Complex association of body mass index and outcomes in patients with relapsed and refractory multiple myeloma treated with CAR-T cell immunotherapy.

BACKGROUND AIMS: Chimeric antigen receptor-T (CAR-T) cells have exhibited remarkable efficacy in treating refractory or relapsed multiple myeloma (R/R MM). Although obesity has a favorable value in enhancing the response to immunotherapy, less is known about its predictive value regarding the efficacy and prognosis of CAR-T cell immunotherapy. METHODS: We conducted a retrospective study of 111 patients with R/R MM who underwent CAR-T cell treatment. Using the body mass index (BMI) classification, the patients were divided into a normal-weight group (73/111) and an overweight group (38/111). We investigated the effect of BMI on CAR-T cell therapy outcomes in patients with R/R MM. RESULTS: The objective remission rates after CAR-T cell infusion were 94.7% and 89.0% in the overweight and normal-weight groups, respectively. The duration of response and overall survival were not significant difference between BMI groups. Compared to normal-weight patients, overweight patients had an improved median progression-free survival. There was no significant difference in cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome between the subgroups. In terms of hematological toxicity, the erythrocyte, hemoglobin, platelet, leukocyte and neutrophil recovery was accelerated in the overweight group. Fewer patients in the overweight group displayed moderate percent CD4 and CD4/CD8 ratios compared to the normal-weight group. Furthermore, the percent CD4 ratios were positively correlated with the levels of cytokines [interleukin-2 (IL-2) (day 14), interferon gamma (IFN-γ) (day 7) and tumor necrosis factor alpha (TNF-α) (days 14 and 21)] after cells infusion. On the other hand, BMI was positively associated with the levels of IFN-γ (day 7) and TNF-α (days 14 and 21) after CAR-T cells infusion. CONCLUSIONS: Overall, this study highlights the potential beneficial effect of a higher BMI on CAR-T cell therapy outcomes.

Design, synthesis and biological evaluation of MNK-PROTACs.

Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) can regulate cellular mRNA translation by controlling the phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E), which plays an important role in tumor initiation, development, and metastasis. Although small-molecule MNK inhibitors have made significant breakthroughs in the treatment of various malignancies, their clinical application can be limited by drug resistance, target selectivity and other factors. The strategy of MNK-PROTACs which selectively degrades MNK kinases provides a new approach for developing small-molecule drugs for related diseases. In this study, DS33059, a small-molecule compound modified based on the ongoing clinical trials drug ETC-206, was chosen as the target protein ligand. A series of novel MNK-PROTACs were designed, synthesized and evaluated biological activity. Several compounds showed good inhibitory activities against MNK1/2. Besides, compounds exhibited moderate to excellent anti-proliferative activity in A549 and TMD-8 cells in vitro. In particular, compound II-5 significantly inhibited A549 (IC50 = 1.79 µM) and TMD-8 (IC50 = 1.07 µM) cells. The protein degradation assay showed that compound II-5 had good capability to degrade MNK1. The MNK-PROTACs strategy represents a new direction in treating tumors and deserves further exploration.

High-Performance Sliding Ferroelectric Transistor Based on Schottky Barrier Tuning.

Sliding ferroelectricity associated with interlayer translation is an excellent candidate for ferroelectric device miniaturization. However, the weak polarization gives rise to the poor performance of sliding ferroelectric transistors with a low on/off ratio and a narrow memory window, which restricts its practical application. To address the issue, we propose a facile strategy by regulating the Schottky barrier in sliding ferroelectric semiconductor transistors based on γ-InSe, in which a high performance with a large on/off ratio (106) and a wide memory window (4.5 V) was ultimately acquired. Additionally, the memory window of the device can be further modulated by electrostatic doping or light excitation. These results open up new ways for designing novel ferroelectric devices based on emerging sliding ferroelectricity.

Magnetic ε-Phosphorene for Sensing Greenhouse Gas Molecules.

