Characterization of TGFß1-induced tendon-like structure in the scaffold-free three-dimensional tendon cell culture system.

The biological mechanisms regulating tenocyte differentiation and morphological maturation have not been well-established, partly due to the lack of reliable in vitro systems that produce highly aligned collagenous tissues. In this study, we developed a scaffold-free, three-dimensional (3D) tendon culture system using mouse tendon cells in a differentially adherent growth channel. Transforming Growth Factor-ß (TGFß) signaling is involved in various biological processes in the tendon, regulating tendon cell fate, recruitment and maintenance of tenocytes, and matrix organization. This known function of TGFß signaling in tendon prompted us to utilize TGFß1 to induce tendon-like structures in 3D tendon constructs. TGFß1 treatment promoted a tendon-like structure in the peripheral layer of the constructs characterized by increased thickness with a gradual decrease in cell density and highly aligned collagen matrix. TGFß1 also enhanced cell proliferation, matrix production, and morphological maturation of cells in the peripheral layer compared to vehicle treatment. TGFß1 treatment also induced early tenogenic differentiation and resulted in sufficient mechanical integrity, allowing biomechanical testing. The current study suggests that this scaffold-free 3D tendon cell culture system could be an in vitro platform to investigate underlying biological mechanisms that regulate tenogenic cell differentiation and matrix organization.

Norterpene Cyclic Peroxides from the Marine Sponge Diacarnus spinipoculum, Inhibitors of Transient Receptor Potential Ankyrin 1.

Bioassay-guided isolation of the extract from the marine sponge Diacarnus spinipoculum showing inhibitory activity against human transient receptor potential ankyrin 1 (hTRPA1) resulted in the isolation of 12 norditerpene cyclic peroxides (1-12) and eight norsesterterpene cyclic peroxides (13-20). Among these, 10 (5-7, 11, 12, 16-20) are unprecedented analogs. Compounds with either a hydroxy (5, 11) or a methoxy (6, 12) group attached to the cyclohexanone moiety were obtained as epimeric mixtures at C-11, while compounds 4, 6, 10, and 12 are likely the artifacts of isolation. The absolute configurations of the new compounds were established based on an NMR-based empirical method and comparison of specific rotation values. Mosher ester analysis revealed the absolute configurations of compounds 17-20. The inhibitory activity of the isolated compounds against hTRPA1 varied significantly depending on their structures, with the norsesterterpenoid 19 displaying the most potent activity (IC50 2.0 µM).

Primary Intracranial Ewing Sarcoma With EWSR1-FLI1 Gene Translocation Mimicking a Meningioma and a Multidisciplinary Therapeutic Approach: A Case Report and Systematic Review of Literatures.

Ewing sarcoma and peripheral primitive neuroectodermal tumor (ES/pPNET) is an undifferentiated malignant tumor that is most prevalent in children and young adults and often radiologically mimics a meningioma. A 38-year-old female patient visited our hospital with complaints of right-sided tinnitus, right hemiparesis, and imbalance. She underwent preoperative imaging and was subsequently diagnosed as having a meningioma on the petrous ridge. After partial resection, EWSR1-FLI1 gene fusion was confirmed, and she was diagnosed with ES/pPNET. The tumor was successfully treated using a multidisciplinary approach of adjuvant chemo- and radiotherapy. This case is noteworthy because it is an extremely rare case of an intracranial ES/pPNET, and it is worth sharing our clinical experience that the tumor was successfully treated through a multidisciplinary therapeutic approach even though complete resection was not achieved.

Trabecular structural difference between the superior and inferior regions of the vertebral body: a cadaveric and clinical study.

