Non-genetic heterogeneity and immune subtyping in breast cancer: Implications for immunotherapy and targeted therapeutics

Breast cancer (BC) is a complex and multifactorial disease, driven by genetic alterations that promote tumor growth and progression. However, recent research has highlighted the importance of non-genetic factors in shaping cancer evolution and influencing therapeutic outcomes. Non-genetic heterogeneity refers to diverse subpopulations of cancer cells within breast tumors, exhibiting distinct phenotypic and functional properties. These subpopulations can arise through various mechanisms, including clonal evolution, genetic changes, epigenetic changes, and reversible phenotypic transitions. Although genetic and epigenetic changes are important points of the pathology of breast cancer yet, the immune system also plays a crucial role in its progression. In clinical management, histologic and molecular classification of BC are used. Immunological subtyping of BC has gained attention in recent years as compared to traditional techniques. Intratumoral heterogeneity revealed by immunological microenvironment (IME) has opened novel opportunities for immunotherapy research. This systematic review is focused on non-genetic variability to identify and interlink immunological subgroups in breast cancer. This review provides a deep understanding of adaptive methods adopted by tumor cells to withstand changes in the tumor microenvironment and selective pressure imposed by medications. These adaptive methods include alterations in drug targets, immune system evasion, activation of survival pathways, and alterations in metabolism. Understanding non-genetic heterogeneity is essential for the development of targeted therapies

PIAS family in cancer: from basic mechanisms to clinical applications

Protein inhibitors of activated STATs (PIAS) are proteins for cytokine signaling that activate activator-mediated gene transcription. These proteins, as versatile cellular regulators, have been described as regulators of approximately 60 proteins. Dysregulation of PIAS is associated with inappropriate gene expression that promotes oncogenic signaling in multiple cancers. Multiple lines of evidence have revealed that PIAS family members show modulated expressions in cancer cells. Most frequently reported PIAS family members in cancer development are PIAS1 and PIAS3. SUMOylation as post-translational modifier regulates several cellular machineries. PIAS proteins as SUMO E3 ligase factor promotes SUMOylation of transcription factors tangled cancer cells for survival, proliferation, and differentiation. Attenuated PIAS-mediated SUMOylation mechanism is involved in tumorigenesis. This review article provides the PIAS/SUMO role in the modulation of transcriptional factor control, provides brief update on their antagonistic function in different cancer types with particular focus on PIAS proteins as a bonafide therapeutic target to inhibit STAT pathway in cancers, and summarizes natural activators that may have the ability to cure cancer

Jaceosidin Induces Apoptosis in U87 Glioblastoma Cells through G2/M Phase Arrest

Artemisia argyi is a widely used medicinal plant in China. The present study was designed to identify the bioactive constituents with antiglioma activity from leaves of Artemesia argyi. A bioactivity guided approach based on MTT assay for cells growth inhibition led to the isolation of a flavonoid, “jaceosidin” from ethanol extract of leaves of Artemesia argyi. The growth inhibitory effect of jaceosidin was explored using flow cytometry and Western blot studies. Our results showed that jaceosidin exerts growth inhibitory effect by arresting the cells at G2/M phase and induction of apoptosis. Furthermore, our study revealed that induction of apoptosis was associated with cell cycle arrest at G2/M phase, upregulation of p53 and Bax, decrease in mitochondrial membrane potential, release of cytochrome c, and activation of caspase 3. This mitochondrial-caspase-3-dependent apoptosis pathway was confirmed by pretreatment with caspase 3 inhibitor, Ac-DEVD-CHO. Our findings suggested that jaceosidin induces mitochondrial-caspase-3-dependent apoptosis in U87 cells by arresting the cell cycle at G2/M phase

Chemical Biology Toolsets for Drug Discovery and Target Identification

Chemical biology is the scientific discipline that deals with the application of chemical techniques and often small molecules produced through synthetic chemistry, to the manipulation and study of biological systems. Its working framework ranges from simple chemical entities to complex drugs by employing the principles of biological origin. This chapter particularly focuses on the principles and working models of chemical biology to discover new drug leads. Drug discovery is an extensive and multifaceted complex process. Chemical biology uses both natural and synthetic compounds with the best therapeutic potential and verifies them by employing the best possible chemical toolsets. Screening of compounds is done by the use of phenotypic as well as the target-based screening to identify and characterize the potent hits. After the identification of target, it is characterized, and validated by extensive testing. The next step is the validation of hits obtained, and lead compounds are tested in clinical trials before introducing them for commercial application

Mixotrophic cultivation of Scenedesmus dimorphus in sugarcane bagasse hydrolysate