It is critical for gas sensors that sense greenhouse gas molecules to have both good sensitivity and selectivity for water molecules in the ambient environment. Here, we study the charge transfer, IV curves, and electric field tuning of vanadium-doped monolayer ϵ-phosphorene as a sensor for NO, NO2, and H2O gas molecules via first-principle and transport calculations. We find that the paramagnetic toxic molecules of NO and NO2 have a high adsorption energy on V-ϵ-phosphorene, which originates from a large amount of charge transfer driven by the hybridisation of the localised spin states of the host with the molecular frontier orbital. Using the non-equilibrium Green's function, we investigate the IV responses with respect to the adsorption of different molecules to study the performance of gas molecule sensors. Our IV curves show a larger amount of changes in resistance of the paramagnetic NO and NO2 than nonmagnetic H2O gas molecules, suggesting both sensitivity and selectivity. Moreover, our calculations show that an applied external electric field (gate voltage) can effectively tune the amount of charge transfer. More charge transfer makes the sensor more sensitive to the molecule, while less charge transfer can reduce the adsorption energy and remove the adsorbed molecules, allowing for the repeated use of the sensor.

Safety and efficacy of a humanized CD19 chimeric antigen receptor T cells for relapsed/refractory acute lymphoblastic leukemia.

CD19-targeted chimeric antigen receptor T (CAR-T) cells using murine single-chain variable fragment (scFv) has shown substantial clinical efficacy in treating relapsed/refractory acute lymphoblastic leukemia (R/R ALL). However, potential immunogenicity of the murine scFv domain may limit the persistence of CAR-T cells. In this study, we treated 52 consecutive subjects with R/R ALL with humanized CD19-specific CAR-T cells (hCART19s). Forty-six subjects achieved complete remission (CR) (N = 43) or CR with incomplete count recovery (CRi) (N = 3) within 1 month post infusion. During the follow-up with a median time of 20 months, the 1-year cumulative incidence of relapse was 25% (95% confidence interval [CI] 13-46), and 1-year event-free survival was 45% (95% CI 29-60). To the cutoff date, 20 patients presented CD19+ relapse and 2 had CD19- relapse. Among the 22 relapsed patients, 14 had treatment-mediated and treatment-boosted antidrug antibodies (ADA) as detected in a sensitive and specific cell-based assay. ADA positivity was correlated with the disease relapse risk. ADA-positive patients had a significantly lower CAR copy number than ADA-negative patients at the time of recurrence (p < .001). In conclusion, hCART19s therapy is safe and highly active in R/R ALL patients, and the hCART19s treatment could induce the emergence of ADA, which is related to the recurrence of the primary disease.

Therapeutic options for perifolliculitis capitis abscedens et suffodens: A review.

Perifolliculitis capitis abscedens et suffodiens (PCAS) is a chronic skin inflammatory disease characterized by relapsing folliculitis and painful, fluctuant abscesses, sinus tracts, and scars. The treatment of PCAS is challenging and clinical practice varies a lot, and how to choose the best treatment for PCAS is a real problem for clinicians. We reviewed articles providing treatment options for patients with PCAS in different databases. Dermatologists may find this review helpful to meet the challenges of PCAS management, but there is still a lack of authoritative guidelines. In the future, more robust randomized control trials are needed to determine the best treatment for PCAS.

Nano-Hydroxyapatite Particle Brushes via Direct Initiator Tethering and Surface-Initiated Atom Transfer Radical Polymerization for Dual Responsive Pickering Emulsion.