Background: Osteoporotic vertebral compression fractures commonly involve the superior vertebral body; however, their associated causes have not yet been clearly established. This study aimed to determine the trabecular structural differences between the superior and inferior regions of the vertebral body using cadaveric and clinical studies. Materials and methods: First, five vertebrae were collected from three human cadavers. The trabecular structures of the superior and inferior regions of each vertebral body were analyzed using micro-computed tomography (micro-CT), finite element analysis (FEA), and biomechanical test. Based on the results of the ex vivo study, we conducted a clinical study. Second, spine CT images were retrospectively collected. Bone volume and Hounsfield unit were analyzed for 192 vertebral bodies. Finally, after sample size calculation based on the pilot study, prospectively, 200 participants underwent dual-energy X-ray absorptiometry (DXA) of the lateral spine. The bone mineral densities (BMDs) of the superior and inferior regions of each lumbar vertebral body were measured. The paired t-test and Wilcoxon signed-rank test were used for the statistical analyses, and p-value < 0.05 was considered significant. Results: Cadaver studies revealed differences between the superior and inferior trabecular bone structures. The bone volume ratio, BMD, and various other trabecular parameters advocated for decreased strength of the superior region. Throughout the biomechanical study, the limitations of the compression force were 3.44 and 4.63 N/m2 for the superior and inferior regions, respectively. In the FEA study, the inferior region had a lower average displacement and higher von Mises stress than the superior region. In the clinical spine CT-based bone volume and BMD study, the bone volume was significantly higher in the inferior region than in the superior region. In the lateral spine DXA, the mean BMD of the superior region of vertebral bodies was significantly lower compared with that of the inferior region. Conclusion: The superior trabecular structure of the lumbar vertebral bodies possesses more biomechanical susceptibility compared with the inferior trabecular structure, confirming its dominant role in causing osteoporotic vertebral fractures. Physicians should also focus on the BMD values of the superior region of the vertebral body using lateral spine DXA to evaluate osteoporosis.

Cyclized proteins with tags as permeable and stable cargos for delivery into cells and liposomes.

Despite the therapeutic potential of recombinant proteins, their cell permeabilities and stabilities remain significant challenges. Here we demonstrate that cyclized recombinant proteins can be used as universal cargos for permeable and stable delivery into cells and polydiacetylene liposomes. Utilizing a split intein-mediated process, cyclized model fluorescent proteins containing short tetraarginine (R4) and hexahistidine (H6) tags were generated without compromising their native protein functions. Strikingly, as compared to linear R4/H6-tagged proteins, the cyclized counterparts have substantially increased permeabilities in both cancer cells and synthetic liposomes, as well as higher resistances to enzymatic degradation in cancer cells. These properties are likely a consequence of structural constraints imposed on the proteins in the presence of short functional peptides. Additionally, photodynamic therapy by cyclized photoprotein-loaded liposomes in cancer cells was significantly improved in comparison to that by their non-cyclized counterparts. These findings suggest that our strategy will be universally applicable to intercellular delivery of proteins and therapeutics.

Coscinoderines A-J: Trisubstituted Pyridinium-Containing Norterpenoids Isolated from Coscinoderma bakusi, a Tropical Marine Sponge.

Ten new norterpene alkaloids, coscinoderines A-J (1-10), were isolated from the marine sponge Coscinoderma bakusi. Each coscinoderine contains a 1,2,5-trisubstituted pyridinium moiety bearing a terpene unit at the C-2 position. Their structures were elucidated by analysis of NMR and HRMS data, and the absolute stereochemistry of 4 with a 2-methylbutyl group attached to the nitrogen was determined from a comparison of the calculated and measured ECD spectra. The isolation of coscinoderines expands the repertoire of pyridinium alkaloids isolated from marine sponges.

Bottom-up Solution Synthesis of Graphene Nanoribbons with Precisely Engineered Nanopores.

