Recovery from Bell's palsy after treatment using uncultured umbilical cord-derived mesenchymal stem cells: A case report.

BACKGROUND: Bell's palsy is an idiopathic facial palsy with an unknown cause, and 75% of patients heal spontaneously. However, the other 25% of patients continue experiencing mild or severe disabilities, resulting in a reduced quality of life. Currently, various treatment methods have been developed to treat this disease. However, there is controversy regarding their effectiveness, and new alternative treatments are needed. CASE SUMMARY: The patient suffered from left-sided facial paralysis due to Bell's palsy for 7 years. The patient received an uncultured umbilical cord-derived mesenchymal stem cell transplant eight times for treatment. After follow-up for 32 mo, the paralysis was cured, and there was no recurrence. CONCLUSION: Uncultured umbilical cord-derived mesenchymal stem cell transplantation may be a potential treatment for patients with Bell's palsy who do not spontaneously recover.

Treatment of acute ischemic stroke by minimally manipulated umbilical cord-derived mesenchymal stem cells transplantation: A case report.

BACKGROUND: Stroke is one of the major causes of disability and death worldwide. Some treatments for stroke exist, but existing treatment methods have limitations such as difficulty in the regeneration of damaged neuronal cells of the brain. Recently, mesenchymal stem cells (MSCs) have been studied as a therapeutic alternative for stroke, and various preclinical and case studies have been reported. CASE SUMMARY: A 55-year-old man suffered an acute stroke, causing paralysis in the left upper and lower limbs. He intravenously transplanted the minimally manipulated human umbilical cord-derived MSCs (MM-UC-MSCs) twice with an 8-d interval. At 65 wk after transplantation, the patient returned to his previous occupation as a veterinarian with no adverse reactions. CONCLUSION: MM-UC-MSCs transplantation potentially treats patients who suffer from acute ischemic stroke.

Psoriasis treatment using minimally manipulated umbilical cord-derived mesenchymal stem cells: A case report.

BACKGROUND: Psoriasis is a chronic autoimmune disease that usually manifests as a red scaly epidermis, induration, and hyperproliferation of basal keratinocytes. About 2% of the world's population suffers from psoriasis but there are no clear therapeutics yet. Recently, mesenchymal stem cells (MSCs) have been regarded as a therapeutic alternative for autoimmune diseases, as they possess immunosuppressive effects without risks. Human umbilical cord-derived MSCs effectively regulate immune cells and are characterized by low immunogenicity, which has many advantages in treating immune diseases. CASE SUMMARY: The patient was a 47-year-old male, diagnosed with psoriasis in 1995. He had received various treatments for 25 years, but the psoriatic condition was not significantly improved. He was given three rounds of minimally manipulated umbilical cord-derived MSCs over 2 wk. The erythema gradually disappeared. Three months after the 1st round, all erythema completely disappeared, and the psoriasis did not recur. CONCLUSION: Minimally manipulated umbilical cord-derived MSC transplantation can potentially treat patients who suffer from psoriasis.

Discovery of the first chemical tools to regulate MKK3-mediated MYC activation in cancer.

The transcription master regulator MYC plays an essential role in regulating major cellular programs and is a well-established therapeutic target in cancer. However, MYC targeting for drug discovery is challenging. New therapeutic approaches to control MYC-dependent malignancy are urgently needed. The mitogen-activated protein kinase kinase 3 (MKK3) binds and activates MYC in different cell types, and disruption of MKK3-MYC protein-protein interaction may provide a new strategy to target MYC-driven programs. However, there is no perturbagen available to interrogate and control this signaling arm. In this study, we assessed the drugability of the MKK3-MYC complex and discovered the first chemical tool to regulate MKK3-mediated MYC activation. We have designed a short 44-residue inhibitory peptide and developed a cell lysate-based time-resolved fluorescence resonance energy transfer (TR-FRET) assay to discover the first small molecule MKK3-MYC PPI inhibitor. We have optimized and miniaturized the assay into an ultra-high-throughput screening (uHTS) 1536-well plate format. The pilot screen of ~6,000 compounds of a bioactive chemical library followed by multiple secondary and orthogonal assays revealed a quinoline derivative SGI-1027 as a potent inhibitor of MKK3-MYC PPI. We have shown that SGI-1027 disrupts the MKK3-MYC complex in cells and in vitro and inhibits MYC transcriptional activity in colon and breast cancer cells. In contrast, SGI-1027 does not inhibit MKK3 kinase activity and does not interfere with well-known MKK3-p38 and MYC-MAX complexes. Together, our studies demonstrate the drugability of MKK3-MYC PPI, provide the first chemical tool to interrogate its biological functions, and establish a new uHTS assay to enable future discovery of potent and selective inhibitors to regulate this oncogenic complex.

Alopecia treatment using minimally manipulated human umbilical cord-derived mesenchymal stem cells: Three case reports and review of literature.

BACKGROUND: Alopecia areata (AA) is a common autoimmune disease characterized by hair loss. AA appears in extensive forms, such as progressive and diffusing hair loss (diffuse AA), a total loss of scalp hair (alopecia totalis), and complete loss of hair over the entire body (alopecia universalis). Recently, mesenchymal stem cells (MSCs) have been identified as a therapeutic alternative for autoimmune diseases. For this reason, preclinical and case studies of AA and related diseases using MSCs have been conducted. CASE SUMMARY: Case 1: A 55-year-old woman suffered from AA in two areas of the scalp. She was given 15 rounds of minimally manipulated umbilical cord-MSCs (MM-UC-MSCs) over 6 mo. The AA gradually improved 3 mo after the first round. The patient was cured, and AA did not recur. Case 2: A 30-year-old woman, with history of local steroid hormone injections, suffered from AA in one area on the scalp. She was given two rounds of MM-UC-MSCs over 1 mo. The AA immediately improved after the first round. The patient was cured, and AA did not recur. Case 3: A 20-year-old woman, who was diagnosed with alopecia universalis at the age of 12, was given 14 rounds of MM-UC-MSCs over 12 mo. Her hair began to grow about 3 mo after the first round. The patient was cured, and alopecia universalis did not recur. CONCLUSION: MM-UC-MSC transplantation potentially treats patients who suffer from AA and related diseases.

