IL-2 regulates tumor-reactive CD8+ T cell exhaustion by activating the aryl hydrocarbon receptor.

CD8+ T cell exhaustion dampens antitumor immunity. Although several transcription factors have been identified that regulate T cell exhaustion, the molecular mechanisms by which CD8+ T cells are triggered to enter an exhausted state remain unclear. Here, we show that interleukin-2 (IL-2) acts as an environmental cue to induce CD8+ T cell exhaustion within tumor microenvironments. We find that a continuously high level of IL-2 leads to the persistent activation of STAT5 in CD8+ T cells, which in turn induces strong expression of tryptophan hydroxylase 1, thus catalyzing the conversion to tryptophan to 5-hydroxytryptophan (5-HTP). 5-HTP subsequently activates AhR nuclear translocation, causing a coordinated upregulation of inhibitory receptors and downregulation of cytokine and effector-molecule production, thereby rendering T cells dysfunctional in the tumor microenvironment. This molecular pathway is not only present in mouse tumor models but is also observed in people with cancer, identifying IL-2 as a novel inducer of T cell exhaustion.

Surface Proteins of Bifidobacterium Bifidum DNG6 Growing in 2'-FL Alleviating LPS-Induced Intestinal Barrier Injury in vitro.

Human milk oligosaccharides (HMOs) promote the growth and adhesion of bifidobacteria, thus exerting multiple biological functions on intestinal epithelial cells. Bacterial surface proteins play an important role in bacterial-host intestinal epithelial interactions. In this study, we aim to investigate the effects of surface proteins extracted from Bifidobacterium bifidum DNG6 (B. bifidum DNG6) consuming 2'-fucosyllactose (2'-FL) on Caco-2 cells monolayer barrier injury induced by lipopolysaccharide, compared with lactose (Lac) and galacto-oligosaccharides (GOS). Our results indicated that 2'-FL may promote the surface proteins of B. bifidum DNG6 to improve intestinal barrier injury by positively regulating the NF-κB signaling pathway, reducing inflammation(TNF-α reduced to 50.34%, IL-6 reduced to 22.83%, IL-1ß reduced to 37.91%, and IL-10 increased to 63.47%)and strengthening tight junction (ZO-1 2.39 times, Claudin-1 2.79 times, and Occludin 4.70 times). The findings of this study indicate that 2'-FL can further regulate intestinal barrier damage by promoting the alteration of B. bifidum DNG6 surface protein. The findings of this research will also provide theoretical support for the development of synbiotic formulations.

AMCC nonlinear baseband superimposition and extraction aided by proposed interference cancellation for WDM-PON used in 5G mobile fronthaul.

As the demand for mobile Internet capacity explodes, the research on fifth-generation (5G) mobile communication systems has gradually deepened, which has stringent requirements for latency and transmission capacity, especially in the section called mobile fronthaul (MFH). Wavelength division multiplexing passive optical network (WDM-PON) is an attractive technology for 5G MFH which requires an auxiliary management and control channel (AMCC) to achieve efficient network deployment. In previous studies, more research has been done on AMCC superimposition methods and transmission performance on 10 Gbps WDN-PON systems, and the role of AMCC in wavelength management has been studied at the system level. In this paper, we realize non-linear baseband modulation of AMCC signals up to 20 Mbps in a single wavelength 25-Gbps PON system through the distributed feed-back laser and Mach-Zehnder modulator. At the receiving end, we propose a low-complexity interference cancellation method to suppress the interference caused by WDM-PON signals and significantly reduce the bit error rate of AMCC signals. The method realizes a simplified scheme to reconstruct the PON signals by analyzing the characteristics of nonlinear modulation and the reconstructed signals can be applied to the original AMCC signals through filtering and subtraction to eliminate interference. These operations have low complexity and can be easily implemented by analog circuits, thus making it an effective way to improve the quality of AMCC signals. With the help of the proposed method, AMCC transmission at 20 Mbps can be achieved with different modulation depths, which is very promising for 5G MFH.

Effect of arbuscular mycorrhizal fungi (Glomus mosseae) and elevated air temperature on Cd migration in the rhizosphere soil of alfalfa.

