MicroRNAs and proteolytic cleavage of receptors in cancers: A comprehensive review of regulatory interactions and therapeutic implications.

Cancer remains a challenging disease worldwide, necessitating innovative approaches to better comprehend its underlying molecular mechanisms and devise effective therapeutic strategies. Over the past decade, microRNAs (miRNAs) have emerged as crucial players in cancer progression due to their regulatory roles in various cellular processes. Moreover, the involvement of unwanted soluble receptors has gained increasing attention because they contribute to tumorigenesis or drug resistance by disrupting normal signaling pathways and neutralizing ligands. This comprehensive review explores the intricate interplay between miRNAs and unwanted-soluble receptors in the context of cancer biology. This study provides an analysis of the regulatory interactions between miRNAs and these receptors, elucidating how miRNAs can either suppress or enhance their expression. MiRNAs can directly target receptor transcripts, thereby regulating soluble receptor levels. They also modulate the proteolytic cleavage of membrane-bound receptors into soluble forms by targeting sheddases, such as ADAMs and MMPs. Furthermore, the review delves into the therapeutic potential of manipulating miRNAs to modulate unwanted soluble receptors. Various strategies, including synthetic miRNA mimics or anti-miRNAs, hold promise for restoring or inhibiting miRNA function to counteract aberrant receptor activity. Moreover, exploring miRNA-based delivery systems may provide targeted and precise therapies that minimizing off-target effects. In conclusion, this review sheds light on the intricate regulatory networks involving miRNAs and unwanted soluble receptors in cancer biology thereby uncovering novel therapeutic targets, and paving the way for developing innovative anti-cancer therapies.

A photocrosslinkable and hemostatic bilayer wound dressing based on gelatin methacrylate hydrogel and polyvinyl alcohol foam for skin regeneration.

The enormous potential of multifunctional bilayer wound dressings in various medical interventions for wound healing has led to decades of exploration into this field of medicine. However, it is usually difficult to synthesize a single hydrogel with all the required capabilities simultaneously. This paper proposes a bilayer model with an outer layer intended for hydrogel wound treatment. By adding gelatin methacrylate (GelMA) and tannic acid (TA) to the hydrogel composition and using polyvinyl alcohol-carboxymethyl chitosan (PVA-CMCs) foam layer as supports, a photocrosslinkable hydrogel with an optimal formulation was created. The hydrogels were then examined using a range of analytical procedures, including mechanical testing, rheology, chemical characterization, and in vitro and in vivo tests. The resulting bilayer wound dressing has many desirable properties, namely uniform adhesion and quick crosslinking by UV light. When used against Gram-positive and Gram-negative bacterial strains, bilayer wound dressings demonstrated broad antibacterial efficacy. In bilayer wound dressings with GelMA and TA, better wound healing was observed. Those without these elements showed less effectiveness in healing wounds. Additionally, encouraging collagen production and reducing wound infection has a major therapeutic impact on wounds. The results of this study could have a significant impact on the development of better-performing wound dressings.

Optimization of Spore Production in Bacillus coagulans Using Response Surface Methodology Approach.

Due to its spore-forming ability, Bacillus coagulans has advantages over the other non-spore-forming probiotics. Among them, survival and stability during food processing and storage, resistance to acid pH, and digestive enzymes are important. However, there are few studies on the quality and amount of sporulation in B. coagulans. This study investigated the spore densities and formation efficiency of B. coagulans. The optimal medium formulation consisted of yeast extract (1.00 g L-1), potassium acetate (20.00 g L-1), and MnSO4 (0.01 g L-1 and 0.03 g L-1). After reaching the optimal medium, a response surface regression equation was established based on the results of central composite design (CCD) experimental designs to optimize time, temperature, and pH parameters. The predicted results thus obtained were in good agreement (R2 = 95.19%) with the results obtained by performing experiments. Multiple regression analysis and analysis of variance (ANOVA) showed that pH is negative, and temperature and time dose are positive factors. The maximum spore cell densities by optimization plots have obtained 9.80 log at temperature 83.77 °C, pH 3.05, and time 111.19 h, considering that B. coagulans needs special environmental and cellular conditions to enter the sporulation stage. In this study, the composition of the culture medium and factors such as temperature, time, and pH were considered influencing factors in B. coagulans sporulation.

