Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): preclinical and clinical trial in osteoarthritis of the knee joint

BACKGROUND: Osteoarthritis (OA) is a common and debilitating chronic degenerative disease of the joints. Currently, cell-based therapy is being explored to address the repair of damaged articular cartilage in the knee joint. METHODS: The in vitro differentiation potential of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®) was determined by differentiating the cells toward the chondrogenic lineage and quantifying sulfated glycosaminoglycan (sGAG). The mono-iodoacetate (MIA)-induced preclinical model of OA has been used to demonstrate pain reduction and cartilage formation. In the clinical study, 60 OA patients were randomized to receive different doses of cells (25, 50, 75, or 150 million cells) or placebo. Stempeucel® was administered by intra-articular (IA) injection into the knee joint, followed by 2 ml hyaluronic acid (20 mg). Subjective evaluations—visual analog scale (VAS) for pain, intermittent and constant osteoarthritis pain (ICOAP), and Western Ontario and McMaster Universities Osteoarthritis (WOMAC-OA) index—were performed at baseline and at 1, 3, 6, and 12 months of follow-up. Magnetic resonance imaging of the knee was performed at baseline, and at 6 and 12 months follow-up for cartilage evaluation. RESULTS: Stempeucel® differentiated into the chondrogenic lineage in vitro with downregulation of Sox9 and upregulation of Col2A genes. Furthermore, Stempeucel® differentiated into chondrocytes and synthesized a significant amount of sGAG (30 ± 1.8 μg/μg GAG/DNA). In the preclinical model of OA, Stempeucel® reduced pain significantly and also repaired damaged articular cartilage in rats. In the clinical study, IA administration of Stempeucel® was safe, and a trend towards improvement was seen in the 25-million-cell dose group in all subjective parameters (VAS, ICOAP, andWOMAC-OA scores), although this was not statistically significant when compared to placebo. Adverse events were predominant in the higher dose groups (50, 75, and 150 million cells). Knee pain and swelling were the most common adverse events. The whole-organ magnetic resonance imaging score of the knee did not reveal any difference from baseline and the placebo group. CONCLUSION: Intra-articular administration of Stempeucel® is safe. A twenty-five-million-cell dose may be the most effective among the doses tested for pain reduction. Clinical studies with a larger patient population are required to demonstrate a robust therapeutic efficacy of Stempeucel® in OA. TRIAL REGISTRATION: Clinicaltrials.gov NCT01453738. Registered 13 October 2011

A Comparison Of Weak Supervision Methods For Knowledge Base Construction

We present a comparison of weak and distant supervision methods for producing proxy examples for supervised relation extraction. We find that knowledge-based weak supervision tends to outperform popular distance supervision techniques, providing a higher yield of positive examples and more accurate models

Expansion and characterization of bone marrow derived human mesenchymal stromal cells in serum-free conditions

AbstractBone marrow-derived mesenchymal stromal cells (BM-MSCs) are gaining increasing importance in the field of regenerative medicine. Although therapeutic value of MSCs is now being established through many clinical trials, issues have been raised regarding their expansion as per regulatory guidelines. Fetal bovine serum usage in cell therapy poses difficulties due to its less-defined, highly variable composition and safety issues. Hence, there is a need for transition from serum-based to serum-free media (SFM). Since SFM are cell type-specific, a precise analysis of the properties of MSCs cultured in SFM is required to determine the most suitable one. Six different commercially available low serum/SFM with two different seeding densities were evaluated to explore their ability to support the growth and expansion of BM-MSCs and assess the characteristics of BM-MSCs cultured in these media. Except for one of the SFM, all other media tested supported the growth of BM-MSCs at a low seeding density. No significant differences were observed in the expression of MSC specific markers among the various media tested. In contrary, the population doubling time, cell yield, potency, colony-forming ability, differentiation potential, and immunosuppressive properties of MSCs varied with one another. We show that SFM tested supports the growth and expansion of BM-MSCs even at low seeding density and may serve as possible replacement for animal-derived serum.</jats:p

Benzoylfuran- and Thiophene-Based Thermally Activated Delayed Fluorescence Emitters for Organic Light-Emitting Diodes

