Acquired immunodeficiency syndrome (AIDS) is an enormous global health threat stemming from human immunodeficiency virus (HIV-1) infection. Up to now, the tremendous advances in combination antiretroviral therapy (cART) have shifted HIV-1 infection from a fatal illness into a manageable chronic disorder. However, the presence of latent reservoirs, the multifaceted nature of HIV-1, drug resistance, severe off-target effects, poor adherence, and high cost restrict the efficacy of current cART targeting the distinct stages of the virus life cycle. Therefore, there is an unmet need for the discovery of new therapeutics that not only bypass the limitations of the current therapy but also protect the body\'s health at the same time. The main goal for complete HIV-1 eradication is purging latently infected cells from patients\' bodies. A potential strategy called \"lock-in and apoptosis\" targets the budding phase of the life cycle of the virus and leads to susceptibility to apoptosis of HIV-1 infected cells for the elimination of HIV-1 reservoirs and, ultimately, for complete eradication. The current work intends to present the main advantages and disadvantages of United States Food and Drug Administration (FDA)-approved anti-HIV-1 drugs as well as plausible strategies for the design and development of more anti-HIV-1 compounds with better potency, favorable pharmacokinetic profiles, and improved safety issues.

Aurora kinases (AURKs) are a family of serine /threonine protein kinases that have a crucial role in cell cycle process mainly in the event of chromosomal segregation, centrosome maturation and cytokinesis. The family consists of three members including Aurora kinase A (AURK-A), Aurora kinase B (AURK-B) and Aurora kinase C (AURK-C). All AURKs contain a conserved kinase domain for their activity but differ in their cellular localization and functions. AURK-A and AURK-B are expressed mainly in somatic cells while the expression of AURK-C is limited to germ cells. AURK-A promotes G2 to M transition of cell cycle by controlling centrosome maturation and mitotic spindle assembly. AURK-B and AURK-C form the chromosome passenger complex (CPC) that ensures proper chromosomal alignments and segregation. Aberrant expression of AURK-A and AURK-B has been detected in several solid tumours and malignancies. Hence, they have become an attractive therapeutic target against cancer. The first part of this review focuses on AURKs structure, functions, subcellular localization, and their role in tumorigenesis. The review also highlights the functional and clinical impact of selective as well as pan kinase inhibitors. Currently, >60 compounds that target AURKs are in preclinical and clinical studies. The drawbacks of existing inhibitors like selectivity, drug resistance and toxicity have also been addressed. Since, majority of inhibitors are Aurora kinase inhibitor (AKI) type-1 that bind to the active (DFGin and Cin) conformation of the kinase, this information may be utilized to design highly selective kinase inhibitors that can be combined with other therapeutic agents for better clinical outcomes.

UNASSIGNED: Tumor budding is gaining importance as a prognostic factor in various carcinomas due to its association with epithelial-mesenchymal transition (EMT) and hence clinical outcome. Reporting tumor budding in breast cancer lacks homogeneity. We aim to systematically review the existing literature and conduct a meta-analysis to assess the prognostic implication of tumor budding in breast carcinoma. A systematic search was performed to identify studies that compared different prognostic variables between high- and low-grade tumor budding. Quality assessment was performed using a modified Newcastle Ottawa Scale. Dichotomous variables were pooled using the odds ratio using the Der-Simonian-Laird method. Meta-analysis was conducted to study the association between low/high-grade tumor budding and tumor grade, lymph node metastasis, lymphovascular invasion, ER, PR, HER2neu, KI67, and the molecular subtype triple-negative breast carcinoma. Thirteen studies with a total of 1763 patients were included. A moderate risk of bias was noted. The median bias scoring was 7 (6-9). High-grade tumor budding was significantly associated with lymph node metastasis (OR: 2.25, 95% CI: 1.52-3.34, P < 0.01) and lymphovascular invasion (OR: 3.14, 95% CI: 2.10-4.71, P < 0.01), and low-grade budding was significantly associated with triple-negative breast carcinoma (OR: 0.61, 95% CI: 0.39-0.95, P = 0.03)There was significant heterogeneity in the assessment and grading of tumor budding; thus, a checklist of items was identified that lacked standardization. Our meta-analysis concluded that tumor budding can act as an independent prognostic marker for breast cancer.

