To evaluate therapeutic efficacy of mesenchymal stem cells in patients with severe acute pancreatitis.

While rapid healing of diabetic foot ulcers (DFUs) is highly desirable to avoid infections, amputations and life-threatening complications, DFUs often respond poorly to standard treatment. GMP-manufactured skin-derived ABCB5+ mesenchymal stem cells (MSCs) might provide a new adjunctive DFU treatment, based on their remarkable skin wound homing and engraftment potential, their ability to adaptively respond to inflammatory signals, and their wound healing-promoting efficacy in mouse wound models and human chronic venous ulcers.

Use of kinase inhibitors such as dasatinib and imatinib might increase the risk of opportunistic infections, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections. However, the effect of sorafenib on EBV and CMV infections remains unclear. The aim of this study was to investigate the effect of sorafenib maintenance post-transplantation on the incidence and mortality of EBV and CMV infections in patients with FLT3-ITD acute myeloid leukemia.

The present study investigated clinical and histomorphometric data after sinus lift procedures performed with and without mesenchymal stem cells (MSCs) added to a graft. Twenty-four patients underwent maxillary sinus lift for implant placement. Twelve patients each were assigned to control (Group 1) and test (Group 2) groups. An MSC suspension was added to the graft used in patients of Group 2. Five of 12 patients in both groups underwent crestal-approach sinus lift with immediate implant placement, while seven patients received a lateral-approach sinus lift. The MSC suspension was obtained using the Rigenera protocol. Samples from the grafted site were evaluated, processed, and stained using three staining techniques 90 days after surgery. Histomorphometric analysis was performed using an imaging software (ImageJ). Two types of tissues were defined: Type 1 'mature bone' and Type 2 'osteoid tissue'. The mean Type 1 tissue percentage was 27.24% in Group 1 and 44.45% in Group 2 (P < 0.05). The mean Type 2 tissue percentage was 10.86% and 7.04% in Groups 1 and 2, respectively. The mean Type 1 tissue percentages for the crestal approach were 24.52% for Group 1 and 50.78% for Group 2, while the mean Type 1 tissue percentages for the lateral approach were 29.18% for Group 1 and 39.92% for Group 2. Patients treated with grafts containing MSCs showed 63.18% increased bone formation compared to those treated with grafts not containing MSCs (P < 0.05). Although our data showed a positive trend in patients treated with MSCs, differences between subgroups were not significant (P > 0.05).

Using patient-derived induced pluripotent stem cells, neurodegenerative disease phenotypes have been recapitulated and their pathogenesis analysed leading to significant progress in drug screening. In amyotrophic lateral sclerosis, high-throughput screening using induced pluripotent stem cells-derived motor neurons has identified candidate drugs. Owing to induced pluripotent stem cell-based drug evaluation/screening, three compounds, retigabine, ropinirole and bosutinib, have progressed to clinical trials. Retigabine blocks hyperexcitability and improves survival in amyotrophic lateral sclerosis patient-derived motor neurons. In a randomized clinical trial (n = 65), treatment with retigabine reduced neuronal excitability after 8 weeks. Ropinirole, identified in a high-throughput screening, attenuates pathological phenotypes in patient-derived motor neurons. In a trial limited by a small sample size (n = 20), ropinirole was tolerable and had clinical benefits on function and survival. A phase 1 study of bosutinib has reported safety and tolerability for 12 weeks. Thus, these clinical trials show safety and positive effects and confirm the reliability of stem cell-based drug discovery. This novel strategy leads to reduced costs and time when compared to animal testing and opens new avenues for therapy in intractable diseases.

