Novel Pt(IV) complexes containing salvigenin ligand reverse cisplatin-induced resistance by inhibiting Rap1b-mediated cancer cell stemness in esophageal squamous cell carcinoma treatments.

Esophageal squamous cell carcinoma (ESCC) is a malignant tumor that is highly susceptible to metastasis, recurrence and resistance, and few therapeutic targets have been identified and proven effective. Herein, we demonstrated for the first time that Rap1b can positively regulate ESCC cell stemness, as well as designed and synthesized a novel class of Pt(IV) complexes that can effectively inhibit Raplb. In vitro biological studies showed that complex-1 exhibited stronger cytotoxicity than cisplatin and oxaliplatin against a variety of ESCC cells, and effectively reversed cisplatin-induced resistance of TE6 cells by increasing cellular accumulation of platinum and inhibiting cancer cell stemness. Significantly, complex-1 also exhibited strong ability to reversal cisplatin-induced cancer cell resistance and inhibit tumor growth in TE6/cDDP xenograft mice models, with a tumor growth inhibition rate of 73.3 % at 13 mg/kg and did not show significant systemic toxicity. Overall, Rap1b is a promising target to be developed as an effective treatment for ESCC. Complex-1, as the first Pt(IV) complex that can strongly inhibit Rap1b, is also worthy of further in-depth study.

Vaccination coverage survey of children aged 1-3 years in Beijing, China, 2005-2021.

BACKGROUND: The routine immunization program for children is a primary strategy and a core part of vaccination. Achieving and maintaining high level of vaccination coverage are important to reduce morbidity and mortality caused by vaccine-preventable diseases. In Beijing, annual coverage surveys have been conducted since 2005. It is necessary and possible to assess the level and trend of routine vaccination coverage of children in Beijing as well as the disruption of coronavirus disease 2019 (COVID-19) pandemic and provide the reference for the further improve the vaccination coverage. METHODS: The data of 61,521 children aged 1-3 years in the vaccination coverage surveys during 2005-2021 were analyzed by Beijing Center for Disease Control and Prevention. Descriptive epidemiological method was used to analyze the data and the difference of vaccination coverage within the time period. RESULTS: More than 99 % of participants had immunization cards and electronic immunization records. The concordance rate of both records were also over 99 %. During 2011-2019, the rates of on-time and in-time vaccination of each routine vaccine reached 96 % or more and increased significantly (all P values <0.05), compared with that of 2005-2010. All rates of the investigated vaccine, except for Bacillus Calmette-Guérin vaccine (BCG) and the first dose of hepatitis B vaccine (HepB), decreased in 2020-2021 significantly (all P values <0.05). For the causes of failing to vaccinate on time, delayed vaccination accounted for 47.82 %. The top two vaccines to be missed were the first dose of hepatitis A vaccine and the 4th dose of diphtheria-tetanus-acellular pertussis vaccine, accounting for 21.41 % and 20.79 %, respectively. The main reason for zero-dose/drop-out vaccination was "Guardians regarded the immunization service time as inappropriate", accounting for 72.27 %. CONCLUSION: The coverage level and service quality of routine immunization in Beijing were relatively high. However, as influenced by COVID-19 epidemics, both on-time and in-time vaccination rates decreased significantly, except for BCG and HepB. Under the background of COVID-19 pandemic, the keys to maintain high level of vaccination coverage include flexible immunization service time to ensure the guardians bringing their children for vaccination timely, and more attention from providers to the doses after children's first birthday.

MiR-223-3p affects the proliferation and apoptosis of HCAECs in Kawasaki disease by regulating the expression of FOXP3.

