Repeated infusion of autologous adipose tissue-derived stem cells for Parkinson's disease.

BACKGROUND: Mesenchymal stem cells are expected to have a therapeutic effect on progressive neurodegenerative diseases for which there is currently no fundamental treatment. AIMS OF THE STUDY: The aim is to confirm that repeated infusion of autologous adipose tissue-derived stem cells (ADSCs) can be safely administered to patients with Parkinson's disease, and to investigate the effects of this as a pilot study. METHODS: Three patients with Parkinson's disease received five or six repeated infusions of ADSCs at intervals of approximately one month. Observations were based on medical examinations by a neurologist and interviews with the patient and caregivers. The severity of Parkinson's disease was assessed using the Hoehn & Yahr staging scale and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). RESULTS: No adverse events were observed during the observation period from the start of treatment to six months after the end of the last dose. MDS-UPDRS improved in all three patients. CONCLUSIONS: Repeated administration of Autologous ADSCs for Parkinson's disease was safe and feasible. The results of this pilot study provide insight into the value of further research.

"Evaluation of neprilysin activity in Adipose-Derived stem cells from Alzheimer's disease patients".

INTRODUCTION: The antibody drugs targeting ß-amyloid in Alzheimer's disease pose risks of inflammation and vascular damage. It is known that neprilysin, an endogenous enzyme responsible for ß-amyloid degradation, is reduced in areas with ß-amyloid deposition. Supplementation of neprilysin could potentially contribute to Alzheimer's disease treatment. When considering the use of adipose tissue-derived stem cells (ADSCs) for Alzheimer's disease therapy, it is crucial to ensure that Alzheimer's disease patient-derived ADSCs maintain neprilysin activity. If so, the use of autologous ADSCs may lead to a treatment with minimal risks of rejection or infection. Therefore, we investigated the neprilysin activity in Alzheimer's disease patient-derived adipose tissue-derived stem cells to assess their potential in Alzheimer's disease treatment. METHODS: Five Alzheimer's disease patients (MSC1-5) and two Chronic Obstructive Pulmonary Disease (COPD) patients (MSC6-7) were enrolled. ADSCs were cultured for 6 days with varying seeding densities. On the 3rd day, the medium was replaced, and on the 6th day, ADSCs were harvested. Cells were stained for PE-Cy7 Mouse IgG1 κ Isotype control and PE-Cy Mouse Anti-Human CD10, and CD10 expression was assessed by flow cytometry. Ethical approval and informed consent were obtained. RESULTS: Neprilysin activity, crucial for ß-amyloid degradation, was assessed in ADSCs. Positivity rates for CD10 expression in ADSCs from Alzheimer's patients were consistently high: 99.6%, 99.5%, 99.9%, 99.3%, 99.8%, and 100.0%. Control ADSCs from COPD patients (MSC6-7) exhibited comparable positivity rates. Flow cytometry plots for all seven cases are presented in Figures 1-7. DISCUSSION: This study confirms the presence and maintenance of neprilysin activity in ADSCs from Alzheimer's disease patients. The high positivity rates for CD10 expression in these cells suggest that neprilysin, a key enzyme in ß-amyloid degradation, remains active. The implications are significant, as ADSCs offer immune-compatible and low infection risk advantages. The study underscores the potential of autologous ADSCs as a therapeutic approach in Alzheimer's disease. Their ability to naturally harbor neprilysin activity, coupled with their safety profile, makes them a promising candidate for further exploration. While acknowledging the need for larger, more diverse cohorts and long-term studies, these findings contribute to the growing body of evidence supporting the development of stem cell-based interventions in Alzheimer's disease treatment.

Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes.

The ezrin-radixin-moesin (ERM) family of proteins crosslink actin filaments and integral membrane proteins. Radixin (encoded by Rdx) is the dominant ERM protein in the liver of wildtype mice and is concentrated at bile canalicular membranes (BCMs). Here we show that Rdx(-/-) mice are normal at birth, but their serum concentrations of conjugated bilirubin begin to increase gradually around 4 weeks, and they show mild liver injury after 8 weeks. This phenotype is similar to human conjugated hyperbilirubinemia in Dubin-Johnson syndrome, which is caused by mutations in the multidrug resistance protein 2 (MRP2, gene symbol ABCC2), although this syndrome is not associated with overt liver injury. In wildtype mice, Mrp2 concentrates at BCMs to secrete conjugated bilirubin into bile. In the BCMs of Rdx(-/-) mice, Mrp2 is decreased compared with other BCM proteins such as dipeptidyl peptidase IV (CD26) and P-glycoproteins. In vitro binding studies show that radixin associates directly with the carboxy-terminal cytoplasmic domain of human MRP2. These findings indicate that radixin is required for secretion of conjugated bilirubin through its support of Mrp2 localization at BCMs.