The incorporation of nanopores into graphene nanostructures has been demonstrated as an efficient tool in tuning their band gaps and electronic structures. However, precisely embedding the uniform nanopores into graphene nanoribbons (GNRs) at the atomic level remains underdeveloped especially for in-solution synthesis due to the lack of efficient synthetic strategies. Herein we report the first case of solution-synthesized porous GNR (pGNR) with a fully conjugated backbone via the efficient Scholl reaction of tailor-made polyphenylene precursor (P1) bearing pre-installed hexagonal nanopores. The resultant pGNR features periodic subnanometer pores with a uniform diameter of 0.6 nm and an adjacent-pores-distance of 1.7 nm. To solidify our design strategy, two porous model compounds (1 a, 1 b) containing the same pore size as the shortcuts of pGNR, are successfully synthesized. The chemical structure and photophysical properties of pGNR are investigated by various spectroscopic analyses. Notably, the embedded periodic nanopores largely reduce the π-conjugation degree and alleviate the inter-ribbon π-π interactions, compared to the nonporous GNRs with similar widths, affording pGNR with a notably enlarged band gap and enhanced liquid-phase processability.

A local water molecular-heating strategy for near-infrared long-lifetime imaging-guided photothermal therapy of glioblastoma.

Owing to the strong absorption of water in the near-infrared (NIR) region near 1.0 µm, this wavelength is considered unsuitable as an imaging and analytical signal in biological environments. However, 1.0 µm NIR can be converted into heat and used as a local water-molecular heating strategy for the photothermal therapy of biological tissues. Herein, we describe a Nd-Yb co-doped nanomaterial (water-heating nanoparticles (NPs)) as strong 1.0 µm emissive NPs to target the absorption band of water. Furthermore, introducing Tm ions into the water-heating NPs improve the NIR lifetime, enabling the development of a NIR imaging-guided water-heating probe (water-heating NIR NPs). In the glioblastoma multiforme male mouse model, tumor-targeted water-heating NIR NPs reduce the tumor volume by 78.9% in the presence of high-resolution intracranial NIR long-lifetime imaging. Hence, water-heating NIR NPs can be used as a promising nanomaterial for imaging and photothermal ablation in deep-tissue-bearing tumor therapy.

A phase 1 first-in-human study of GS-0189, an anti-signal regulatory protein alpha (SIRPα) monoclonal antibody, in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL).

Signal regulatory protein alpha (SIRPα) is the receptor for cluster of differentiation (CD)47, a potent "don't eat me" signal for macrophages. Disruption of CD47-SIRPα signaling in the presence of prophagocytic signals can lead to enhanced phagocytosis of tumor cells, resulting in a direct antitumor effect; agents targeting this pathway have shown efficacy in non-Hodgkin lymphoma (NHL) and other tumor types. GS-0189 is a novel anti-SIRPα humanized monoclonal antibody. Here we report: (1) clinical safety, preliminary activity, and pharmacokinetics of GS-0189 as monotherapy and in combination with rituximab from a phase 1 clinical trial in patients with relapsed/refractory NHL (NCT04502706, SRP001); (2) in vitro characterization of GS-0189 binding to SIRPα; and (3) in vitro phagocytic activity. Clinically, GS-0189 was well tolerated in patients with relapsed/refractory NHL with evidence of clinical activity in combination with rituximab. Receptor occupancy (RO) of GS-0189 was highly variable in NHL patients; binding affinity studies showed significantly higher affinity for SIRPα variant 1 than variant 2, consistent with RO in patient and healthy donor samples. In vitro phagocytosis induced by GS-0189 was also SIRPα variant-dependent. Although clinical development of GS-0189 was discontinued, the CD47-SIRPα signaling pathway remains a promising therapeutic target and should continue to be explored.

Anti-cancer Effect of Unique Cartilage Matrix-associated Protein in Breast Cancer Cells Depends on γ-Carboxylation.