Pyrano[2,3-b]chromone derivatives as novel dual inhibitors of α-glucosidase and α-amylase: Design, synthesis, biological evaluation, and in silico studies.

Inhibition of α-glucosidase and α-amylase is an important target for treatment of type 2 diabetes. In this work, a novel series of pyrano[2,3-b]chromene derivatives 5a-m was designed based on potent α-glucosidase and α-amylase inhibitors and synthesized by simple chemical reactions. These compounds were evaluated against the latter enzymes. Most of the title compounds exhibited high inhibitory activity against α-glucosidase and α-amylase in comparison to standard inhibitor (acarbose). Representatively, the most potent compound, 4-methoxy derivative 5d, was 30.4 fold more potent than acarbose against α-glucosidase and 6.1 fold more potent than this drug against α-amylase. In silico molecular modeling demonstrated that compound 5d attached to the active sites of α-glucosidase and α-amylase with a favorable binding energies and established interactions with important amino acids. Dynamics of compound 5d also showed that this compound formed a stable complex with the α-glucosidase active site. In silicodrug-likeness as well as ADMET prediction of this compound was also performed and satisfactory results were obtained.

Targeting Efficient Features of Urate Oxidase to Increase Its Solubility.

With the demand for mass production of protein drugs, solubility has become a serious issue. Extrinsic and intrinsic factors both affect this property. A homotetrameric cofactor-free urate oxidase (UOX) is not sufficiently soluble. To engineer UOX for optimum solubility, it is important to identify the most effective factor that influences solubility. The most effective feature to target for protein engineering was determined by measuring various solubility-related factors of UOX. A large library of homologous sequences was obtained from the databases. The data was reduced to six enzymes from different organisms. On the basis of various sequence- and structure-derived elements, the most and the least soluble enzymes were defined. To determine the best protein engineering target for modification, features of the most and least soluble enzymes were compared. Metabacillus fastidiosus UOX was the most soluble enzyme, while Agrobacterium globiformis UOX was the least soluble. According to the comparison-constant method, positive surface patches caused by arginine residue distribution are appropriate targets for modification. Two Arg to Ala mutations were introduced to the least soluble enzyme to test this hypothesis. These mutations significantly enhanced the mutant's solubility. While different algorithms produced conflicting results, it was difficult to determine which proteins were most and least soluble. Solubility prediction requires multiple algorithms based on these controversies. Protein surfaces should be investigated regionally rather than globally, and both sequence and structural data should be considered. Several other biotechnological products could be engineered using the data reduction and comparison-constant methods used in this study.

Nanotechnology in toothpaste: Fundamentals, trends, and safety.

Several studies have revealed that healthcare nanomaterials are widely used in numerous areas of dentistry, including prevention, diagnosis, treatment, and repair. Nanomaterials in dental cosmetics are utilized to enhance the efficacy of toothpaste and other mouthwashes. Nanoparticles are added to toothpastes for a variety of reasons, including dental decay prevention, remineralization, hypersensitivity reduction, brightening, and antibacterial qualities. In this review, the benefits and uses of many common nanomaterials found in toothpaste are outlined. Additionally, the capacity and clinical applications of nanoparticles as anti-bacterial, whitening, hypersensitivity, and remineralizing agents in the treatment of dental problems and periodontitis are discussed.

Formulation and evaluation of antioxidant and antibacterial activity of a peel-off facial masks moisturizer containing curcumin and Rosa Damascena extract.

