Past, present, and future of cell replacement therapy for parkinson's disease: a novel emphasis on host immune responses.

Parkinson's disease (PD) stands as the second most common neurodegenerative disorder after Alzheimer's disease, and its prevalence continues to rise with the aging global population. Central to the pathophysiology of PD is the specific degeneration of midbrain dopamine neurons (mDANs) in the substantia nigra. Consequently, cell replacement therapy (CRT) has emerged as a promising treatment approach, initially supported by various open-label clinical studies employing fetal ventral mesencephalic (fVM) cells. Despite the initial favorable results, fVM cell therapy has intrinsic and logistical limitations that hinder its transition to a standard treatment for PD. Recent efforts in the field of cell therapy have shifted its focus towards the utilization of human pluripotent stem cells, including human embryonic stem cells and induced pluripotent stem cells, to surmount existing challenges. However, regardless of the transplantable cell sources (e.g., xenogeneic, allogeneic, or autologous), the poor and variable survival of implanted dopamine cells remains a major obstacle. Emerging evidence highlights the pivotal role of host immune responses following transplantation in influencing the survival of implanted mDANs, underscoring an important area for further research. In this comprehensive review, building upon insights derived from previous fVM transplantation studies, we delve into the functional ramifications of host immune responses on the survival and efficacy of grafted dopamine cells. Furthermore, we explore potential strategic approaches to modulate the host immune response, ultimately aiming for optimal outcomes in future clinical applications of CRT for PD.

Jeongeuplla avenae gen. nov., sp. nov., a novel ß-carotene-producing bacterium that alleviates salinity stress in Arabidopsis.

A novel endophytic bacterium, designated DY-R2A-6T, was isolated from oat (Avena sativa L.) seeds and found to produces ß-carotene. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain DY-R2A-6T had 96.3% similarity with Jiella aquimaris LZB041T, 96.0% similarity with Aurantimonas aggregate R14M6T and Aureimonas frigidaquae JCM 14755T, and less than 95.8% similarity with other genera in the family Aurantimonadaceae. The complete genome of strain DY-R2A-6T comprised 5,929,370 base pairs, consisting of one full chromosome (5,909,198 bp) and one plasmid (20,172 bp), with a G + C content was 69.1%. The overall genome-related index (OGRI), including digital DNA-DNA hybridization (<20.5%), ANI (<79.2%), and AAI (<64.2%) values, all fell below the thresholds set for novel genera. The major cellular fatty acids (>10%) of strain DY-R2A-6T were C16:0, C19:0 cyclo ω8c, and summed feature 8 (C18:1ω7c and/or C18:1ω6c). Ubiquinone-10 was the main respiratory quinone. We identified the gene cluster responsible for carotenoid biosynthesis in the genome and found that the pink-pigment produced by strain DY-R2A-6T is ß-carotene. In experiment with Arabidopsis seedlings, co-cultivation with strain DY-R2A-6T led to a 1.4-fold increase in plant biomass and chlorophyll content under salt stress conditions, demonstrating its capacity to enhance salt stress tolerance in plants. Moreover, external application of ß-carotene to Arabidopsis seedlings under salt stress conditions also mitigated the stress significantly. Based on these findings, strain DY-R2A-6T is proposed to represent a novel genus and species in the family Aurantimonadaceae, named Jeongeuplla avenae gen. nov., sp. nov. The type strain is DY-R2A-6T (= KCTC 82985T = GDMCC 1.3014T). This study not only identified a new taxon but also utilized genome analysis to predict and confirm the production of ß-carotene by strain DY-R2A-6T. It also demonstrated the ability of this strain to enhance salt stress tolerance in plants, suggesting potential application in agriculture to mitigate environmental stress in crops.

Sphingomonas abietis sp. nov., an Endophytic Bacterium Isolated from Korean Fir.

