The Effects of Thiamine Supplementation on General Health and Infertility Treatment Outcomes in Women with Polycystic Ovary Syndrome: A Triple-Blinded Randomized Placebo-Controlled Clinical Trial.

BACKGROUND: The aim of this study was to evaluate the effects of thiamine (vitamin B1) on general health and infertility treatment outcomes in women with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: The study is a triple-blinded, randomized, placebo-controlled clinical trial performed on 64 infertile women with PCOS referred to Sarem Hospital in Tehran, Iran. The primary outcomes of the study were general health and infertility treatment outcomes. Eligible women were randomly assigned to the vitamin B1 group (n=32, vitamin B1 tablet at a dose of 300 mg/day for 4 weeks) or the placebo group (n=32, placebo tablet daily for 4 weeks). A general health questionnaire was completed before and after the intervention by both groups, and treatment success was evaluated at the end of the study. Data were analyzed using SPSS software ver.16 P<0.05 was considered statistically significant. RESULTS: The mean age of participants in the vitamin B1 (VB1) group was 30.4 ± 3.27 years and in the placebo (Pl) group was 29.1 ± 2.66 years with the mean duration of marriage 12.7 ± 3.01 and 13.2 ± 2.97 years respectively. Our results showed that there were significant differences between the two groups in overall score (P<0.001) and scores for all domains of the general health questionnaire including somatic symptoms (P<0.001), anxiety and insomnia (P<0.001), social dysfunction (P=0.028), and severe depression (P<0.001) after the intervention. Four weeks consumption of vitamin B1 also resulted in higher numbers of positive pregnancy tests (P=0.006), although the number of fetuses was not significantly different between the two groups after the intervention. CONCLUSION: The results of the current study support a possible favourable effect of vitamin B1 on improving general health, infertility treatment outcome, and retrieved follicle count without changing the number of fetuses in women with polycystic ovary syndrome (registration number: IRCT201510266917N3).

Low-Dose Interleukin-2 Therapy: Fine-tuning Treg in Solid Organ Transplantation?

Regulatory T cells (Treg), a subset of CD4+ T cells, are potent regulators of immune reactions, which have been shown to be a promising therapeutic alternative to toxic immunosuppressive drugs. Data support the utility of Treg in managing immunopathologies, including solid organ transplant rejection, graft-versus-host disease, and autoimmune disorders. Notably, reports suggest that interleukin-2 (IL-2) is critical to survival of Treg, which constitutively express high levels of CD25, that is, the IL-2 receptor α-chain, and are exquisitely sensitive to IL-2, even at very low concentrations in contrast to effector T cells, which only upregulate IL-2 receptor α-chain on activation. This has led to the notion of using low doses of exogenous IL-2 therapeutically to modulate the immune system, specifically Treg numbers and function. Here, we summarize developments of clinical experience with low-dose IL-2 (LD-IL-2) as a therapeutic agent. So far, no clinical data are available to support the therapeutic use of LD-IL-2 therapy in the solid organ transplant setting. For the latter, fine-tuning by biotechnological approaches may be needed because of the narrow therapeutic window and off-target effects of LD-IL-2 therapy and so to realize the therapeutic potential of this molecule.

Investigating the relationship between menopausal women's health anxiety and sexual performance and attitude towards menopause.

BACKGROUND: Menopause is a natural event in the life of women. Women's concerns during menopause and the role of health anxiety in the attitude and sexual performance of women during this period affect the quality of life. Therefore, the present study was conducted with the aim of determining the relationship between health anxiety and sexual performance and attitude towards menopause in postmenopausal women. MATERIALS AND METHODS: The present study was a cross-sectional study of communication type that was conducted on 200 postmenopausal women with records in Sabzevar Comprehensive Health Centers in 2021-2022. In order to collect information, standard questionnaires of health anxiety, attitude towards menopause, and sexual performance were used. The collected data were analyzed by SPSS version 16 software and descriptive and analytical statistical tests (Spearman). A significance level of less than 0.05 was considered. RESULT: The results of data analysis showed that health anxiety has a significant relationship with the dimensions of desire (p = 0.045 and r = -0.142) and sexual pain (p < 0.001 and r = 0.274). Also, there was a significant relationship between the attitude towards menopause with sexual performance (p < 0.001 and r = 0.244) and health anxiety with the attitude towards menopause (p < 0.001 and r = 0.27). CONCLUSION: The results of this study showed that there is an inverse relationship between health anxiety and sexual desire and a significant direct relationship with sexual pain. Also, the attitude towards menopause has a significant direct relationship with sexual behavior and health anxiety. Therefore, it is suggested to pay attention to the mental health of postmenopausal women along with the physical aspect and to pay attention to educational programs to improve the care and health programs of these women.