BACKGROUND/AIM: Unique cartilage matrix-associated protein (UCMA), a recently discovered vitamin K-dependent protein (VKDP) with a large number of γ-carboxyglutamic acid (Gla) residues, is associated with ectopic calcifications. Although the function of VKDPs is related to their γ-carboxylation status, the carboxylation status of UCMA in breast cancer is still unknown. Here, we investigated the inhibitory effect of UCMA with differing γ-carboxylation status on breast cancer cell lines, such as MDA-MB-231, 4T1, and E0771 cells. MATERIALS AND METHODS: Undercarboxylated UCMA (ucUCMA) was generated by mutating the γ-glutamyl carboxylase (GGCX) recognition sites. The ucUCMA and carboxylated UCMA (cUCMA) proteins were collected from culture media of HEK293-FT cells that had been transfected with mutated GGCX and wild-type UCMA expression plasmids, respectively. Boyden Transwell and colony formation assays were performed to evaluate cancer cell migration, invasion, and proliferation. RESULTS: Culture medium containing cUCMA protein inhibited the migration, invasion, and colony formation of MDA-MB-231 and 4T1 cells to a greater degree than medium containing ucUCMA protein. Significant reductions in the migration, invasion, and colony formation were also observed in cUCMA-treated E0771 cells compared to those in ucUCMA-treated cells. CONCLUSION: The inhibitory role of UCMA in breast cancer is closely related to its γ-carboxylation status. The results of this study may be a basis for the development of UCMA-based anti-cancer drugs.

Systemic C-peptide supplementation ameliorates retinal neurodegeneration by inhibiting VEGF-induced pathological events in diabetes.

Diabetic retinopathy (DR) is caused by retinal vascular dysfunction and neurodegeneration. Intraocular delivery of C-peptide has been shown to be beneficial against hyperglycemia-induced microvascular leakage in the retina of diabetes; however, the effect of C-peptide on diabetes-induced retinal neurodegeneration remains unknown. Moreover, extraocular C-peptide replacement therapy against DR to avoid various adverse effects caused by intravitreal injections has not been studied. Here, we demonstrate that systemic C-peptide supplementation using osmotic pumps or biopolymer-conjugated C-peptide hydrogels ameliorates neurodegeneration by inhibiting vascular endothelial growth factor-induced pathological events, but not hyperglycemia-induced vascular endothelial growth factor expression, in the retinas of diabetic mice. C-peptide inhibited hyperglycemia-induced activation of macroglial and microglial cells, downregulation of glutamate aspartate transporter 1 expression, neuronal apoptosis, and histopathological changes by a mechanism involving reactive oxygen species generation in the retinas of diabetic mice, but transglutaminase 2, which is involved in retinal vascular leakage, is not associated with these pathological events. Overall, our findings suggest that systemic C-peptide supplementation alleviates hyperglycemia-induced retinal neurodegeneration by inhibiting a pathological mechanism, involving reactive oxygen species, but not transglutaminase 2, in diabetes.

2D Materials in the Display Industry: Status and Prospects.

With advances in flexible electronics, innovative foldable, rollable, and stretchable displays have been developed to maintain their performance under various deformations. These flexible devices can develop more innovative designs than conventional devices due to their light weight, high space efficiency, and practical convenience. However, developing flexible devices requires material innovation because the devices must be flexible and exhibit desirable electrical insulating/semiconducting/metallic properties. Recently, emerging 2D materials such as graphene, hexagonal boron nitride, and transition metal dichalcogenides have attracted considerable research attention because of their outstanding electrical, optical, and mechanical properties, which are ideal for flexible electronics. The recent progress and challenges of 2D material growth and display applications are reviewed and perspectives for exploring 2D materials for display applications are discussed.

Dopamine ameliorates hyperglycemic memory-induced microvascular dysfunction in diabetic retinopathy.

Dopamine is a neurotransmitter that mediates visual function in the retina and diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of blindness; however, the role of dopamine in retinal vascular dysfunction in DR remains unclear. Here, we report a mechanism of hyperglycemic memory (HGM)-induced retinal microvascular dysfunction and the protective effect of dopamine against the HGM-induced retinal microvascular leakage and abnormalities. We found that HGM induced persistent oxidative stress, mitochondrial membrane potential collapse and fission, and adherens junction disassembly and subsequent vascular leakage after blood glucose normalization in the mouse retinas. These persistent hyperglycemic stresses were inhibited by dopamine treatment in human retinal endothelial cells and by intravitreal injection of levodopa in the retinas of HGM mice. Moreover, levodopa supplementation ameliorated HGM-induced pericyte degeneration, acellular capillary and pericyte ghost generation, and endothelial apoptosis in the mouse retinas. Our findings suggest that dopamine alleviates HGM-induced retinal microvascular leakage and abnormalities by inhibiting persistent oxidative stress and mitochondrial dysfunction.

