Prospects of Treating Prostate Cancer through Apalutamide: A Mini-Review.

BACKGROUND: Prostate cancer is considered the second most diagnosed cancer, and one of the most common causes of death from cancer in men. Apalutamide is an effective, safe, and well-tolerated agent used for the treatment of men with non-metastatic Castration-Resistant Prostate Cancer (nmCRPC) and metastatic Hormone-Naive Prostate Cancer (mHNPC). Androgen receptor signaling is a leading factor that drives these prostate tumors. USFDA has approved apalutamide on 14 February 2018 as an agent that targets androgen receptor signaling through inhibition causing significant improvement in metastasis-free survival in patients with prostate cancer. OBJECTIVE: In this review, various aspects related to apalutamide have been summarized which involve the mechanism of action, chemistry, synthesis, pharmacokinetics, pharmacodynamics, adverse reactions, and safety parameters. METHODS: The literature was thoroughly searched in the relevant databases to identify studies published in this field during recent years. Special attention has been given to apalutamide clinical trials phases and its promising future as one of the first-line agents for the treatment of patients with advanced prostate cancer. RESULTS: Ongoing trials are progressing for apalutamide monotherapy and also for its combinations in other disease settings. The expected results of such trials will shape the future scenario of prostate cancer therapy. CONCLUSION: This review article has highlighted different aspects of Apalutamide like its mechanism of action, adverse effects, pharmacokinetics, pharmacodynamics, clinical trials among others. The contents of this article should make an excellent read for prospective researchers in this field.

Prospects of Treating Tenosynovial Giant Cell Tumor through Pexidartinib: A Review.

BACKGROUND: Tenosynovial giant cell tumor refers to a group of rarely occurring tumors that are formed in the joints, which are characterized by pain, swelling, and limitation of movement of the joint. Surgery is the main treatment strategy, but the tumor is likely to recur, especially in pigmented villonodular synovitis, which is the diffuse-type giant cell tumor. Pexidartinib was approved in August 2019 by the Food and Drug Administration (FDA) with a brand name TURALIO as the first systemic approved therapy for patients having Tenosynovial Giant Cell Tumors (TGCT). OBJECTIVE: In this review, different aspects pertaining to pexidartinib have been summarized, including the pathophysiology of TGCT, chemistry, pharmacokinetics and pharmacodynamics of pexidartinib. Special attention is given to various reported clinical trials of pexidartinib. METHODS: A comprehensive literature search was conducted in the relevant databases to identify studies published in this field during recent years. CONCLUSION: Pexidartinib acts by inhibiting the Colony-Stimulating Factor (CSF1)/CSF1 receptor pathway, which leads to the inhibition of the cell lines proliferation and promotes the autophosphorylation process of the ligand-induced CSF1 receptor. Pexidartinib emerged as a potential drug candidate for the treatment of TGCT.

Modelling farmer choices for water security measures in the Litani river basin in Lebanon.

Lebanon is facing an increasing water supply deficit due to the increasing demand for freshwater, decreasing surface and groundwater resources and malfunctioning water governance structures. Technological and policy changes are needed to alleviate the impact of water scarcity and secure water in the future. This paper investigates farmers' preferences and willingness to pay (WTP) in a choice experiment for a series of water saving measures at plot and irrigation district level, including more timely information of water delivery. These measures are expected to strengthen water security and use water more efficiently. Farmers are willing to pay higher water prices of $0.32/m3 and $0.22/m3 to support the implementation of water saving measures at plot level and the installation of water metering devices across the irrigation district, respectively. They are not willing to pay extra for obtaining information related to their water delivery earlier in time if this means that they will also have to pay earlier in the year for the water. Farmers with higher income and education levels who decide on their cropping pattern based on expected rainfall data are more interested in taking action than farmers whose cropping decisions are primarily based on last year's sales prices. The study shows that when aiming to design more effective sustainable water management strategies, accounting for farmers' needs and preferences, their age also has to be considered: younger farmers (<40 years) are on average more interested in and willing to pay more for new water saving measures than older farmers (>40 years).