Well-defined polymer-grafted solid inorganic nanoparticles (NPs) are imperative for practical applications in various fields based on the prerequisite of facile initiator immobilization. Direct atom transfer radical polymerization (ATRP) initiator-tethered solid NPs are described using 2-bromo-2-methylpropionic acid as a tetherable initiator. To illustrate the versatility of the proposed strategy, nano-hydroxyapatite (n-HAP) nanocrystals (NCs) were selected to demonstrate the morphology-controlled synthesis of 2-bromo-2-methylpropionate (2-BrMP) group-immobilized n-HAP (n-HAP-Br) NCs. When water was employed as the sole solvent, the continually introduced 2-BrMP groups altered the surface hydrophobic capacity of the n-HAP-Br NC and thus led to unavoidable aggregation of n-HAP-Br NCs. The synthesis of individually dispersed n-HAP-Br NCs was achieved by rational adjusting polarity of the aqueous medium through adding a portion of water-miscible organic solvents. The type and concentration of added water-miscible organic solvents had critical effects on the morphology and particle size of n-HAP-Br NCs. To verify the efficiency of the tethered initiator, n-HAP-g-poly2-(dimethylamino) ethyl methacrylate (n-HAP-g-PDMAEMA), n-HAP-g-polyacrylonitrile (n-HAP-g-PAN), and n-HAP-g-polymethyl methacrylate (n-HAP-g-PMMA) were fabricated by surface-initiated ATRP (SI-ATRP). Acting as a solid particle emulsifier, the designed n-HAP-g-PDMAEMA-stabilized Pickering emulsion displayed dual pH and temperature response with reversible behaviors. This work presents a versatile and simple way for the fabrication of initiator-immobilized solid NPs (e.g., n-HAP NCs, gibbsite nanoplatelets, and γ-FeOOH nanofibers) ready for polymer grafting and thus enables promising performance in widespread applications.

Decoupling Ionic and Electronic Pathways in Low-Dimensional Hybrid Conductors.

The construction of two-dimensional (2D) layered compounds for nanofluidic ion transport has recently attracted increasing interest due to the facile fabrication, tunable channel size, and high flux of these materials. Here we design a nacre-mimetic graphite-based nanofluidic structure in which the nanometer-thick graphite flakes are wrapped by negatively charged nanofibrillated cellulose (NFC) fibers to form multiple 2D confined spacings as nanochannels for rapid cation transport. At the same time, the graphite-NFC structure exhibits an ultralow electrical conductivity (σe ≤ 10-9 S/cm), even when the graphite concentration is up to 50 wt %, well above the percolation threshold (∼1 wt %). By tuning the hydration degree of graphite-NFC composites, the surface-charge-governed ion transport in the confined ∼1 nm spacings exhibits nearly 12 times higher ionic conductivity (1 × 10-3 S/cm) than that of a fully swollen structure (∼1.5 nm, 8.5 × 10-5 S/cm) at salt concentrations up to 0.1 M. The resulting charge selective conductor shows intriguing features of both high ionic conductivity and low electrical conductivity. Moreover, the inherent stability of the graphite and NFC components contributes to the strong functionality of the nanofluidic ion conductors in both acidic and basic environments. Our work demonstrates this 1D-2D material hybrid system as a suitable platform to study nanofluidic ion transport and provides a promising strategy to decouple ionic and electronic pathways, which is attractive for applications in new nanofluidic device designs.

Design Multifunctional Catalytic Interface: Toward Regulation of Polysulfide and Li2 S Redox Conversion in Li-S Batteries.

The polysulfide shuttle effect and sluggish reaction kinetics hamper the practical applications of lithium-sulfur (Li-S) batteries. Incorporating a functional interlayer to trapping and binding polysulfides has been found effective to block polysulfide migration. Furthermore, surface chemistry at soluble polysulfides/electrolyte interface is a crucial step for Li-S battery in which stable cycling depends on adsorption and reutilization of blocked polysulfides in the electrolyte. A multifunctional catalytic interface composed of niobium nitride/N-doped graphene (NbN/NG) along the soluble polysulfides/electrolyte is designed and constructed to regulate corresponding interface chemical reaction, which can afford long-range electron transfer surfaces, numerous strong chemisorption, and catalytic sites in a working lithium-sulfur battery. Both experimental and theoretical calculation results suggest that a new catalytic interface enabled by metal-like NbN with superb electrocatalysis anchored on NG is highly effective in regulating the blocked polysulfide redox reaction and tailoring the Li2 S nucleation-growth-decomposition process. Therefore, the Li-S batteries with multifunctional NbN/NG barrier exhibit excellent rate performance (621.2 mAh g-1 at 3 C) and high stable cycling life (81.5% capacity retention after 400 cycles). This work provides new insights to promote Li-S batteries via multifunctional catalytic interface engineering.