Cadmium (Cd) migration in the rhizosphere soil is easily affected by plants and microorganisms. Global warming significantly affects plant growth, and arbuscular mycorrhizal fungi (AMF) can chelate heavy metals by mycelium, cell wall components, and mycelial secretion. Here, we investigated the regulation of Glomus mosseae on Cd migration in the rhizosphere soil of alfalfa under elevated temperature (ET, + 3 °C). Elevated temperature significantly decreased G. mosseae colonization rate in the roots by 49.5% under Cd exposure. Under ET + G. mosseae + Cd relative to ET + Cd, the contents of free amino acids, total and easily extractable glomalin-related soil protein (GRSP), and root Cd increased significantly; however, the changes in DTPA-Cd in the rhizosphere soil and Cd in the shoots were insignificant. In addition, G. mosseae colonization enhanced the bioconcentration factor of Cd in the roots and the total removal rate of Cd in the rhizosphere soil by 63.4% and 16.3%, respectively, under ET + Cd. However, the changes in the expression of iron-regulated transport 1 (IRT1) and natural resistance-associated macrophage protein 1 genes were insignificant under ET + G. mosseae + Cd relative to ET + Cd. In summary, temperature and G. mosseae significantly affected Cd fate in the rhizosphere soil, and IRT1 gene and rhizosphere soil pH, N, and C/N ratio were significant factors influencing Cd migration. Additionally, G. mosseae improved the remediation efficiency of Cd-contaminated soils by alfalfa under ET. The results will help us understand the regulation of AMF on the phytoremediation of heavy metal-contaminated soils under global warming scenarios.

miR-17-3p promotes the proliferation of multiple myeloma cells by downregulating P21 expression through LMLN inhibition.

Multiple myeloma (MM), a hematological malignancy, has a poor prognosis and requires an invasive procedure. Reports have implicated miRNAs in the diagnosis, treatment and prognosis of hematological malignancies. In our study, we evaluated the expression profiles of miR-17-3p in plasma and bone marrow mononuclear cells of monoclonal gammopathy of undetermined significance (MGUS) and MM patients and healthy subjects. The results showed that the plasma and mononuclear cell expression levels of miR-17-3p in MM patients were higher than those in MGUS patients and normal controls. In addition, the expression of miR-17-3p was positively correlated with diagnostic indexes, such as marrow plasma cell abundance and serum M protein level, and positively correlated with the International Staging System stage of the disease. Receiver operating characteristic curve analysis suggested that miR-17-3p might be a diagnostic index of MM. Moreover, miR-17-3p regulated cell proliferation, apoptosis and the cell cycle through P21 in MM cell lines and promoted MM tumor growth in vivo. Furthermore, we predicted and verified LMLN as a functional downstream target gene of miR-17-3p. Negatively regulated by miR-17-3p, LMLN inhibits MM cell growth, exerting a tumor suppressive function through P21. Taken together, our data identify miR-17-3p as a promising diagnostic biomarker for MM in the clinic and unveil a new miR-17-3p-LMLN-P21 axis in MM progression.

The combined effects of elevated atmospheric CO2 and cadmium exposure on flavonoids in the leaves of Robinia pseudoacacia L. seedlings.

Flavonoids participate in several plant processes such as growth and physiological protection in adverse environments. In this study, we investigated the combined effects of eCO2 and cadmium (Cd)-contaminated soils on the total flavonoid and monomer contents in the leaves of Robinia pseudoacacia L. seedlings. Elevated CO2, Cd, and eCO2+ Cd increased the total flavonoids in the leaves relative to the control, and eCO2 mostly increased (p < 0.05) the total flavonoid content under Cd exposure. Elevated CO2 increased (p < 0.05) robinin, rutin, and acacetin contents in the leaves of 45-day seedlings and decreased (p < 0.05) the content of robinin and acacetin at 90 and 135 d under Cd exposure except for robinin at day 45 under Cd1 and acacetin on day 135 under Cd1. Quercetin content decreased (p < 0.05) under the combined conditions relative to Cd alone. Kaempferol in the leaves was only detected under eCO2 on day 135. The responses of total chlorophyll, total soluble sugars, starch, C, N, S, and the C/N ratio in the leaves to eCO2 significantly affected the synthesis of total flavonoids and monomers under Cd exposure. Overall, rutin was more sensitive to eCO2+ Cd than the other flavonoids. Cadmium, CO2, and time had significant interactive effects on the synthesis of flavonoids in the leaves of R. pseudoacacia L. seedlings. Elevated CO2 may improve the protection and defense system of seedlings grown in Cd-contaminated soils by promoting the synthesis of total flavonoids, although robinin, rutin, quercetin, and acacetin yields may reduce with time. Additionally, increased Cd in the leaves suggested that eCO2 could improve the phytoremediation of Cd-contaminated soils.