Sexual and reproductive health aspects in women with polycystic ovary syndrome: An integrative review.

Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women worldwide, affecting their sexual and reproductive health (SRH). Objective: This integrative review aimed to identify SRH aspects in women with PCOS by consolidating the findings from previous studies. Materials and Methods: The present integrative review was conducted through an electronic systematic review search of 1052 manuscripts published from April 2000 to March 2020 using PubMed, SCOPUS, Web of Science, Embase, Google Scholar, MEDLINE, Science Direct, Ovid, and the Cochrane Library. After at least 2 researchers evaluated the articles based on the inclusion and exclusion criteria, 27 papers were accepted. The data were analyzed by thematic analysis. Results: 9 main themes of SRH were obtained: 1) the impact of PCOS-related complications on reproductive health; 2) the lifelong effect of PCOS on reproductive patterns; 3) PCOS and adverse reproductive and pregnancy outcomes; 4) women's need for understanding complications; 5) the financial burden of the disease; 6) women's life experiences and quality of life; 7) sexual disorders; 8) psychological concerns and issues; and 9) femininity feelings and roles. Conclusion: We were able to identify and categorize various aspects of SRH needs for women with PCOS. These categories can facilitate a more comprehensive assessment of SRH, including previously neglected areas. We suggest that these aspects should be considered in the health plans of women with PCOS.

In vitro and in vivo evidence that the switch from calcineurin to mTOR inhibitors may be a strategy for immunosuppression in Epstein-Barr virus-associated post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder is a life-threatening complication of immunosuppression following transplantation mediated by failure of T cells to control Epstein-Barr virus (EBV)-infected and transformed B cells. Typically, a modification or reduction of immunosuppression is recommended, but insufficiently defined thus far. In order to help delineate this, we characterized EBV-antigen-specific T cells and lymphoblastoid cell lines from healthy donors and in patients with a kidney transplant in the absence or presence of the standard immunosuppressants tacrolimus, cyclosporin A, prednisolone, rapamycin, and mycophenolic acid. Phenotypes of lymphoblastoid cell-lines and T cells, T cell-receptor-repertoire diversity, and T-cell reactivity upon co-culture with autologous lymphoblastoid cell lines were analyzed. Rapamycin and mycophenolic acid inhibited lymphoblastoid cell-line proliferation. T cells treated with prednisolone and rapamycin showed nearly normal cytokine production. Proliferation and the viability of T cells were decreased by mycophenolic acid, while tacrolimus and cyclosporin A were strong suppressors of T-cell function including their killing activity. Overall, our study provides a basis for the clinical decision for the modification and reduction of immunosuppression and adds information to the complex balance of maintaining anti-viral immunity while preventing acute rejection. Thus, an immunosuppressive regime based on mTOR inhibition and reduced or withdrawn calcineurin inhibitors could be a promising strategy for patients with increased risk of or manifested EBV-associated post-transplant lymphoproliferative disorder.

The most effective sexual function and dysfunction interventions in individuals with multiple sclerosis: A systematic review and meta-analysis.

