A preliminary study of phosphodiesterases and adenylyl cyclase signaling pathway on red blood cell deformability of sickle cell patients

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by chronic anemia, intravascular hemolysis, and the occurrence of vaso-occlusive crises due to the mechanical obstruction of the microcirculation by poorly deformable red blood cells (RBCs). RBC deformability is a key factor in the pathogenesis of SCD, and is affected by various factors. In this study, we investigated the effects of adenylyl cyclase (AC) signaling pathway modulation and different phosphodiesterase (PDE) modulatory molecules on the deformability and mechanical stress responses of RBC from SCD patients (HbSS genotype) by applying 5 Pa shear stress with an ektacytometer (LORRCA). We evaluated RBC deformability before and after the application of shear stress. AC stimulation with Forskolin had distinct effects on RBC deformability depending on the application of 5 Pa shear stress. RBC deformability was increased by Forskolin before shear stress application but decreased after 5 Pa shear stress. AC inhibition with SQ22536 and protein kinase A (PKA) inhibition with H89 increased RBC deformability before and after the shear stress application. Non-selective PDE inhibition with Pentoxifylline increased RBC deformability. However, modulation of the different PDE types had distinct effects on RBC deformability, with PDE1 inhibition by Vinpocetine increasing deformability while PDE4 inhibition by Rolipram decreased RBC deformability after the shear stress application. The effects of the drugs varied greatly between patients suggesting some could benefit from one drug while others not. Developing drugs targeting the AC signaling pathway could have clinical applications for SCD, but more researches with larger patient cohorts are needed to identify the differences in the responses of sickle RBCs

Proteomic Analysis of the Role of the Adenylyl Cyclase–cAMP Pathway in Red Blood Cell Mechanical Responses

Red blood cell (RBC) deformability is modulated by the phosphorylation status of the cytoskeletal proteins that regulate the interactions of integral transmembrane complexes. Proteomic studies have revealed that receptor-related signaling molecules and regulatory proteins involved in signaling cascades are present in RBCs. In this study, we investigated the roles of the cAMP signaling mechanism in modulating shear-induced RBC deformability and examined changes in the phosphorylation of the RBC proteome. We implemented the inhibitors of adenylyl cyclase (SQ22536), protein kinase A (H89), and phosphodiesterase (PDE) (pentoxifylline) to whole blood samples, applied 5 Pa shear stress (SS) for 300 s with a capillary tubing system, and evaluated RBC deformability using a LORRCA MaxSis. The inhibition of signaling molecules significantly deteriorated shear-induced RBC deformability (p p p < 0.05). AC is the core element of this signaling pathway, and PDE works as a negative feedback mechanism that could have potential roles in SS-induced RBC deformability. The cAMP/PKA pathway could regulate RBC deformability during capillary transit by triggering significant alterations in the phosphorylation state of RBCs

Proteomic Analysis of the Role of the Adenylyl Cyclase&ndash;cAMP Pathway in Red Blood Cell Mechanical Responses

Red blood cell (RBC) deformability is modulated by the phosphorylation status of the cytoskeletal proteins that regulate the interactions of integral transmembrane complexes. Proteomic studies have revealed that receptor-related signaling molecules and regulatory proteins involved in signaling cascades are present in RBCs. In this study, we investigated the roles of the cAMP signaling mechanism in modulating shear-induced RBC deformability and examined changes in the phosphorylation of the RBC proteome. We implemented the inhibitors of adenylyl cyclase (SQ22536), protein kinase A (H89), and phosphodiesterase (PDE) (pentoxifylline) to whole blood samples, applied 5 Pa shear stress (SS) for 300 s with a capillary tubing system, and evaluated RBC deformability using a LORRCA MaxSis. The inhibition of signaling molecules significantly deteriorated shear-induced RBC deformability (p &lt; 0.05). Capillary SS slightly increased the phosphorylation of RBC cytoskeletal proteins. Tyrosine phosphorylation was significantly elevated by the modulation of the cAMP/PKA pathway (p &lt; 0.05), while serine phosphorylation significantly decreased as a result of the inhibition of PDE (p &lt; 0.05). AC is the core element of this signaling pathway, and PDE works as a negative feedback mechanism that could have potential roles in SS-induced RBC deformability. The cAMP/PKA pathway could regulate RBC deformability during capillary transit by triggering significant alterations in the phosphorylation state of RBCs

Radiotherapy applications of patients with malignant mesothelioma: A single center experience