Feasibility and Safety of Adjuvant Chemotherapy for Resected Colorectal Cancer in Patients With Renal Insufficiency: A Pooled Analysis of Individual Patient Data from Five Japanese Large-scale Clinical Trials.

BACKGROUND/AIM: The incidence of chemotherapy-related adverse events in colorectal cancer patients with renal insufficiency has been compared to patients with normal renal function in only a few studies. The purpose of this analysis was to verify the feasibility and safety of adjuvant chemotherapy for postoperative colorectal cancer patients with renal insufficiency. PATIENTS AND METHODS: Adverse events and discontinuation of adjuvant chemotherapy for patients with curatively resected locally advanced colorectal cancer were examined using a combined database of individual patient data obtained from five large-scale clinical trials (n=4,106). The renal function of patients was classified into Level (L) 1-2: ≥60 ml/min and L3-4: <60 ml/min. RESULTS: As Grade 3 adverse events, hematological toxicities, such as neutropenia and anemia, and gastrointestinal disorders, such as diarrhea and vomiting, were significantly more frequent in the L3-4 group. Moreover, the time-to-treatment discontinuation in the L3-4 group was higher (hazard ratio=1.21, p=0.0012). T factor, N factor, and creatinine clearance level were found to be independent risk factors for the discontinuation of adjuvant chemotherapy. In the subgroup analysis of FOLFOX, neutropenia and diarrhea were significantly common in the L3-4 group, but neurotoxicities were not different. There was no significant difference in the discontinuation of adjuvant FOLFOX. CONCLUSION: Adverse events of adjuvant chemotherapy in patients with resected colorectal cancer were associated with renal insufficiencies. Since adverse events have the potential to shorten the duration of treatment, especially when using chemotherapy without oxaliplatin, careful management, including dose reduction, may be important in patients with renal insufficiency.

[A new strategy for locally advanced rectal cancer using a nerve-regeneration tube].

In surgery for the treatment of locally advanced rectal cancers affecting the intrapelvic nerves, when an affected nerve is resected in extended surgery to achieve radical cure, the resection results in functional disturbance in the organ it controls. On the other hand, when the nerve remains intact after function-preserving surgery, the risk of local recurrence is high because of possible remnant cancer cells. Thus in performing surgery to treat such cancers, there is a dilemma between the selection of extended surgery or function-preserving surgery. To resolve this, we devised a new strategy in which the cancer is removed radically in extended surgery and organ function is recovered by regeneration of the resected nerve using a nerve-regenerating tube. After animal experiments had confirmed the regeneration of nerve functions with nerve-regenerating tubes, we followed this new strategy to treat 17 patients with locally advanced cancers who underwent extended surgery plus the regeneration of the resected nerve using the nerve-regenerating tube. Nerve function was restored to a significant degree in 16 of the 17 patients.

Perspectives on Stem Cell-Based Regenerative Medicine with a Particular Emphasis on Mesenchymal Stem Cell Therapy.

Regenerative medicine is a medical treatment that aims to restore lost human body functions by regenerating missing or dysfunctional organs and tissues using stem cells, etc. There are three major types of stem cells used in regenerative medicine: induced pluripotent stem cells (iPS cells), embryonic stem cells (ES cells), and mesenchymal stem cells (MSCs). MSCs are expected to be widely applied to regenerative medicine because of their ability to differentiate into various types of cells, repair cells and tissues; anti-inflammatory effects; secretion of various growth factors; and resolution of abnormally accumulated protein amyloid. MSCs can be derived from bone marrow, dental pulp, and other sources, but adipose tissue-derived stem cells (ADSCs) may be superior in that they can be harvested with the least amount of invasion, and therefore, a sufficient amount of stem cells can be cultured relatively easily. When MSCs are administered systemically by intravenous infusion, they tend to accumulate at the site of disease, a property known as "homing," which is extremely advantageous for clinical applications. In Japan, stem cell therapy can be performed only after the research or treatment plan has been reviewed and approved by the "Committee for Specific Approval of Regenerative Medicine" and submitted to the Ministry of Health, Labor and Welfare for approval in accordance with the "Act on Securing the Safety of Regenerative Medicine" and after approval by the ethics committee of the facility where the therapy is performed. In this review, the characteristics of MSCs, the actual status of their clinical application, and their future prospects are presented.

Final Analysis of 3 Versus 6 Months of Adjuvant Oxaliplatin and Fluoropyrimidine-Based Therapy in Patients With Stage III Colon Cancer: The Randomized Phase III ACHIEVE Trial.