Background: Sexual dysfunction has many factors in multiple sclerosis, but there is no reliable treatment for this challenge. Objective: Determining effective sexual function or dysfunction interventions in individuals with multiple sclerosis. Materials and Methods: To find the relevant published interventional studies that at least had an English abstract or in Persian, we searched International Statistical Institute, PubMed, Scopus, Cochrane, Medline, PsycINFO, EMBASE, CINAHL, and Google Scholar from January 1990 to June 2021. The results were analyzed using RevMan 5.3 software. The p < 0.05 was considered significant. Results: Out of 568 articles, 41 were included after deleting the duplicate and irrelevant articles. Studies were divided into 2 groups of sexual function (n = 27) and dysfunction (n = 14). Interventions in each category have 4 subgroups: psychoeducational, exercise and rehabilitation, and medical and multi-type interventions. For improving sexual function, more than half of psychoeducational interventions showed a significant improvement after interventions (p = 0.0003). In sexual dysfunction studies, most of the interventions (n = 13/14) had improved at least one subscale of sexual dysfunction. Medical interventions were effective on men's sexual dysfunction, and psychoeducational interventions had been more effective in women's sexual dysfunction. Conclusion: Psychoeducational and medical interventions are the commonest effective interventions. The psychoeducational studies conducted specifically on women had a positive impact, and only 4 articles with medical interventions were specifically targeted at men, which had a positive effect.

Pharmacological interventions enhance virus-free generation of TRAC-replaced CAR T cells.

Chimeric antigen receptor (CAR) redirected T cells are potent therapeutic options against hematological malignancies. The current dominant manufacturing approach for CAR T cells depends on retroviral transduction. With the advent of gene editing, insertion of a CD19-CAR into the T cell receptor (TCR) alpha constant (TRAC) locus using adeno-associated viruses for gene transfer was demonstrated, and these CD19-CAR T cells showed improved functionality over their retrovirally transduced counterparts. However, clinical-grade production of viruses is complex and associated with extensive costs. Here, we optimized a virus-free genome-editing method for efficient CAR insertion into the TRAC locus of primary human T cells via nuclease-assisted homology-directed repair (HDR) using CRISPR-Cas and double-stranded template DNA (dsDNA). We evaluated DNA-sensor inhibition and HDR enhancement as two pharmacological interventions to improve cell viability and relative CAR knockin rates, respectively. While the toxicity of transfected dsDNA was not fully prevented, the combination of both interventions significantly increased CAR knockin rates and CAR T cell yield. Resulting TRAC-replaced CD19-CAR T cells showed antigen-specific cytotoxicity and cytokine production in vitro and slowed leukemia progression in a xenograft mouse model. Amplicon sequencing did not reveal significant indel formation at potential off-target sites with or without exposure to DNA-repair-modulating small molecules. With TRAC-integrated CAR+ T cell frequencies exceeding 50%, this study opens new perspectives to exploit pharmacological interventions to improve non-viral gene editing in T cells.

Effect of sex education on sexual function and sexual quality of life in women with endometriosis: A quasi-experimental study.

OBJECTIVE: To evaluate the effect of a sex education program on sexual function and sexual quality of life in women with endometriosis. METHODS: In a quasi-experimental study, women with endometriosis who had undergone laparoscopic surgery were assigned to an intervention group (n = 36) or a control group (n = 36). The intervention group received a sex education program consisting of two sessions a week (90 min each) for two consecutive weeks; the control group received none. Both groups were followed for 12 weeks. Sexual function and sexual quality of life were assessed on the Female Sexual Function Index (FSFI) and the Sexual Quality of life-Female (SQOL-F) questionnaire before the intervention, as well as 8 and 12 weeks after the intervention. Outcomes were analyzed using Student t test, the χ2 test, Fisher exact test, and repeated measures analysis of variance. RESULTS: The mean age of the study participants was 36.9 ± 5.7 years. The two groups did not differ significantly in terms of demographics and pre-intervention clinical characteristics. At the end of the study, sex education reduced female sexual dysfunction by 58.1% in the intervention group. The mean FSFI score increased significantly in the intervention group from pre-intervention to 8 and 12 weeks post-intervention compared with the scores in the control group (P < 0.001). CONCLUSIONS: Sex education appears to be a promising intervention for reducing sexual dysfunction and improving sexual function and sexual quality of life in women with endometriosis. Future studies should encompass longer periods of follow up to obtain further data on the efficacy of sex education in this setting.

Tacrolimus-resistant SARS-CoV-2-specific T cell products to prevent and treat severe COVID-19 in immunosuppressed patients.