BACKGROUND: Acne is a common skin issue that typically occurs during adolescence. It causes long-lasting redness and swelling in the skin. An alternative approach to treating acne could involve using a cosmetic facial mask containing herbal ingredients such as Curcumin and Rosa Damascena extract for its antibacterial properties. AIMS: This study aims to create and try out a peel-off mask gel made from Curcumin and R. Damascena extract. This gel is intended to have the ability to kill bacteria such as Staphylococcus aureus, Escherichia coli, and Propionibacterium acnes and remove dead cells from the skin surface. METHODS: The peel-off mask was made using polyvinyl alcohol (PVA) in 8% and 10% as solidifier. The evaluation of peel-off masks comprises the examination of physiochemical and mechanical aspects. Furthermore, their longevity, effectiveness, and antibacterial properties are also considered. RESULTS: The white color, pleasant smell, and soft texture were the defining features of the peel-off gel mask. The changes in PVA affect the pH level, thickness, and how quickly the peel-off mask dries. The stability test found that the peel-off mask had no significant physical changes when exposed to freezing and thawing. However, there were some differences in color and separation when using the real-time method. A prepared peel-off mask containing 10% PVA and curcumin works best against P. acne. The amount of PVA in the formula affected the physical and chemical qualities, but it did not impact on the antibacterial abilities of the peel-off mask gel. The best formula that gives the best results uses 10% PVA + curcumin. CONCLUSIONS: Using the Curcumin and R. Damascena extract in the creation of the peel-off mask gel ensures its efficacy and safety for skin application.

Collagen-Based Medical Devices for Regenerative Medicine and Tissue Engineering.

Assisted reproductive technologies are key to solving the problems of aging and organ defects. Collagen is compatible with living tissues and has many different chemical properties; it has great potential for use in reproductive medicine and the engineering of reproductive tissues. It is a natural substance that has been used a lot in science and medicine. Collagen is a substance that can be obtained from many different animals. It can be made naturally or created using scientific methods. Using pure collagen has some drawbacks regarding its physical and chemical characteristics. Because of this, when collagen is processed in various ways, it can better meet the specific needs as a material for repairing tissues. In simpler terms, collagen can be used to help regenerate bones, cartilage, and skin. It can also be used in cardiovascular repair and other areas. There are different ways to process collagen, such as cross-linking it, making it more structured, adding minerals to it, or using it as a carrier for other substances. All of these methods help advance the field of tissue engineering. This review summarizes and discusses the current progress of collagen-based materials for reproductive medicine.

Optimizing expression, purification, structural and functional assessments of a novel dimeric incretin (GLP-1cpGLP-1).

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that reduces postprandial glycemic excursions by enhancing insulin secretion. In this study, a new dimeric GLP-1 analogue (GLP-1cpGLP-1) was designed by inserting human insulin C-peptide (CP) in the middle of a dimer of [Gly8] GLP-1 (7-36). Then, the dimeric incretin (GLP-1cpGLP-1) was ligated to human αB-crystallin (αB-Cry) to create a hybrid protein, abbreviated as αB-GLP-1cpGLP-1. The constructed gene was well expressed in the bacterial host system. After specific chemical release from the hybrid protein, the dimeric incretin was purified by size exclusion chromatography (SEC). Finally, the RP-HPLC analysis indicated a purity of >99 % for the dimeric incretin. The secondary structure assessments by various spectroscopic methods, and in silico analysis suggested that the dimeric incretin has α-helical rich structure. The dynamic light scattering (DLS) analysis indicates that our dimeric incretin forms large oligomeric structures. This incretin analogue significantly reduced blood glucose levels in both healthy and diabetic mice while effectively triggering insulin release. The size exclusion HPLC also indicates the interaction of the new incretin analogue with human serum albumin, the main carrier protein in the bloodstream. Consistent with the results obtained from the biological activity assessments, this significant interaction indicates its potential as a viable therapeutic agent with a long-lasting effect. The results of our research represent a significant breakthrough in the successful design of an active incretin dimer capable of effectively controlling blood sugar levels and inducing insulin secretion in the realm of diabetes treatment.

Development of Ag NPs/allantoin loaded PCL/GEL electrospun nanofibers for topical wound treatment.