OBJECTIVE: Kawasaki disease (KD) can lead to permanent damage to coronary structures, the pathogenesis of which remains unknown. This experiment was designed to investigate whether miR-223-3p secreted in the serum of KD patients affects the proliferation and apoptosis of HCAECs in KD by regulating FOXP3. METHODS: Blood samples were collected in acute febrile phase of KD, after IVIG treatment, and from healthy controls. Transfected into HCAECs cells by synthetic FOXP3 siRNA/NC. A co-culture system was established between HCAECs cells transfected with FOXP3 siRNA/NC and THP1 cells added with three sera. RESULTS: Compared with the control group, the expressions of miR-223-3p, RORγt, and Th17 in serum of KD patients were significantly upregulated, and the expressions of TGF-ß1, FOXP3 and Treg were significantly downregulated. At the same time, the levels of IL-6, IL-17, and IL-23 were significantly increased, and the levels of IL-10 and FOXP3 were significantly decreased. After IVIG treatment, the patient's above results were reversed. The serum of KD patients increased the expression of miR-223-3p and inhibited the expression of FOXP3 in HCAECs cells. IVIG serum is the opposite. Overexpression of miR-223-3p also promoted the apoptosis of HCAECs. In addition, serum from KD patients promoted apoptosis, whereas serum after IVIG treatment inhibited apoptosis. KD patient serum downregulated the expression of FOXP3, Bcl2, TGF-ß1 and IL-10 in cells, and upregulated the expression of caspase3, Bax, IL-17, IL-6, and IL-23. The opposite results were obtained with IVIG-treated sera. CONCLUSION: miR-223-3p secreted in serum of KD patients can regulate the expression of FOXP3 and affect the proliferation, apoptosis, and inflammation of cells.

Impact of 1,25-dihydroxyvitamin D3 PLGA-nanoparticles/chitosan hydrogel on osteoimmunomodulation.

Severe bone defects that extend beyond a critical size do not heal on their own, increasing the risk of complications and leading to poor outcomes for patients. Healing is a highly coordinated and complex process in which immune cells have an important function making the design and preparation of biomaterials with immunomodulatory functions an important new therapeutic strategy. 1,25-dihydroxyvitamin D3 (VD3) is crucial for bone metabolism and immune regulation. For post-defect bone regeneration, we developed a drug delivery system (DDS) based on chitosan (CS) and nanoparticles (NPs) to sustain the release effect of VD3 and desirable biological characteristics. The hydrogel system was physically characterized and confirmed to have good mechanical strength, degradation rate, and drug release rate. In vitro experiments showed that the cells had good biological activity when the hydrogel was co-cultured with MC3T3-E1 and RAW264.7. The high expression of ARG-1 and low expression of iNOS in macrophages confirmed that VD3-NPs/CS-GP hydrogel transformed lipopolysaccharide-induced M1 macrophages into M2 macrophages. Alkaline phosphatase and alizarin red staining showed that VD3-NPs/CS-GP hydrogel promoted osteogenic differentiation under inflammatory conditions. In conclusion, VD3-NPs/CS-GP hydrogel with synergistic anti-inflammatory and pro-osteogenic differentiation effects may serve as a potential immunomodulatory biomaterial for bone repair and regeneration in cases of bone defects.

Influence factors of channel geometry for separation of circulating tumor cells by four-ring inertial focusing microchannel.

Inertial microfluidics is a high-throughput and high-efficiency cell separation approach to which attention has been progressively paid in recent years. However, research on the influencing factors that compromise the efficiency of cell separation is still lacking. Therefore, the aim of this study was to evaluate the cell separation efficiency by changing the influencing factors. A four-ring inertial focusing spiral microchannel was designed to separate two kinds of circulating tumor cells (CTCs) from blood. Human breast cancer (MCF-7) cells and human epithelial cervical cancer (HeLa) cells enter the four-ring inertial focusing spiral microchannel together with blood cells, and cancer cells and blood cells were separated from each other at the outlet of the channel by inertial force. The cell separation efficiency at the inlet flow rate in the Reynolds number range of 40-52 was studied by changing the influencing factors such as the cross-sectional shape of the microchannel, the average thickness of the cross-section, and the trapezoidal inclination angle. The results showed that the reduction of the channel thickness and the increase of a certain trapezoidal inclination enhanced the cell separation efficiency to a certain extent, the study showed that when the channel inclination was 6 ° and the average channel thickness was 160 µm. The two kinds of CTC cells could be completely separated from the blood and the efficiency could reached 100%.

Predicting the prognosis of esophageal cancer based on extensive analysis of new inflammatory response-related signature.