Solid organ transplant (SOT) recipients receive therapeutic immunosuppression that compromises their immune response to infections and vaccines. For this reason, SOT patients have a high risk of developing severe coronavirus disease 2019 (COVID-19) and an increased risk of death from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Moreover, the efficiency of immunotherapies and vaccines is reduced due to the constant immunosuppression in this patient group. Here, we propose adoptive transfer of SARS-CoV-2-specific T cells made resistant to a common immunosuppressant, tacrolimus, for optimized performance in the immunosuppressed patient. Using a ribonucleoprotein approach of CRISPR-Cas9 technology, we have generated tacrolimus-resistant SARS-CoV-2-specific T cell products from convalescent donors and demonstrate their specificity and function through characterizations at the single-cell level, including flow cytometry, single-cell RNA (scRNA) Cellular Indexing of Transcriptomes and Epitopes (CITE), and T cell receptor (TCR) sequencing analyses. Based on the promising results, we aim for clinical validation of this approach in transplant recipients. Additionally, we propose a combinatory approach with tacrolimus, to prevent an overshooting immune response manifested as bystander T cell activation in the setting of severe COVID-19 immunopathology, and tacrolimus-resistant SARS-CoV-2-specific T cell products, allowing for efficient clearance of viral infection. Our strategy has the potential to prevent severe COVID-19 courses in SOT or autoimmunity settings and to prevent immunopathology while providing viral clearance in severe non-transplant COVID-19 cases.

Preparing for CAR T cell therapy: patient selection, bridging therapies and lymphodepletion.

Chimeric antigen receptor (CAR) T cells have emerged as a potent therapeutic approach for patients with certain haematological cancers, with multiple CAR T cell products currently approved by the FDA for those with relapsed and/or refractory B cell malignancies. However, in order to derive the desired level of effectiveness, patients need to successfully receive the CAR T cell infusion in a timely fashion. This process entails apheresis of the patient's T cells, followed by CAR T cell manufacture. While awaiting infusion at an authorized treatment centre, patients may receive interim disease-directed therapy. Most patients will also receive a course of pre-CAR T cell lymphodepletion, which has emerged as an important factor in enabling durable responses. The time between apheresis and CAR T cell infusion is often not a simple journey, with each milestone being a critical step that can have important downstream consequences for the ability to receive the infusion and the strength of clinical responses. In this Review, we provide a summary of the many considerations for preparing patients with B cell non-Hodgkin lymphoma or acute lymphoblastic leukaemia for CAR T cell therapy, and outline current limitations and areas for future research.

Advanced Therapy Medicinal Products' Translation in Europe: A Developers' Perspective.

Advanced Therapy Medicinal Products (ATMPs) comprising cell, gene, and tissue-engineered therapies have demonstrated enormous therapeutic benefits. However, their development is complex to be managed efficiently within currently existing regulatory frameworks. Legislation and regulation requirements for ATMPs must strike a balance between the patient safety while promoting innovations to optimize exploitation of these novel therapeutics. This paradox highlights the importance of on-going dynamic dialogue between all stakeholders and regulatory science to facilitate the development of pragmatic ATMP regulatory guidelines.

Clinical adoptive regulatory T Cell therapy: State of the art, challenges, and prospective.

Rejection of solid organ transplant and graft versus host disease (GvHD) continue to be challenging in post transplantation management. The introduction of calcineurin inhibitors dramatically improved recipients' short-term prognosis. However, long-term clinical outlook remains poor, moreover, the lifelong dependency on these toxic drugs leads to chronic deterioration of graft function, in particular the renal function, infections and de-novo malignancies. These observations led investigators to identify alternative therapeutic options to promote long-term graft survival, which could be used concomitantly, but preferably, replace pharmacologic immunosuppression as standard of care. Adoptive T cell (ATC) therapy has evolved as one of the most promising approaches in regenerative medicine in the recent years. A range of cell types with disparate immunoregulatory and regenerative properties are actively being investigated as potential therapeutic agents for specific transplant rejection, autoimmunity or injury-related indications. A significant body of data from preclinical models pointed to efficacy of cellular therapies. Significantly, early clinical trial observations have confirmed safety and tolerability, and yielded promising data in support of efficacy of the cellular therapeutics. The first class of these therapeutic agents commonly referred to as advanced therapy medicinal products have been approved and are now available for clinical use. Specifically, clinical trials have supported the utility of CD4+CD25+FOXP3+ regulatory T cells (Tregs) to minimize unwanted or overshooting immune responses and reduce the level of pharmacological immunosuppression in transplant recipients. Tregs are recognized as the principal orchestrators of maintaining peripheral tolerance, thereby blocking excessive immune responses and prevent autoimmunity. Here, we summarize rationale for the adoptive Treg therapy, challenges in manufacturing and clinical experiences with this novel living drug and outline future perspectives of its use in transplantation.