High expression of miR-363 predicts poor prognosis and guides treatment selection in acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a highly heterogeneous malignancy with various outcomes, and therefore needs better risk stratification tools to help select optimal therapeutic options. METHODS: In this study, we identify miRNAs that could predict clinical outcome in a heterogeneous AML population using TCGA dataset. RESULTS: We found that MiR-363 is a novel prognostic factor in AML patients undergoing chemotherapy. In multivariable analyses, high miR-363 remained predictive for shorter OS (HR = 2.349, P = 0.012) and EFS (HR = 2.082, P = 0.001) independent of other well-known prognostic factors. More importantly, allogeneic hematopoietic stem cell transplantation (allo-HSCT) overcame the adverse outcomes related to high miR-363 expression. In gene expression profiling, high miR-363 expression was positively correlated with the amounts of leukemogenic transcription factors, including Myb, RUNX3, GATA3, IKZF3, ETS1 and MLLT3. Notably, we found that the in silico predicted target genes (EZH2, KLF6 and PTEN) of miR-363 were downregulated in association with high miR-363 expression. CONCLUSIONS: In summary, miR-363 expression may help identify patients in need of strategies to select the optimal therapy between chemotherapeutic and allo-HCST regimens. AML patients with high miR-363 expression may be highly recommended for early allo-HSCT regimen.

Emerging role of stem cell memory-like T cell in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by autoantibody-mediated platelet destruction. Multiple factors have been implicated in ITP pathogenesis, including T-lymphocyte dysfunctions. Increasing studies have indicated that stem cell memory-like T cell (TSCM) plays an important role in the development of multiple autoimmune diseases. This study aimed to explore the clinical correlation between the TSCM subset and ITP. The percentages of peripheral blood naïve T cells (TNs), TSCMs, central memory T cells (TCMs), effector memory T cells (TEMs) and effector T cells (TEs) among CD4+ and CD8+ T cells in 20 ITP patients before and after treatment were detected using flow cytometry. Our results showed that the percentages of peripheral blood CD4+ and CD8+ T cells in ITP patients were imbalanced. The percentage of CD8+ TSCMs in peripheral blood before treatment in ITP patients was significantly higher than that in healthy controls, whereas the percentages of the other T cell subsets did not exhibit significant differences. Our study further analysed the correlation between the change in the percentage of CD8+ TSCMs and the treatment efficacy. The results showed that the percentage of peripheral blood CD8+ TSCMs in ITP patients after glucocorticoid treatment significantly decreased and the changes of the percentages of CD8+ TSCMs before and after treatment in complete response (CR) and response (R) patients were obvious. Our finding showed that the imbalance of the percentage of CD8+ TSCMs might be involved in the development of ITP and might serve as a novel indicator of efficacy.

High expression of miR-25 predicts favorable chemotherapy outcome in patients with acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) pertains to a hematologic malignancy with heterogeneous therapeutic responses. Improvements in risk stratification in AML patients are warranted. MicroRNAs have been associated with the pathogenesis of AML. METHODS: To examine the prognostic value of miR-25, 162 cases with de novo AML were classified into two groups according to different treatment regimens. RESULTS: In the chemotherapy group, cases with upregulated miR-25 expression showed relatively longer overall survival (OS; P = 0.0086) and event-free survival (EFS; P = 0.019). Multivariable analyses revealed that miR-25 upregulation is an independent predictor for extended OS (HR = 0.556, P = 0.015) and EFS (HR = 0.598, P = 0.03). In addition, allogeneic hematopoietic stem cell transplantation (allo-HSCT) circumvented the poor prognosis that was related to miR-25 downregulation with chemotherapy. The expression level pattern of miR-25 coincided with AML differentiation and proliferation, which included HOXA and HOXB cluster members, as well as the HOX cofactor MEIS1. The MYH9 gene was identified as a direct target of miR-25. CONCLUSIONS: The miR-25 levels are correlated with prognosis in AML independently of other powerful molecular markers. The expression of miR-25 may contribute to the selection of the optimal treatment regimen between chemotherapy and allo-HCST for AML patients.

