Multiple myeloma (MM) is an incurable hematological malignancy. Chimeric antigen receptor (CAR)-expressing T cells have been demonstrated successfully in the clinic to treat B-lymphoid malignancies. ...However, the potential utility of antigen-specific CAR-engineered natural-killer (NK) cells to treat MM has not been explored. In this study, we determined whether CS1, a surface protein that is highly expressed on MM cells, can be targeted by CAR NK cells to treat MM. We successfully generated a viral construct of a CS1-specific CAR and expressed it in human NK cells. In vitro, CS1-CAR NK cells displayed enhanced MM cytolysis and interferon-γ (IFN-γ) production, and showed a specific CS1-dependent recognition of MM cells. Ex vivo, CS1-CAR NK cells also showed similarly enhanced activities when responding to primary MM tumor cells. More importantly, in an aggressive orthotopic MM xenograft mouse model, adoptive transfer of NK-92 cells expressing CS1-CAR efficiently suppressed the growth of human IM9 MM cells and also significantly prolonged mouse survival. Thus, CS1 represents a viable target for CAR-expressing immune cells, and autologous or allogeneic transplantation of CS1-specific CAR NK cells may be a promising strategy to treat MM.
Oral cancer has a high mortality rate, and its treatment often causes debilitating complications. More than 90% of oral cancers are oral squamous cell carcinomas (OSCCs) that may develop from ...clinically recognizable oral premalignant lesions (OPLs). To eradicate OPLs before they turn into cancers, a non‐invasive topical formulation is developed based on a novel combination of synergistically acting oxaliplatin (OXP) and mycophenolate (MPS) embedded in a controlled‐release mucoadhesive patch fabricated by computer‐aided 3D printing. After multiple rounds of testing and optimization, a v6.4 ChemoPatch is designed, which shows sustained release of OXP and MPS in vitro, minimal side leakage of drugs, an average elastic modulus of 2.38 MPa, and suitable drug stability at 4 °C or below for up to 12 months. In vivo analyses show almost all patches adhere to the dorsal tongue surface for 4 hours, and display a sustained release of OXP and MPS to tongue tissue for 3–4 hours. When applied in the 4‐nitroquinoline‐1‐oxide‐induced OPL rat model, the OXP‐MPS patch significantly ablates dysplastic lesions with no damage to normal epithelial cells and minimal systemic absorption and side effects. This study reports the design of a novel mucoadhesive ChemoPatch as a noninvasive therapy to treat OPLs.
A mucoadhesive ChemoPatch is invented to provide a non‐invasive therapeutic option for treating oral premalignant lesions, thereby preventing oral cancer formation. The design is based on synergistically acting drug pairs, delivered by a 3D‐printed multi‐layered mucoadhesive patch formulation in a controlled and sustained manner. Analyses of the ChemoPatch confirm its preclinical potential in treating oral precancer.
Background and Objectives
Quality control (QC) data collected by blood services are used to monitor production and to ensure compliance with regulatory standards. We demonstrate how analysis of ...quality control data can be used to highlight the sources of variability within red cell concentrates (RCCs).
Materials and Methods
We merged Canadian Blood Services QC data with manufacturing and donor records for 28 227 RCC between June 2011 and October 2014. Units were categorized based on processing method, bag manufacturer, donor age and donor sex, then assessed based on product characteristics: haemolysis and haemoglobin levels, unit volume, leucocyte count and haematocrit.
Results
Buffy‐coat method (top/bottom)‐processed units exhibited lower haemolysis than units processed using the whole‐blood filtration method (top/top). Units from female donors exhibited lower haemolysis than male donations. Processing method influenced unit volume and the ratio of additive solution to residual plasma.
Conclusions
Stored red blood cell characteristics are influenced by prestorage processing and donor factors. Understanding the relationship between processing, donors and RCC quality will help blood services to ensure the safety of transfused products.
Background
The Internet Gaming Disorder Scale–Short-Form (IGDS9-SF) is among the best with regard to its psychometric properties. Therefore, clinical psychologists are likely guided to use the ...IGDS9-SF if they want to assess or screen the disordered gaming in their practice. However, the information, especially psychometric evidence, concerning the IGDS9-SF has not been fully examined and summarized.