In the present study, the allantoin and silver nanoparticle (Ag NPs) loaded poly caprolactone/gelatin (PCL/GEL) nanofibers produced using electrospinning technique and their cyto-compatibility and wound healing activity were evaluated in vitro and in vivo. The SEM imaging revealed diameters of 278.8 ± 10 and 240.6 ± 12 nm for PCL/GEL/Ag NPs and PCL/GEL/Ag NPs/allantoin scaffolds. The Ag NPs entrapment into scaffolds was evaluated by FTIR analysis and EDX mapping. Both scaffolds containing Ag NPs and Ag NPs/allantoin exhibited valuable wound healing activity in Wistar rat animal model. The profound granulation tissue formation, high collagen deposition in coordination with low level of edema and inflammatory cells in Ag NPs/allantoin loaded scaffolds resulted in complete and mature re-epithelialization in giving the healing score (12 out of 12) equal to positive control group to the wounds treated with these scaffolds. It was concluded that the Ag NPs/allantoin loaded scaffolds regarding to their good antibacterial activity and excellent wound healing activity could be introduced as new effective wound dressing materials.

Discovery of novel 4,5-diphenyl-imidazol-α-aminophosphonate hybrids as promising anti-diabetic agents: Design, synthesis, in vitro, and in silico enzymatic studies.

Herein, a novel series of 4,5-diphenyl-imidazol-α-aminophosphonate hybrids 4a-m was designed, synthesized, and evaluated as new anti-diabetic agents. These compounds were evaluated against two important target enzymes in the diabetes treatment: α-glucosidase and α-amylase. These new compounds were synthesized in three steps and characterized by different spectroscopic techniques. The in vitro evaluations demonstrated that all the synthesized compounds 4a-m were more potent that standard inhibitor acarbose against studied enzymes. Among these compound, the most potent compound against both studied enzymes was 3-bromo derivative 4l. The latter compound with IC50 = 5.96 nM was 18-times more potent than acarbose (IC50 = 106.63 nM) against α-glucosidase. Moreover, compound 4l with IC50 = 1.62 nM was 27-times more potent than acarbose (IC50 = 44.16 nM) against α-amylase. Molecular docking analysis revealed that this compound well accommodated in the binding site of α-glucosidase and α-amylase enzymes with notably more favorable binding energy as compared to acarbose.

LYZ2-SH3b as a novel and efficient enzybiotic against methicillin-resistant Staphylococcus aureus.

BACKGROUND: Enzybiotics are promising alternatives to conventional antibiotics for drug-resistant infections. Exolysins, as a class of enzybiotics, show antibacterial effects against methicillin-resistant Staphylococcus aureus (MRSA). This study evaluated a novel exolysin containing an SH3b domain for its antibacterial activity against MRSA. METHODS: This study designed a chimeric exolysin by fusing the Cell-binding domain (SH3b) from Lysostaphin with the lytic domain (LYZ2) from the gp61 enzyme. Subsequently, LYZ2-SH3b was cloned and expressed in Escherichia coli (E. coli). Finally, the antibacterial effects of LYZ2-SH3b compared with LYZ2 and vancomycin against reference and clinical isolates of MRSA were measured using the disc diffusion method, the minimal inhibitory concentration (MIC), and the minimal bactericidal concentration (MBC) assays. RESULTS: Analysis of bioinformatics showed that LYZ2-SH3b was stable, soluble, and non-allergenic. Protein purification was performed with a 0.8 mg/ml yield for LYZ2-SH3b. The plate lysis assay results indicated that, at the same concentrations, LYZ2-SH3b has a more inhibitory effect than LYZ2. The MICs of LYZ2 were 4 µg/mL (ATCC 43,300) and 8 µg/mL (clinical isolate ST239), whereas, for LYZ2-SH3b, they were 2 µg/mL (ATCC 43,300) and 4 µg/mL (clinical isolate ST239). This suggests a higher efficiency of LYZ2-SH3b compared to LYZ2. Furthermore, the MBCs of LYZ2 were 4 µg/mL (ATCC 43,300) and 8 µg/mL (clinical isolate ST239), whereas, for LYZ2-SH3b, they were 2 µg/mL (ATCC 43,300) and 4 µg/mL (clinical isolate ST239), thus confirming the superior lytic activity of LYZ2-SH3b over LYZ2. CONCLUSIONS: The study suggests that phage endolysins, such as LYZ2-SH3b, may represent a promising new approach to treating MRSA infections, particularly in cases where antibiotic resistance is a concern. But further studies are needed.

