New insight into strategies used to develop long-acting G-CSF biologics for neutropenia therapy.

Over the last 20 years, granulocyte colony-stimulating factors (G-CSFs) have become the major therapeutic option for the treatment of patients with neutropenia. Most of the current G-CSFs require daily injections, which are inconvenient and expensive for patients. Increased understanding of G-CSFs' structure, expression, and mechanism of clearance has been very instrumental in the development of new generations of long-acting G-CSFs with improved efficacy. Several approaches to reducing G-CSF clearance via conjugation techniques have been investigated. PEGylation, glycosylation, polysialylation, or conjugation with immunoglobulins or albumins have successfully increased G-CSFs' half-lives. Pegfilgrastim (Neulasta) has been successfully approved and marketed for the treatment of patients with neutropenia. The rapidly expanding market for G-CSFs has increased demand for G-CSF biosimilars. Therefore, the importance of this review is to highlight the principle, elimination's route, half-life, clearance, safety, benefits, and limitations of different strategies and techniques used to increase the half-life of biotherapeutic G-CSFs. Understanding these strategies will allow for a new treatment with more competitive manufacturing and lower unit costs compared with that of Neulasta.

Bax/Bcl-2 Cascade Is Regulated by the EGFR Pathway: Therapeutic Targeting of Non-Small Cell Lung Cancer.

Non-small cell lung carcinoma (NSCLC) comprises 80%-85% of lung cancer cases. EGFR is involved in several cancer developments, including NSCLC. The EGFR pathway regulates the Bax/Bcl-2 cascade in NSCLC. Increasing understanding of the molecular mechanisms of fundamental tumor progression has guided the development of numerous antitumor drugs. The development and improvement of rationally planned inhibitors and agents targeting particular cellular and biological pathways in cancer have been signified as a most important paradigm shift in the strategy to treat and manage lung cancer. Newer approaches and novel chemotherapeutic agents are required to accompany present cancer therapies for improving efficiency. Using natural products as a drug with an effective delivery system may benefit therapeutics. Naturally originated compounds such as phytochemicals provide crucial sources for novel agents/drugs and resources for tumor therapy. Applying the small-molecule inhibitors (SMIs)/phytochemicals has led to potent preclinical discoveries in various human tumor preclinical models, including lung cancer. In this review, we summarize recent information on the molecular mechanisms of the Bax/Bcl-2 cascade and EGFR pathway in NSCLC and target them for therapeutic implications. We further described the therapeutic potential of Bax/Bcl-2/EGFR SMIs, mainly those with more potent and selectivity, including gefitinib, EGCG, ABT-737, thymoquinone, quercetin, and venetoclax. In addition, we explained the targeting EGFR pathway and ongoing in vitro and in vivo and clinical investigations in NSCLC. Exploration of such inhibitors facilitates the future treatment and management of NSCLC.

In silico modeling of the interaction between TEX19 and LIRE1, and analysis of TEX19 gene missense SNPs.

BACKGROUND: Testis expressed 19 (TEX19) is a specific human stem cell gene identified as cancer-testis antigen (CTA), which emerged as a potential therapeutic drug target. TEX19.1, a mouse paralog of human TEX19, can interact with LINE-1 retrotransposable element ORF1 protein (LIRE1) and subsequently restrict mobilization of LINE-1 elements in the genome. AIM: This study aimed to predict the interaction of TEX19 with LIRE1 and analyze TEX19 missense polymorphisms. TEX19 model was generated using I-TASSER and the interaction between TEX19 and LIRE1 was studied using the HADDOCK software. METHODS: The stability of the docking formed complex was studied through the molecular dynamic simulation using GROMACS. Missense SNPs (n=102) of TEX19 were screened for their potential effects on protein structure and function using different software. RESULTS: Outcomes of this study revealed amino acids that potentially stabilize the predicted interaction interface between TEX19 and LIRE1. Of these SNPs, 37 were predicted to play a probably damaging role for the protein, three of them (F35S, P61R, and E55L) located at the binding site of LIRE1 and could disturb this binding affinity. CONCLUSION: This information can be verified by further in vitro and in vivo experimentations and could be exploited for potential therapeutic targets.

Prostate cancer and therapeutic challenges.

Prostate cancer (PC) is the most prevalent type of cancer in men worldwide. In Saudi Arabia, the rate of PC is increasing annually. The sex steroid hormones androgens and their receptors have critical roles in PC development and progression. Additionally, apoptosis-related proteins such as heat-shock proteins are vital molecules in PC development. Steroid hormone-deprivation therapies remain the essential treatment for patients with metastatic PCs; however, acquired resistance to hormone deprivation and the transition to PC androgen independence is a major health obstacle. In this review, we aim to detail the roles of androgens, androgen receptors and sex steroid hormones in inducing apoptosis in PC.