Objective
This systematic review evaluated the psychometric properties of different language versions of the IGDS9-SF and assessed its methodological quality in order to improve the clinicians’ understanding of the IGDS9-SF and facilitate its use.
Methods
Systematic literature searches were carried out using Embase, MEDLINE, PsycINFO, PubMed, ScienceDirect, Scopus, and Web of Science. The review included English-language studies of any research design that have reported at least one psychometric property of the IGDS9-SF, as defined by the COnsensus-based Standards for the selection of health status Measurement INstrument (COSMIN), and have aimed at testing the psychometric properties of the IGDS9-SF.
Results
In total, 21 studies comprising 15 language versions of the IGDS9-SF were included. Overall, the IGDS9-SF showed adequate internal consistency (although some items did not have satisfactory item-total correlation IT), excellent criterion validity, and the ability to distinguish different subgroups with measurement invariance being supported across gender and age. In terms of factor structure, the IGDS9-SF was shown to have a unidimensional factor structure across all 21 studies.
Conclusions
Although there is insufficient evidence regarding the responsiveness and properties of the IGDS9-SF using item response theory, the existing evidence supports its use in assessing disordered gaming among individuals.
•Nucleostemin expression differentiates early and late oral carcinogenic lesions.•p-STAT3, a nucleostemin target, increases during oral precancer progression.•Nucleolar signals of nucleostemin ...discern static and progressive dysplasia.•Nucleostemin may be used to assess the cancer risk of low-grade dysplasia.
Most low-grade oral epithelial dysplasia remains static or regress, but a significant minority of them (4–11%) advances to oral squamous cell carcinoma (OSCC) within a few years. To monitor the progression of epithelial dysplasia for early cancer detection, we investigated the expression profiles of nucleostemin (NS) and phospho-STAT3 (p-STAT3) in rodent and human samples of dysplasia and OSCCs. In a 4NQO-induced rat oral carcinogenesis model, the number and distribution of NS and p-STAT3-positive cells increased in hyperplastic, dysplastic, and neoplastic lesions compared to normal epithelium. In human samples, the NS signal significantly increased in high-grade dysplasia and poorly differentiated OSCC, whereas p-STAT3 was more ubiquitously expressed than NS and showed increased intensity in high-grade dysplasia and both well and poorly differentiated OSCC. Analyses of human dysplastic samples with longitudinally followed outcomes revealed that cells with prominent nucleolar NS signals were more abundant in low-grade dysplasia that advanced to OSCC in 2 or 3 years than those remaining static for 7–14 years. These results suggest that NS upregulation and STAT3 activation are early events in the progression of low-grade dysplasia to OSCC.
Summary
Background
Vitiligo is an autoimmune chronic depigmentation disorder caused by melanocyte loss. Previous studies found that CD4+CD25+ regulatory T‐cell (Treg) dysfunction was involved in the ...pathogenesis of vitiligo and that gene polymorphisms in forkhead box P3 (FOXP3) – a master regulator of Treg development and function – were associated with susceptibility to some autoimmune disorders. Therefore, we hypothesized that functional polymorphisms of the FOXP3 gene might be associated with vitiligo via dysregulation of Treg cells.
Objectives
To evaluate whether FOXP3 polymorphisms are associated with vitiligo risk.
Material and methods
In this hospital‐based case–control study of 682 patients with vitiligo and 682 vitiligo‐free age‐ and sex‐matched controls, we genotyped three single nucleotide polymorphisms (SNPs) of the FOXP3 gene – rs2232365, rs3761548 and rs5902434 – by performing polymerase chain reaction with sequence‐specific primers (PCR‐SSP).