Although 5‑fluorouracil (5‑FU)‑based chemotherapy is the major treatment for colorectal cancer, it has disadvantages such as systemic toxicity, lack of effectiveness and selectivity, and development of resistance. Capecitabine, a prodrug form of 5‑FU, was designed to overcome these drawbacks, to fulfill the need for more convenient therapy, and to improve safety, tolerability and intratumor drug concentration levels through a tumor‑specific conversion to the active 5‑FU drug. The purpose of the present review is to provide a comprehensive comparison between 5‑FU therapy and capecitabine. In the current review, anticancer drug classification was discussed and the development of capecitabine from the original fluorinated analogue (5‑FU) to overcome its drawbacks was explained. Specifically, 5‑FU is compared with capecitabine therapy regarding various properties, including drug metabolism, cellular mechanism, effect on the apoptosis pathway and cell cycle phases, safety and tolerability. Moreover, three metabolizing enzymes required for the activation of capecitabine to 5‑FU were discussed. Capecitabine, as monotherapy or in combination with other chemotherapies, exhibited improved drug efficacy and survival. However, the changes that mediate the chemoresistance of capecitabine treatment were classified as intracellular, extracellular or cell surface factors, or cell‑phenotype state. Future studies should examine the efficacy of capecitabine combined with novel and safe drugs other than chemotherapeutic agents that play a role in the inhibition of tumor initiation, progression and metastasis.

Quiescence, the temporary and reversible arrest of cell growth, is a fundamental biological process. However, the lack of standardization in terms of reporting the experimental details of quiescent cells and populations can cause confusion and hinder knowledge transfer. We employ the systematic review methodology to comprehensively analyze the diversity of approaches used to study the quiescent state, focusing on all published research addressing the budding yeast Saccharomyces cerevisiae. We group research articles into those that consider all cells comprising the stationary-phase (SP) population as quiescent and those that recognize heterogeneity within the SP by distinguishing phenotypically distinct subpopulations. Furthermore, we investigate the chronological age of the quiescent populations under study and the methods used to induce the quiescent state, such as gradual starvation or abrupt environmental change. We also assess whether the strains used in research are prototrophic or auxotrophic. By combining the above features, we identify 48 possible experimental setups that can be used to study quiescence, which can be misleading when drawing general conclusions. We therefore summarize our review by proposing guidelines and recommendations pertaining to the information included in research articles. We believe that more rigorous reporting on the features of quiescent populations will facilitate knowledge transfer within and between disciplines, thereby stimulating valuable scientific discussion.

MicroRNAs (miRNAs/miRs) are a group of small non‑coding RNAs that serve as post‑transcriptional gene modulators. miRNAs have been demonstrated to serve a pivotal role in carcinogenesis and the dysregulated expression of miRNAs is a well‑understood characteristic of cancer. In recent years, miR‑370 has been established as a key miRNA in various cancers. The expression of miR‑370 is dysregulated in various types of cancer and varies markedly across different tumor types. miR‑370 can regulate multiple biological processes, including cell proliferation, apoptosis, migration, invasion, as well as cell cycle progression and cell stemness. Moreover, it has been reported that miR‑370 affects the response of tumor cells to anticancer treatments. Additionally, the expression of miR‑370 is modulated by multiple factors. The present review summarizes the role and mechanism of miR‑370 in tumors, and demonstrates its potential as a molecular marker for cancer diagnosis and prognosis.

As bacteria proliferate, DNA replication, chromosome segregation, cell wall synthesis, and cytokinesis occur concomitantly and need to be tightly regulated and coordinated. Although these cell cycle processes have been studied for decades, several mechanisms remain elusive, specifically in coccus-shaped cells such as Staphylococcus aureus. In recent years, major progress has been made in our understanding of how staphylococci divide, including new, fundamental insights into the mechanisms of cell wall synthesis and division site selection. Furthermore, several novel proteins and mechanisms involved in the regulation of replication initiation or progression of the cell cycle have been identified and partially characterized. In this review, we will summarize our current understanding of the cell cycle processes in the spheroid model bacterium S. aureus, with a focus on recent advances in the understanding of how these processes are regulated.