Analysis of normal epithelial cell specific-1 (NES1)/kallikrein 10 mRNA expression by in situ hybridization, a novel marker for breast cancer.

PURPOSE: Normal epithelial cell specific-1 (NES1)/kallikrein 10 gene is expressed in normal mammary and prostate epithelial cells, but the expression of NES1 mRNA and protein is markedly reduced in established breast and prostate cancer cell lines although the NES1 gene is intact. Here, we wished to assess whether NES1 expression is down-regulated in primary breast cancers. EXPERIMENTAL DESIGN: We developed and used an in situ hybridization technique with an antisense NES1 probe to detect NES1 mRNA in sections of normal breast specimens, typical and atypical ductal hyperplasia, ductal carcinoma in situ, and infiltrating ductal carcinoma. RESULTS: All of the 30 normal breast specimens showed high NES1 expression. Notably, 18 (75%) of 24 typical and atypical breast hyperplasia specimens showed high NES1 expression, with weak-to-moderate expression in 6 (25%). Significantly, 13 (46%) of 28 ductal carcinoma in situ specimens lacked NES1 expression, and the remaining 15 (54%) showed weak-to-moderate expression. Finally, 29 of 30 (97%) infiltrating ductal carcinoma grades I-III samples lacked NES1 mRNA, with weak expression in the remaining one sample. CONCLUSIONS: Our results demonstrate that NES1 mRNA is expressed in normal breast tissue and benign lesions, with loss of NES1 expression during tumor progression. We suggest that NES1 expression may serve as a molecular tool in the study of breast cancer progression. Studies with larger series of specimens should help assess whether NES1 expression can be a diagnostic and/or prognostic marker in breast and other cancers.

1,2,5,6-Diepoxyhexane and 1,2,7,8-diepoxyoctane cross-link duplex DNA at 5'-GNC sequences.

The carcinogenicity of epoxide compounds has been attributed to covalent binding to DNA. Whereas monoepoxides form only monoadducts, diepoxides can form both monoadducts and interstrand cross-links. The latter are believed to be the more significant cytotoxic lesions as diepoxides are frequently more carcinogenic and mutagenic than their monoepoxide analogues. We therefore examined the relative DNA interstrand cross-linking capabilities of several diepoxides with respect to chain length, molecular flexibility, reported carcinogenic potential, and DNA sequences targeted. Using denaturing polyacrylamide gel electrophoresis, we found that 1,2,5,6-diepoxyhexane and 1,2,7,8-diepoxyoctane share the 5'-GNC target sequence previously found for 1,2,3,4-diepoxybutane [Millard, J.T., and White, M.M. (1993) Biochemistry 32, 2120-2124] and that the efficiency of cross-linking this sequence may reflect carcinogenicity, 1,2,5,6-Diepoxycyclooctane, the biologically inactive rigid analogue of 1,2,5,6-diepoxyhexane, was found to be a poor cross-linker of all DNA sequences examined. Moreover, increasing the diepoxyalkane chain length did not result in enhanced cross-linking ability.

Aneurisma dissecante de arteria pulmonar associado a esquistossomose pulmonar.Relato de um caso. / Dissecting aneurysm of the pulmonary artery, associated with pulmonary schistosomiasis. Report of a case

Os autores relatam um caso de aneurisma de arteria pulmonar, em pacientes com 26 anos, portadora de esquistossomose pulmonar. O eletrocardiograma, radiografia de torax e cateterismo cardiaco mostraram sobrecarga ventricular direita e hiperrtensao pulmonar. A necropsia revelou tratar-se de aneurisma dissecante de arteria pulmonar com necrose cistica de media e lesoes angiomatoide e plexiforme na vasculatura pulmonar. A evolucao clinica e etiologia do aneurisma sao discutidos, concluindo os autores que a hipertensao e o fator descisivo para a formacao do aneurisma, sendo que a necrose cistica da media aparece secundariamente