Genomic predictions under different genetic architectures are impacted by mating designs.

Mating in animal communities must be managed in a way that assures the performance increase in the progenies without increasing the rate of inbreeding. It has currently become possible to identify millions of single nucleotide polymorphisms (SNPs), and it is feasible to select animals based on genome-wide marker profiles. This study aimed to evaluate the impact of five mating designs among individuals (random, positive and negative assortative, minimized and maximized inbreeding) on genomic prediction accuracy. The choice of these five particular mating designs provides a thorough analysis of the way genetic diversity, relatedness, inbreeding, and biological conditions influence the accuracy of genomic predictions. Utilizing a stochastic simulation technique, various marker and quantitative trait loci (QTL) densities were taken into account. The heritabilities of a simulated trait were 0.05, 0.30, and 0.60. A validation population that only had genotypic records was taken into consideration, and a reference population that had both genotypic and phenotypic records was considered for every simulation scenario. By measuring the correlation between estimated and true breeding values, the prediction accuracy was calculated. Computing the regression of true genomic breeding value on estimated genomic breeding value allowed for the examination of prediction bias. The scenario with a positive assortative mating design had the highest accuracy of genomic prediction (0.733 ± 0.003 to 0.966 ± 0.001). In a case of negative assortative mating, the genomic evaluation's accuracy was lowest (0.680 ± 0.011 to 0.899 ± 0.003). Applying the positive assortative mating design resulted in the unbiased regression coefficients of true genomic breeding value on estimated genomic breeding value. Based on the current results, it is suggested to implement positive assortative mating in genomic evaluation programs to obtain unbiased genomic predictions with greater accuracy. This study implies that animal breeding programs can improve offspring performance without compromising genetic health by carefully managing mating strategies based on genetic diversity, relatedness, and inbreeding levels. To maximize breeding results and ensure long-term genetic improvement in animal populations, this study highlights the importance of considering different mating designs when evaluating genomic information. When incorporating positive assortative mating or other mating schemes into genomic evaluation programs, it is critical to consider the complex relationship between gene interactions, environmental influences, and genetic drift to ensure the stability and effectiveness of breeding efforts. Further research and comprehensive analyzes are needed to fully understand the impact of these factors and their possible complex interactions on the accuracy of genomic prediction and to develop strategies that optimize breeding outcomes in animal populations.

Effects of routine repetitive transcranial magnetic stimulation on the sleep duration of patients with treatment-resistant depression: A prospective cohort study.

Aim: The aim of this study was to evaluate the short-term and long-term effects of routine repetitive transcranial magnetic stimulation (rTMS) on the sleep duration, depressive symptoms, and quality of life of patients with treatment-resistant depression (TRD). Methods: In this prospective cohort study, 25 participants with TRD were assessed using the Insomnia Severity Index (ISI) and four sleep duration components of the Pittsburgh Sleep Quality Index (PSQI). Depression severity was measured with Hamilton's Depression Rating Scale (HDRS) and Beck's Depression Inventory (BDI-II), and patient-perceived quality of life with the 36-Item Short-Form Survey (SF-36). All of these measures were evaluated at baseline (T0), and immediately (T1), 6 weeks (T2), and 12 weeks (T3) after the end of intervention. Results: At T1 endpoint, HDRS, BDI, SF-36, ISI, and three PSQI items (time to wake up, time taken to fall asleep, and Real Sleep Time) significantly improved, though these gains were reduced at follow-up endpoints (T2 and T3). Adjusting for confounders (age, sex, occupational status, BMI, and hypnotic medication) revealed that only improvements in HDRS, BDI, and time taken to fall asleep at T1 remained statistically significant. Linear regression analyses showed no significant association between reduced time taken to fall asleep and depression symptoms, suggesting rTMS can independently enhance this parameter, irrespective of depression resolution. Conclusion: Routine rTMS therapy can potentially enhance sleep duration in TRD individuals, alongside improved depressive symptoms and quality of life. However, these benefits tend to decrease over long-term follow-up, emphasizing a more pronounced short-term efficacy of rTMS.

Precise Engineering of Growth Factor Presentation Using Extracellular Microenvironment-Mimicking Microfluidic Microparticles.