PAMB 00755T, a bacterial strain, was isolated from Korean fir leaves. The strain exhibits yellow colonies and consists of Gram-negative, non-motile, short rods or ovoid-shaped cells. It displays optimal growth conditions at 20°C, 0% NaCl, and pH 6.0. Results of 16S rRNA gene-based phylogenetic analyses showed that strain PAMB 00755T was most closely related to Sphingomonas chungangi MAH-6T (97.7%) and Sphingomonas polyaromaticivorans B2-7T (97.4%), and ≤96.5% sequence similarity to other members of the genus Sphingomonas. The values of average nucleotide identity (79.9-81.3%), average amino acid identity (73.3-75.9%), and digital DNA-DNA hybridization (73.3-75.9%) were significantly lower than the threshold values for species boundaries; these overall genome-related indexes (OGRI) analyses indicated that the strain represents a novel species. Genomic analysis revealed that the strain has a 4.4-Mbp genome encoding 4,083 functional genes, while the DNA G+C content of the whole genome is 66.1%. The genome of strain PAMB 00755T showed a putative carotenoid biosynthetic cluster responsible for its antioxidant activity. The respiratory quinone was identified as ubiquinone 10 (Q-10), while the major fatty acids in the profile were identified as C18:1ω7c and/or C18:1ω6c (summed feature 8). The major polar lipids of strain PAMB 00755T were diphosphatidylglycerol, phosphatidylethanolamine, sphingoglycolipid, and phosphatidylcholine. Based on a comprehensive analysis of genomic, phenotypic, and chemotaxonomic characteristics, we proposed the name Sphingomonas abietis sp. nov. for this novel species, with PAMB 00755T as the type strain (= KCTC 92781T = GDMCC 1.3779T).

Co-transplantation of autologous Treg cells in a cell therapy for Parkinson's disease.

The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson's disease, which makes cell replacement a promising therapeutic approach1-4. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes5-8. Here we show that the surgical procedure itself (referred to here as 'needle trauma') triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells and brain cell death. When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH- grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson's disease with 6-hydroxydopamine lesions. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH- grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons. Together, these data emphasize the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson's disease.

Effects of Carbohydrates on Rosmarinic Acid Production and In Vitro Antimicrobial Activities in Hairy Root Cultures of Agastache rugosa.

Agastache rugosa (popularly known as Korean mint) belongs to the Lamiaceae family and comprises 22 species of perennial aromatic medicinal species native to East Asian countries, such as Korea, Taiwan, Japan, and China. A. rugosa contains many phenolic compounds that exhibit pharmacological and physiological activities, including antioxidant, anticancer, antiviral, antifungal, and antibacterial activities. The highest concentrations of rosmarinic acid and its isomers have been reported in the roots of A. rugosa. In this in vitro study, hairy roots of A. rugosa were obtained and the carbohydrates (sorbitol, mannitol, glucose, maltose, galactose, mannose, and sucrose) were evaluated to determine those that were optimal for rosmarinic acid production and hairy root growth. Antioxidant and antibacterial activities of extracts of A. rugosa were also assessed. The best carbon source for A. rugosa hairy root cultures was sucrose, considering biomass productivity (0.460 ± 0.034 mg/30 mL), rosmarinic acid production (7.656 ± 0.407 mg/g dry weight), and total phenolic content (12.714 ± 0.202 mg/g gallic acid equivalent). Antioxidant and antimicrobial activities were displayed by A. rugosa hairy roots cultured in liquid medium supplemented with 100 mM sucrose. Twenty-five bacterial strains, including multidrug-resistant bacteria and one pathogenic yeast strain, were used for antimicrobial screening of A. rugosa hairy roots. The hairy root extracts displayed antibacterial activity against Micrococcus luteus (KCTC 3063) and Bacillus cereus (KCTC 3624). The inhibition of these bacteria was greater using A. rugosa hairy roots with the highest levels of phenolic compounds cultured in the presence of sucrose, compared to hairy roots with the lowest levels of phenolic compounds cultured in the presence of fructose. Considering hairy root biomass, phenolic compound production, and antibacterial activity, sucrose is the best carbon source for A. rugosa hairy root cultures.

A nostoxanthin-producing bacterium, Sphingomonas nostoxanthinifaciens sp. nov., alleviates the salt stress of Arabidopsis seedlings by scavenging of reactive oxygen species.