Direct Reprogramming to Human Induced Neuronal Progenitors from Fibroblasts of Familial and Sporadic Parkinson's Disease Patients.

In Parkinson's disease (PD) research, human neuroblastoma and immortalized neural cell lines have been widely used as in vitro models. The advancement in the field of reprogramming technology has provided tools for generating patient-specific induced pluripotent stem cells (hiPSCs) as well as human induced neuronal progenitor cells (hiNPCs). These cells have revolutionized the field of disease modeling, especially in neural diseases. Although the direct reprogramming to hiNPCs has several advantages over differentiation after hiPSC reprogramming, such as the time required and the simple procedure, relatively few studies have utilized hiNPCs. Here, we optimized the protocol for hiNPC reprogramming using pluripotency factors and Sendai virus. In addition, we generated hiNPCs of two healthy donors, a sporadic PD patient, and a familial patient with the LRRK2 G2019S mutation (L2GS). The four hiNPC cell lines are highly proliferative, expressed NPC markers, maintained the normal karyotype, and have the differentiation potential of dopaminergic neurons. Importantly, the patient hiNPCs show different apoptotic marker expression. Thus, these hiNPCs, in addition to hiPSCs, are a favorable option to study PD pathology.

Assessment of the modulation degrees of intensity-modulated radiation therapy plans.

BACKGROUND: To evaluate the modulation indices (MIs) for predicting the plan delivery accuracies of intensity-modulated radiation therapy (IMRT) plans. METHODS: A total of 100 dynamic IMRT plans that used TrueBeam STx and 102 dynamic IMRT plans that used Trilogy were selected. For each plan, various MIs were calculated, which included the modulation complexity score (MCS), plan-averaged beam area (PA), plan-averaged beam irregularity (PI), plan-averaged beam modulation (PM), MI quantifying multi-leaf collimator (MLC) speeds (MIs), MI quantifying MLC acceleration (MIa), and MI quantifying MLC acceleration and segment aperture irregularity (MIc,IMRT). To determine plan delivery accuracy, global gamma passing rates, MLC errors of log files, and dose-volumetric parameter differences between original and log file-reconstructed IMRT plans were obtained. To assess the ability of each MI for predicting plan delivery accuracy, Spearman's rank correlation coefficients (rs) between MIs and plan delivery accuracy measures were calculated. RESULTS: PI showed moderately strong correlations with gamma passing rates in MapCHECK2 measurements of both TrueBeam STx and Trilogy (rs = - 0.591 with p <  0.001 and - 0.427 with p <  0.001 to with gamma criterion of 2%/2 mm, respectively). For ArcCHECK measurements, PI also showed moderately strong correlations with the gamma passing rates in the ArcCHECK measurements of TrueBeam STx and Trilogy (rs = - 0.545 with p <  0.001 and rs = - 0.581 with p <  0.001 with gamma criterion of 2%/2 mm, respectively). The PI showed the second strongest correlation with MLC errors in both TrueBeam STx and Trilogy (rs = 0.861 with p <  0.001 and rs = 0.767 with p <  0.001, respectively). In general, the PI showed moderately strong correlations with every plan delivery accuracy measure. CONCLUSIONS: The PI showed moderately strong correlations with every plan delivery accuracy measure and therefore is a useful predictor of IMRT delivery accuracy.

Leucine-Rich Repeat Kinase 2 (LRRK2) phosphorylates p53 and induces p21(WAF1/CIP1) expression.

BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) is a gene in which a mutation causes Parkinson's disease (PD), and p53 is a prototype tumor suppressor. In addition, activation of p53 in patient with PD has been reported by several studies. Because phosphorylation of p53 is critical for regulating its activity and LRRK2 is a kinase, we tested whether p53 is phosphorylated by LRRK2. RESULTS: LRRK2 phosphorylates threonine (Thr) at TXR sites in an in vitro kinase assay, and the T304 and T377 were identified as putative phosphorylated residues. An increase of phospho-Thr in the p53 TXR motif was confirmed in the cells overexpressing G2019S, and human induced pluripotent stem (iPS) cells of a G2019S carrier. Interactions between LRRK2 and p53 were confirmed by co-immunoprecipitation of lysates of differentiated SH-SY5Y cells. LRRK2 mediated p53 phosphorylation translocalizes p53 predominantly to nucleus and increases p21(WAF1/CIP1) expression in SH-SY5Y cells based on reverse transcription-polymerase chain reaction and Western blot assay results. The luciferase assay using the p21(WAF1/CIP1) promoter-reporter also confirmed that LRRK2 kinase activity increases p21 expression. Exogenous expression of G2019S and the phosphomimetic p53 T304/377D mutants increased expression of p21(WAF1/CIP1) and cleaved PARP, and cytotoxicity in the same cells. We also observed increase of p21 expression in rat primary neuron cells after transient expression of p53 T304/377D mutants and the mid-brain lysates of the G2019S transgenic mice. CONCLUSION: p53 is a LRRK2 kinase substrate. Phosphorylation of p53 by LRRK2 induces p21(WAF1/CIP1) expression and apoptosis in differentiated SH-SY5Y cells and rat primary neurons.