One of the main challenges in tissue engineering is finding a way to deliver specific growth factors (GFs) with precise spatiotemporal control over their presentation. Here, we report a novel strategy for generating microscale carriers with enhanced affinity for high content loading suitable for the sustained and localized delivery of GFs. Our developed microparticles can be injected locally and sustainably release encapsulated growth factors for up to 28 days. Fine-tuning of particles' size, affinity, microstructures, and release kinetics is achieved using a microfluidic system along with bioconjugation techniques. We also describe an innovative 3D micromixer platform to control the formation of core-shell particles based on superaffinity using a polymer-peptide conjugate for further tuning of release kinetics and delayed degradation. Chitosan shells block the burst release of encapsulated GFs and enable their sustained delivery for up to 10 days. The matched release profiles and degradation provide the local tissues with biomimetic, developmental-biologic-compatible signals to maximize regenerative effects. The versatility of this approach is verified using three different therapeutic proteins, including human bone morphogenetic protein-2 (rhBMP-2), vascular endothelial growth factor (VEGF), and stromal cell-derived factor 1 (SDF-1α). As in vivo morphogenesis is typically driven by the combined action of several growth factors, the proposed technique can be developed to generate a library of GF-loaded particles with designated release profiles.

Dental-derived stem cells in tissue engineering: the role of biomaterials and host response.

Dental-derived stem cells (DSCs) are attractive cell sources due to their easy access, superior growth capacity and low immunogenicity. They can respond to multiple extracellular matrix signals, which provide biophysical and biochemical cues to regulate the fate of residing cells. However, the direct transplantation of DSCs suffers from poor proliferation and differentiation toward functional cells and low survival rates due to local inflammation. Recently, elegant advances in the design of novel biomaterials have been made to give promise to the use of biomimetic biomaterials to regulate various cell behaviors, including proliferation, differentiation and migration. Biomaterials could be tailored with multiple functionalities, e.g., stimuli-responsiveness. There is an emerging need to summarize recent advances in engineered biomaterials-mediated delivery and therapy of DSCs and their potential applications. Herein, we outlined the design of biomaterials for supporting DSCs and the host response to the transplantation.

Efficacy and safety of celecoxib for treatment of mild to moderate postpartum depression: a randomized, double-blind, placebo-controlled trial.

PURPOSE: Evidence has demonstrated the roles of inflammatory processes in pathogenesis of depression. We aim to assess the effects of adjunctive celecoxib with cognitive behavioral therapy (CBT), an anti-inflammatory agent, in treatment of postpartum depression and on levels of Brain-derived neurotrophic factor (BDNF) and inflammatory cytokines. METHODS: This was a randomized, double-blind, placebo-controlled trial to investigate the effects of adjunctive celecoxib with CBT on postpartum depression. Fifty outpatient women with postpartum depression, participated in this study. Patients randomly received either a celecoxib capsule twice a day or a placebo capsule twice a day for 6 weeks. Patients were assessed using the Hamilton Depression Rating Scale (HDRS) and the adverse event checklist at baseline and weeks 2, 4, and 6. RESULTS: Patients in the celecoxib group showed a greater decline in HDRS scores from baseline to all three study time points compared to the placebo group (p = 0.12 for week 2, p = 0.001 for week 4, p < 0.001 for week 6). Rate of response to treatment was significantly higher in the celecoxib group compared to the placebo group at week 4 (60 vs 24%, p = 0.010) and week 6 (96 vs 44%, p < 0.001). Rate of remission was significantly higher in the celecoxib group compared to the placebo group at week 4 (52 vs 20%, p = 0.018) and week 6 (96 vs 36%, p < 0.001). Levels of most inflammatory markers were significantly lower in the celecoxib group compared to the placebo group at week 6. Levels of BDNF were significantly higher in the celecoxib group compared to the placebo group at week 6 (p < 0.001). CONCLUSIONS: Findings suggest adjunctive celecoxib is an effective treatment for the improvement of postpartum depressive symptoms.

Evaluation of mechanical, optical, and fluoride-releasing properties of a translucent bulk fill glass hybrid restorative dental material.