PURPOSE: The phase III ACHIEVE trial conducted in Japan was one of six prospective studies included in the International Duration Evaluation of Adjuvant Therapy collaboration, which explored whether 3 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) therapy would be noninferior to 6 months of treatment in patients with curatively resected stage III colon cancer. We report the final analyses of survival and long-term safety. PATIENTS AND METHODS: Eligible patients were randomly assigned (1:1) to either 3 or 6 months of adjuvant chemotherapy (modified [m]FOLFOX6 or CAPOX, as selected by the treating physician). Random assignment was stratified according to number of involved lymph nodes, center, regimen, primary site, and age. The primary end point was disease-free survival, assessed in the modified intention-to-treat population. Overall survival (OS) was a secondary end point. RESULTS: The modified intention-to-treat population comprised 1,291 patients: 641 in the 6-month treatment group and 650 in the 3-month treatment group. Median follow-up for this analysis was 74.7 months. Five-year OS rates were comparable: 87.0% in the 3-month treatment group and 86.4% in the 6-month treatment group (hazard ratio, 0.91; 95% CI, 0.69 to 1.20; P = .51). Subgroup analysis of OS did not reveal a significant interaction between baseline characteristics and treatment duration. Peripheral sensory neuropathy lasting longer than 5 years was more common in the 6- compared with 3-month treatment group (16% v 8%, respectively), and in those receiving mFOLFOX6 compared with CAPOX (14% v 11%, respectively). CONCLUSION: In Asian patients, shortening adjuvant therapy duration from 6 to 3 months did not compromise efficacy and reduced the rate of long-lasting peripheral sensory neuropathy. In this setting, 3 months of CAPOX therapy is an appropriate adjuvant treatment option.

Hypothesis: Intravenous administration of mesenchymal stem cells is effective in the treatment of Alzheimer's disease.

We propose the intravenous administration of autologous adipose-derived stem cells as a new treatment for Alzheimer's disease. We hypothesize that the stem cells will secrete neprilysin in the brain to break down and remove amyloid deposits in the Alzheimer's brain. We have shown a case of skin amyloid deposition that disappeared after stem cell administration and confirmed that the stem cells administered had neprilysin activity. In addition to neprilysin secretion, other mechanisms of action of stem cells include nerve regeneration, nerve repair, growth factor secretion, anti-inflammatory effects, and angiogenesis. The harvesting of adipose-derived stem cells is minimally invasive, and intravenous administration can be safely repeated. We hope that the efficacy of this new treatment will be verified and that it will bring a ray of hope to patients suffering from this incurable disease.

Isolation of adipose tissue-derived stem cells by direct membrane migration and expansion for clinical application.

Mesenchymal stem cells (MSCs) have recently made significant progression in multiple clinical trials targeting several clinical disorders and in the modulation of immune responses. In the present study, we isolated human adipose tissue-derived stem cells (ADSCs) by direct membrane migration method without using enzymatic digestion via collagenase, and tried to extract adequate number of cells for clinical application. Hydroxyapatite-treated nonwoven fabric membrane made up of synthetic macromolecular fiber materials, polyethylene and polyester terephthalene was used. Expansion culture of ADSCs having plastic flask adherent characteristic in serum-free condition was successfully established, and adequate number of cells were obtained for clinical application. They were found to be positive for CD44, CD73, CD90 and CD105 and negative for CD11b, CD34, CD45, CD80 and HLA-DR. The resulting immunological marker profile satisfied the immunophenotype of previously reported MSCs. Also, microscopic findings demonstrated trilineage differentiation into adipogenic, osteogenic and chondrogenic cells as the characteristics of MSCs. The isolation by nonwoven fabric membrane and expanded cells under serum-free condition satisfied the criteria of MSCs, as proposed by the International Society for Cellular Therapy. Our direct membrane migration method without enzyme digestion is useful as ADSCs can be obtained from small pieces of adipose tissue and expanded under serum-free culture condition. This method was considered to be feasible for clinical application.

Multicenter phase II study of weekly paclitaxel plus S-1 combination chemotherapy in patients with advanced gastric cancer.

BACKGROUND: A multicenter phase II study was conducted to evaluate the efficacy and safety of a combination regimen of weekly paclitaxel plus S-1 in patients with advanced gastric cancer. METHODS: Patients with previously untreated metastatic or recurrent gastric cancer received intravenous paclitaxel 50 mg/m(2) on days 1, 8, and 15, plus oral S-1 40 mg/m(2) b.i.d. on days 1 to 14 followed by 2 weeks off, in a 28-day cycle. RESULTS: A total of 54 patients were registered. All of them had measurable disease and were determined to be eligible for the present study. Two complete responses and 23 partial responses were confirmed, giving an overall response rate of 46.3%. At a final follow up of 3 years, the median progression-free survival and median overall survival were 6.0 and 14.3 months, respectively. Grade 3 neutropenia occurred in 14 patients, and grade 4 in 1 patient (total, 27.8%). The most serious nonhematological toxicity was diarrhea, where grade 3 occurred in 5 patients (9.3%). There were no treatment-related deaths. CONCLUSION: A combination of weekly paclitaxel plus S-1 was found to be well tolerated and effective in patients with advanced gastric cancer. Further investigation with comparative trials is needed for confirmation.