Unexpectedly High Adsorption Capacity of Esterified Hydroxyapatite for Heavy Metal Removal.

Nanohydroxyapatite (n-HAP) as an environmentally friendly adsorbent of heavy metal ions still requires the rational design of the pore structure and surface characteristic for enhancing their adsorption capacity toward heavy metal ions. A novel one-step strategy was developed to regulate the pore structure and surface characteristic of esterified HAP (n-EHAP) nanocrystals (NCs) for enhancing the adsorption capacity by incorporation of 2-bromo-2-methylpropionate (2-BrMP) groups on the surface of n-EHAP NCs. When using water as the sole solvent, the aggregation of n-EHAP NCs became unavoidable because of incorporation of hydrophobic 2-BrMP groups on n-HAP particle surfaces. The synthesis of uniform and individual n-EHAP NCs was achieved by rational adjustment of the aqueous dispersion medium to avoid agglomeration and precipitation, which was induced by the changing surface characteristic of n-EHAP NCs during the continuing incorporation of hydrophobic 2-BrMP groups in the water/acetone system. The successful incorporation of hydrophobic 2-BrMP groups on the surface of n-EHAP NCs was characterized by X-ray powder diffraction, field-emission scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, and liquid nitrogen adsorption isotherms. To explore the potential application in water treatment, a series of systematically designed batch experiments were conducted to determine the influences of the adsorbent dosage, solution pH, and contact time on the adsorption behavior of n-EHAP NCs. Experimental results indicated that the addition of water-soluble acetone greatly promoted the formation of individual n-EHAP NCs without aggregation, and furthermore, the successful incorporation of hydrophobic 2-BrMP groups led to formation of porously structured n-EHAP NCs with a higher surface area and an increasing micro-/mesopore ratio. Compared with pristine n-HAP, n-EHAP NCs exhibited lower crystallinity with smaller crystallite size and demonstrated an ultrahigh adsorption capacity for Pb(II) in acidic solution with a record of close to 2400 mg/g. The improved performance of n-EHAP NCs originated from both the suitable porous structure with a higher micro-/mesoporosity ratio and the existing tethered 2-BrMP group-induced the ester bond, providing more adsorption active affinity sites for heavy metal ions. The highly efficient adsorption (99.99%) was further achieved using tap water spiked with traces of Pb(II) (63 ppb). The presented findings promise the application of n-EHAP NCs in water treatment as an alternative, low-cost, and ecofriendly adsorbent for environmental remediation.

NLRP3 regulates platelet integrin αIIbß3 outside-in signaling, hemostasis and arterial thrombosis.