A novel, nostoxanthin-producing, endophytic bacterium, designated as AK-PDB1-5T, was isolated from the needle-like leaves of the Korean fir (Abies koreana Wilson) collected from Mt. Halla in Jeju, South Korea. A 16S rRNA sequence comparison indicated that the closest phylogenetic neighbors were Sphingomonas crusticola MIMD3T (95.6%) and Sphingomonas jatrophae S5-249T (95.3%) of the family Sphingomonadaceae. Strain AK-PDB1-5T had a genome size of 4,298,284 bp with a 67.8% G + C content, and digital DNA-DNA hybridization and OrthoANI values with the most closely related species of only 19.5-21% and 75.1-76.8%, respectively. Cells of the strain AK-PDB1-5T were Gram-negative, short rods, oxidase- and catalase-positive. Growth occurred at pH 5.0-9.0 (optimum pH 8.0) in the absence of NaCl at 4-37°C (optimum 25-30°C). Strain AK-PDB1-5T contained C14:0 2OH, C16:0 and summed feature 8 as the major cellular fatty acids (> 10%), while sphingoglycolipid, phosphatidylethanolamine, phosphatidylglycerol, phospholipids and lipids were found to be the major polar lipids. The strain produces a yellow carotenoid pigment; natural products prediction via AntiSMASH tool found zeaxanthin biosynthesis clusters in the entire genome. Biophysical characterization by ultraviolet-visible absorption spectroscopy and ESI-MS studies confirmed the yellow pigment was nostoxanthin. In addition, strain AK-PDB1-5T was found significantly promote Arabidopsis seedling growth under salt conditions by reducing reactive oxygen species (ROS). Based on the polyphasic taxonomic analysis results, strain AK-PDB1-5T was determined to be a novel species in the genus Sphingomonas with the proposed name Sphingomonas nostoxanthinifaciens sp. nov. The type strain is AK-PDB1-5T (= KCTC 82822T = CCTCC AB 2021150T).

Current Status and Future Perspectives on Stem Cell-Based Therapies for Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, affecting 1%-2% of the population over the age of 65. As the population ages, it is anticipated that the burden on society will significantly escalate. Although symptom reduction by currently available pharmacological and/or surgical treatments improves the quality of life of many PD patients, there are no treatments that can slow down, halt, or reverse disease progression. Because the loss of a specific cell type, midbrain dopamine neurons in the substantia nigra, is the main cause of motor dysfunction in PD, it is considered a promising target for cell replacement therapy. Indeed, numerous preclinical and clinical studies using fetal cell transplantation have provided proof of concept that cell replacement therapy may be a viable therapeutic approach for PD. However, the use of human fetal cells remains fraught with controversy due to fundamental ethical, practical, and clinical limitations. Groundbreaking work on human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, coupled with extensive basic research in the stem cell field offers promising potential for hPSC-based cell replacement to become a realistic treatment regimen for PD once several major issues can be successfully addressed. In this review, we will discuss the prospects and challenges of hPSC-based cell therapy for PD.

Dual encoder-decoder-based deep polyp segmentation network for colonoscopy images.

Detection of colorectal polyps through colonoscopy is an essential practice in prevention of colorectal cancers. However, the method itself is labor intensive and is subject to human error. With the advent of deep learning-based methodologies, and specifically convolutional neural networks, an opportunity to improve upon the prognosis of potential patients suffering with colorectal cancer has appeared with automated detection and segmentation of polyps. Polyp segmentation is subject to a number of problems such as model overfitting and generalization, poor definition of boundary pixels, as well as the model's ability to capture the practical range in textures, sizes, and colors. In an effort to address these challenges, we propose a dual encoder-decoder solution named Polyp Segmentation Network (PSNet). Both the dual encoder and decoder were developed by the comprehensive combination of a variety of deep learning modules, including the PS encoder, transformer encoder, PS decoder, enhanced dilated transformer decoder, partial decoder, and merge module. PSNet outperforms state-of-the-art results through an extensive comparative study against 5 existing polyp datasets with respect to both mDice and mIoU at 0.863 and 0.797, respectively. With our new modified polyp dataset we obtain an mDice and mIoU of 0.941 and 0.897 respectively.