Prognostic value of systemic immune-inflammation index in patients with urologic cancers: a meta-analysis.

BACKGROUND: Several studies have reported that the systemic immune-inflammation index (SII) is associated with the prognosis of patients with urologic cancers (UCs). The aim of this study was to systematically evaluate the prognostic value of SII in UC patients. METHODS: We searched public databases for relevant published studies on the prognostic value of SII in UC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted and pooled to assess the relationships between SII and overall survival (OS), progression-free survival (PFS), cancer-specific survival (CSS), overall response rate (ORR) and disease control rate (DCR). RESULTS: A total of 14 studies with 3074 patients were included. From the pooled results, we found that high SII was associated with worse overall survival (OS) in patients with UC (HR 2.58, 95% CI 1.59-4.21). Patients with high SII values also had poorer PFS (HR 1.92, 95% CI 1.29-2.88) and CSS (HR 2.58, 95% CI 1.36-4.91) as well as lower ORRs (HR 0.40, 95% CI 0.22-0.71) than patients with low SII values. In addition, the subgroup analysis of OS and PFS showed that the prognosis of patients with high SII was worse than that of patients with low SII. CONCLUSIONS: SII might be a promising noninvasive predictor in patients with UC. However, more samples and multicenter studies are needed to confirm the effectiveness of SII in predicting the prognosis of patients with UC.

A single molecule analysis of H-NS uncouples DNA binding affinity from DNA specificity.

Heat-stable nucleoid structuring protein (H-NS) plays a crucial role in gene silencing within prokaryotic cells and is important in pathogenesis. It was reported that H-NS silences nearly 5% of the genome, yet the molecular mechanism of silencing is not well understood. Here, we employed a highly-sensitive single-molecule counting approach, and measured the dissociation constant (KD) of H-NS binding to single DNA binding sites. Charged residues in the linker domain of H-NS provided the most significant contribution to DNA binding affinity. Although H-NS was reported to prefer A/T-rich DNA (a feature of pathogenicity islands) over G/C-rich DNA, the dissociation constants obtained from such sites were nearly identical. Using a hairpin unzipping assay, we were able to uncouple non-specific DNA binding steps from nucleation site binding and subsequent polymerization. We propose a model in which H-NS initially engages with non-specific DNA via reasonably high affinity (∼60 nM KD) electrostatic interactions with basic residues in the linker domain. This initial contact enables H-NS to search along the DNA for specific nucleation sites that drive subsequent polymerization and gene silencing.

Charged residues in the H-NS linker drive DNA binding and gene silencing in single cells.

Nucleoid-associated proteins (NAPs) facilitate chromosome organization in bacteria, but the precise mechanism remains elusive. H-NS is a NAP that also plays a major role in silencing pathogen genes. We used genetics, single-particle tracking in live cells, superresolution microscopy, atomic force microscopy, and molecular dynamics simulations to examine H-NS/DNA interactions in single cells. We discovered a role for the unstructured linker region connecting the N-terminal oligomerization and C-terminal DNA binding domains. In the present work we demonstrate that linker amino acids promote engagement with DNA. In the absence of linker contacts, H-NS binding is significantly reduced, although no change in chromosome compaction is observed. H-NS is not localized to two distinct foci; rather, it is scattered all around the nucleoid. The linker makes DNA contacts that are required for gene silencing, while chromosome compaction does not appear to be an important H-NS function.

Puerarin Prevents LPS-Induced Osteoclast Formation and Bone Loss via Inhibition of Akt Activation.

