the M1. (193/200). V.Fipronil (FPN) is a widely used phenylpyrazole pesticide for the control of insects and removal of veterinary pet fleas, ticks, etc. Although FPN presents moderate hazards to human health, people are readily exposed in daily life. FPN acts by impairing the central nervous systems of insects by blocking gamma-aminobutyric acid (GABA) and glutamate-activated chloride channels. A previous study demonstrated that GABA and GABAAR are present in spermatozoa and play various roles in the process of sperm capacitation, which is required for fertilization. However, the effects of FPN on mammalian fertility are not yet fully understood. Therefore, the present study was designed to investigate the effects of FPN on spermatozoa. Herein, we treated various concentrations of FPN (0.1, 1, 10, 100, and 300 μM) or a control treatment with mouse spermatozoa. FPN treatment significantly reduced sperm motility, motion kinematic parameters, and intracellular ATP level, whereas the acrosome reaction was enhanced. Levels of phospho-PKA and phospho-tyrosine substrate were significantly decreased in a dose-dependent manner. Meanwhile, there was no difference between control and treatment groups in the level of GABAAR β-3. Only the ratio of GABAAR β-3 pS408/pS409 was significantly decreased at higher concentrations of FPN. Moreover, cleavage and blastocyst formation rates were also significantly decreased by FPN treatments. Taken together, these data suggest that FPN can directly and indirectly suppress various sperm functions. Therefore, FPN can negatively affect male fertility leading to infertility. From these results, we suggest that the use of FPN as a pesticide requires the attention of reproductive toxicity.