Metabolic Analyses and Evaluation of Antioxidant Activity in Purple Kohlrabi Sprouts after Exposed to UVB Radiation.

Various metabolites act as plant defense molecules due to their antioxidant abilities. This study aimed to investigate the influence of UVB irradiation on the accumulation of metabolites, including primary metabolites (sugar, sugar alcohols, amino acids, organic acids, and an amine) and secondary metabolites (anthocyanins, fatty acids, and phenolic acids), and its synergistic antioxidant ability, in purple kohlrabi sprouts. Metabolite analyses revealed a total of 92 metabolites in the sprouts. Specifically, the levels of most amino acids increased after 24 h of UVB treatment, and then slightly decreased in the kohlrabi sprouts. The levels of most sugars and sugar alcohols increased after 24 h of UVB treatment and then decreased. The levels of TCA cycle intermediates and phenolic acids gradually increased during the UVB treatment. Furthermore, the levels of some fatty acids gradually increased during the UVB treatment, and the levels of the other fatty acids increased after 6 h of UVB treatment and then decreased. In particular, the levels of most anthocyanins, known to be strong antioxidants, gradually increased after 24 h of UVB treatment. In the in vitro ABTS scavenging assay, UVB-treated purple kohlrabi sprouts showed increased scavenging ability. This may be attributed to the increased accumulation of metabolites acting as antioxidants, in response to UVB treatment. This study confirmed that UVB irradiation induced the alteration of primary and secondary metabolism in the kohlrabi sprouts.

SIRT2 regulates mitochondrial dynamics and reprogramming via MEK1-ERK-DRP1 and AKT1-DRP1 axes.

During somatic reprogramming, cellular energy metabolism fundamentally switches from predominantly mitochondrial oxidative phosphorylation toward glycolysis. This metabolic reprogramming, also called the Warburg effect, is critical for the induction of pluripotency, but its molecular mechanisms remain poorly defined. Notably, SIRT2 is consistently downregulated during the reprogramming process and regulates glycolytic switch. Here, we report that downregulation of SIRT2 increases acetylation of mitogen-activated protein kinase (MAPK) kinase-1 (MEK1) at Lys175, resulting in activation of extracellular signal-regulated kinases (ERKs) and subsequent activation of the pro-fission factor dynamin-related protein 1 (DRP1). In parallel, downregulation of SIRT2 hyperacetylates the serine/threonine protein kinase AKT1 at Lys20 in a non-canonical way, activating DRP1 and metabolic reprogramming. Together, our study identified two axes, SIRT2-MEK1-ERK-DRP1 and SIRT2-AKT1-DRP1, that critically link mitochondrial dynamics and oxidative phosphorylation to the somatic reprogramming process. These upstream signals, together with SIRT2's role in glycolytic switching, may underlie the Warburg effect observed in human somatic cell reprogramming.

Structural and Functional Characterizations of Cancer Targeting Nanoparticles Based on Hepatitis B Virus Capsid.

Cancer targeting nanoparticles have been extensively studied, but stable and applicable agents have yet to be developed. Here, we report stable nanoparticles based on hepatitis B core antigen (HBcAg) for cancer therapy. HBcAg monomers assemble into spherical capsids of 180 or 240 subunits. HBcAg was engineered to present an affibody for binding to human epidermal growth factor receptor 1 (EGFR) and to present histidine and tyrosine tags for binding to gold ions. The HBcAg engineered to present affibody and tags (HAF) bound specifically to EGFR and exterminated the EGFR-overexpressing adenocarcinomas under alternating magnetic field (AMF) after binding with gold ions. Using cryogenic electron microscopy (cryo-EM), we obtained the molecular structures of recombinant HAF and found that the overall structure of HAF was the same as that of HBcAg, except with the affibody on the spike. Therefore, HAF is viable for cancer therapy with the advantage of maintaining a stable capsid form. If the affibody in HAF is replaced with a specific sequence to bind to another targetable disease protein, the nanoparticles can be used for drug development over a wide spectrum.