Glucarpidase (carboxypeptidase G2): Biotechnological production, clinical application as a methotrexate antidote, and placement in targeted cancer therapy.

Patients receiving high-dose methotrexate (HDMTX) for malignancies are exposed to diverse complications, including nephrotoxicity, hepatotoxicity, mucositis, myelotoxicity, neurological symptoms, and death. Glucarpidase is a recombinant carboxypeptidase G2 (CPG2) that converts MTX into nontoxic metabolites. In this study, the role of vector type, gene optimization, orientation, and host on the expression of CPG2 is investigated. The effectiveness of various therapeutic regimens containing glucarpidase is classified and perspectives on the dose adjustment based on precision medicine are provided. Conjugation with cell-penetrating peptides, human serum albumin, and polymers such as PEG and dextran for delivery, higher stability, and production of the biobetter variants of CPG2 is highlighted. Conjugation of CPG2 to F(ab՜)2 or scFv antibody fragments against tumor-specific antigens and the corresponding prodrugs for tumor-targeted drug delivery using the antibody-directed enzyme prodrug therapy (ADEPT) is communicated. Trials to reduce the off-target effects and the possibility of repeated ADEPT cycles by adding pro-domains sensitive to tumor-overexpressed proteases, antiCPG2 antibodies, CPG2 mutants with immune-system-unrecognizable epitopes, and protective polymers are reported. Intracellular cpg2 gene expression by gene-directed enzyme prodrug therapy (GDEPT) and the concerns regarding the safety and transfection efficacy of the GDEPT vectors are described. A novel bifunctional platform using engineered CAR-T cell micropharmacies, known as Synthetic Enzyme-Armed KillER (SEAKER) cells, expressing CPG2 to activate prodrugs at the tumor niche is introduced. Taken together, integrated data in this review and recruiting combinatorial strategies in novel drug delivery systems define the future directions of ADEPT, GDEPT, and SEAKER cell therapy and the placement of CPG2 therein.

Identification of potential RapJ hits as sporulation pathway inducer candidates in Bacillus coagulans via structure-based virtual screening and molecular dynamics simulation studies.

BACKGROUND: The bacterium Bacillus coagulans has attracted interest because of its ability to produce spores and advantageous probiotic traits, such as facilitating food digestion in the intestine, managing some disorders, and controlling the symbiotic microbiota. Spore-forming probiotic bacteria are especially important in the probiotic industry compared to non-spore-forming bacteria due to their stability during production and high resistance to adverse factors such as stomach acid. When spore-forming bacteria are exposed to environmental stresses, they enter the sporulation pathway to survive. This pathway is activated by the final phosphorylation of the master regulator of spore response, Spo0A, and upon achieving the phosphorylation threshold. Spo0A is indirectly inhibited by some enzymes of the aspartate response regulator phosphatase (Rap) family, such as RapJ. RapJ is one of the most important Rap enzymes in the sporogenesis pathway, which is naturally inhibited by the pentapeptides. METHODS: This study used structure-based virtual screening and molecular dynamics (MD) simulation studies to find potential RapJ hits that could induce the sporulation pathway. The crystal structures of RapJ complexed with pentapeptide clearly elucidated their interactions with the enzyme active site. RESULTS: Based on the binding compartment, through molecular docking, MD simulation, hydrogen bonds, and binding-free energy calculations, a series of novel hits against RapJ named tandutinib, infigratinib, sitravatinib, linifanib, epertinib, surufatinib, and acarbose were identified. Among these compounds, acarbose obtained the highest score, especially in terms of the number of hydrogen bonds, which plays a major role in stabilizing RapJ-ligand complexes, and also according to the occupancy percentages of hydrogen bonds, its hydrogen bonds were more stable during the simulation time. Consequently, acarbose is probably the most suitable hit for RapJ enzyme. Notably, experimental validation is crucial to confirm the effectiveness of the selected ligands.

Gamma-Aminobutyric Acid (GABA) Biosynthesis from Lactobacillus plantarum subsp. plantarum IBRC10817 Optimized and Modeled in Response to Heat and Ultrasonic Shock.