BackgroundIn the management of malignant pleural mesothelioma, radiotherapy has been used for the purpose of prophylaxis to reduce the incidence of recurrence at surgical insertion sites or palliate the symptoms.AimThe purpose of the study was to evaluate the techniques and effectiveness of radiotherapy in malignant pleural mesothelioma.Materials and methodsForty-four (18 female, 26 male) patients diagnosed with malignant pleural mesothelioma were retrospectively evaluated. All patients had surgery or thoracoscopic biopsy for diagnosis, staging or treatment and all received palliative or prophylactic radiotherapy. Fifty-seven percent of the patients received chemotherapy.ResultsProphylactic radiation was applied to 27 patients with 4–15[[ce:hsp sp="0.25"/]]MeV electron energies. The median radiotherapy dose was 30[[ce:hsp sp="0.25"/]]Gy with 3[[ce:hsp sp="0.25"/]]Gy daily fraction dose. During treatment, 12 patients had grade 1 erythema according to the RTOG scale. In 3 (12%) patients, a local failure at treatment field was observed. Palliative radiotherapy was applied to 17 patients for pain palliation. The median radiation dose was 40[[ce:hsp sp="0.25"/]]Gy with 2[[ce:hsp sp="0.25"/]]Gy daily fraction dose by using 6–18[[ce:hsp sp="0.25"/]]MV photon and/or 4–12[[ce:hsp sp="0.25"/]]MeV electron energies. Two patients had grade 1 erythema and one patient had grade 2 odynophagy according to the RTOG scale. For 10 (59%) patients, palliation of chest pain was delivered. No late toxicity was observed for all cases.ConclusionOur experience showed that prophylactic and palliative radiotherapy are effective and safe therapy modalities in malignant pleural mesothelioma in preventing seeding metastasis at intervention sites or relieving pain. Prospective randomized studies are still needed to determine the benefits of radiotherapy application and to indicate optimum dose schemes

Evaluation of Economic Structure of Cherry Growing in Turkey

Gul, Mevlut/0000-0002-0147-7228; POLAT, MEHMET/0000-0002-2415-4229; Ormeci Kart, Murside Cagla/0000-0002-9822-9908WOS: 000513347600002Cherry production has a vital role regarding income source for producers and export sources for Turkey. in Turkey, several studies have done regarding the technical practices, and most of them were not considered the economic dimension of cherry production. This research aimed to determine the production inputs, costs and profitability of cherry production. This study aims to reveal the relationship between orchard size and profitability by using general economic calculations based on Afyonkarahisar, Denizli, Isparta, Izmir, Konya and Manisa provinces, in Turkey. It is assumed that this study may be able to close the existing gap regarding other studies in the literature to a certain extent. This study support that more prominent cherry orchards had higher profits compared to smaller. the relative profit varies between 2.2 to 3.0 in the farm size groups. in this study, it was found that relative profit is the highest in the bigger-scale orchards. the most crucial problem for producers is to achieve a profitable cherry selling price. This study found the output/input ratio is high. Orchard size and production cost have a significant influence on the economic success of a cherry orchard. Production cost has a negative influence on profitability with a low cherry yield. in other words, cherry production is profitable in the research region, but some recommendations can be made within the framework of research findings to get better

Purified Protein Derivative Response in Juvenile Idiopathic Arthritis

Objective. To examine the Purified protein derivative (PPD) response that develops depending upon Th1 immune response in children With juvenile idiopathic arthritis (JIA)

Does radiotherapy planning without breath control compensate intra-fraction heart and its compartments' movement?

This prospective study investigated radiation dose and volume changes during breathing cycle. Ten patients with left breast carcinoma receiving radiotherapy were included. Treatment planning images were obtained as three different sets of series taken: without breath control (F), deep inspiration (I), and end of expiration (E), with 3-mm intervals. As such, whole breath cycle was simulated. CT images taken during I and E were registered to F, according to DICOM coordinates. Each patient's target and organ at risk volumes were contoured by the primary radiation oncologist except heart components which were contoured by radiologist on F, I and E series. Radiotherapy planning was done on F series, then planning and beam data were transferred from F to I and E image series. Target and organs at risk (OAR) dose distributions for E and I image series were obtained. Dose changes between F, E, and I phases for whole heart and components, namely, left ventricle (LV), right ventricle (RV), left auricle (LA), right auricle (RA), and left anterior descendent artery (LAD) were examined. Furthermore, the issue of any compartment representing the maximum heart dose was investigated. Volume and dose variations for heart, LV, RV, LA, RA, and LAD were observed during breath cycle. Exposured dose was more than defined tolerance level for LV, RV, and LAD in some patients. However, dose differences between F-I and F-E were not statistically significant. Radiotherapy planning without breath control is not capable of compensating for whole intra-fraction heart and its components' volumes and dose changes