Scalarane Sesterterpenoids Isolated from the Marine Sponge Hyrtios erectus and their Cytotoxicity.

Eighteen scalarane sesterterpenoids (1-18), including eight new derivatives (1-8), were isolated from the sponge Hyrtios erectus (family Thorectidae), the extract of which showed cytotoxicity against the HeLa and MCF-7 cell lines. Of the new derivatives, six compounds (1-6) were found to contain a γ-hydroxybutenolide moiety capable of reversible stereoinversion at the hydroxylated carbon center. Under the influence of other adjacent functional groups, each derivative exhibited a different stereochemical behavior, which was fully deduced by ROESY experiments. All the isolated compounds were examined for their cytotoxicity by MTS assay using staurosporine as a positive control (IC50 0.18 and 0.13 µΜ against HeLa and MCF-7 cells, respectively), and they were found to show weak growth inhibitory activities against HeLa and MCF-7 cells, with a minimal IC50 value of 20.0 µΜ. The compounds containing a γ-hydroxybutenolide moiety (1-3, 10, 12) showed cytotoxicity, with IC50 values ranging from 24.3 to 29.9 µΜ, and the most potent derivative was heteronemin (16). Although the cytotoxicities of isolated compounds were insufficient to discuss the structure-activity relationship, this research could contribute to expanding the structural diversity of scalaranes and understanding the stereochemical behavior of γ-hydroxybutenolides.

Transcriptional and toxic responses to saxitoxin exposure in the marine copepod Tigriopus japonicus.

Saxitoxin (STX) is a highly toxic marine neurotoxin produced by phytoplankton and a growing threat to ecosystems worldwide due to the spread of toxic algae. Although STX is an established sodium channel blocker, the overall profile of transcriptional levels in STX-exposed organisms has yet to be described. Here, we describe a toxicity assay and transcriptome analysis of the copepod Tigriopus japonicus exposed to STX. The half-maximal lethal concentration of STX was 12.35 µM, and a rapid mortality slope was evident at concentrations between 12 and 13 µM. STX induced changes in swimming behavior among the copepods after 10 min of exposure. In transcriptome analysis, gene ontology revealed that the genes involved in nervous system and gene expression were highly enriched. In addition, the congenital neurological disorder and nuclear factor erythroid 2-related factor 2-mediated oxidative stress pathways were identified to be the most significant in network analysis and toxicity pathway analysis, respectively. This study provides valuable information about the effects of STX and related transcriptional responses in T. japonicus.

Factors Affecting the Occurrence of Mental Health Problems in Female Cancer Survivors: A Nationwide Cohort Study.

