Signaling crosstalk between mesenchymal stem cells and tumor cells: Implications for tumor suppression or progression.

Mesenchymal stem cells (MSCs) have been extensively used in various therapeutic applications over the last two decades, particularly in regenerative medicine and cancer treatment. MSCs have the ability to differentiate into mesodermal and non-mesodermal lineages, which makes them a popular choice in tissue engineering and regenerative medicine. Studies have shown that MSCs have inherent tumor-suppressive properties and can affect the behavior of multiple cells contributing to tumor development. Additionally, MSCs possess a tumor tropism property and have a hypoimmune nature. The intrinsic features of MSCs along with their potential to undergo genetic manipulation and be loaded with various anticancer therapeutics have motivated researchers to use them in different cancer therapy approaches without considering their complex dynamic biological aspects. However, despite their desirable features, several reports have shown that MSCs possess tumor-supportive properties. These contradictory results signify the sophisticated nature of MSCs and warn against the potential therapeutic applications of MSCs. Therefore, researchers should meticulously consider the biological properties of MSCs in preclinical and clinical studies to avoid any undesirable outcomes. This manuscript reviews preclinical studies on MSCs and cancer from the last two decades, discusses how MSC properties affect tumor progression and explains the mechanisms behind tumor suppressive and supportive functions. It also highlights critical cellular pathways that could be targeted in future studies to improve the safety and effectiveness of MSC-based therapies for cancer treatment. The insights obtained from this study will pave the way for further clinical research on MSCs and development of more effective cancer treatments.

Spinoculation and retronectin highly enhance the gene transduction efficiency of Mucin-1-specific chimeric antigen receptor (CAR) in human primary T cells.

BACKGROUND: Producing an appropriate number of engineered cells is considered as one of the influential factors in the successful treatments with chimeric antigen receptor (CAR) T cells. To this aim, the transduction rate of the viral vectors can play a significant role. In addition, improving transduction rates can affect the success rate of this treatment due to hard-transduced T lymphocytes. RESULTS: In this study, activated T cells were transduced using different transduction methods such as spinoculation, retronectin, polybrene, spinoculation + retronectin, and spinoculation + polybrene after selecting the most efficient transfection method to produce recombinant viral particles containing MUC1 CAR. PEI and lipofectamine with the amount of 73.72 and 72.53%, respectively, showed the highest transfection rates with respect to calcium phosphate (14.13%) for producing lentiviral particles. However, the cytotoxicity of transfection methods was not significantly different. Based on the results, spinoculation + retronectin leads to the highest transduction rates of T cells (63.19 ± 4.45%) relative to spinoculation + polybrene (34.6 ± 4.44%), polybrene (10.23 ± 0.79%), retronectin (10.37 ± 1.85%), and spinoculation (21.11 ± 1.55%). Further, the polybrene (40.02%) and spinoculation + polybrene (48.83% ± 4.83) increased cytotoxicity significantly compared to other groups. CONCLUSION: Improving transduction conditions such as using spinoculation with retronectin can ameliorate the production of CAR-T cells by increasing the rate of transduction, as well as the success rate of treatment.

The Role of MicroRNAs in the Induction of Pancreatic Differentiation.

Stem cell-based therapy is one of the therapeutic options with promising results in the treatment of diabetes. Stem cells from various sources are expanded and induced to generate the cells capable of secreting insulin. These insulin-producing cells [IPCs] could be used as an alternative to islets in the treatment of patients with diabetes. Soluble growth factors, small molecules, geneencoding transcription factors, and microRNAs [miRNAs] are commonly used for the induction of stem cell differentiation. MiRNAs are small non-coding RNAs with 21-23 nucleotides that are involved in the regulation of gene expression by targeting multiple mRNA targets. Studies have shown the dynamic expression of miRNAs during pancreatic development and stem cell differentiation. MiR- 7 and miR-375 are the most abundant miRNAs in pancreatic islet cells and play key roles in pancreatic development as well as islet cell functions. Some studies have tried to use these small RNAs for the induction of pancreatic differentiation. This review focuses on the miRNAs used in the induction of stem cells into IPCs and discusses their functions in pancreatic ß-cells.