BACKGROUNDDuring aging, there is a functional decline in the pool of muscle stem cells (MuSCs) that influences the functional and regenerative capacity of skeletal muscle. Preclinical evidence has suggested that nicotinamide riboside (NR) and pterostilbene (PT) can improve muscle regeneration, e.g., by increasing MuSC function. The objective of this study was to investigate if supplementation with NR and PT (NRPT) promotes skeletal muscle regeneration after muscle injury in elderly individuals by improved recruitment of MuSCs.METHODSThirty-two elderly individuals (55-80 years of age) were randomized to daily supplementation with either NRPT (1,000 mg NR and 200 mg PT) or matched placebo. Two weeks after initiation of supplementation, skeletal muscle injury was induced by electrically induced eccentric muscle work. Skeletal muscle biopsies were obtained before, 2 hours after, and 2, 8, and 30 days after injury.RESULTSA substantial skeletal muscle injury was induced by the protocol and associated with release of myoglobin and creatine kinase, muscle soreness, tissue edema, and a decrease in muscle strength. MuSC content, proliferation, and cell size revealed a large demand for recruitment after injury, but this was not affected by NRPT. Furthermore, histological analyses of muscle fiber area, central nuclei, and embryonic myosin heavy chain showed no NRPT supplementation effect.CONCLUSIONDaily supplementation with 1,000 mg NR and 200 mg PT is safe but does not improve recruitment of the MuSC pool or other measures of muscle recovery in response to injury or subsequent regeneration in elderly individuals.TRIAL REGISTRATIONClinicalTrials.gov NCT03754842.FUNDINGNovo Nordisk Foundation (NNF17OC0027242) and Novo Nordisk Foundation CBMR.

Administration of azithromycin after allogeneic hematopoietic stem cell transplantation for hematologic malignancies has been associated with relapse in a randomized phase 3 controlled clinical trial. Studying 240 samples from patients randomized in this trial is a unique opportunity to better understand the mechanisms underlying relapse, the first cause of mortality after transplantation. We used multi-omics on patients' samples to decipher immune alterations associated with azithromycin intake and post-transplantation relapsed malignancies. Azithromycin was associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles. In vitro, azithromycin exposure inhibited T-cell cytotoxicity against tumor cells and impaired T-cell metabolism through glycolysis inhibition, down-regulation of mitochondrial genes, and up-regulation of immunomodulatory genes, notably SOCS1. These results highlight that azithromycin directly affects immune cells that favor relapse, which raises caution about long-term use of azithromycin treatment in patients at high risk of malignancies. The ALLOZITHRO trial was registered at www.clinicaltrials.gov as #NCT01959100.

Interleukin 17 (IL17)-expressing CD4+ T cells and IL-17/IL-23 pathway play a key role in the pathogenesis of axial spondyloarthritis (axSpA). Synbiotics have been suggested due to their immunomodulatory effects in the treatment of autoimmune diseases. This randomized double-blind, placebo-controlled trial was designed to assess the effects of synbiotic supplement on IL-17/IL-23 pathway and disease activity in patients with axSpA.

The current randomized controlled trial assessed for the first time the effect of a low-speed platelet-rich fibrin (PRF) with open flap debridement (OFD) versus OFD alone in the treatment of periodontal intra-osseous defects of stage-III periodontitis patients.

Background: : Patients with severe COVID-19 had a higher increase in pro-inflammatory and anti-inflammatory cytokines than patients with moderate COVID-19. Excessive release of cytokine and chemokines can lead to multi-organ failure, increasing disease severity, length of stay, and mortality rate. Mesenchymal stem cells (MSCs) are known to have immunomodulatory, anti-inflammatory, anti-apoptotic, and angiogenesis effects that are useful for relieving inflammation, recovery, and protection of lung tissues in COVID-19 patients. Secretome, a secretory product of MSCs, has several advantages over MSCs. Therefore, we conducted a study to investigate secretomes' effectiveness and safety profile as a treatment for severe COVID-19. Methods: This study was a double-blind, multicentered, randomized, placebo-controlled trial. This study involved 40 subjects recruited from three top COVID-19 referral hospitals in the Greater Jakarta area, Indonesia. Eligible subjects (n=40) were randomized in a 1:1 ratio to intervention group (n=20) and a control group (n=20). The primary outcome of this study was the improvement of inflammatory markers levels, measured by changes in inflammatory markers, and ratio of inflammatory to anti-inflammatory markers. The secondary outcomes of this study included clinical outcome, laboratory outcome, radiological outcome, RT-PCR result conversion, and safety profile of MSC secretome. Results: IL-6 marker in the control group was increased on the 14 th day after the intervention compared to before intervention [4.110 (2.403-12.820) at baseline to 13.320 (2.958-33.285) on 14 th day after intervention, p=0.017]. In the intervention group, there was no increase in the IL-6/IL-10 ratio. In contrast, in the control group, there was a significant increase in the IL-6/IL-10 ratio (p=0.036) on the 14 th day after the intervention compared to before the intervention. We also found that on the seventh day after the intervention, most of the subjects who received placebo had high levels of IL-6 and ferritin (p=0.043). There was no significant difference in the laboratory outcome, radiological outcome, RT-PCR result conversion, and safety profile between both groups. Conclusions: Our study showed an increase of inflammation markers in the control group on the 14 th day after the intervention, compared to the intervention group. The ratio of inflammatory to anti-inflammatory markers on the seventh and 14 th days after intervention also did not increase in the intervention group. On the seventh day after intervention, most of the subjects in the control group also had high IL-6 levels and high ferritin levels. There is no adverse event reported. MSC secretome is a safe and promising treatment modality for severe COVID-19.