Results
Significantly increased vitiligo risk was associated with the rs2232365 GG odds ratio (OR) 1·68, 95% confidence interval (CI) 1·17–2·39, P = 0·004 and rs3761548 AA (OR 1·82, 95% CI 1·10–3·01, P = 0·033) genotypes compared with the rs2232365 AA and rs3761548 CC genotypes. On combined analysis of these three variant alleles, we found that individuals carrying 2–6 variant alleles had significantly increased vitiligo risk (OR 1·34, 95% CI 1·08–1·66). This risk was more pronounced in the following subgroups: age > 20 years, male sex, active vitiligo, nonsegmental vitiligo and other accompanying autoimmune diseases.
Conclusions
FOXP3 gene polymorphisms contributed to vitiligo risk in a Han Chinese population.
What's already known about this topic?
Previous findings have suggested that forkhead box P3 (FOXP3) is a master regulator of regulatory T cells (Tregs) for maintaining immune tolerance and abrogating autoimmune diseases.
Dysfunction of Tregs is involved in the autoimmune mechanism of vitiligo.
FOXP3 polymorphisms negatively affect the expression and functions of FOXP3 as well as of its target genes.
What does this study add?
Our study suggests an association between FOXP3 gene polymorphisms and vitiligo susceptibility.
Mitochondrial reactive oxygen species (mtROS) homeostasis plays an essential role in preventing oxidative injury in endothelial cells, an initial step in atherogenesis. Resveratrol (RSV) possesses a ...variety of cardioprotective activities, however, little is known regarding the effects of RSV on mtROS homeostasis in endothelial cells. Sirt3 is a mitochondrial deacetylase, which plays a key role in mitochondrial bioenergetics and is closely associated with oxidative stress. The goal of the study is to investigate whether RSV could attenuate oxidative injury in endothelial cells via mtROS homeostasis regulation through Sirt3 signaling pathway. We found that pretreatment with RSV suppressed tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in human umbilical vein endothelial cells (HUVECs) by increasing cell viability, inhibiting cell apoptosis, repressing collapse of mitochondrial membrane potential and decreasing mtROS generation. Moreover, the enzymatic activities of isocitrate dehydrogenase 2 (IDH2), glutathione peroxidase (GSH-Px) and manganese superoxide dismutase (SOD2) as well as deacetylation of SOD2 were increased by RSV pretreatment, suggesting RSV notably enhanced mtROS scavenging in t-BHP-induced endothelial cells. Meanwhile, RSV remarkably reduced mtROS generation by promoting Sirt3 enrichment within the mitochondria and subsequent upregulation of forkhead box O3A (FoxO3A)-mediated mitochondria-encoded gene expression of ATP6, CO1, Cytb, ND2 and ND5, thereby leading to increased complex I activity and ATP synthesis. Furthermore, RSV activated the expressions of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and Sirt3, as well as estrogen-related receptor-α (ERRα)-dependent Sirt3 mRNA transcription, which were abolished in the presence of AMPK inhibitor and AMPK, PGC-1α or Sirt3 siRNA transfection, indicating the effects of RSV on mtROS homeostasis regulation were dependent on AMPK-PGC-1α-ERRα-Sirt3 signaling pathway. Our findings indicated a novel mechanism that RSV-attenuated oxidative injury in endothelial cells through the regulation of mtROS homeostasis, which, in part, was mediated through the activation of the Sirt3 signaling pathway.
Abstract It is widely accepted that hypoperfusion and changes in capillary morphology are involved in the etiopathogenesis of Alzheimer's disease (AD). This is difficult to reconcile with the ...hyperperfusion observed in young high-risk subjects. Differences in the way cerebral blood flow (CBF) is coupled with the local metabolic needs during different phases of the disease can explain this apparent paradox. This review describes this coupling in terms of a model of cerebral oxygen availability that takes into consideration the heterogeneity of capillary blood flow patterns. The model predicts that moderate increases in heterogeneity requires elevated CBF in order to maintain adequate oxygenation. However, with progressive increases in heterogeneity, the resulting low tissue oxygen tension will require a suppression of CBF in order to maintain tissue metabolism. The observed biphasic nature of CBF responses in preclinical AD and AD is therefore consistent with progressive disturbances of capillary flow patterns. Salient features of the model are discussed in the context of AD pathology along with potential sources of increased capillary flow heterogeneity.
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