Thermally activated delayed fluorescent (TADF) emitters have received much attention in organic light-emitting diodes (OLEDs) due to a number of advantages, including 100% internal quantum efficiency, no heavy-metal doping, and the ability to prevent shortages of conventional fluorescent and phosphorescent materials. Herein, we report two TADF emitters, namely, [3,5-bis(3,6-di-tert-butyl-9H-carbazol-9-yl)phenyl](furan-2-yl)methanone (2BFu-mTCz) and [3,5-bis(3,6-di-tert-butyl-9H-carbazol-9-yl)phenyl](thiophen-2-yl)methanone (2BTp-mTCz). The emission maxima of the emitters have been observed in the sky-blue region, which are well in accordance with theoretical (density functional theory and time-dependent density functional theory) calculations. The singlet–triplet energy gap (ΔEST) of the emitters shows the TADF nature due to the small ΔEST values (ΔEST = 0.09 eV for 2BFu-mTCz and 0.12 eV for 2BTp-mTCz). Compared with the solution state, the photoluminescence quantum yield increased significantly in the solid state, reaching 40% for 2BFu-mTCz and 46% for 2BTp-mTCz. The maximum external quantum efficiency of 9.6 and 9.0% and sky-blue emission with Commission internationale de l’éclairage coordinates of (0.19, 0.36) and (0.20, 0.36) were observed for 2BFu-mTCz and 2BTp-mTCz, respectively. This work paves a direction to finetune the kRISC values and lifetimes by introducing the heavy atom in direct conjugation

A Phase Ii Dose Escalation Study of Intraarterial (Hepatic) Adult Human Bone Marrow Derived, Cultured, Pooled, Allogeneic Mesenchymal Stromal Cells&amp;nbsp;(Stempeucel®) in Patients with Alcoholic Liver Cirrhosis

Abstract Background: Alcoholic liver cirrhosis is an end stage alcoholic liver disease with poor prognosis. The definitive treatment of alcoholic liver cirrhosis is orthotopic liver transplantation, which is expensive, requires long term immunosuppression and is limited by supply of organs. Being an unmet medical need, cell therapy is under investigation for alcoholic liver cirrhosis.Aims: This study was designed primarily for assessing the safety and feasibility of administering stempeucel® through the hepatic artery in alcoholic liver cirrhosis and secondarily to assess possible efficacy and dose-response.Methods: Forty patients with alcoholic cirrhosis (18-65 years/Child Pugh class B or C/Model for End-Stage Liver Disease score of minimum 10) were included in 4 groups: 2.5 million cells/kg Body Weight (2.5M Cell) and respective control (2.5M Control); 5 million cells/kg Body Weight (5M Cell) and respective control (5M Control) with 10 patients in each group. Cell groups received stempeucel® administered via hepatic artery by catheterization through femoral artery (Seldinger technique) and Standard Protocol of Care. Control group received Standard Protocol of Care. Patients were followed up at 1 week, 1 month, 3 months and 6 months. Safety evaluations included clinical examination, Electrocardiogram and laboratory investigations. Efficacy evaluations included liver function test, Model for End-Stage Liver Disease score, Child Pugh score, Short Form-36 questionnaire, liver stiffness using Fibroscan (Transient Elastography), and liver volume using Computerized Tomography scan. Results: stempeucel® injection was well tolerated. Common treatment emergent adverse events were in Gastrointestinal disorders, General disorders and administration site conditions and Infections and infestations. Most of the treatment emergent adverse events were unrelated / remotely related to stempeucel®. Thirty serious adverse events occurred in 10 patients (3 in 2.5M Cell, 5 in 5M Cell and one each in control groups). Three patients died due to SAEs: Two in 2.5M and one in 5M Cell group, none were related to stempeucel®. There was no significant difference in efficacy evaluations at 6 months versus baseline compared to control at both the dose levels of stempeucel®. Statistically significant improvement was seen in 2.5M group compared to control group in Short Form-36 score: bodily pain, mental component summary, vitality and social functioning. Conclusions: stempeucel® was safe, well tolerated and subjective improvement in few component scores of Short Form-36 was seen 2.5M cell group.Trial registrationClinicaltrials.gov: NCT01591200Clinical Trial Registry – India: CTRI/2009/091/000432</jats:p