Development and validation of a guideline on sexual and reproductive health services for polycystic ovary syndrome in Iran: a mixed-methods study protocol.

BACKGROUND: Sexual and reproductive health (SRH) is an important aspect of women's health. Polycystic ovary syndrome is a common disease among women and has long-term negative effects on women's health. Evidence shows that polycystic ovary syndrome has different impacts on SRH needs among women. The aim of this study is to design and validate an SRH services guideline for healthcare providers in treating women with polycystic ovary syndrome. METHODS: The guideline will be developed and validated using an exploratory sequential mixed-methods approach in three phases based on the National Institute for Health and Care Excellence (NICE) model: (1) scoping phase (describing the SRH needs of women with polycystic ovary syndrome from the results of both review and qualitative studies); (2) development phase (developing a primary guideline for SRH services); (3) validation phase (validation of the guideline will be performed by a panel of experts and stakeholders using the AGREE [Appraisal of Guidelines for Research and Evaluation] tool). DISCUSSION: A specific and practical guideline on the SRH of Iranian women with polycystic ovary syndrome will be developed, which will be compatible with their specific needs and culture, considering the limited resources available. It will help service providers identify and address the specific needs of women with polycystic ovary syndrome.

Strong Expansion of Human Regulatory T Cells for Adoptive Cell Therapy Results in Epigenetic Changes Which May Impact Their Survival and Function.

Adoptive transfer of regulatory T cells (Treg) is a promising new therapeutic option to treat detrimental inflammatory conditions after transplantation and during autoimmune disease. To reach sufficient cell yield for treatment, ex vivo isolated autologous or allogenic Tregs need to be expanded extensively in vitro during manufacturing of the Treg product. However, repetitive cycles of restimulation and prolonged culture have been shown to impact T cell phenotypes, functionality and fitness. It is therefore critical to scrutinize the molecular changes which occur during T cell product generation, and reexamine current manufacturing practices. We performed genome-wide DNA methylation profiling of cells throughout the manufacturing process of a polyclonal Treg product that has proven safety and hints of therapeutic efficacy in kidney transplant patients. We found progressive DNA methylation changes over the duration of culture, which were donor-independent and reproducible between manufacturing runs. Differentially methylated regions (DMRs) in the final products were significantly enriched at promoters and enhancers of genes implicated in T cell activation. Additionally, significant hypomethylation did also occur in promoters of genes implicated in functional exhaustion in conventional T cells, some of which, however, have been reported to strengthen immunosuppressive effector function in Tregs. At the same time, a set of reported Treg-specific demethylated regions increased methylation levels with culture, indicating a possible destabilization of Treg identity during manufacturing, which was independent of the purity of the starting material. Together, our results indicate that the repetitive TCR-mediated stimulation lead to epigenetic changes that might impact functionality of Treg products in multiple ways, by possibly shifting to an effector Treg phenotype with enhanced functional activity or by risking destabilization of Treg identity and impaired TCR activation. Our analyses also illustrate the value of epigenetic profiling for the evaluation of T cell product manufacturing pipelines, which might open new avenues for the improvement of current adoptive Treg therapies with relevance for conventional effector T cell products.

Yoga Effects on Anthropometric Indices and Polycystic Ovary Syndrome Symptoms in Women Undergoing Infertility Treatment: A Randomized Controlled Clinical Trial.