OBJECTIVE: Measure and compare the mechanical properties, translucency, and fluoride-releasing capabilities of EQUIA Forte HT against Fuji IX GP and ChemFil Rock. MATERIALS AND METHODS: Ten specimens of each material were fabricated for compressive strength (CS), flexural strength (FS), and surface hardness analysis at 24 h and 7 days. The L*a*b* values were measured against a black-and-white background using a spectrophotometer to analyze the translucency parameter (TP). Fluoride release was recorded after 2 months of immersion in distilled water. The mean data was analyzed by 1- and 2-way ANOVA (α = 0.5). RESULTS: EQUIA Forte HT showed higher CS, surface hardness, and FS values (p < 0.05) compared with Fuji IX GIC, while no significant difference was found in FS values between EQUIA Forte HT and Chemfil Rock (p > 0.05). The EQUIA Forte HT exhibited significantly higher translucency in comparison to both ChemFil Rock (p < 0.001) and Fuji IX GICs (p < 0.05). An increase (p > 0.05) of fluoride release was observed for EQUIA Forte HT. CONCLUSION: The EQUIA Forte HT Glass-ionomer cements (GIC) offers enhanced translucency, improved strength, and enhanced fluoride-releasing properties compared to the traditionally used Fuji IX GIC and ChemFil Rock GICs. This material might have a wide range of clinical applications due to its improved strength and optical properties. CLINICAL SIGNIFICANCE: Glass-ionomer dental restorative materials possess unique advantageous characteristics. However, its poor mechanical and optical properties have typically limited its clinical applications. Efforts to improve these properties have resulted in enhanced GICs. EQUIA Forte HT GIC offers enhanced mechanical and optical properties with potential applications in posterior and anterior restorative procedures.

Efficacy and safety of celecoxib monotherapy for treatment of moderate depressive symptoms following COVID-19 infection: A randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Celecoxib, a nonsteroidal anti-inflammatory agent, was found to be an effective add-on treatment for unipolar and bipolar depression. We investigated the potential beneficial effect of celecoxib monotherapy on depressive symptoms after Coronavirus disease (COVID-19). METHODS: This was a randomized, double-blind, placebo-controlled clinical trial investigating the therapeutic effects of celecoxib monotherapy in patients with moderate depressive symptoms following COVID-19 infection. Patients were randomized to receive either a celecoxib capsule (100 mg) twice daily or a placebo capsule twice daily for 6 weeks. Participants were assessed with the Hamilton Depression Rating Scale (HDRS) and the side effect checklist at baseline and weeks 3 and 6. RESULTS: A total of 62 patients were included. GLM repeated-measures showed a significant effect of time × treatment (F = 12.95, df = 1.98, p < 0.001) for celecoxib, suggesting superior improvement of depressive symptoms in celecoxib compared to placebo from baseline to the study endpoint. HDRS scores in the celecoxib group showed a greater decline from baseline to both week 3 (t = 4.12, p < 0.001, Cohen's d = 1.10) and week 6 (t = 4.76, p < 0.001, Cohen's d = 1.27), compared to the placebo group. Rate of response to treatment (70% vs 9%, p < 0.001) and remission (67% vs 0%, p < 0.001) was significantly higher in celecoxib compared to the placebo group at week 6. Adverse event frequencies were not significantly different between the two groups. CONCLUSION: We demonstrated that treatment with celecoxib significantly improved depression scores of patients with depressive symptoms following COVID-19 infection. Further trials with larger sample sizes and longer study periods should assess our findings before any suggestion for clinical use. The trial was prospectively registered at the Iranian registry of clinical trials (www.irct.ir; registration number: IRCT20090117001556N142).

Phase 1 dose-escalation study of SEA-CD40: a non-fucosylated CD40 agonist, in advanced solid tumors and lymphomas.

BACKGROUND: SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma. METHODS: SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 µg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity. RESULTS: A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10-30 µg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma. CONCLUSIONS: SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen. TRIAL REGISTRATION NUMBER: NCT02376699.

Effect of famotidine on cognitive and behavioral dysfunctions induced in post-COVID-19 infection: A randomized, double-blind, and placebo-controlled study.