Overuse of the fossil fuels to fulfill existing energy requirements has generated various environmental problems like global warming. Emergence of environmental issues due to burning of the fossil fuel resources has provoked researchers to explore alternative sources of fuel. In this scenario, microalgal biofuels could present a promising alternative fuel if produced cost-effectively without competing for freshwater resources and arable land. Aim of the present study was to grow microalgae by employing lignocellulosic waste for production of lipids. Scenedesmus dimorphus NT8c was chosen based on its ability to tolerate heat, rapid growth, and ease of harvesting by overnight settling. Biochemical composition and growth parameters of microalgae were analyzed when cultivated mixotrophically on sugarcane bagasse hydrolysate, a low-value agricultural by-product, that is, currently underutilized. Despite a slight increase in turbidity in the medium, S. dimorphus NT8c cultures raised mixotrophically in 5 g/L sugarcane bagasse hydrolysate displayed significantly higher growth rates compared to photoautotrophic cultivation with an overall biomass productivity of 119.5 mg L d, protein contents of 34.82% and fatty acid contents of 15.41%. Thus, microalgae cultivated mixotrophically are capable of photosynthesizing while metabolizing and assimilating organic carbon, significant increases of biomass and lipid productivity can be achieved. However, high supplementation with organic carbon can result in unfavorable levels of turbidity and bacterial growth, reducing microalgal biomass productivity

Epidemiological Data of Neurological Disorders in Pakistan and Neighboring Countries: A Review

Neurological disorders are the impairments of nervous system and are an important and growing cause of morbidity, mortality, and disability. In addition to health costs, those suffering from these conditions are also frequently victimized of stigmatization and discrimination. Stigmatization further minimizes the patients\u27 access to treatment and social activities. These disorders, therefore, require special attention particularly in developing countries where unfortunately, the burden of these disorders remains largely unrecognized. Moreover, the burden imposed by such chronic neurological conditions in general can be expected to be particularly devastating in poor populations. These conditions are emerging as severe public health concerns in the developing countries due to the facts such as unawareness, Illiteracy, large numbers of people who are untreated, and unavailability of inexpensive but effective interventions. Regrettably, reliable population-based data from developing countries including Pakistan on the epidemiology of neurological disorders are extremely limited. Although, some information on epidemiological aspects of neurological diseases are available from some developing countries (Pakistan, Iran, India, Sri Lanka, Saudi Arabia and China) but disease prevalence and pattern are based on geographical, social, cultural, religious, and ethnic factors. In this review, w e critically analyzed data of 209 studies regarding the burden and prevalence of hypertension, depression, Stroke, Alzheimer\u27s disease (AD), epilepsy, and Parkinson\u27s disease (PD) in Pakistan and neighboring countries

Tubeimoside-1 up-regulates p21 expression and induces apoptosis and G2/M phase cell cycle arrest in human bladder cancer T24 cells

Tubeimoside-1 (TBMS1) is a triterpenoid saponin with potent anticancer properties. In this study, for the first, we examined the anti-proliferative effects of TBMS1 in human bladder cancer T24 cells and its ability to induce apoptosis and cell cycle arrest. Our results demonstrated that TBMS1 decreased the cell viability of bladder cancer T24 cells in a dose-dependent manner. Flow cytometric analysis showed that TBMS1 significantly triggered apoptosis in T24 cells and arrested cell cycle at G2/M phase in a dose-dependent manner. Further characterization demonstrated that TBMS1-induced apoptosis is associated with dissipation in mitochondrial membrane potential (??m), down-regulation of Bcl-2, and up-regulation of Bax and p21 in TBMS1-treated T24 cells. These in vitro results suggested that TBMS1 is an effective anti-bladder cancer natural compound that worth further mechanistic and therapeutic studies in human bladder cancer

Dengue Fever: A General Perspective

Dengue Fever or commonly known as Dengue, a mosquito-borne arboviral infection has emerged as havoc around the globe. Annually, about 50 million infections are reported, resulting in 22,000 deaths and almost 2.5 billion people are reported living at risk. Dengue infection is caused by Dengue Virus (DENV), which is a member of genus Flavivirus and comprised of ten proteins; three proteins, capsid (C), membrane (M), and envelope (E), play structural role and seven are identified as non-structural that direct DENV replication. Four distinct serotypes: DENV-1, DENV-2, DENV-3 and DENV-4 are transmitted via Aedes mosquitoes. Clinically, Dengue patients can be categorized into three groups according to WHO 2009 revised classification. Typical symptoms of dengue include: extreme fatigue; sudden fever (from 3-7 days), headache, joint, muscle, and back pain; vomiting and diarrhea, appetite loss; skin rash along minor bleeding. Aedes aegypti is geographically distributed in tropical areas and breeds in artificially filled water containers i.e. drums, tyres, flower vases plastic food containers, tin cans, etc. Due to four viral serotypes and non-availability of the model animal for dengue, producing vaccines is a challenging task. Thus, Dengue can be managed using various vector control strategies through physical, chemical and biological means