The aim of this study was to investigate the effects of yoga exercises on anthropometric parameter and clinical sign of PCOS among women undergoing infertility treatment. This clinical trial study was performed on 61 women with PCOS who have undergone infertility treatment at Sarem Hospital in Tehran, Iran. The patients were first selecting based on purposeful and then randomly assigning to the intervention and control groups. In the intervention group, yoga exercises were performed for 6 weeks and the patients in the control group only received routine care. Anthropometric parameters and clinical signs were performed and recorded. After the intervention, here was a significant reduction in hirsutism, abdominal circumference, and hip circumference scores in the intervention group compared to the control group (P < 0.05). Given the effects of yoga exercises on the improvement of hirsutism, abdominal circumference, and hip circumference, it is suggested to use yoga as a treatment strategy in women with PCOS.

The Effect of Combined Vitamin C and Vitamin E Supplementation on Oxidative Stress Markers in Women with Endometriosis: A Randomized, Triple-Blind Placebo-Controlled Clinical Trial.

Background: Endometriosis is a chronic and estrogen-dependent pelvic inflammatory disease, which may have various causes, such as oxidative stress. Dysmenorrhea, dyspareunia, and pelvic pain are well-known symptoms of endometriosis. The present clinical trial assessed the role of supplementation with antioxidant vitamins on the indices of oxidative stress as well as the severity of pain in women with endometriosis. Materials and Methods: We enrolled 60 reproductive-aged (15-45 years) women with pelvic pain in this triple-blind clinical trial. They had 1-3 stages of laparoscopic-proven endometriosis. The participants were randomized to group A (n = 30), given vitamin C (1000 mg/day, 2 tablets of 500 mg each) and vitamin E (800 IU/day, 2 tablets of 400 IU each) combination, or group B (n = 30), given placebo pills daily for 8 weeks. Results: Following treatment with vitamin C and vitamin E, we found a significant reduction in MDA and ROS compared with the placebo group. There was no significant decline in total antioxidant capacity after treatment. However, the severity of pelvic pain (p value <0.001), dysmenorrhea (p value <0.001), and dyspareunia (p value <0.001) significantly decreased in the treatment group after 8 weeks of supplementation. Conclusions: The present findings support the potential role of antioxidants in the management of endometriosis. The intake of vitamin C and vitamin E supplements effectively reduced dysmenorrhea severity and improved dyspareunia and severity of pelvic pain.

Functional Surfactants for Molecular Fishing, Capsule Creation, and Single-Cell Gene Expression.

Creating a single surfactant that is open to manipulation, while maintaining its surface activity, robustness, and compatibility, to expand the landscape of surfactant-dependent assays is extremely challenging. We report an oxidation-responsive precursor with thioethers and multiple 1,2-diols for creating a variety of functional surfactants from one parent surfactant. Using these multifunctional surfactants, we stabilize microfluidics-generated aqueous droplets. The droplets encapsulate different components and immerse in a bioinert oil with distinct interfaces where an azide-bearing surfactant allow fishing of biomolecules from the droplets, aldehyde-bearing surfactant allow fabrication of microcapsules, and hydroxyl-bearing surfactants, with/without oxidized thioethers, allow monitoring of single-cell gene expression. Creating multifunctional surfactants poses opportunities for broad applications, including adsorption, bioanalytics, catalysis, formulations, coatings, and programmable subset of emulsions.

The intratumoral CXCR3 chemokine system is predictive of chemotherapy response in human bladder cancer.