Acne is the most common skin disorder which is known as a chronic inflammatory disease with psychological burden and reduced quality of life. Adipose tissue-derived stromal vascular fraction (SVF) is recognized as a source of regenerative cells and improves the quality of skin by increasing collagen content. To date, a few studies have been performed on the therapeutic role of SVF in the treatment of acne scars.

The most widely used regimens of graft-versus-host disease (GVHD) prophylaxis in HLA-matched unrelated donor peripheral blood stem cell transplantation (MUD-PBSCT) are based on anti-thymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). To improve the efficiency of GVHD prophylaxis, a novel regimen, composed of low-dose PTCy (20 mg/kg on day +3 and +4) and low-dose ATG (6 mg/kg), was evaluted in patients with hematological malignancies ungoing 10/10 HLA MUD-PBSCT in first remission (CR1). In our prospective, multicenter study, 104 patients were randomly assigned one-to-one to low-dose PTCy-ATG (n = 53) or standard-dose ATG (10 mg/kg, n = 51). Both the cumulative incidences (CIs) of grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) at 2 years in low-dose PTCy-ATG cohort were significantly reduced (24.5% vs. 47.1%; P = 0.017; 14.1% vs. 33.3%; P = 0.013). The CI of non-relapse-mortality (NRM) was much lower (13.2% vs. 34.5%; P = 0.049) and GVHD-free, relapse-free survival (GRFS) was significantly improved at 2 years in low-dose PTCy-ATG arm (67.3% vs 42.3%; P = 0.032). The low-dose PTCy-ATG based GVHD prophylaxis is a promising strategy for patients in CR1 after 10/10 HLA MUD-PBSCT.

To evaluate safety and motor function after treatment with allogeneic umbilical cord blood (AlloCB) or umbilical cord tissue-derived mesenchymal stromal cells (hCT-MSC) in children with cerebral palsy (CP).

Traumatic brain injuries (TBI) often produce disability in survivors due to unresolved inflammation and progressive neurodegeneration. The central nervous system in mammals is incapable of self-repair. Two decades of preclinical studies and clinical trials have provided insights into TBI pathophysiology that could be utilized to develop clinically relevant therapy. Our laboratory recently reported efficacy of clinical trial grade fetal human neural stem cells (hNSCs) in immunosuppressed rats with penetrating traumatic brain injury (pTBI). Next, in compliance with the United States Food and Drug Administration (USFDA) guidance, this study explores safety by assessing the tumorigenicity potential of intracranial hNSC transplants in athymic rats with pTBI. First, the maximum tolerated dose (MTD) was determined. Then, forty athymic pTBI rats were randomized to either: Group A. pTBI + vehicle or Group B. pTBI + hNSCs at MTD one week after injury with 6-months survival, sufficient time to uncover transplant associated tumorigenicity. A board-certified Pathologist examined hematoxylin-eosin (H&E), Ki67 immunostained brain and spinal cord, serial sections along with several abnormal peripheral masses for evidence of lesion, transplant, and oncogenesis. There was no evidence of transplant derived tumors or oncogenic tissue necrosis. Consistent with athymic literature, the lesion remained unchanged even after robust hNSC engraftment. This safety study supports the conclusion that hNSCs are safe for transplantation in pTBI. The differences in lesion expansion between immunosuppressed and athymic rats in the presence of hNSCs suggests an unexpected role for thymus derived cells in resolution of trauma induced inflammation.