Osteolysis induced by chronic Gram-negative bacterial infection underlies many bone diseases such as osteomyelitis, septic arthritis, and periodontitis. Drugs that inhibit lipopolysaccharide (LPS)-induced osteolysis are critically needed for the prevention of bone destruction in infective bone diseases. In this study, we assessed the effect of puerarin, a natural isoflavone isolated from Pueraria lobata OHWI root, on LPS-induced osteoclastogenesis and bone loss. Our in vitro study showed that puerarin significantly inhibited LPS-induced osteoclast differentiation from osteoclast precursor RAW264.7 cells. The inhibition occurred through suppressing the production of osteoclast activating factor tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and prostaglandin E2 (PGE2), which led to down-regulating mRNA expression of osteoclastogenic genes including tartrate-resistant acid phosphatase (TRAP), cathepsin K and matrix metalloprotein 9 (MMP-9). Furthermore, LPS triggered activation of Akt in osteoclast precursor RAW264.7 cells, which was inhibited by puerarin treatment. In vivo, puerarin attenuated LPS-induced bone loss in a murine calvarial osteolysis model. Collectively, puerarin prevents LPS-induced osteoclast formation, function and bone loss, where the inhibition of Akt activation plays an important role. These findings provide evidences that puerarin might be beneficial as a promising candidate drug for the prevention and treatment of bacteria-induced bone destruction disease, and give new insights for understanding its possible mechanism.

Rapid, high-throughput tracking of bacterial motility in 3D via phase-contrast holographic video microscopy.

Tracking fast-swimming bacteria in three dimensions can be extremely challenging with current optical techniques and a microscopic approach that can rapidly acquire volumetric information is required. Here, we introduce phase-contrast holographic video microscopy as a solution for the simultaneous tracking of multiple fast moving cells in three dimensions. This technique uses interference patterns formed between the scattered and the incident field to infer the three-dimensional (3D) position and size of bacteria. Using this optical approach, motility dynamics of multiple bacteria in three dimensions, such as speed and turn angles, can be obtained within minutes. We demonstrated the feasibility of this method by effectively tracking multiple bacteria species, including Escherichia coli, Agrobacterium tumefaciens, and Pseudomonas aeruginosa. In addition, we combined our fast 3D imaging technique with a microfluidic device to present an example of a drug/chemical assay to study effects on bacterial motility.

[Effectiveness of transverse double "8"-shaped tension band technique for Lawrence zone â fracture of the fifth metatarsal base].

Objective: To explore the effectiveness of transverse double "8"-shaped tension band technique in the treatment of Lawrence zoneⅠfracture of the 5th metatarsal base. Methods: Between February 2019 and October 2021, 15 patients with Lawrence zoneⅠfracture of the 5th metatarsal base were treated with transverse double "8"-shaped tension band technique. There were 8 males and 7 females, with a median age of 40 years (range, 23-59 years). The fractures were caused by sprains. The time from injury to operation was 3-7 days (mean, 4.1 days). X-ray films were taken to observe the fracture healing and the anchor looseness and detachment. The foot function was evaluated by American Orthopaedic Foot and Ankle Society (AOFAS) score, visual analogue scale (VAS) score, and the eversion angle of the calcaneal talus joint. Results: The incisions healed by first intention after operation in 14 cases and the incision healed poorly in 1 case. All patients were followed up 8-12 months (median, 10 months). The imaging examination showed that all fractures healed well, with a healing time of 10-14 weeks (mean, 11.7 weeks). At last follow-up, AOFAS score was 82-100 (median, 98); 13 cases were excellent and 2 cases were good, with an excellent and good rate of 100%. VAS score was 0-3 (median, 1). Three cases had mild limited ankle joint range of motion, while 12 cases had normal range of motion. The eversion angle of the calcaneal talus joint was 25°-32° (median, 30°). Conclusion: The application of transverse double "8"-shaped tension band technique for Lawrence zone Ⅰ fracture of the 5th metatarsal base has advantages such as simple operation, avoidance of secondary operation, and reduction of foreign body sensation, with definite effectiveness.

Efficient generation of induced pluripotent stem cell lines from healthy donors' peripheral blood mononuclear cells of different genders.

