Tumor Organoid as a Drug Screening Platform for Cancer Research.

A number of studies have been conducted on the application of 3D models for drug discovery, drug sensitivity assessment, and drug toxicity. Most of these studies focused on disease modelling and attempted to control cellular differentiation, heterogeneity, and key physiological features to mimic organ reconstitution so that researchers could achieve an accurate response in drug evaluation. Recently, organoids have been used by various scientists due to their highly organotypic structure, which facilitates the translation from basic research to the clinic, especially in cancer research. With this tool, researchers can perform high-throughput analyses of compounds and determine the exact effect on patients based on their genetic variations, as well as develop personalized and combination therapies. Although there is a lack of standardization in organoid culture, patientderived organoids (PDO) have become widely established and used for drug testing. In this review, we have discussed recent advances in the application of organoids and tumoroids not only in cancer research for drug screening but also in clinical trials to demonstrate the potential of organoids in translational medicine.

The Therapeutic Efficacy of Freeze-Dried Human Amniotic Membrane Allograft Gel for Diabetic Foot Ulcers: A Phase-1 Clinical Trial.

Diabetic foot ulcers (DFUs) are classified as hard-to-heal wounds, which occur in approximately 15% of diabetic patients. Several interventions have shown efficacy in reducing the risk of amputation among patients with DFU, including timely diagnosis and management of infection and ischemia, debridement of necrotic tissues, reducing mechanical pressure on ulcers, and patient education. One major challenge in the management of DFUs is optimizing wound care to improve healing outcomes. Recently, interdisciplinary approaches proposed a new generation of wound dressing which increased efficacy and significantly decreased the healing time. The current study assessed the healing characteristics of chronic DFUs treated with lyophilized amniotic membrane gel (LAMG) in combination with standard care, versus a placebo hydrogel with standard care. In total, 18 patients (8 male, 10 female) were randomly assigned to the control group, which received standard care and a gelatin scaffold (placebo), or the intervention group, which received standard care along with LAMG. We evaluated the reduction in wound size and assessed the patient's health-related quality of life over 9 weeks. In the LAMG group (n = 9) and the Placebo group (n = 9), the wounds were reduced in size by a mean of 73.4% ± 15.3% and 13.1% ± 10.1%, respectively (P = .008). Patients treated with LAMG demonstrated significant improvements in the scores related to physical function, physical limitation, physical pain, general health, social function, emotional problems, and energy levels compared to the control group. The findings of this study indicate that using the LAMG with standard care significantly enhances wound healing.

SWI/SNF complex, promising target in melanoma therapy: Snapshot view.

Therapeutic strategies based on epigenetic regulators are rapidly increasing in light of recent advances in discovering the role of epigenetic factors in response and sensitivity to therapy. Although loss-of-function mutations in genes encoding the SWItch/Sucrose NonFermentable (SWI/SNF) subunits play an important role in the occurrence of ~34% of melanomas, the potential of using inhibitors and synthetic lethality interactions between key subunits of the complex that play an important role in melanoma progression must be considered. Here, we discuss the importance of the clinical application of SWI/SNF subunits as a promising potential therapeutic in melanoma.

In silico analysis of the substitution mutations and evolutionary trends of the SARS-CoV-2 structural proteins in Asia.

Objectives: To address a highly mutable pathogen, mutations must be evaluated. SARS-CoV-2 involves changing infectivity, mortality, and treatment and vaccination susceptibility resulting from mutations. Materials and Methods: We investigated the Asian and worldwide samples of amino-acid sequences (AASs) for envelope (E), membrane (M), nucleocapsid (N), and spike (S) proteins from the announcement of the new coronavirus 2019 (COVID-19) up to January 2022. Sequence alignment to the Wuhan-2019 virus permits tracking mutations in Asian and global samples. Furthermore, we explored the evolutionary tendencies of structural protein mutations and compared the results between Asia and the globe. Results: The mutation analyses indicated that 5.81%, 70.63%, 26.59%, and 3.36% of Asian S, E, M, and N samples did not display any mutation. Additionally, the most relative mutations among the S, E, M, and N AASs occurred in the regions of 508 to 635 AA, 7 to 14 AA, 66 to 88 AA, and 164 to 205 AA in both Asian and total samples. D614G, T9I, I82T, and R203M were inferred as the most frequent mutations in S, E, M, and N AASs. Timeline research showed that substitution mutation in the location of 614 among Asian and total S AASs was detected from January 2020. Conclusion: N protein was the most non-conserved protein, and the most prevalent mutations in S, E, M, and N AASs were D614G, T9I, I82T, and R203M. Screening structural protein mutations is a robust approach for developing drugs, vaccines, and more specific diagnostic tools.