There have been no studies into the direct injection of mesenchymal stem cells (MSCs) for luminal ulcerative colitis (UC). Our aim was to investigate the efficacy of MSCs delivered locally via endoscopic delivery, as is done in the setting of perianal disease, to treat the local site of inflammation directly.

Acute respiratory distress syndrome (ARDS) is the devastating complication of the new COVID-19 pandemic, directly correlated with releasing large amounts of inflammatory cytokines. Due to their immunoregulatory features, mesenchymal stromal cells (MSCs) provide a promising approach against this disease. In this regard, this study was designed as a single-center, open-label, phase 1 clinical trial with a control group to examine the safety and explore the possible potency of three injections of umbilical cord-derived MSCs (UC-MSCs) in mild-moderate COVID-19-induced ARDS patients.

The aim of this study was to investigate safety of treating diabetic foot ulcers with a topically administered mesenchymal stem cell product.

The purple-flesh potato (Solanum tuberosum L.) cultivar "Shadow Queen" (SQ) naturally contains anthocyanins. This randomized, double-blind, placebo-controlled study determines whether ingesting purple potatoes increases the number of mesenchymal stem cells (MSC) and improves stress response, a minor health complaint in healthy adults (registration number: UMIN000038876). A total of 15 healthy subjects (ages: 50-70 years) with minor health complaints were randomly assigned to one of two groups. For 8 weeks, the placebo group received placebo potatoes cv. "Haruka" and the test group received test potato cv. SQ containing 45 mg anthocyanin. The MSC count and several stress responses were analyzed at weeks 0 and 8 of the intake periods. The ingestion of a SQ potato did not affect the MSC count but markedly improved psychological stress response, irritability, and depression as minor health complaints compared with "Haruka". No adverse effects were noted. Hence, an 8-week intake of SQ could improve stress responses.

Background and Objectives: Homogeneous and xenogenic bioengineering structures are actively used as wound coatings in treatment of burns and have already shown their effectiveness. Nevertheless, the disadvantage of such dressings is their high cost. This issue is particularly challenging for developing countries in which the incidence of burns is the highest one. With such needs taken into account, the research team developed and clinically tested a new wound coating based on decellularized bovine peritoneum (DBP). Materials and Methods: A multicenter randomized clinical trial was conducted to evaluate DBP. The following variables were considered in the research study: the number of inpatient days, the number of dressing changes, the level of pain experienced during dressing changes, and the condition of wounds at the time of the follow-up examination. Results: The research involved 68 participants. It was found that the patients who were treated with a DBP experienced less pain with less changes of dressings. However, the number of inpatient days and wound healing failed to demonstrate statistically significant difference compared to the control group. Conclusions: In the given research, DBP showed efficacy in improving patients' quality of life by reducing pain and the number of dressings' changes. However, when comparing this research study with the studies of other animal-derived wound coverings, there were a number of differences and limitations in the parameters. Thus, the results requires further study for a greater comparability of data. Given the above, we expect that DBP will become an inexpensive and effective treatment for burns in developing countries.

Oral mucositis (OM) is a frequent complication of conditioning regimens for hematopoietic stem cell transplantation (HSCT). Damage to the nuclear and non-nuclear materials of the mucosal cells by the production of Reactive Oxygen Species (ROS) and proinflammatory cytokines could result to development and progression of OM. Previous studies have shown the effectiveness of Mucosamin® oral spray in the management of pain and acceleration of OM healing. The aims of the current study were to evaluate prophylactic effects of Mucosamin® oral spray in reducing the incidence and severity of OM in pediatric patients undergoing allogeneic HSCT.