Gamma-aminobutyric acid is one of the major inhibitory neurotransmitters in the nervous system. Although gamma-aminobutyric acid is commonly synthesized by chemical methods, its microbial biosynthesis is regarded as one of the best production methods among the conventional techniques. This study aimed to optimize and model the production of gamma-aminobutyric acid from Lactobacillus plantarum subsp. plantarum IBRC (10,817) under the influence of heat and ultrasonic shock using the response surface methodology. Heat and ultrasonic shock were applied in the lag phase of bacterial growth. Heat shock variables included heat treatment, monosodium glutamate concentration, and incubation time. Also, ultrasonic shock variables were ultrasonic intensity, ultrasonic time, incubation time, and monosodium glutamate concentration. By applying the 30.9 h of incubation, 3.082 g/L of monosodium glutamate, and thermal shock of 49.958 °C for 30 min, the production of 295.04 mg/L of gamma amino butyric acid was predicted. As for ultrasonic shock, using 3.28 (g/L) monosodium glutamate, 70 h of bacterial incubation, 7.7 min ultrasound shock, and ultrasound frequency of 26.58 kHz, the highest amount of metabolite production was anticipated to be 215.19 mg/L. Overall, it was found that the actual values were consistent with the predicted values.

Finding and engineering the newly found bacterial superoxide dismutase enzyme to increase its thermostability and decrease the immunogenicity: a computational and experimental research.

Superoxide dismutase (SOD) is one of the most important antioxidant enzymes that can reduce oxidative stress in the cell environment. Nowadays, bacterial sources of enzyme are commercially applicable in the cosmetics and pharmaceutical industries, but the allergenic effect of proteins from non-human sources has been mentioned as disadvantage of these kinds of enzymes. In this study, to find the suitable bacterial SOD candidate for decreasing immunogenicity, the sequences of five thermophilic bacteria were selected as reference species. Then, linear and conformational B-cell epitopes of the SOD were analyzed by different servers. The stability and immunogenicity of mutant positions were also evaluated. The mutant gene was inserted into the pET-23a expression vector and transformed into E. Coli BL21 (DE3) for expression of the recombinant enzyme. Afterward, the expression of the mutant enzyme was evaluated by SDS-PAGE analysis and the recombinant enzyme activity was assessed. Anoxybacillus gonensis was selected as a reasonable SOD source according to BLAST search, physicochemical properties analysis, and prediction of allergenic features. Regarding our results, five residues including E84, E142, K144, G147, and M148 were predicted as candidates for mutagenesis. Finally, the K144A was chosen as the final modification due to the increase in the stability of the enzyme and decreased immunogenicity of the enzyme as well. The enzyme activity was 240 U/ml at room temperature. Alternation in K144 to alanine caused increased stability of the enzyme. In silico studies confirmed non-antigenic protein after mutation.

The Effect of Ophthalmic and Systemic Formulations of Latilactobacillus sakei on Clinical and Immunological Outcomes of Patients With Dry Eye Disease: A Factorial, Randomized, Placebo-controlled, and Triple-masking Clinical Trial.

Dry eye disease (DED) is one of the most prevalent eye diseases. This study aimed to evaluate the efficacy and safety of Latilactobacillus sakei (L. sakei) either as an ophthalmic bacterial lysate (drops, no live organism) or as an oral probiotic (capsules) on immunological and clinical outcomes of patients with DED. This study was a randomized, placebo-controlled, triple-masking clinical trial with four parallel arms. Patients were randomly assigned in a 2x2 factorial design combining active vs placebo capsules and active vs placebo eye drops in a 1:1x1:1 ratio. The ophthalmic drops are approved for use in the European Union as a medical device (CE registration code 0425-MED-004235). A total of 40 patients were evaluated. DED signs and symptoms decreased significantly by using active drops compared to placebo, as measured by the Ocular Surface Disease Index (OSDI), Tear Break-up Time (TBUT), and Schirmer I tests (all p<0.0001). Conversely, neither active capsules nor their interaction effect with active drops achieved significance vs placebo. There was also a significant decrease in the tear levels of IL-6 (p=0.0007), TNFα (p<0.0001), and IFNγ (p<0.0001) in patients receiving active drops. Intake of both active products (drops and capsules) was well tolerated. Postbiotic ophthalmic formulation containing L. sakei lysate significantly improved the signs and symptoms of DED and suppressed ocular surface inflammatory response. Conversely, oral intake of L.sakei as a probiotic capsule had no effect in these patients (ClinicalTrials.gov: NCT04938908).