The prognosis of esophageal cancer (ESCA) is very poor, with a 5-year survival rate of less than 20%. On the other hand, inflammation is the characteristic hallmark of ESCA; however, the prognostic relationship between inflammatory response-related genes and ESCA has not been clarified yet. Therefore, in the present manuscript, we intend to investigate the correlation and specific signature of inflammation for the prediction of the prognosis of ESCA. A total of 173 samples were obtained from The Cancer Genome Atlas (TCGA) database, including 162 tumors and 11 normal specimens. The prognostic signature was established by least absolute shrinkage and selection operator Cox regression analysis. The transcription factor regulatory network with genes of the prognostic signature was analyzed from the transcriptional regulatory relationships unravelled by sentence-based text-mining database. Chemotherapy sensitivity and immunotherapy analysis were also performed. Multivariate Cox analysis showed that the signature was an independent prognostic risk factor. The low-risk group had poorer outcomes than the high-risk group. In the high-risk group, the infiltration of most immune cells was high and strongly correlated with the riskScore. In chemotherapeutic drug sensitivity analysis, OSM, AHR, and BTG2 were significantly correlated with the current chemotherapeutic drugs of ESCA. We have demonstrated a valid prognostic signature of inflammatory response-related genes and found strong associations with immune cells, targeted genes, and chemotherapeutic agents.

Effect of viscoelastic properties of cellulose nanocrystal/collagen hydrogels on chondrocyte behaviors.

Cartilage tissue engineering technology provides a solution for treating osteoarthritis. Based on the viscoelastic nature of articular cartilage, many viscoelastic hydrogel scaffolds have been developed for investigating the effects on chondrocyte behaviors. However, cellulose nanocrystal/collagen (CNC/COL) hydrogels have not been used as a viscoelastic microenvironment to study chondrocyte growth. Here, we prepared CNC/COL hydrogels with tunable viscoelastic properties and investigated their influences on chondrocyte behaviors. The results showed that CNC and COL within the hydrogels are bonded by hydrogen bonds. The hydrogels had a microporous structure, and the viscoelastic properties were enhanced by increasing the concentration of CNC. Moreover, enhancing the hydrogel viscoelastic properties, including stress relaxation, creep, storage modulus, and loss modulus, promoted the cell shape change, proliferation, and matrix deposition and reduced the IL-1ß level. Using a principal component analysis (PCA), stress relaxation was assessed to have the strongest correlation with chondrocytes behaviors, with an authority weight value of 62.547%. More importantly, FAK and YAP were involved in the chondrocytes' response to the rapid relaxing hydrogel by immunofluorescence staining.

Study on the anhydrous condensation of collagen polypeptide and tricyanogen chloride.

The molecular weight of collagen-degrading polypeptides (CDPs) extracted using the alkali method from leather scraps must be expanded to improve its utilization effect. A novel polymer (CPP) was synthesized from tricyanogen chloride (TC) and CDP by mechanical force without water. According to the solution viscosity and content of water-soluble matter, the optimal condensation conditions of the n(TC)/n(CDP) and temperature were obtained and the properties of CPP, such as the molecular weight, thermal properties, and isoelectric point were tested and analyzed. The synthesis of CPP was simulated by the substitution of l-threonine containing hydroxyl and amino groups for the condensation reaction of CDP and TC. The result illustrated that only amino groups were involved in the substitution of chlorine accomplished by the SN2 pathway. Based on this, a probable formation mechanism of CPP was proposed. As an illustration, CPP has good utilization values in the preparation of a corrugated paper jelly instead of gelatin. The preparation of polypeptide water-based adhesive by a mechanochemical method not only has good controllability in the production process but also can save water and energy.

Tannic acid-reinforced zwitterionic hydrogels with multi-functionalities for diabetic wound treatment.