The purpose of this study is to determine the effect of cancer survivorship stage and health-related behaviors on the risk of developing mental health problems (depressive and anxiety disorders) in women who have experienced cancers that affect women (breast cancer, cervical cancer, ovarian cancer, endometrial cancer). Using the healthcare utilization and medical checkup data from 2010 to 2020 provided by the National Health Insurance Service, the occurrence of mental health problems since 2020 was tracked for 36,801 women diagnosed with cancer. The occurrence of mental health problems was defined as the cases in which the disease code was assigned to anxiety disorders (F40~F44, F48) and depressive disorders (F32~34, F41.2, F92) as presented in ICD-10. To evaluate the effect of cancer survivorship stage and health-related behaviors on the development of mental health problems, the hazard ratio (HR) and 95% confidence intervals (CI) were calculated using the Cox proportional hazard model. During the follow-up period of 5.6 years, anxiety disorder occurred in 14,698 (39.9%), and by cancer type, breast cancer survivors accounted for the most at 1.02 per 1000 person-years. The risk of anxiety disorders increased in those who experienced cervical cancer (AHR, 1.08, 95% CI, 1.03-1.13) and those in the acute survivorship stage (AHR, 1.38, 95% CI, 1.22-1.55). In terms of health-related behaviors, the risk of developing anxiety disorder was shown to be reduced in drinkers (AHR, 0.91, 95% CI, 0.87-0.96), former smokers (AHR, 0.86, 95% CI, 0.77-0.97), and current smokers (AHR, 0.80, 95% CI, 0.71-0.90). During the follow-up period of 5.6 years, depressive disorder occurred in 6168(16.8%), and by cancer type, ovarian cancer survivors accounted for the most at 1.30 per 1000 person-years. The risk of developing depressive disorders was highest in those who experienced ovarian cancer (AHR, 1.40, 95% CI, 1.27-1.53) and those in the acute survivorship stage (AHR, 2.99, 95% CI, 2.60-3.42). For health-related behaviors, the risk of developing depressive disorders was increased in former smokers (AHR, 1.32, 95% CI, 1.14-1.54), current smokers (AHR, 1.21, 95% CI, 1.04-1.41), and those with insufficient physical activity (AHR, 1.09, 95% CI, 1.02-1.15). It has been confirmed that cancer type, cancer survivorship stage, and health-related behaviors, such as smoking, drinking, and physical activity, are significantly related to the risk of mental health problems. Thus, it is necessary to develop strategies to cope with mental health problems at the individual and national levels and to develop interventions to promote a more active lifestyle.

Three-dimensional linear and volumetric computed tomography analysis of the frontal sinus.

The frontal sinus is one of the four paranasal sinuses in humans, and knowledge of its anatomy is important when performing surgery involving the frontal bone or sinus. Although many studies have measured the frontal sinus using radiography and computed tomography (CT), few studies have evaluated by using three-dimensional (3D) analysis. The purpose of this study was to analyze the frontal sinus using 3D reconstruction analysis and determine the differences in linear and volumetric measurements between sexes, sides, and ages. The sample comprised 281 facial CT scans: 173 and 108 from males and females, respectively. The width, height, and length of each frontal sinus and total volume were all larger in males than in females. Almost all linear and volumetric measurements were larger in young adults than in older for both sexes, but not all of the differences were statistically significant. Linear and volumetric measurements were larger for males than females regardless of age group. There were no statistically significant differences between the right and left sides except the width in males. The size of the frontal sinus was strongly influenced by sex and age. The measurements reported here might be useful for improving surgical procedures involving the frontal sinus.

Midazolam Ameliorates Hyperglycemia-Induced Glomerular Endothelial Dysfunction by Inhibiting Transglutaminase 2 in Diabetes.

Midazolam is an anesthetic widely used for anxiolysis and sedation; however, to date, a possible role for midazolam in diabetic kidney disease remains unknown. Here, we investigated the effect of midazolam on hyperglycemia-induced glomerular endothelial dysfunction and elucidated its mechanism of action in kidneys of diabetic mice and human glomerular microvascular endothelial cells (HGECs). We found that, in diabetic mice, subcutaneous midazolam treatment for 6 weeks attenuated hyperglycemia-induced elevation in urine albumin/creatinine ratios. It also ameliorated hyperglycemia-induced adherens junction disruption and subsequent microvascular leakage in glomeruli of diabetic mice. In HGECs, midazolam suppressed high glucose-induced vascular endothelial-cadherin disruption and endothelial cell permeability via inhibition of intracellular Ca2+ elevation and subsequent generation of reactive oxygen species (ROS) and transglutaminase 2 (TGase2) activation. Notably, midazolam also suppressed hyperglycemia-induced ROS generation and TGase2 activation in glomeruli of diabetic mice and markedly improved pathological alterations in glomerular ultrastructure in these animals. Analysis of kidneys from diabetic Tgm2-/- mice further revealed that TGase2 played a critical role in microvascular leakage. Overall, our findings indicate that midazolam ameliorates hyperglycemia-induced glomerular endothelial dysfunction by inhibiting ROS-mediated activation of TGase2.