SARS-CoV-2 Non-Structural Protein 1(NSP1) Mutation Virulence and Natural Selection: Evolutionary Trends in the Six Continents.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an unsegmented positivesense single-stranded RNA virus that belongs to the ß-coronavirus . This virus was the cause of a novel severe acute respiratory syndrome in 2019 (COVID-19) that emerged in Wuhan, China at the early stage of the pandemic and rapidly spread around the world. Rapid transmission and reproduction of SARS-CoV-2 threaten worldwide health with a high mortality rate from the virus. According to the significant role of non-structural protein 1 (NSP1) in inhibiting host mRNA translation, this study focuses on the link between amino acid sequences of NSP1 and alterations of them spreading around the world. The SARS-CoV-2 NSP1 protein sequences were analyzed and FASTA files were processed by Python language programming libraries. Reference sequences compared with each NSP1 sample to identify every mutation and categorize them were based on continents and frequencies. NSP1 mutations rate divided into continents were different. Based on continental studies, E87D in global vision and also in Europe notably increased. The E87D mutation has significantly risen especially in the last months of the study as the first frequent mutation observed. The remarkable mutations, H110Y and R24C, have the second and third frequencies, respectively. Based on this mutational information, despite NSP1 being a conserved sequence occurrence, these mutations change the rate of flexibility and stability of the NSP1 protein, which can eventually affect inhibiting the host translation. IMPORTANCE: In this study, we analyzed 6,510,947 sequences of non-structural protein 1 as a conserved region of SARS-CoV-2. According to the obtained results, 93.4819% of samples had no mutant regions on their amino acid sequences. Heat map data of mutational samples demonstrated high percentages of mutations that occurred in the region of 72 to 126 amino acids indicating a hot spot region of the protein. Increased rates of E87D, H110Y, and R24C mutations in the timeline of our study were reported as significant compared to available mutant samples. Analyzing the details of replacing amino acids in the most frequent E87D mutation reveals the role of this alteration in increasing molecule flexibility and destabilizing the structure of the protein.

A Two-Color Haploid Genetic Screen Identifies Novel Host Factors Involved in HIV-1 Latency.

To identify novel host factors as putative targets to reverse HIV-1 latency, we performed an insertional mutagenesis genetic screen in a latent HIV-1 infected pseudohaploid KBM7 cell line (Hap-Lat). Following mutagenesis, insertions were mapped to the genome, and bioinformatic analysis resulted in the identification of 69 candidate host genes involved in maintaining HIV-1 latency. A select set of candidate genes was functionally validated using short hairpin RNA (shRNA)-mediated depletion in latent HIV-1 infected J-Lat A2 and 11.1 T cell lines. We confirmed ADK, CHD9, CMSS1, EVI2B, EXOSC8, FAM19A, GRIK5, IRF2BP2, NF1, and USP15 as novel host factors involved in the maintenance of HIV-1 latency. Chromatin immunoprecipitation assays indicated that CHD9, a chromodomain helicase DNA-binding protein, maintains HIV-1 latency via direct association with the HIV-1 5' long terminal repeat (LTR), and its depletion results in increased histone acetylation at the HIV-1 promoter, concomitant with HIV-1 latency reversal. FDA-approved inhibitors 5-iodotubercidin, trametinib, and topiramate, targeting ADK, NF1, and GRIK5, respectively, were characterized for their latency reversal potential. While 5-iodotubercidin exhibited significant cytotoxicity in both J-Lat and primary CD4+ T cells, trametinib reversed latency in J-Lat cells but not in latent HIV-1 infected primary CD4+ T cells. Importantly, topiramate reversed latency in cell line models, in latently infected primary CD4+ T cells, and crucially in CD4+ T cells from three people living with HIV-1 (PLWH) under suppressive antiretroviral therapy, without inducing T cell activation or significant toxicity. Thus, using an adaptation of a haploid forward genetic screen, we identified novel and druggable host factors contributing to HIV-1 latency. IMPORTANCE A reservoir of latent HIV-1 infected cells persists in the presence of combination antiretroviral therapy (cART), representing a major obstacle for viral eradication. Reactivation of the latent HIV-1 provirus is part of curative strategies which aim to promote clearance of the infected cells. Using a two-color haploid screen, we identified 69 candidate genes as latency-maintaining host factors and functionally validated a subset of 10 of those in additional T-cell-based cell line models of HIV-1 latency. We further demonstrated that CHD9 is associated with HIV-1's promoter, the 5' LTR, while this association is lost upon reactivation. Additionally, we characterized the latency reversal potential of FDA compounds targeting ADK, NF1, and GRIK5 and identify the GRIK5 inhibitor topiramate as a viable latency reversal agent with clinical potential.