TSA Promotes CRISPR/Cas9 Editing Efficiency and Expression of Cell Division-Related Genes from Plant Protoplasts.

Trichostatin A (TSA) is a representative histone deacetylase (HDAC) inhibitor that modulates epigenetic gene expression by regulation of chromatin remodeling in cells. To investigate whether the regulation of chromatin de-condensation by TSA can affect the increase in the efficiency of Cas9 protein-gRNA ribonucleoprotein (RNP) indel formation from plant cells, genome editing efficiency using lettuce and tobacco protoplasts was examined after several concentrations of TSA treatments (0, 0.1, 1 and 10 µM). RNP delivery from protoplasts was conducted by conventional polyethylene glycol (PEG) transfection protocols. Interestingly, the indel frequency of the SOC1 gene from TSA treatments was about 3.3 to 3.8 times higher than DMSO treatment in lettuce protoplasts. The TSA-mediated increase of indel frequency of the SOC1 gene in lettuce protoplasts occurred in a concentration-dependent manner, although there was not much difference. Similar to lettuce, TSA also increased the indel frequency by 1.5 to 1.8 times in a concentration-dependent manner during PDS genome editing using tobacco protoplasts. The MNase test clearly showed that chromatin accessibility with TSA treatments was higher than that of DMSO treatment. Additionally, TSA treatment significantly increased the level of histone H3 and H4 acetylation from lettuce protoplasts. The qRT-PCR analysis showed that expression of cell division-related genes (LsCYCD1-1, LsCYCD3-2, LsCYCD6-1, and LsCYCU4-1) was increased by TSA treatment. These findings could contribute to increasing the efficiency of CRISPR/Cas9-mediated genome editing. Furthermore, this could be applied for the development of useful genome-edited crops using the CRISPR/Cas9 system with plant protoplasts.

Inhibition of melanogenesis by Aster yomena callus pellet extract in melanoma cells and patients with skin pigmentation.

Plant tissue culture holds immense potential for the production of secondary metabolites with various physiological functions. We recently established a plant tissue culture system capable of producing secondary metabolites from Aster yomena. This study aimed to uncover the mechanisms underlying the potential therapeutic effects of Aster yomena callus pellet extract (AYC-P-E) on photoaging-induced skin pigmentation. Excessive melanogenesis was induced in B16F10 melanoma cells using α-melanocyte stimulating hormone (α-MSH). The effects of AYC-P-E treatment on melanin biosynthesis inducers and melanin synthesis inhibition were assessed. Based on the results, a clinical study was conducted in subjects with skin pigmentation. AYC-P-E inhibited melanogenesis in α-MSH-treated B16F10 cells, accompanied by decreased mRNA and protein expression of melanin biosynthesis inducers, including cyclic AMP response element-binding protein (CREB), tyrosinase, microphthalmia-associated transcription factor (MITF), tyrosinase related protein-1 (TRP-1), and TRP-2. This anti-melanogenic effect was mediated by mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) phosphorylation. Treatment of subjects with skin pigmentation with AYC-P-E-containing cream formulations resulted in 3.33%, 7.06%, and 8.68% improvement in the melanin levels at 2, 4, and 8 weeks, respectively. Our findings suggest that AYC-P-E inhibits excessive melanogenesis by activating MEK/ERK and AKT signaling, potentiating its cosmetic applications in hyperpigmentation treatment.

Pedobacter endophyticus sp. nov., an endophytic bacterium isolated from Carex pumila.