Diabetic wounds remain one of the most prevalent hard-to-heal wounds in the clinic. The causative factors impeding the wound healing process include not only the elevated oxidative stress and bacterial infections but also the high and repetitive plantar stress (including compressive pressure and shear stress). Conventional hydrogel dressings are mechanically weak and fragile, limiting their applications in the high stress-loading conditions of diabetic foot ulcers. As such, mechanically tough hydrogel dressings with appropriate bioactivities are highly desirable for diabetic wound treatment. In this study, a mechanically reinforced hydrogel with multiple biofunctionalities was developed via a facile and straightforward strategy of incorporation of tannic acid (TA) in zwitterionic poly(sulfobetaine methacrylate) (polySBMA) hydrogel. The polySBMA hydrogel reinforced by TA showed excellent mechanical property, with the tensile stress and compressive stress up to 93.7 kPa and 18.4 MPa, respectively, and it could resist cyclic compressive stress at ∼200 kPa (maximum in-shoe plantar pressure) for up to 3500 cycles. The TA-reinforced zwitterionic hydrogel exhibited strong adhesion to skin tissue (20.2 kPa), which was expected to reduce the shear stress on the foot. The plantar pressure on the foot was significantly reduced by the application of the resilient hydrogel. Attributed to the antioxidant and antibacterial properties of TA, the hydrogel showed rapid radical scavenging capability and strong bactericidal efficacy against Gram-positive and Gram-negative bacteria. In vitro and in vivo studies confirmed that the hydrogel has good cytocompatibility and negligible skin irritation, and promoted healing of diabetic wounds in mice. Such tough and effective hydrogel with a straightforward preparation strategy holds great promise as wound dressings for diabetic wound treatment.

The role of adjuvant chemotherapy after neoadjuvant chemotherapy or chemoradiotherapy plus esophagectomy in patients with esophageal cancer: a retrospective cohort study.

Background: The 5-year survival rate of patients with locally advanced esophageal cancer is still low after neoadjuvant therapy plus esophagectomy, and additional adjuvant treatment may be required. Some studies have shown that patients can still benefit from adjuvant chemotherapy (AC) despite its toxic and side effects. This study was designed to explore which patients could benefit from AC. Methods: A retrospective cohort study based on patients who received neoadjuvant therapy plus esophagectomy with complete survival information between December 2014 and November 2020 was conducted. The inclusion criteria were as follows: esophageal cancer was diagnosed by pathological biopsy; neoadjuvant chemotherapy; neoadjuvant chemoradiotherapy; R0 resection. The exclusion criteria were as follows: neoadjuvant chemotherapy combined with targeted therapy or immunotherapy; adjuvant radiotherapy, adjuvant chemoradiotherapy, immunotherapy, or targeted therapy; dead within 90 days of surgery; nonradical (R1/R2) resection; one cycle of postoperative chemotherapy. Patients were divided into AC group (AC) and non-AC group [AC(-)] according to whether AC was performed. We obtained the tumor recurrence and survival status of the patients through inpatient medical records, outpatient electronic medical records, and telephone follow-up of the First Affiliated Hospital of Zhengzhou University. Overall survival (OS) and recurrence-free survival (RFS) were investigated as the outcome measures via Kaplan-Meier curves and Cox analyses. Results: In total, 318 patients were enrolled, among which 214 patients received AC while the other 104 patients did not [AC(-)]. There were significant differences in age and lymph nodes dissected between patients who received AC and those who did not receive AC (P<0.05). Survival curves were plotted using the Kaplan-Meier method, and in the overall group and subgroup, AC was beneficial for OS but not for RFS. In the overall group, sex (P=0.027) and age (P=0.027) were independent prognostic factors for OS. Subgroup multivariate Cox proportional hazards analysis showed that age (P=0.026) and AC (P=0.023) were independent prognostic factors for patients. Conclusions: For patients with locally advanced esophageal cancer who have residual disease after surgery, adjuvant therapy after neoadjuvant chemoradiotherapy and surgery may be a better treatment.

CircTUBGCP3 facilitates the tumorigenesis of lung adenocarcinoma by sponging miR-885-3p.