In addition to their hemostatic function, platelets play an important role in regulating the inflammatory response. The platelet NLRP3 inflammasome not only promotes interleukin-1ß secretion, but was also found to be upregulated during platelet activation and thrombus formation in vitro However, the role of NLRP3 in platelet function and thrombus formation in vivo remains unclear. In this study, we aimed to investigate the role of NLRP3 in platelet integrin αIIbß3 signaling transduction. Using NLRP3-/- mice, we showed that NLRP3-deficient platelets do not have significant differences in expression of the platelet-specific adhesive receptors αIIbß3 integrin, GPIba or GPVI; however, NLRP3-/- platelets transfused into wild-type mice resulted in prolonged tail-bleeding time and delayed arterial thrombus formation, as well as exhibiting impaired spreading on immobilized fibrinogen and defective clot retraction, concomitant with decreased phosphorylation of c-Src, Syk and PLCγ2 in response to thrombin stimulation. Interestingly, addition of exogenous recombinant interleukin-1ß reversed the defect in NLRP3-/- platelet spreading and clot retraction, and restored thrombin-induced phosphorylation of c-Src/Syk/PLCγ2, whereas an anti-interleukin-1ß antibody blocked spreading and clot retraction mediated by wild-type platelets. Using the direct NLRP3 inhibitor, CY-09, we demonstrated significantly reduced human platelet aggregation in response to threshold concentrations of collagen and ADP, as well as impaired clot retraction in CY-09-treated human platelets, supporting a role for NLRP3 also in regulating human platelet αIIbß3 outside-in signaling. This study identifies a novel role for NLRP3 and interleukin-1ß in platelet function, and provides a new potential link between thrombosis and inflammation, suggesting that therapies targeting NLRP3 or interleukin-1ß might be beneficial for treating inflammation-associated thrombosis.

Potent anti-leukemia activities of humanized CD19-targeted Chimeric antigen receptor T (CAR-T) cells in patients with relapsed/refractory acute lymphoblastic leukemia.

Chimeric antigen receptor T (CAR-T) cell therapy has shown promising results for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). The immune response induced by murine single-chain variable fragment (scFv) of the CAR may limit CAR-T cell persistence and thus increases the risk of leukemia relapse. In this study, we developed a novel humanized scFv from the murine FMC63 antibody. A total of 18 R/R ALL patients with or without prior murine CD19 CAR-T therapy were treated with humanized CD19-targeted CAR-T cells (hCART19s). After lymphodepletion chemotherapy with cyclophosphamide and fludarabine, the patients received a single dose (1 × 106 /kg) of autologous hCART19s infusion. Among the 14 patients without previous CAR-T therapy, 13 (92.9%) achieved complete remission (CR) or CR with incomplete count recovery (CRi) on day 30, whereas 1 of the 3 patients who failed a second murine CAR-T infusion achieved CR after hCART19s infusion. At day 180, the overall and leukemia-free survival rates were 65.8% and 71.4%, respectively. The cumulative incidence of relapse was 22.6%, and the nonrelapse mortality rate was 7.1%. During treatment, 13 patients developed grade 1-2 cytokine release syndrome (CRS), 4 patients developed grade 3-5 CRS, and 1 patient experienced reversible neurotoxicity. These results indicated that hCART19s could induce remission in patients with R/R B-ALL, especially in patients who received a reinfusion of murine CAR-T.

High expression of CPNE3 predicts adverse prognosis in acute myeloid leukemia.

CPNE3, a member of a Ca2+ -dependent phospholipid-binding protein family, was identified as a ligand of ERBB2 and has a more general role in carcinogenesis. Here, we identified the prognostic significance of CPNE3 expression in acute myeloid leukemia (AML) patients based on two datasets. In the first microarray dataset (n = 272), compared to low CPNE3 expression (CPNE3low ), high CPNE3 expression (CPNE3high ) was associated with adverse overall survival (OS, P < 0.001) and event-free survival (EFS, P < 0.001). In the second independent group of AML patients (TCGA dataset, n = 179), CPNE3high was also associated with adverse OS and EFS (OS, P = 0.01; EFS, P = 0.036). Notably, among CPNE3high patients, those received allogenic hematopoietic cell transplantation (HCT) had longer OS and EFS than those with chemotherapy alone (allogeneic HCT, n = 40 vs chemotherapy, n = 46), but treatment modules played an insignificant role in the survival of CPNE3low patients (allogeneic HCT, n = 32 vs chemotherapy, n = 54). These results indicated that CPNE3high is an independent, adverse prognostic factor in AML and might guide treatment decisions towards allogeneic HCT. To understand its inherent mechanisms, we investigated genome-wide gene/microRNA expression signatures and cell signaling pathways associated with CPNE3 expression. In conclusion, CPNE3high is an adverse prognostic biomarker for AML. Its effect may be attributed to the distinctive genome-wide gene/microRNA expression and related cell signaling pathways.