Peripheral blood mononuclear cell (PBMC) are recognized as a conveniently collected reprogramming resource. Several methods are available in academia to reprogram PBMC into induced pluripotent stem cells (iPSC). In this research, we reprogrammed PBMC of different genders by using non-integrative non-viral liposome electrotransfer containing the reprogramming factors OCT4, SOX2, KLF4, and c-MYC. The three obtained iPSC cell lines were karyotypically normal and showed significant tritiated differentiation potential in vitro and in vivo. Our study provided an efficient procedure for reprogramming PBMC into iPSC and obtained three well-functioning iPSC, that may contribute to advance personalized cell therapy in the future.

Phosphodiesterases catalyze hydrolysis of cAMP-bound to regulatory subunit of protein kinase A and mediate signal termination.

Although extensive structural and biochemical studies have provided molecular insights into the mechanism of cAMP-dependent activation of protein kinase A (PKA), little is known about signal termination and the role of phosphodiesterases (PDEs) in regulatory feedback. In this study we describe a novel mode of protein kinase A-anchoring protein (AKAP)-independent feedback regulation between a specific PDE, RegA and the PKA regulatory (RIα) subunit, where RIα functions as an activator of PDE catalysis. Our results indicate that RegA, in addition to its well-known role as a PDE for bulk cAMP in solution, is also capable of hydrolyzing cAMP-bound to RIα. Furthermore our results indicate that binding of RIα activates PDE catalysis several fold demonstrating a dual function of RIα, both as an inhibitor of the PKA catalytic (C) subunit and as an activator for PDEs. Deletion mutagenesis has localized the sites of interaction to one of the cAMP-binding domains of RIα and the catalytic PDE domain of RegA whereas amide hydrogen/deuterium exchange mass spectrometry has revealed that the cAMP-binding site (phosphate binding cassette) along with proximal regions important for relaying allosteric changes mediated by cAMP, are important for interactions with the PDE catalytic domain of RegA. These sites of interactions together with measurements of cAMP dissociation rates demonstrate that binding of RegA facilitates dissociation of cAMP followed by hydrolysis of the released cAMP to 5'AMP. cAMP-free RIα generated as an end product remains bound to RegA. The PKA C-subunit then displaces RegA and reassociates with cAMP-free RIα to regenerate the inactive PKA holoenzyme thereby completing the termination step of cAMP signaling. These results reveal a novel mode of regulatory feedback between PDEs and RIα that has important consequences for PKA regulation and cAMP signal termination.

Efficacy of arthroscopic internal fixation with countersunk screw in the treatment of talus fracture.

Objective: To explore clinical effects of arthroscopic internal fixation with countersunk screw in the treatment of talus fracture. Methods: Forty-eight patients with talus fracture treated in hospital of Chengde Medical University from February 2015 to December 2019 were enrolled for present investigation. The patients with talus fracture were randomly assigned into two groups, with twenty-four patients per group. The patients with talus fracture in the observation group were treated with arthroscopic internal fixation with countersunk screw, while the traditional open reduction and internal fixation were applied for the ones in control group. The clinical efficacy of the patients was evaluated three months after the operation, and the preoperative and postoperative ankle joint functions, fracture-healing time, hospital stay, and complications were carefully compared between observation and control group. Results: A total efficiency as high as 91.67% was showed in observation group, which is distinctly better than the effective rate of control group (66.67%, P<0.05). Before operation, ankle function scores (AOFAS) of control group and observation group is 42.08 ± 4.29 and 41.75±5.31 with no significantly difference (P>0.05); while after the surgery, AOFAS scores of control group is significantly lower than that of observation group: (66.28±7.51 vs. 53.0 ±6.79, P<0.05). Moreover, healing time and hospitalized duration of observation group are 3.19±1.04 months and 3.57±0.97 days, which are also significantly shorter than 4.18±1.25 months and 8.28±2.54 days in control group, respectively, (P < 0.05). And the total complication rate in control group is 20.83%, which is higher than 8.33% in observation group (P >0.05). Conclusion: Arthroscopic internal fixation with countersunk screw can significantly improve the efficacy and ankle joint functions, shorten the fracture-healing time and hospital stays without increasing the incidence of complications.