Everolimus and temsirolimus are not the same second-line in metastatic renal cell carcinoma: a systematic review and meta-analysis.

OBJECTIVE: Renal cell carcinoma (RCC) is the most common type of kidney cancer. VEGF inhibitors and mTORs are the most common therapeutic options among the different classes of available treatments. In this study, the effectiveness of Everolimus was compared to Temsirolimus, and Everolimus plusLenvatinib in renal cell carcinoma patients by review of the international clinical evidence. MATERIALS AND METHODS: A systematic review was conducted and all relevant published clinical studies on the efficacy and cost-effectiveness of Everolimus, Temsirolimus, and Lenvatinib plus Everolimus were searched comprehensively in electronic databases including Pubmed, Scopus, Medline, Cochrane Library, and ISI web of science. The Q score and I2 test checked the Heterogeneity and publication bias test, respectively. Egger's test and Begg's test were used to checking publication bias. The hazard ratio (HR) of included studies and subclass analysis were estimated by fixed and random effect models. RESULTS: Out of 1816 found studies, ultimately, were included considering inclusion and exclusion criteria. None of these studies evaluated all three treatment strategies together and each study was about one strategy. Only one study was found for Everolimus plus Lenvatinib, so it was excluded from meta-analysis. Overall, data from 526 patients on Temsirolimus and 648 patients on Everolimus were included in Meta-Analysis. Accordingly, the efficacy of Everolimus and Temsirolimus was not statistically significant in assessed outcomes (PFS, TTSF, and death). However, Everlimus is superior to Temsirolimus in OS (Q = 3.61, p-value: 0.462, I2 = 0%). No heterogeneity or bias was detected. CONCLUSION: According to the results of this study, Everolimus could be related to an increase of OS versus Temsirolimus as a second line treatment of ORCC patients.

Understanding the regulation of "Don't Eat-Me" signals by inflammatory signaling pathways in the tumor microenvironment for more effective therapy.

INTRODUCTION: Receptor/ligand pair immune checkpoints are inhibitors that regulate immunity as vital "Don't Find-Me" signals to the adaptive immune system, additionally, the essential goals of anti-cancer therapy. Moreover, the immune checkpoints are involved in treatment resistance in cancer therapy. The immune checkpoints as a signal from "self" and their expression on healthy cells prevent phagocytosis. Cells (e.g., senescent and/or apoptotic cells) with low immune checkpoints, such as low CD47 and/or PD-L1, are phagocytosed, which is necessary for tissue integrity and homeostasis maintenance. In other words, cancer cells induce increased CD47 expression in the tumor microenvironment (TME), avoiding their clearance by immune cells. PD-L1 and/or CD47 expression tumors have also been employed as biomarkers to guide cure prospects. Thus, targeting innate and adaptive immune checkpoints might improve the influence of the treatments on tumor cells. However, the CD47 regulation in the TME stands intricate, so much of this process has stayed a riddle. In this line, less attention has been paid to cytokines in TME. Cytokines are significant regulators of tumor immune surveillance, and they do this by controlling the actions of the immune cell. Recently, it has been suggested that different types of cytokines at TME might cooperate with others that contribute to the regulation of CD47 and/or PD-L1. MATERIALS AND METHODS: The data were searched in available databases and a Web Search engine (PubMed, Scopus, and Google Scholar) using related keywords in the title, abstract, and keywords. CONCLUSION: Given the significant role of pro/anti-inflammatory signaling in the TME, we discuss the present understanding of pro/anti-inflammatory signaling implications in "Don't Eat-Me" regulation signals, particularly CD47, in the pathophysiology of cancers and come up with innovative opinions for the clinical transformation and personalized medicine.