Melatonin as a Therapeutic Agent for the Inhibition of Hypoxia-Induced Tumor Progression: A Description of Possible Mechanisms Involved.

Hypoxia has an important role in tumor progression via the up-regulation of growth factors and cellular adaptation genes. These changes promote cell survival, proliferation, invasion, metastasis, angiogenesis, and energy metabolism in favor of cancer development. Hypoxia also plays a central role in determining the resistance of tumors to chemotherapy. Hypoxia of the tumor microenvironment provides an opportunity to develop new therapeutic strategies that may selectively induce apoptosis of the hypoxic cancer cells. Melatonin is well known for its role in the regulation of circadian rhythms and seasonal reproduction. Numerous studies have also documented the anti-cancer properties of melatonin, including anti-proliferation, anti-angiogenesis, and apoptosis promotion. In this paper, we hypothesized that melatonin exerts anti-cancer effects by inhibiting hypoxia-induced pathways. Considering this action, co-administration of melatonin in combination with other therapeutic medications might increase the effectiveness of anti-cancer drugs. In this review, we discussed the possible signaling pathways by which melatonin inhibits hypoxia-induced cancer cell survival, invasion, migration, and metabolism, as well as tumor angiogenesis.

Glioblastoma cancer stem cell biology: Potential theranostic targets.

Glioblastoma multiforme (GBM) is among the most incurable cancers. GBMs survival rate has not markedly improved, despite new radical surgery protocols, the introduction of new anticancer drugs, new treatment protocols, and advances in radiation techniques. The low efficacy of therapy, and short interval between remission and recurrence, could be attributed to the resistance of a small fraction of tumorigenic cells to treatment. The existence and importance of cancer stem cells (CSCs) is perceived by some as controversial. Experimental evidences suggest that the presence of therapy-resistant glioblastoma stem cells (GSCs) could explain tumor recurrence and metastasis. Some scientists, including most of the authors of this review, believe that GSCs are the driving force behind GBM relapses, whereas others however, question the existence of GSCs. Evidence has accumulated indicating that non-tumorigenic cancer cells with high heterogeneity, could undergo reprogramming and become GSCs. Hence, targeting GSCs as the "root cells" initiating malignancy has been proposed to eradicate this devastating disease. Most standard treatments fail to completely eradicate GSCs, which can then cause the recurrence of the disease. To effectively target GSCs, a comprehensive understanding of the biology of GSCs as well as the mechanisms by which these cells survive during treatment and develop into new tumor, is urgently needed. Herein, we provide an overview of the molecular features of GSCs, and elaborate how to facilitate their detection and efficient targeting for therapeutic interventions. We also discuss GBM classifications based on the molecular stem cell subtypes with a focus on potential therapeutic approaches.

Skin care and rejuvenation by cosmeceutical facial mask.

Skin health is an important aspect of aesthetics. Dermatologists and scientists try to develop novel methods and materials to fulfill this aim. Facial cosmetics keep skin moist and remove sebum from the skin to maintain proper skin health. The use of suitable cosmetics according to the facial skin type results in healthy skin. Facial masks are the most prevalent cosmetic products utilized for skin rejuvenation. Facial masks are divided into four groups: (a) sheet masks; (b) peel-off masks; (c) rinse-off masks; and (d) hydrogels. Each of these has some advantages for specific skin types based on the ingredients used. The following article presents the available information about the facial mask. Also, we have focused on the facial masks available in the market. Despite several developments in this field, extensive research is required for performing successful and precise clinical trials in the future. Further improvements would enable the researchers to develop new products in this field. In this review, we present the most recent breakthroughs in the field of skin care and rejuvenation by cosmeceutical facial mask. This information is valuable to get the picture of the latest trends and also helpful for clinicians and related manufacturing companies.