A VHH-Based Anti-MUC1 Chimeric Antigen Receptor for Specific Retargeting of Human Primary T Cells to MUC1-Positive Cancer Cells.

OBJECTIVE: Immunotherapy with redirected T cells that express a chimeric antigen receptor (CAR) is a promising prospect in cancer treatment. Most CARs use murine-derived single-chain variable fragments (scFvs) as an antigen targeting moiety, which may lead to host immunogenic responses and engineered T cell disappearance. It seems that development of less immunogenic CARs, such as CARs composed of the camelid variable domain of heavy chain antibodies (VHHs) may likely overcome this obstacle. Here, we improved the expression of the VHH-based anti-MUC1 CAR gene construct using a third generation lentiviral vector in primary human T cells and assessed its effect on antigen specific targeting, activation and cytotoxicity of redirected human T cells. MATERIALS AND METHODS: In this experimental study, we established a second generation novel CAR (VHH-based anti- MUC1 CAR) that contained a camelid-derived anti-MUC1 VHH followed by an IgG3 hinge, a CD28 transmembrane domain and signalling endodomains of CD28 and CD3ζ. Next, we constructed lentiviral vectors that contained this CAR gene construct using an optimized transiently virus production method and transduced it into human T cells. Cell surface expression of CAR, cytokine secretion and cytotoxic activity were assessed in the transduced CD3+ T cells. RESULTS: The transduced T cells had high levels of surface expression of CAR. T cells that expressed anti-MUC1 CAR showed significantly increased secretion of Th1 cytokines, including IL-2, TNF alpha and IFN-γ, as well as cytotoxic activity upon recognition of MUC1 on tumour cells after co-incubation with T47D or MCF-7 (MUC1-positive) compared with A431 (MUC1-negative) or untransduced T cells. CONCLUSION: Our results suggested that, given the unique properties of VHHs to prevent immunogenic responses and tonic signalling, our novel VHH-based anti-MUC1 CAR might be effective for clinical purposes in cancer immunotherapy.

Fibrin Scaffold Incorporating Platelet Lysate Enhance Follicle Survival and Angiogenesis in Cryopreserved Preantral Follicle Transplantation.

BACKGROUND: Transplantation of cryopreserved follicles can be regarded as a promising strategy for preserving fertility in cancer patients under chemotherapy and radiotherapy by reducing the risk of cancer recurrence. The present study aimed to evaluate whether fibrin hydrogel supplemented with platelet lysate (PL) could be applied to enhance follicular survival, growth, and angiogenesis in cryopreserved preantral follicle grafts. MATERIALS AND METHODS: Preantral follicles were extracted from 15 four-week-old NMRI mice, cryopreserved by cryotop method, and encapsulated in fibrin-platelet lysate for subsequent heterotopic (subcutaneous) auto-transplantation into the neck. Transplants were assessed in three groups including fresh follicles in fibrin-15%PL, cryopreserved follicles in fibrin-15%PL, and cryopreserved follicles in fibrin-0% PL. Two weeks after transplantation, histological, and immunohistochemistry (CD31) analysis were applied to evaluate follicle morphology, survival rate, and vascular formation, respectively. RESULTS: Based on the results, fibrin-15% PL significantly increased neovascularization and survival rate (SR) both in cryopreserved (SR=66.96%) and fresh follicle (SR=90.8%) grafts, compared to PL-less fibrin cryopreserved transplants (SR=28.46%). The grafts supplemented with PL included a significantly higher percentage of preantral and antral follicles. Also, no significant difference was observed in the percentage of preantral follicles between cryopreserved and fresh grafts of fibrin-15% PL. However, a significantly lower (P=0.03) percentage of follicles (23.37%) increased to the antral stage in cryopreserved grafts of fibrin-15%PL, compared to fresh grafts (35.01%). CONCLUSION: The findings demonstrated that fibrin-PL matrix could be a promising strategy to improve cryopreserved follicle transplantation and preserve fertility in cancer patients at the risk of ovarian failure.