Effect of Glomus mosseae, cadmium, and elevated air temperature on main flavonoids and phenolic acids contents in alfalfa.

Global warming and heavy metal-contaminated soils co-occur in natural ecosystems. Flavonoids and phenolic acids in plants have significant antioxidant activity and free radical scavenging ability, which can quickly increase under adverse environments. Arbuscular mycorrhizal fungi (AMF) colonization can affect the synthesis of flavonoids and phenolic acids in host plants. This study focused on the main effect of Glomus mosseae, cadmium (Cd, 8 mg kg-1 dry soils), and elevated temperature (ET, + 3 °C) on main flavonoids and phenolic acids in 120-d Medicago sativa L. (alfalfa). Elevated temperature decreased G. mosseae colonization ratio by 49.5% under Cd exposure. Except for p-hydroxybenzoic acid, flavonoids and phenolic acids content in shoots increased (p < 0.05) under G. mosseae + Cd relative to Cd only. G. mosseae and Cd showed significant effects on rutin, quercetin, apigenin, liquiritigenin, gallic acid, p-hydroxybenzoic acid, p-coumaric acid, and ferulic acid, and G. mosseae colonization led to increases in these compounds by 41.7%, 35.4%, 32.2%, 267.8%, 84.7%, 33.5%, 102.8%, and 89.4%, respectively, under ET + Cd. Carbon, N, and Cd in alfalfa and G. mosseae colonization rate were significant factors on flavonoids and phenolic acids accumulation. Additionally, P content in shoots significantly influenced flavonoids content. G. mosseae inoculation significantly stimulated the synthesis of main flavonoids and phenolic acids in alfalfa shoots under ET + Cd, which was helpful to understand the regulation of AMF on non-enzyme antioxidant system of plants grown in heavy metal-contaminated soils under global change scenarios.

Efficient generation of induced pluripotent stem cell lines from peripheral blood mononuclear cells.

Peripheral blood mononuclear cells (PBMCs) have been widely considered as a more convenient and almost unlimited reprogramming resource, while the reprogramming procedure and efficiency still need to be improved. We reprogrammed the PBMCs by using non-integrative non-viral vectors liposome electrotransfer containing the reprogramming factors OCT4, SOX2, KLF4, and c-MYC. The iPSC lines exhibited a normal karyotype with their corresponding PBMCs and exhibited significant cellular pluripotency. Teratoma formation assay revealed that the iPSCs we generated could differentiate into three embryonic germ layers. Our study provides a more effective procedure for peripheral blood monocyte reprogramming to iPSC, and promotes its future application.

Glomus mosseae improved the adaptability of alfalfa (Medicago sativa L.) to the coexistence of cadmium-polluted soils and elevated air temperature.

The coexistence of heavy metal-polluted soils and global warming poses serious threats to plants. Many studies indicate that arbuscular mycorrhizal fungi (AMF) can enhance the resistance of plants to adverse environments such as heavy metals and high temperature. However, few studies are carried out to explore the regulation of AMF on the adaptability of plants to the coexistence of heavy metals and elevated temperature (ET). Here, we investigated the regulation of Glomus mosseae on the adaptability of alfalfa (Medicago sativa L.) to the coexistence of cadmium (Cd)-polluted soils and ET. G. mosseae significantly enhanced total chlorophyll and carbon (C) content in the shoots by 15.6% and 3.0%, respectively, and Cd, nitrogen (N), and phosphorus (P) uptake by the roots by 63.3%, 28.9%, and 85.2%, respectively, under Cd + ET. G. mosseae significantly increased ascorbate peroxidase activity, peroxidase (POD) gene expression, and soluble proteins content in the shoots by 13.4%, 130.3%, and 33.8%, respectively, and significantly decreased ascorbic acid (AsA), phytochelatins (PCs), and malondialdehyde (MDA) contents by 7.4%, 23.2%, and 6.5%, respectively, under ET + Cd. Additionally, G. mosseae colonization led to significant increases in POD (13.0%) and catalase (46.5%) activities, Cu/Zn-superoxide dismutase gene expression (33.5%), and MDA (6.6%), glutathione (22.2%), AsA (10.3%), cysteine (101.0%), PCs (13.8%), soluble sugars (17.5%), and proteins (43.4%) contents in the roots and carotenoids (23.2%) under ET + Cd. Cadmium, C, N, G. mosseae colonization rate, and chlorophyll significantly influenced shoots defenses and Cd, C, N, P, G. mosseae colonization rate, and sulfur significantly affected root defenses. In conclusion, G. mosseae obviously improved the defense capacity of alfalfa under ET + Cd. The results could improve our understanding of the regulation of AMF on the adaptability of plants to the coexistence of heavy metals and global warming and phytoremediation of heavy metal-polluted sites under global warming scenarios.

