Signal Transduction Therapies for Treatment of Chronic Leukemias

The term signal transduction includes the interaction of external signals that are driven by hormones, growth factors, chemokines, cytokines and small molecules such as ATP in order to receive a cellular response. These responses in turn effect gene transcription and translation, cell division, survival and death upon many signaling networks related with malignancies. Since almost all diseases exhibit dysfunctional aspects of the signaling pathways, drug discovery studies in means of signal transduction therapies have an accelerating importance including chronic leukemias. Among chronic leukemias, chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are being investigated extensively for abnormalities of cellular signaling pathways. This review focuses on targeting B-cell antigen receptor (BCR) signaling and Wnt/?-Catenin/LEF-1 signaling pathways and their inhibitors that provided new opportunities for development of more effective therapies for CLL. Besides this, signaling network systems such as RAS/RAF/MAPK and JAK/STAT will be discussed that contribute high oncogenic activity of BCR-ABL1 oncoprotein in CML. Finally the molecular targets in treatment duration with clinical insights will be discussed

The Great Mimicker: Zona Zoster at the Mastectomy Site Causing Contralateral Intramammary Lymph Node Enlargement

Zona zoster is rarely observed in patients with malignancy; when present, it follows a dermatomal fashion. Involvement of widely separated regions is very rare. Hereby, zona zoster causing enlarged intramammary lymph nodes (IMLN) in the opposite breast is reported for the first time in literature. The masses were hypoechoic on US with no hilum and hypervascular on color Doppler US. MRI showed hypointense masses with type 3 time-intensity curve and adjacent vessel sign. The complete regression of the nodes after the antiviral therapy confirmed the diagnosis. In breast cancer patients, IMLN enlargements may mimic breast cancer metastasis, and zona zoster infection of the mastectomy site may present with contralateral IMLN enlargement due to altered lymphatic drainage. When breast US is not sufficient for the differential diagnosis, breast MRI may warrant proper diagnosis, and prevent unnecessary biopsies. Antiviral treatment with followup would be sufficient for management

Decolorization and partial mineralization of a polyazo dye by Bacillus firmus immobilized within tubular polymeric gel

The degradation of C.I. Direct red 80, a polyazo dye, was investigated using Bacillus firmus immobilized by entrapment in tubular polymeric gel. This bacterial strain was able to completely decolorize 50 mg/L of C.I. Direct red 80 under anoxic conditions within 12 h and also degrade the reaction intermediates (aromatic amines) during the subsequent 12 h under aerobic conditions. The tubular gel harboring the immobilized cells consisted of anoxic and aerobic regions integrated in a single unit which was ideal for azo dye degradation studies. Results obtained show that effective dye decolorization (97.8%), chemical oxygen demand (COD) reduction (91.7%) and total aromatic amines removal were obtained in 15 h with the immobilized bacterial cell system whereas for the free cells, a hydraulic residence time of 24 h was required for an equivalent performance in a sequential anoxic and aerobic process. Repeated-batch experiments indicate the immobilized cells could decolorize C.I. Direct red 80 and reduce medium COD in five successive batch runs with enhanced activity obtained after each consecutive run, thus suggesting its stability and potential for repeated use in wastewater treatment. UV–visible spectrophotometry and HPLC analysis were used to confirm the partial mineralization of the dye. Data from this study could be used as a reference for the development of effective industrial scale biotechnological process for the removal of dyes and their metabolites in textile wastewater

STAT5 inhibitor Pimozide as a probable therapeutic option in overcoming Ponatinib resistance in K562 leukemic cells

Signal Transducer and Activator of Transcription 5 (STAT5) is a transcription factor that plays a key role in neoplasia, triggered by the fusion oncogene BCR-ABL1; it is not only an essential protein for the pathogenesis of chronic myeloid leukemia (CML), but also its overexpression is associated with drug resistance developed toward various generations of Tyrosine Kinase Inhibitors (TKIs); these are still accepted as gold standard therapeutics for the treatment of CML. In this study, it was investigated whether suppression of STAT5 via a “STAT5 inhibitor” Pimozide resulted in any regain of chemosensitivity to third-generation TKI Ponatinib. Accordingly, the experimental work was designed on both parental CML cell line K562WT and its 1 nM Ponatinib-resistant counterpart, indicated as K562-Pon1. Based on the experimental results, Pimozide was more effective in resistant cells compared to wild-type cells for inducing apoptosis and block cell arrest. Combination therapy of Pimozide and Ponatinib demonstrated that STAT5 was a significant protein for regaining chemosensitivity to Ponatinib when its expression was suppressed both at mRNA and protein level. In conclusion, we consider that STAT5 inhibitor Pimozide can be a good alternative or combination therapy with TKIs for patients suffering from chemotherapeutic drug resistance. Communicated by Ramaswamy H. Sarma. © 2021 Informa UK Limited, trading as Taylor ; Francis Group.This study was supported by Ege University Scientific Research Projects Coordination Unit (Project Number: 18-TIP034).Ege Üniversitesi: 18-TIP03

Comparison of 3D dose distributions for HDR Ir-192 brachytherapy sources with normoxic polymer gel dosimetry and treatment planning system

Radiation fluence changes caused by the dosimeter itself and poor spatial resolution may lead to lack of 3-dimensional (3D) information depending on the features of the dosimeter and quality assurance of dose distributions for high-dose rate (HDR) iridium-192 (Ir-192) brachytherapy sources is challenging and experimental dosimetry methods used for brachytherapy sources are limited. In this study, we investigated 3D dose distributions of Ir-192 brachytherapy sources for irradiation with single and multiple dwell positions using a normoxic gel dosimeter and compared them with treatment planning system (TPS) calculations. For dose calibration purposes, 100-mL gel-containing vials were irradiated at predefined doses and then scanned in an magnetic resonance (MR) imaging unit. Gel phantoms prepared in 2 spherical glasses were irradiated with Ir-192 for the calculated dwell positions, and MR scans of the phantoms were obtained. The images were analyzed with MATLAB software. Dose distributions and profiles derived with 1-mm resolution were compared with TPS calculations. Linearity was observed between the delivered dose and the reciprocal of the T2 relaxation time constant of the gel. The x-, y-, and z-axes were defined as the sagittal, coronal, and axial planes, respectively, the sagittal and axial planes were defined parallel to the long axis of the source while the coronal plane was defined horizontally to the long axis of the source. The differences between measured and calculated profile widths of 3-cm source length and point source for 70%, 50%, and 30% isodose lines were evaluated at 3 dose levels using 18 profiles of comparison. The calculations for 3-cm source length revealed a difference of >3 mm in 1 coordinate at 50% profile width on the sagittal plane and 3 coordinates at 70% profile width and 2 coordinates at 50% and 30% profile widths on the axial plane. Calculations on the coronal plane for 3-cm source length showed >3-mm difference in 1 coordinate at 50% and 70% and 2 coordinates at 30% profile widths. The point source measurements and calculations for 50% profile widths revealed a difference >3 ram in 1 coordinate on the sagittal plane and 2 coordinates on the axial plane. The doses of 3 coordinates on the sagittal plane and 4 coordinates on the axial plane could not be evaluated in 30% profile width because of low doses. There was good agreement between the gel dosimetry and TPS results. Gel dosimetry provides dose distributions in all 3 planes at the same time, which enables us to define the dose distributions in any plane with high resolution. It can be used to obtain 3D dose distributions for HDR Ir-192 brachytherapy sources and 3D dose verification of TPS. (C) 2014 American Association of Medical Dosimetrists