A Phase II Dose Escalation Study of Intraarterial (Hepatic) Adult Human Bone Marrow Derived, Cultured, Pooled, Allogeneic Mesenchymal Stromal Cells (Stempeucel®) in Patients with Alcoholic Liver Cirrhosis

Background: Alcoholic liver cirrhosis is an end-stage alcoholic liver disease with a poor prognosis. The definitive treatment of alcoholic liver cirrhosis is orthotopic liver transplantation, which is expensive, requires long-term immunosuppression and is limited by the supply of organs. Being an unmet medical need, cell therapy is under investigation for alcoholic liver cirrhosis. Aims: This study was designed primarily for assessing the safety and feasibility of administering stempeucel® through the hepatic artery in alcoholic liver cirrhosis and secondarily to assess possible efficacy and dose-response. Methods: Sixty patients with alcoholic cirrhosis (18-65 years/Child-Pugh class B or C/Model for End-Stage Liver Disease score of minimum 10) were planned to be included in 6 groups: 2.5 million cells/kg Body Weight (2.5M Cell) and respective control (2.5M Control); 5 million cells/kg Body Weight (5M Cell) and respective control (5M Control); 7.5 million cells/kg Body Weight (5M Cell) and respective control (7.5M Control) with 10 patients in each group. Cell groups received stempeucel® administered via hepatic artery by catheterization through the femoral artery (Seldinger technique) and Standard Protocol of Care. The control group received Standard Protocol of Care. Patients were followed up at 1 week, 1 month, 3 months and 6 months. Efficacy evaluations included liver function test, Model for End-Stage Liver Disease score, Child-Pugh score, Short Form-36 questionnaire, liver stiffness using Fibroscan (Transient Elastography), and liver volume using Computerized Tomography scan. Results: Stempeucel® injection was well tolerated. Common treatment-emergent adverse events were gastrointestinal disorders, general disorders and administration site conditions and infections and infestations. Most of the treatment-emergent adverse events were unrelated / remotely related to stempeucel®. Thirty serious adverse events occurred in 10 patients (3 in 2.5M Cell, 5 in 5M Cell and one each in control groups). Three patients died due to SAEs: Two in 2.5M and one in 5M Cell group, none were related to stempeucel®. Statistically significant improvement was seen in 2.5M group compared to the control group in Short Form-36 score: bodily pain, mental component summary, vitality and social functioning. Conclusion: Stempeucel® was safe, well-tolerated and subjective improvement in Short Form-36 (bodily pain, mental component summary, vitality and social functioning and mental health) score was seen in the 2.5M cell group.</jats:p

Phase IV Postmarketing Surveillance Study Shows Continued Efficacy and Safety of Stempeucel in Patients with Critical Limb Ischemia Due to Buerger's Disease

Abstract Buerger's disease or thromboangiitis obliterans is a type of obstructive vascular diseases categorized as vasculitis and usually present in 95% of young smoker men. The main pathogenetic mechanism is interplay between immune system and inflammation. Earlier our phase II study has shown that Stempeucel is safe when injected at 2 million cells/kg body weight by virtue of its anti-inflammatory, immunomodulatory, and angiogenetic properties. The present study was conducted to further assess the safety and efficacy of Stempeucel in critical limb ischemia due to Buerger's disease after obtaining approval from Indian FDA based on the data generated in the phase II study. This is an open label, multicenteric phase IV PMS study conducted across India with experienced vascular surgeons. Fifty patients of critical limb ischemia due to Buerger's disease with Rutherford III-5 or III-6 were included in the study and each individual received a dose of 2 million cells/kg body weight of Stempeucel in the calf muscles and around the ulcer. These patients were evaluated over 12 months from drug administration. The present study showed the continued long term efficacy over a period of 12 months follow up in these patients corroborating the result obtained in the previous phase II studies. There was significant improvement in rest pain, ankle systolic pressure, and ankle brachial pressure index with accelerated ulcer healing. In conclusion, the present study shows that the intramuscular administration of Stempeucel continues to be safe, tolerable, and effective alternative treatment in patients with Buerger's disease.</jats:p