High expression of ETS2 predicts poor prognosis in acute myeloid leukemia and may guide treatment decisions.

BACKGROUND: ETS2 is a downstream effector of the RAS/RAF/ERK pathway, which plays a critical role in the development of malignant tumor. However, the clinical impact of ETS2 expression in AML remains unknown. METHODS: In this study, we evaluated the prognostic significance of ETS2 expression using two relatively large cohorts of AML patients. RESULTS: In the first cohort, compared to low expression of ETS2 (ETS2 low), high expression of ETS2 (ETS2 high) showed significant shorter OS, EFS and RFS in the current treatments including the allogeneic HCT group (n = 72) and the chemotherapy group (n = 100). Notably, among ETS2 high patients, those received allogeneic HCT had longer OS, EFS and RFS than those with chemotherapy alone (allogeneic HCT, n = 39 vs. chemotherapy, n = 47), but treatment modules play insignificant role in the survival of ETS2 low patients (allogeneic HCT, n = 33 vs. chemotherapy, n = 53). Moreover, gene/microRNA expression data provides insights into the biological changes associated with varying ETS2 expression levels in AML. The prognostic value of ETS2 was further validated in the second AML cohort (n = 329). CONCLUSIONS: Our results indicate that ETS2 high is a poor prognostic factor in AML and may guide treatment decisions towards allogeneic HCT.

Cytotoxic T Lymphocyte Antigen-4 Down-Regulates T Helper 1 Cells by Increasing Expression of Signal Transducer and Activator of Transcription 3 in Acute Graft-versus-Host Disease.

Numerous previous studies have suggested that cytotoxic T lymphocyte antigen-4 (CTLA-4) plays an important role in acute graft-versus-host disease (GVHD). How CTLA-4 acts in regulating acute GVHD remains unknown, however. In the present study, we found that, compared with healthy controls, CTLA-4 plasma and relative mRNA levels in patients with acute GVHD were initially decreased and then markedly elevated after 28 days of treatment. CTLA-4 levels were higher in patients with grade I-II acute GVHD compared with those with grade III-IV acute GVHD both before and after treatment. Up-regulation of CTLA-4 significantly increased the luciferase activity and degree of phosphorylation of signal transducer and activator of transcription 3 (STAT3). Meanwhile, T cell activation was significantly inhibited, and levels of IFN-γ, IL-17, and IL-22 decreased. These findings suggest that CTLA-4 might be involved in the pathogenesis of acute GVHD, and may down-regulate T helper 1 cells by increasing STAT3 expression in acute GVHD.

In Situ Fabrication of Vertical Multilayered MoS2/Si Homotype Heterojunction for High-Speed Visible-Near-Infrared Photodetectors.

c2D transition metal dichalcogenides (TMDCs)-based heterostructures have been demonstrated to achieve superior light absorption and photovoltaic effects theoretically and experimentally, making them extremely attractive for realizing optoelectronic devices. In this work, a vertical multilayered n-MoS2/n-silicon homotype heterojunction is fabricated, which takes advantage of multilayered MoS2 grown in situ directly on plane silicon. Electrical characterization reveals that the resultant device exhibits high sensitivity to visible-near-infrared light with responsivity up to 11.9 A W(-1). Notably, the photodetector shows high-speed response time of ≈ 30.5 µs/71.6 µs and capability to work under higher pulsed light irradiation approaching 100 kHz. The high response speed could be attributed to a good quality of the multilayer MoS2 , as well as in situ device fabrication process. These findings suggest that the multilayered MoS2 /Si homotype heterojunction have great potential application in the field of visible-near-infrared detection and might be used as elements for construction of high-speed integrated optoelectronic sensor circuitry.