An aerobic, Gram-stain-negative, weak-motile, short-rod-shaped bacterial strain, designated JBR3-12T, was isolated from halophyte Carex pumila plants, and its taxonomic position was investigated by using a polyphasic taxonomic approach. The strain produced a pink pigment on tryptic soy agar and grew optimally at 25 °C, pH 8 and in the presence of 3 % (w/v) NaCl. Results of phylogenetic analysis based on 16S rRNA gene sequences showed that strain JBR3-12T formed a lineage within the genus Pedobacter and was most closely related to Pedobacter sandarakinus DS-27T (98.0 %) and Pedobacter agri PB92T (97.6 %). The DNA G+C content of the genome was 41.3 mol%; the whole genome length was 5 426 070 bp. The major fatty acids of JBR3-12T were iso-C15 : 0, summed feature 3 (comprising C16 : 1 ω6c and/or C16 : 1 ω7c) and iso-C17 : 0 3-OH. The predominant polar lipid was phosphatidylethanolamine. The predominant quinone was menaquinone-7. Based on its phenotypic, phylogenetic and genotypic features, strain JBR3-12T is proposed to represent a novel species of the genus Pedobacter, for which the name is Pedobacter endophyticus sp. nov. The type strain is JBR3-12T (=KCTC 82363T=NBRC 114901T).

Overexpression of VlPRX21 and VlPRX35 genes in Arabidopsis plants leads to bioconversion of trans-resveratrol to δ-viniferin.

Stilbenes, including resveratrol and viniferins, a small family of polyphenols, are considered the most important phytoalexin group in Vitis species. In a previous study, we found that co-treatment of methyl jasmonate (MJ) and stevioside (STE) resulted in enhanced extracellular production of viniferins in grapevine cell suspension cultures. Thus, to further understand the mechanisms of viniferin production in grapevine cell cultures, we performed transcriptome analysis and isolated seven candidates of grapevine peroxidase genes (VlAPX6, VlGPX5, VlPRX13, VlPRX21, VlPRX35, VlPRX40, and VlPRX50). Bioconversion of trans-resveratrol to δ-viniferin was examined using crude protein extracts isolated from agroinfiltration-based transient expression of VlPRXs in Nicotiana benthamiana. In addition, we found that crude protein extracts from VlPRX21-, VlPRX35-, and VlPRX40-overexpressing (OX) transgenic Arabidopsis plants led to the conversion of trans-resveratrol to δ-viniferin. We found that in vitro experiments with crude protein extracts from VlPRX21-OX and VlPRX35-OX Arabidopsis plants catalyzed the dimerization of trans-resveratrol to δ-viniferin. Our results suggest that VlPRX21 and VlPRX35 encode functional grapevine class III peroxidases and catalyze the oxidative dimerization of trans-resveratrol to form δ-viniferin in grapevine.

The Effect of Sodium Butyrate on Adventitious Shoot Formation Varies among the Plant Species and the Explant Types.

Histone acetylation plays an important role in plant growth and development. Here, we investigated the effect of sodium butyrate (NaB), a histone deacetylase inhibitor, on adventitious shoot formation from protoplast-derived calli and cotyledon explants of tobacco (Nicotiana benthamiana) and tomato (Solanum lycopersicum). The frequency of adventitious shoot formation from protoplast-derived calli was higher in shoot induction medium (SIM) containing NaB than in the control. However, the frequency of adventitious shoot formation from cotyledon explants of tobacco under the 0.1 mM NaB treatment was similar to that in the control, but it decreased with increasing NaB concentration. Unlike in tobacco, NaB decreased adventitious shoot formation in tomato explants in a concentration-dependent manner, but it did not have any effect on adventitious shoot formation in calli. NaB inhibited or delayed the expression of D-type cyclin (CYCD3-1) and shoot-regeneration regulatory gene WUSCHEL (WUS) in cotyledon explants of tobacco and tomato. However, compared to that in control SIM, the expression of WUS was promoted more rapidly in tobacco calli cultured in NaB-containing SIM, but the expression of CYCD3-1 was inhibited. In conclusion, the effect of NaB on adventitious shoot formation and expression of CYCD3-1 and WUS genes depended on the plant species and whether the effects were tested on explants or protoplast-derived calli.

Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson's Disease.

We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson's disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.).

The positive feedback loop between Nrf2 and phosphogluconate dehydrogenase stimulates proliferation and clonogenicity of human hepatoma cells.