Chemotherapy has direct toxic effects on cancer cells; however, long-term cancer control and complete remission are likely to involve CD8+ T cell immune responses. To study the role of CD8+ T cell infiltration in the success of chemotherapy, we examined patients with muscle invasive bladder cancer (MIBC) who were categorized on the basis of the response to neoadjuvant chemotherapy (NAC). We identified the intratumoral CXCR3 chemokine system (ligands and receptor splice variants) as a critical component for tumor eradication upon NAC in MIBC. Through characterization of CD8+ T cells, we found that stem-like T cell subpopulations with abundant CXCR3alt, a variant form of the CXCL11 receptor, responded to CXCL11 in culture as demonstrated by migration and enhanced effector function. In tumor biopsies of patients with MIBC accessed before treatment, CXCL11 abundance correlated with high numbers of tumor-infiltrating T cells and response to NAC. The presence of CXCR3alt and CXCL11 was associated with improved overall survival in MIBC. Evaluation of both CXCR3alt and CXCL11 enabled discrimination between responder and nonresponder patients with MIBC before treatment. We validated the prognostic role of the CXCR3-CXCL11 chemokine system in an independent cohort of chemotherapy-treated and chemotherapy-naïve patients with MIBC from data in TCGA. In summary, our data revealed stimulatory activity of the CXCR3alt-CXCL11 chemokine system on CD8+ T cells that is predictive of chemotherapy responsiveness in MIBC. This may offer immunotherapeutic options for targeted activation of intratumoral stem-like T cells in solid tumors.

Effects of Placenta Location in Pregnancy Outcomes of Placenta Accreta Spectrum (PAS): A Retrospective Cohort Study.

Objective: Placenta Accreta Spectrum (PAS) affects approximately one in a thousand deliveries. Very few studies evaluated PAS risk factors based on their location. In this study, we have investigated the effects of placenta location on placental adhesion-related complications, its risk factors, and outcomes. Materials and methods: We performed a retrospective cohort study of pathology-confirmed cases of PAS from patients with peripartum hysterectomy, at a large educational hospital in Qazvin, Iran, from 2009 to 2019. Placenta location was found by ultrasound reports and intraoperative evaluation. We measured demographic features, basic characteristics, maternal and neonatal outcomes based on placental location including anterior, posterior, and lateral in Placenta Accreta Spectrum. Chi-square, t-test, and one-way ANOVA were used to examine the relation of complications, risk factors, and outcomes in PAS. Results: A review of 70 cases showed the distribution of placenta location as follows: 57% anterior, 27% posterior, and 16% lateral. The mean gestational age at delivery was 35 (33-39) weeks. In 78.6% (n=55) of the patients, an association with placenta previa and in 94/2% (n=66) of cases a history of cesarean section was found, however, it was not significantly correlated with placenta location (p=0.082). We found that surgery duration was significantly longer in patients with lateral PAS (155±38, vs 129.35±33.8 and 133.15±31.5 for anterior and posterior placenta respectively, p=0.09). Patients with lateral PAS also bled more than the remaining two groups (2836 ml for lateral PAS vs 2002 and 1847 for anterior and posterior placenta respectively, p=0.022). Moreover, women with a history of uterine surgery were more likely to have posterior PAS compared to those with anterior and lateral PAS (p=0.035). Conclusion: Differences in complications, risk factors, and outcomes of PAS based on placenta location may lead to improved diagnosis and decreased morbidity in women.

CRISPR-Cas9-Edited Tacrolimus-Resistant Antiviral T Cells for Advanced Adoptive Immunotherapy in Transplant Recipients.

Viral infections, such as with cytomegalovirus (CMV), remain a major risk factor for mortality and morbidity of transplant recipients because of their requirement for lifelong immunosuppression (IS). Antiviral drugs often cause toxicity and sometimes fail to control disease. Thus, regeneration of the antiviral immune response by adoptive antiviral T cell therapy is an attractive alternative. Our recent data, however, show only short-term efficacy in some solid organ recipients, possibly because of malfunction in transferred T cells caused by ongoing IS. We developed a vector-free clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-based good manufacturing practice (GMP)-compliant protocol that efficiently targets and knocks out the gene for the adaptor protein FK506-binding protein 12 (FKBP12), required for the immunosuppressive function of tacrolimus. This was achieved by transient delivery of ribonucleoprotein complexes into CMV-specific T cells by electroporation. We confirmed the tacrolimus resistance of our gene-edited T cell products in vitro and demonstrated performance comparable with non-tacrolimus-treated unmodified T cells. The alternative calcineurin inhibitor cyclosporine A can be administered as a safety switch to shut down tacrolimus-resistant T cell activity in case of adverse effects. Furthermore, we performed safety assessments as a prerequisite for translation to first-in-human applications.