Production of CAR T-cells by GMP-grade lentiviral vectors: latest advances and future prospects.

Chimeric antigen receptor (CAR) T-cells represent a paradigm shift in cancer immunotherapy and a new milestone in the history of oncology. In 2017, the Food and Drug Administration approved two CD19-targeted CAR T-cell therapies (Kymriah™, Novartis, and Yescarta™, Kite Pharma/Gilead Sciences) that have remarkable efficacy in some B-cell malignancies. The CAR approach is currently being evaluated in multiple pivotal trials designed for the immunotherapy of hematological malignancies as well as solid tumors. To generate CAR T-cells ex vivo, lentiviral vectors (LVs) are particularly appealing due to their ability to stably integrate relatively large DNA inserts, and to efficiently transduce both dividing and nondividing cells. This review discusses the latest advances and challenges in the design and production of CAR T-cells, and the good manufacturing practices (GMP)-grade production process of LVs used as a gene transfer vehicle. New developments in the application of CAR T-cell therapy are also outlined with particular emphasis on next-generation allogeneic CAR T-cells.

Knee sonography as a diagnostic test for medial meniscal tears in young patients.

PURPOSE: To prospectively evaluate whether age of patient affects diagnostic accuracy of sonography and magnetic resonance imaging (MRI) in the diagnosis of medial meniscal tears. METHODS: We prospectively evaluated 74 consecutive patients (54 males and 20 females), in two different groups [group A (37 patients ≤ 30 years; mean age: 23.5 ± 5 years) and group B (37 patients > 30 years; mean age: 43.5 ± 9.35 years)] with clinical suspicion of medial meniscal tear. After inclusion, patients underwent ultrasonography and then MRI for signs of tearing. The ultrasonographic and MRI findings were compared with arthroscopic findings, which served as a gold standard for accurate detection of meniscal tearing. RESULTS: The sensitivity, specificity, positive and negative predictive values and accuracy of ultrasonography in detecting medial meniscal tears in group A were 100, 88.9, 96.5, 100, 97.3% and in group B were 83.3, 71.4, 92.6, 50, 81.1%, respectively. The sensitivity, specificity, positive and negative predictive values and accuracy of MRI in group A were 100, 88.9, 96.5, 100, 97.3% and in group B were 96.7, 85.7, 96.7, 85.7, 94.6%, respectively. CONCLUSIONS: Given the fact that the sensitivity and specificity of the results of knee sonography matched that of MRI in patients who were 30 years old or less, we suggest ultrasonography as an effective initial investigation for tears of medial meniscus in this group of patients. Patients with negative ultrasonographic findings will need no further investigation. LEVEL OF EVIDENCE: Diagnostic studies-investigating a diagnostic test, Level II.

Caesarean or normal vaginal delivery: overview of physicians' self-preference and suggestion to patients.

PURPOSE: Caesarean delivery in the absence of any medical indications has become a major issue of concern among the women's health professionals. The patients' choice of caesarean is influenced by several factors predominating by their physicians' suggestion. Our objective was to examine factors that may affect the physicians' responses to patients consulting the mode of delivery. METHODS: Questionnaires were posted to 1,000 female obstetricians and gynaecologists practicing in Tehran in winter 2007. Questionnaires included demographic information of physicians and their history of pregnancy and delivery. Finally, they were asked their preferred mode of delivery and the mode they suggest when being consulted by parturient. RESULTS: From 1,000 physicians, 785 cases (78.5%) responded to the survey. The rate of responses in favour of suggesting normal vaginal delivery, Caesarean Section and painless vaginal delivery was 60.8, 25.6 and 13.6%, respectively. There was a correlation between the suggested and the preferred mode of delivery, it means that the physicians mostly suggested their self-preferred mode of delivery to their patients. CONCLUSIONS: Physicians normally suggest to their patients as the safe mode of delivery what they prefer for themselves. This preference and subsequent suggestion is influenced by different factors including their age, marital status, and previous modes of delivery. As conclusion, it is inferred that informing a physician to choose the right mode of delivery for herself leads to better suggestions to the patients.