Recent studies report that nuclear factor-erythroid-2-related factor 2 (Nrf2) facilitates tumor progression through metabolic reprogramming in cancer cells. However, the molecular mechanism underlying the oncogenic functions of Nrf2 is not yet well understood. Some of the pentose phosphate pathway (PPP) enzymes are considered to play a role in the cancer progression. The present study was intended to explore the potential role of phosphogluconate dehydrogenase (PGD), one of the PPP enzymes, in the proliferation and migration of human hepatoma HepG2 cells. Genetic ablation of Nrf2 attenuated the expression of PGD at both transcriptional and translational levels. Notably, Nrf2 regulates the transcription of PGD through direct binding to the antioxidant response element in its promoter region. Nrf2 overexpression in HepG2 cells led to increased proliferation, survival, and migration, and these events were suppressed by silencing PGD. Interestingly, knockdown of the gene encoding this enzyme not only attenuated the proliferation and clonogenicity of HepG2 cells but also downregulated the expression of Nrf2. Thus, there seems to exist a positive feedback loop between Nrf2 and PGD which is exploited by hepatoma cells for their proliferation and survival. Treatment of HepG2 cells with ribulose-5-phosphate, a catalytic product of PGD, gave rise to a concentration-dependent upregulation of Nrf2. Collectively, the current study shows that Nrf2 promotes hepatoma cell growth and progression, partly through induction of PGD transcription.

Total Hip Arthroplasty With Subtrochanteric Shortening Osteotomy in Patients With High Hip Dislocation Secondary to Childhood Septic Arthritis: A Matched Comparative Study With Crowe IV Developmental Dysplasia.

BACKGROUND: Total hip arthroplasty (THA) with subtrochanteric shortening osteotomy (SSO) is performed to manage hips with high dislocations. We compared outcomes of THA with SSO in patients with high hip dislocation resulting from childhood septic arthritis and Crowe IV developmental dysplasia of the hip (DDH). METHODS: We reviewed 60 THAs with SSO performed between May 1996 and December 2013. Thirty-one cases were classified as sequelae of childhood infection and 29 as DDH. Twenty-five hips were selected for each group after the propensity score was matched with preoperative demographics and leg length discrepancy (LLD). Clinical scores, complication and reoperation rates, radiographic results, and survivorships were compared. The mean duration of follow-up was 12.3 (range 5-22) years. RESULTS: The average correction in LLD was 2.5 cm for childhood infection and 3.6 cm for DDH (P = .002). The infection group received more transfusions (mean 3.3 vs 2.0 units, P = .002), required more time for union of osteotomy site (mean 6.8 vs 5.2 months, P = .042), and reported lower Harris Hip Score (mean 85.1 vs 91.3, P = .017). Reoperations were performed in 11 (44%) previously infected hips and 3 (12%) DDHs (P = .012). Kaplan-Meier survivorship with an endpoint of revision for any reason was lower in the infection group (83.6%) than in the DDH group (100%) at 10 years (log rank, P = .040). CONCLUSION: THA with SSO in high hip dislocation secondary to childhood septic arthritis demonstrated less favorable clinical outcomes with increased risks of complication, compared with those performed in Crowe IV DDH with similar degree of chronic dislocation.

Colorectal adenocarcinoma-derived EGFR mutants are oncogenic and sensitive to EGFR-targeted monoclonal antibodies, cetuximab and panitumumab.

Somatic mutations of epidermal growth factor receptor (EGFR) occur in ~3% of colorectal cancer (CRC) patients. Here, through systematic functional screening of 21 recurrent EGFR mutations selected from public data sets, we show that 11 colon cancer-derived EGFR mutants (G63R, E114K, R165Q, R222C, S492R, P596L, K708R, E709K, G719S, G724S and L858R) are oncogenic and able to transform cells in a ligand-independent manner. We demonstrate that cellular transformation by these mutants requires receptor dimerization. Importantly, the EGF-induced and constitutive oncogenic potential of these EGFR mutants are inhibited by cetuximab or panitumumab in vivo and in vitro. Taken together, we propose that a subset of EGFR mutations can serve as genomic predictors for response to anti-EGFR antibodies and that metastatic CRC patients with such mutations may benefit from these drugs as part of the first-line therapy.