OBJECTIVES: This is an investigation of the efficacy and safety of famotidine, a selective histamine H2 receptor antagonist, on improvement of cognitive impairment, depression and anxiety symptoms developing post-COVID-19, in a 12-week, randomized controlled trial. METHODS: A total of 50 patients with a confirmed diagnosis of COVID-19 and a score ≤ 23 on the Mini-Mental State Examination (MMSE) test or a score ≤ 22 on the Montreal Cognitive Assessment (MoCA) were randomly assigned to either the famotidine (40 mg twice daily) or the placebo group. Changes in MMSE scores at weeks 6 and 12 were the primary outcome, while changes in other scales were the secondary outcomes. Participants and evaluators were blinded. RESULTS: At weeks 6 and 12, patients in the famotidine group had significantly higher MMSE scores (p = 0.014, p < 0.001, respectively). Regarding the MoCA scale, the famotidine group had a significantly higher score at weeks 6 and 12 (p = 0.001, p < 0.001, respectively). Considering the HAM-D scale (Hamilton Depression Rating Scale), at weeks 6 and 12, the famotidine group experienced a larger reduction (p = 0.009, p = 0.02, respectively). Additionally, comparison of the HAM-A scale scores (Hamilton Anxiety Rating Scale) at weeks 6 and 12 showed a statistically significant larger reduction in the famotidine group (p = 0.04, p = 0.02, respectively). The two groups did not differ in the frequency of adverse effects. CONCLUSION: Our study supports safety and efficacy of famotidine in treating cognitive impairment, depression and anxiety symptoms induced by COVID-19. TRIAL REGISTRATION: This trial was registered at the Iranian registry of clinical trials (IRCT: www.irct.ir; registration number: IRCT20090117001556N138).

Efficacy of Transcranial Direct Current Stimulation on Pain Level and Disability of Patients with Fibromyalgia: A Systematic Review of Randomized Controlled Trials with Parallel-Group Design.

Transcranial direct current stimulation (tDCS) has been increasingly applied in fibromyalgia (FM) to reduce pain and fatigue. While results are promising, observed effects are variable, and there are questions about optimal stimulation parameters such as target region (e.g., motor vs. prefrontal cortices). This systematic review aimed to provide the latest update on published randomized controlled trials with a parallel-group design to examine the specific effects of active tDCS in reducing pain and disability in FM patients. Using the PRISMA approach, a literature search identified 14 randomized controlled trials investigating the effects of tDCS on pain and fatigue in patients with FM. Assessment of biases shows an overall low-to-moderate risk of bias. tDCS was found effective in all included studies conducted in patients with FM, except one study, in which the improving effects of tDCS were due to placebo. We recommended tDCS over the motor and prefrontal cortices as "effective" and "probably effective" respectively, and also safe for reducing pain perception and fatigue in patients with FM, according to evidence-based guidelines. Stimulation polarity was anodal in all studies, and one single-session study also examined cathodal polarity. The stimulation intensity ranged from 1-mA (7.14% of studies) to 1.5-mA (7.14% of studies) and 2-mA (85.7% of studies). In all of the included studies, a significant improvement in at least one outcome variable (pain or fatigue reduction) was observed. Moreover, 92.8% (13 of 14) applied multi-session tDCS protocols in FM treatment and reported significant improvement in their outcome variables. While tDCS is therapeutically effective for FM, titration studies that systematically evaluate different stimulation intensities, durations, and electrode placement are needed.

Assessing the Effectiveness of Repetitive Transcranial Magnetic Stimulation in the Treatment of Obsessive- Compulsive Disorder.

Objective. Obsessive-compulsive disorder (OCD) is a frequent and disabling neuropsychiatric disorder with a lifetime prevalence of 3%. About 40% to 60% of patients show no or just partial symptom improvement to treatment with a first-line drug and cognitive behavior therapy. Ten percent of patients remain treatment refractory despite several treatments. For these patients, repetitive Transcranial Magnetic Stimulation (rTMS) has been suggested as a treatment option. Method. We investigated the efficacy of rTMS on the Supplementary Motor Area (SMA) in 16 right handed pharmaco-resistant OCD patients in an outpatient setting. The patients have been diagnosed with OCD by two psychiatrists and referred for rTMS intervention. Patients received 16 sessions of low frequency (0.5 HZ) rTMS on SMA,100% motor threshold, 1200 stimuli/day for 40 minutes every other day. OCD, depression, and anxiety symptoms were measured at baseline, 2, 6, and 12 weeks by Yale-Brown Obsessive Compulsive Scale(Y-BOCS) and Hamilton Depressive and Anxiety rating scales (HAM-D and HAM-A). We assessed the side effects of rTMS by a self-administrative questionnaire. Results. Patients' scores in Y-BOCS, HAM-D, and HAM-A were significantly decreased following rTMS treatment. The baseline and 12 weeks scores of Y-BOCS were 28.94 and 18.31 (P-value < 0.01), HAM-D were 14.69 and 7.94 (P-value <0.01) and HAM-A were 16.38 and 6.94 (P- value < 0.01), respectively. The patients reported no serious side effects of rTMS except two case that reported light headach. Conclusion. This study showed that low-frequency rTMS on SMA improved OCD, anxiety, and depression symptoms after 16 sessions.