The ability to monitor lymphocyte responses is critical for developing our understanding of the immune response in humans. In the current clinical setting, relying on the metabolic incorporation of [3H] thymidine into cellular DNA via a lymphocyte proliferation test (LPT) is the only method that is routinely performed to determine cell proliferation. However, techniques that measure DNA synthesis with a radioactive material such as [3H] thymidine are intrinsically more sensitive to the different stages of the cell cycle, which could lead to over-analyses and the subsequent inaccurate interpretation of the information provided. With cell proliferation assays, the output should preferably provide a direct and accurate measurement of the number of actively dividing cells, regardless of the stimuli properties or length of exposure. In fact, an ideal technique should have the capacity to measure lymphocyte responses on both a quantitative level, i.e., cumulative magnitude of lymphoproliferative response, and a qualitative level, i.e., phenotypical and functional characterization of stimulated immune cells. There are many LPT alternatives currently available to measure various aspects of cell proliferation. Of the nine techniques discussed, we noted that the majority of these LPT alternatives measure lymphocyte proliferation using flow cytometry. Across some of these alternatives, the covalent labelling of cells with a high fluorescence intensity and low variance with minimal cell toxicity while maximizing the number of detectable cell divisions or magnitude of proliferation was achieved. Herein, we review the performance of these different LPT alternatives and address their compatibility with the [3H] thymidine LPT so as to identify the \"best\" alternative to the [3H] thymidine LPT.

TANK-binding kinase 1 (TBK1) regulates various biological processes including, NF-κB signaling, immune response, autophagy, cell division, Ras-mediated oncogenesis, and AKT pro-survival signaling. Enhanced TBK1 activity is associated with autoimmune diseases and cancer, suggesting its role in therapeutic targeting of interferonopathies. In addition, dysregulation of TBK1 activity promotes several inflammatory disorders and oncogenesis. Structural and biochemical study reports provide the molecular process of TBK1 activation and recap the substrate selection about TBK1. This review summarizes recent findings on the molecular mechanisms by which TBK1 is involved in cancer signaling. The IKK-ε and TBK1 are together associated with inflammatory diseases by inducing type I IFNs. Furthermore, TBK1 signaling regulates radiation-induced epithelial-mesenchymal transition by controlling phosphorylation of GSK-3β and expression of Zinc finger E-box-binding homeobox 1, suggesting, TBK1 could be targeted for radiotherapy-induced metastasis therapy. Despite a considerable increase in the list of TBK1 inhibitors, only a few has potential to control cancer. Among them, a compound BX795 is considered a potent and selective inhibitor of TBK1. We discussed the therapeutic potential of small-molecule inhibitors of TBK1, particularly those with high selectivity, which will enable further exploration in the therapeutic management of cancer and inflammatory diseases.

The processes involved in the formation of primordia on the shoor apex are those controlling (1) growth rate, (2) division plane. (3) surface microstructure, and (4) extensibility of the surface. Changes in growth rate and division planes may accompany primordium formation but are considered as probably not in themselves being causal. Changes in surface microstructure may be necessary to delimit the position and area occupied by an incipient primordium. However, attention is directed to changes in surface extensibility as perhaps being the overriding factor in primordium formation. Nevertheless, the position and form of the primordia will also depend on growth rate, division plane, and surface microstructurc being permissive. The relative importance of these four sets of processes may differ from species to species and from one stage of development to another. Chemical and metabolic changes within the apex may first be necessary to determine whether the surface can extend sufficiently for any primordia to form at all, but their positions and time of initiation may depend more on the other factors. The surface microstructure may become more important when patterning is detailed and precise as it is in the developing flower, whereas a less precise mechanism dependent on localized induction of synthesis of a morphogen (auxin?) may provide sufficient information to determine the general position and liming of primordium initiation in vegetative apices. In determining the pattern of primordia on the apex, primordial area at initiation is important and reasons for believing that auxin may be involved in determining this are summarised. The different developmental pathways of primordia seem to diverge from the moment of initiation. Developmental fate of primordia is determined by the hamcotic genes which may in fact be heterochronic genes. How these regulatory genes control the processes involved in differentiation of different types of primordia is so far unknown. Contents Summary 1 I. Introduction 2 II. The mechanism of primordium formation: what causes an outgrowth of the apical surface? 2 III. The positions of successive primordia: what determines their size and localization, so giving rise to pattern? 11 IV. What determines the developmental pathways of the primordia once initiated? 13 V. Conclusions 15 VI. Acknowledgements 16 VII. References 16.