Spatial transcriptomics analysis of esophageal squamous precancerous lesions and their progression to esophageal cancer.

Esophageal squamous precancerous lesions (ESPL) are the precursors of esophageal squamous cell carcinoma (ESCC) including low-grade and high-grade intraepithelial neoplasia. Due to the absence of molecular indicators, which ESPL will eventually develop into ESCC and thus should be treated is not well defined. Indicators, for predicting risks of ESCC at ESPL stages, are an urgent need. We perform spatial whole-transcriptome atlas analysis, which can eliminate other tissue interference by sequencing the specific ESPL regions. In this study, the expression of TAGLN2 significantly increases, while CRNN expression level decreases along the progression of ESCC. Additionally, TAGLN2 protein level significantly increases in paired after-progression tissues compared with before-progression samples, while CRNN expression decreases. Functional studies suggest that TAGLN2 promotes ESCC progression, while CRNN inhibits it by regulating cell proliferation. Taken together, TAGLN2 and CRNN are suggested as candidate indicators for the risk of ESCC at ESPL stages.

Safety evaluation of human umbilical cord-mesenchymal stem cells in type 2 diabetes mellitus treatment: A phase 2 clinical trial.

BACKGROUND: Progressive pancreatic ß cell dysfunction is a fundamental aspect of the pathology underlying type 2 diabetes mellitus (T2DM). Recently, mesenchymal stem cell (MSC) transplantation has emerged as a new therapeutic method due to its ability to promote the regeneration of pancreatic ß cells. However, current studies have focused on its efficacy, and there are few clinical studies on its safety. AIM: To evaluate the safety of human umbilical cord (hUC)-MSC infusion in T2DM treatment. METHODS: An open-label and randomized phase 2 clinical trial was designed to evaluate the safety of hUC-MSC transplantation in T2DM in a Class A hospital. Ten patients in the placebo group received acellular saline intravenously once per week for 3 wk. Twenty-four patients in the hUC-MSC group received hUC-MSCs (1 × 106 cells/kg) intravenously once per week for 3 wk. Diabetic clinical symptoms and signs, laboratory findings, and imaging findings were evaluated weekly for the 1st mo and then at weeks 12 and 24 post-treatment. RESULTS: No serious adverse events were observed during the 24-wk follow-up. Four patients (16.7%) in the hUC-MSC group experienced transient fever, which occurred within 24 h after the second or third infusion; this did not occur in any patients in the placebo group. One patient from the hUC-MSC group experienced hypoglycemic attacks within 1 mo after transplantation. Significantly lower lymphocyte levels (weeks 2 and 3) and thrombin coagulation time (week 2) were observed in the hUC-MSC group compared to those in the placebo group (all P < 0.05). Significantly higher platelet levels (week 3), immunoglobulin levels (weeks 1, 2, 3, and 4), fibrinogen levels (weeks 2 and 3), D-dimer levels (weeks 1, 2, 3, 4, 12, and 24), and neutrophil-to-lymphocyte ratios (weeks 2 and 3) were observed in the hUC-MSC group compared to those in the placebo group (all P < 0.05). There were no significant differences between the two groups for tumor markers (alpha-fetoprotein, carcinoembryonic antigen, and carbohydrate antigen 199) or blood fat. No liver damage or other side effects were observed on chest X-ray. CONCLUSION: Our study suggested that hUC-MSC transplantation has good tolerance and high safety in the treatment of T2DM. It can improve human immunity and inhibit lymphocytes. Coagulation function should be monitored vigilantly for abnormalities.