Engineered Delivery of Dental Stem-Cell-Derived Extracellular Vesicles for Periodontal Tissue Regeneration.

Periodontal disease begins as an inflammatory response to a bacterial biofilm deposited around the teeth, which over time leads to the destruction of tooth-supporting structures and consequently tooth loss. Conventional treatment strategies show limited efficacy in promoting regeneration of damaged periodontal tissues. Here, a delivery platform is developed for small extracellular vesicles (sEVs) derived from gingival mesenchymal stem cells (GMSCs) to treat periodontitis. EVs can achieve comparable therapeutic effects to their cells of origin. However, the short half-lives of EVs after their administration along with their rapid diffusion away from the delivery site necessitate frequent administration to achieve therapeutic benefits. To address these issues, "dual delivery" microparticles are engineered enabling microenvironment-sensitive release of EVs by metalloproteinases at the affected site along with antibiotics to suppress bacterial biofilm growth. GMSC sEVs are able to decrease the secretion of pro-inflammatory cytokines by monocytes/macrophages and T cells, suppress T-cell activation, and induce the formation of T regulatory cells (Tregs) in vitro and in a rat model of periodontal disease. One-time administration of immunomodulatory GMSC sEV-decorated microparticles leads to a significant improvement in regeneration of the damaged periodontal tissue. This approach will have potential clinical applications in the regeneration of a variety of tissues.

A narrative overview of utilizing biomaterials to recapitulate the salient regenerative features of dental-derived mesenchymal stem cells.

Tissue engineering approaches have emerged recently to circumvent many limitations associated with current clinical practices. This elegant approach utilizes a natural/synthetic biomaterial with optimized physiomechanical properties to serve as a vehicle for delivery of exogenous stem cells and bioactive factors or induce local recruitment of endogenous cells for in situ tissue regeneration. Inspired by the natural microenvironment, biomaterials could act as a biomimetic three-dimensional (3D) structure to help the cells establish their natural interactions. Such a strategy should not only employ a biocompatible biomaterial to induce new tissue formation but also benefit from an easily accessible and abundant source of stem cells with potent tissue regenerative potential. The human teeth and oral cavity harbor various populations of mesenchymal stem cells (MSCs) with self-renewing and multilineage differentiation capabilities. In the current review article, we seek to highlight recent progress and future opportunities in dental MSC-mediated therapeutic strategies for tissue regeneration using two possible approaches, cell transplantation and cell homing. Altogether, this paper develops a general picture of current innovative strategies to employ dental-derived MSCs combined with biomaterials and bioactive factors for regenerating the lost or defective tissues and offers information regarding the available scientific data and possible applications.

Whitlockite-Enabled Hydrogel for Craniofacial Bone Regeneration.

Growth-factor-free bone regeneration remains a challenge in craniofacial engineering. Here, we engineered an osteogenic niche composed of a commercially modified alginate hydrogel and whitlockite microparticles (WHMPs), which impart tunable physicochemical properties that can direct osteogenesis of human gingival mesenchymal stem cells (GMSCs). Our in vitro studies demonstrate that WHMPs induce osteogenesis of GMSCs more effectively than previously demonstrated hydroxyapatite microparticles (HApMPs). Alginate-WHMP hydrogels showed higher elasticity without any adverse effects on the viability of the encapsulated GMSCs. Moreover, the alginate-WHMP hydrogels upregulate the mitogen-activated protein kinase (MAPK) pathway, which in turn orchestrates several osteogenic markers, such as RUNX2 and OCN, in the encapsulated GMSCs. Concurrent coculture studies with human osteoclasts demonstrate that GMSCs encapsulated in alginate-WHMP hydrogels downregulate osteoclastic activity, potentially due to release of Mg2+ ions from the WHMPs along with secretion of osteoprotegerin from the GMSCs. In vivo studies demonstrated that the GMSCs encapsulated in our osteogenic niche were able to promote bone repair in calvarial defects in murine models. Altogether, our results confirmed the development of a promising treatment modality for craniofacial bone regeneration based on an injectable growth-factor-free hydrogel delivery system.

RGD-Modified Alginate-GelMA Hydrogel Sheet Containing Gingival Mesenchymal Stem Cells: A Unique Platform for Wound Healing and Soft Tissue Regeneration.