Recombinant Unique Cartilage Matrix-associated Protein Potentiates Osteogenic Differentiation and Mineralization of MC3T3-E1 Cells.

OBJECTIVE: The relative balance of osteoblasts in bone formation and osteoclasts in bone resorption is crucial for maintaining bone health. With age, this balance between osteoblasts and osteoclasts is broken, resulting in bone loss. Anabolic drugs are continuously being developed to counteract this low bone mass. Recombinant proteins are used as biotherapeutics due to being relatively easy to produce on a large scale and are cost-effective through various expression systems. This study aimed to develop a recombinant protein that would positively impact osteoblast differentiation and mineralized nodule formation using unique cartilage matrix-associated protein (UCMA). METHODS: A recombinant glutathione-S-transferase (GST)-UCMA fusion protein was generated in an E.coli system, and purified by affinity chromatography. MC3T3-E1 osteoblast cells and Osterix (Osx)-knockdown stable cells were cultured for 14 days to investigate osteoblast differentiation and nodule formation in the presence of the recombinant GST-UCMA protein. The differentiated cells were assessed by alizarin red S staining and quantitative PCR of the osteoblast differentiation marker osteocalcin. In addition, cell viability in the presence of the recombinant GST-UCMA protein was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell adhesion assay. RESULTS: The isolation of both purified recombinant GST-only and GST-UCMA proteins were confirmed at 26 kDa and 34 kDa, respectively, by Coomassie staining and western blot analysis. Neither dose-dependent nor time-dependent presence of recombinant GST-UCMA affected MC3T3-E1 cell viability. However, MC3T3-E1 cell adhesion to the recombinant GST-UCMA protein increased dose-dependently. Osteoblast differentiation and nodule formation were promoted in both MC3T3-E1 osteoblast cells and Osxknockdown stable cells when cultured in the presence of recombinant GST-UCMA protein. CONCLUSION: A recombinant GST-UCMA protein induces osteogenic differentiation and mineralization, suggesting its potential use as an anabolic drug to increase low bone mass in osteoporotic patients.

PRODIGY: A Phase III Study of Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 Versus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer.

PURPOSE: Adjuvant chemotherapy after D2 gastrectomy is standard for resectable locally advanced gastric cancer (LAGC) in Asia. Based on positive findings for perioperative chemotherapy in European phase III studies, the phase III PRODIGY study (ClinicalTrials.gov identifier: NCT01515748) investigated whether neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 could improve outcomes versus standard treatment in Korean patients with resectable LAGC. PATIENTS AND METHODS: Patients 20-75 years of age, with Eastern Cooperative Oncology Group performance status 0-1, and with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging: T2-3N+ or T4Nany) were randomly assigned to D2 surgery followed by adjuvant S-1 (40-60 mg orally twice a day, days 1-28 every 6 weeks for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1-14 every 3 weeks for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary objective was progression-free survival (PFS) with CSC versus SC. Two sensitivity analyses were performed: intent-to-treat and landmark PFS analysis. RESULTS: Between January 18, 2012, and January 2, 2017, 266 patients were randomly assigned to CSC and 264 to SC at 18 Korean study sites; 238 and 246 patients, respectively, were treated (full analysis set). Follow-up was ongoing in 176 patients at data cutoff (January 21, 2019; median follow-up 38.6 months [interquartile range, 23.5-62.1]). CSC improved PFS versus SC (adjusted hazard ratio, 0.70; 95% CI, 0.52 to 0.95; stratified log-rank P = .023). Sensitivity analyses confirmed these findings. Treatments were well tolerated. Two grade 5 adverse events (febrile neutropenia and dyspnea) occurred during neoadjuvant treatment. CONCLUSION: PRODIGY showed that neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, is effective and tolerable in Korean patients with LAGC.