Soft tissue reconstruction has remained a major clinical challenge in dentistry and regenerative medicine. Although current methods have shown partial success, there are several disadvantages associated with these approaches. Gingival mesenchymal stem cells (GMSCs) can be simply obtained in the oral cavity for soft tissue augmentation. Regenerative potential of mesenchymal stem cells (MSCs) encapsulated in hydrogels is well documented. Here, an alginate-gelatin methacrylate (GelMA) hydrogel formulation is developed encapsulating GMSCs within the developed hydrogel. The results confirm that the encapsulated MSCs remain viable within the hydrogel with enhanced collagen deposition. An excisional wound model in mice is utilized to evaluate the in vivo functionality of the GMSC-hydrogel construct for wound healing and soft tissue regeneration. The histology and immunofluorescence analyses confirm the effectiveness of the GMSC-hydrogel in expediting wound healing via enhancing angiogenesis and suppressing local proinflammatory cytokines. Altogether, the findings demonstrate that GMSCs encapsulated in an engineered hydrogel sheet based on alginate and GelMA can be used to expedite wound healing and soft tissue regeneration, with potential applications in plastic and reconstructive surgery as well as dentistry.

Effect of sertraline on depression severity and prolactin levels in women with polycystic ovary syndrome: a placebo-controlled randomized trial.

There is a paucity of data regarding the safety and efficacy of antidepressant therapy in women with polycystic ovary syndrome and depression. The effect of antidepressant medications on circulating prolactin levels is of concern in this patient population. We aimed to evaluate the effect of sertraline on depression severity and serum prolactin levels in women with polycystic ovary syndrome and mild-to-moderate depression. In a parallel-design, two-center, randomized controlled trial, we stratified participants according to their baseline prolactin level into normal (<25 ng/mL) and high (≥25 ng/mL) prolactin groups. Each group was randomized to receive 50 mg daily sertraline (up-titrated after 25 mg daily for 1 week) or placebo. The enrolling physicians, outcome assessors, and study subjects were all blind to the treatment. Depression severity was assessed by the Hamilton depression rating scale at baseline, the third, and the sixth weeks. The primary efficacy outcome was a change in depression severity. Prolactin levels were checked at baseline and after 6 weeks, and the safety outcome was the alteration in prolactin levels. Overall, 513 women were screened for eligibility in two outpatient clinics. Ultimately, 74 (38 normal prolactin and 36 high prolactin level) individuals were randomized. After 6 weeks of follow-up, depression severity was significantly reduced among patients who received sertraline regardless of the baseline prolactin levels (all between subjects P < 0.001). Furthermore, there was no difference in prolactin levels between the sertraline and placebo arms in normal (P = 0.80) or high prolactin (P = 0.21) groups. Sertraline is a well-tolerated and effective choice for treating depression in women with polycystic ovary syndrome. Future studies with longer follow-up periods are required to draw more robust conclusions.

Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results.

This phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2 to 4. In part 3, both study drugs were dosed, same day, for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (ORR; N = 91) was 85%, with 67% achieving a complete response (CR). At a median follow-up of 34.3 months, the estimated progression-free survival (PFS) rate at 3 years was 77% (95% confidence interval [CI], 65% to 86%) and 91% (95% CI, 79% to 96%) for patients undergoing ASCT directly after study treatment. Overall survival at 3 years was 93% (95% CI, 85% to 97%). The most common adverse events (AEs) prior to ASCT were nausea (52%) and infusion-related reactions (43%), all grade 1 or 2. A total of 16 patients (18%) had immune-related AEs that required systemic corticosteroid treatment. Peripheral blood immune signatures were consistent with an activated T-cell response. Median gene expression of CD30 in tumors was higher in patients who responded compared with those who did not. Longer-term follow-up of BV and Nivo as a first salvage regimen shows durable efficacy and impressive PFS, especially in patients who proceeded directly to transplant, without additional toxicity concerns. This trial was registered at www.clinicaltrials.gov as #NCT02572167.

Genetic assessment of the internal transcribed spacer region (ITS1.2) in Mangifera indica L. landraces.

Mango (Mangifera indica) is one of the most important tropical fruits in the world. Twenty-two genotypes of native mangoes from different regions of southern Iran (Hormozgan and Kerman) were collected and analyzed for the ribosomal genes. GC content was found to be 55.5%. Fu and Li's D* test statistic (0.437), Fu and Li's F* test statistic (0.500) and Tajima's D (1.801) were positive and nonsignificant. A total of 769 positions were identified (319 with insertion or deletion including 250 polymorphic and 69 monomorphic loci; 450 loci without any insertion or deletion including 35 Singletons and 22 haplotypes). Nucleotide diversity of 0.309 and a high genetic differentiation including Chi square of 79.8; P value of 0.3605 and df value of 76 was observed among mango genotypes studied. The numerical value of the ratio dN/dS (0.45) indicated a pure selection in the examined gene and the absence of any key changes. Cluster analysis differentiated the mango used in this research (M. indica L.) into two genotypes but could not differentiate their geographical locations. The results of this study indicated that a high genetic distance exists between HajiGholam (Manojan) and Arbabi (Rodan) genotypes and showed higher genetic diversity in mango of Rodan region. Results of present study suggested that for successful breeding, the genotypes of Rodan region mango especially Arbabi mango can be used as a gene donor and ITS can be a suitable tool for genetic evaluations of inter and intra species.

In situ bone tissue engineering using gene delivery nanocomplexes.

Gene delivery offers promising outcomes for functional recovery or regeneration of lost tissues at cellular and tissue levels. However, more efficient carriers are needed to safely and locally delivery of genetic materials. Herein, we demonstrate microfluidic-assisted synthesis of plasmid DNA (pDNA)-based nanocomplexe (NC) platforms for bone tissue regeneration. pDNA encoding human bone morphogenesis protein-2 (BMP-2) was used as a gene of interest. Formation and fine-tuning of nanocomplexes (NCs) between pDNA and chitosan (CS) as carriers were performed using a micromixer platform. Flow characteristics were adjusted to tune mixing time and consequently size, zeta potential, and compactness of assembled NCs. Subsequently, NCs were immobilized on a nanofibrous Poly(ε-caprolactone) (PCL) scaffold functionalized with metalloprotease-sensitive peptide (MMP-sensitive). This construct can provide an environmental-sensitive and localized gene delivery platform. Osteogenic differentiation of bone marrow-derived mesenchymal stem cells (MSCs) was studied using chemical and biological assays. The presented results converge to indicate a great potential of the developed methodology for in situ bone tissue engineering using immobilized microfluidic-synthesized gene delivery nanocomplexes, which is readily expandable in the field of regenerative nanomedicine. STATEMENT OF SIGNIFICANCE: In this study, we demonstrate microfluidic-assisted synthesis of plasmid DNA (pDNA)-based nanocomplexes (NCs) platforms for bone tissue regeneration. We used pDNA encoding human bone morphogenesis protein-2 (BMP-2) as the gene of interest. Using micromixer platform nanocomplexes (NCs) between pDNA and chitosan (CS) were fabricated and optimized. NCs were immobilized on a nanofibrous polycaprolactone scaffold functionalized with metalloprotease-sensitive peptide. In vitro and in vivo assays confirmed the osteogenic differentiation of mesenchymal stem cells (MSCs). The obtained data indicated great potential of the developed methodology for in situ bone tissue engineering using immobilized microfluidic-synthesized gene delivery nanocomplexes, which is readily expandable in the field of regenerative nanomedicine.

An engineered cell-laden adhesive hydrogel promotes craniofacial bone tissue regeneration in rats.

Cell-laden hydrogels are widely used in tissue engineering and regenerative medicine. However, many of these hydrogels are not optimized for use in the oral environment, where they are exposed to blood and saliva. To address these challenges, we engineered an alginate-based adhesive, photocrosslinkable, and osteoconductive hydrogel biomaterial (AdhHG) with tunable mechanical properties. The engineered hydrogel was used as an injectable mesenchymal stem cell (MSC) delivery vehicle for craniofacial bone tissue engineering applications. Subcutaneous implantation in mice confirmed the biodegradability, biocompatibility, and osteoconductivity of the hydrogel. In a well-established rat peri-implantitis model, application of the adhesive hydrogel encapsulating gingival mesenchymal stem cells (GMSCs) resulted in complete bone regeneration around ailing dental implants with peri-implant bone loss. Together, we have developed a distinct bioinspired adhesive hydrogel with tunable mechanical properties and biodegradability that effectively delivers patient-derived dental-derived MSCs. The hydrogel is photocrosslinkable and, due to the presence of MSC aggregates and hydroxyapatite microparticles, promotes bone regeneration for craniofacial tissue engineering applications.