BACKGROUND: Circular RNAs (circRNAs) act pivotal roles in the progression of multiple malignancies. However, the underlying mechanisms by which hsa_circ_0007031 (circTUBGCP3) contributes to lung adenocarcinoma (LAC) remain largely unknown. METHODS: The association of circTUBGCP3 expression with clinicopathological characteristics and prognosis in patients with LAC was determined by RT-qPCR and fluorescence in situ hybridization. The in vitro functional experiments as well as a subcutaneous tumorigenesis model were executed to estimate the role of circTUBGCP3 in LAC cells. The interaction between circTUBGCP3 and miR-885-3p was confirmed by RNA immunoprecipitation, luciferase gene report and RT-qPCR assays. The effects of circTUBGCP3 on miR-885-3p-mediated Wnt10b/ß-catenin signaling were evaluated by Western blot. RESULTS: The upregulation of circTUBGCP3 or downregulation of miR-885-3p was associated with the pathological stage and poor survival in patients with LAC. Restored expression of circTUBGCP3 facilitated the growth and invasion of LAC cells, but knockdown of circTUBGCP3 harbored the opposite effects. In mechanism, circTUBGCP3 could act as a sponge of miR-885-3p, which suppressed the cell proliferation and colony formation and attenuated the tumor-promoting effects of circTUBGCP3. Wnt10b as a target of miR-885-3p could be upregulated be circTUBGCP3 and indicate poor survival in patient with LAC. CONCLUSIONS: Our findings demonstrated that circTUBGCP3 promoted LAC progression by sponging miR-885-3p, and might represent a prognostic factor for LAC.

PAR1 and PAR4 exert opposite effects on tumor growth and metastasis of esophageal squamous cell carcinoma via STAT3 and NF-κB signaling pathways.

BACKGROUND: Esophageal carcinogenesis is a multifactorial process in which genetic and environmental factors interact to activate intracellular signals, leading to the uncontrolled survival and growth of esophageal squamous cell carcinoma (ESCC) cells. The intracellular pathways of ESCC cells could be regulated by proteinase activated-receptors (PARs), which are comprised of four receptors (i.e., PAR-1, PAR-2, PAR-3, and PAR-4). Therefore, the function and possible mechanism of PAR1 and PAR4 in the progression of ECSS were explored in our study. METHODS: First, we detected the expression levels of PAR1 and PAR4 in 27 cases of ESCC specimens and cell lines by RT-qPCR, IHC and western blot. Meanwhile, the correlation between PAR1/PAR4 expression levels, clinicopathological characteristics, and disease free survival was analyzed. Then, we constructed PAR1/PAR4 knockdown cell models and investigated the role of PAR1/PAR4 knockdown on the proliferation, apoptosis, changes of calcium flow, and metastasis of ESCC cells via MTT, flow cytometry, transwell and wound healing assays in vitro. Further, an experimental metastasis model in vivo was established to explore the role of stable PAR1/PAR4 knockdown on the growth and metastasis of ESCC cells. Finally, the role of nSMase2 in the activation of NF-κB induced by PAR4 and the role of NF-κB and STAT3 signaling pathways in the PAR1/PAR4-mediated tumor promoting or suppressive functions were measured by immunoprecipitation, western blot and immunofluorescence assays. RESULTS: First, the integrated results demonstrated the expression levels of PAR1 and PAR4 are inversely proportional in ESCC. PAR1 potently enhanced tumor growth and metastasis, while PAR4 had an inhibitory effect. Further, the co-activation of STAT3 and NF-κB was involved in the PAR1 activation-induced tumor promoting effect, while only NF-κB participated in the PAR4 activation-induced tumor inhibitory effect in ESCC. To be specific, FAK/PI3K/AKT/STAT3/NF-κB signaling mediated PAR1 activation-induced tumor promoting effect and nSMase2/MAPK/NF-κB signaling mediated PAR4 activation-induced tumor inhibitory effect. CONCLUSIONS: Overall, the study has provided new insights into the potential implication of PAR1 and PAR4 in the pathogenesis of ESCC. Besides, FAK/PI3K/AKT/STAT3/NF-κB and nSMase2/MAPK/NF-κB pathways may be novel targets for regulating tumor growth and metastasis in ESCC patients.

Prognostic factors of patients with small cell lung cancer after surgical treatment.

BACKGROUND: The current National Comprehensive Cancer Network guidelines recommend surgical treatment for patients with stages I-IIA small cell lung cancer (SCLC), but it still cannot deny the effect of surgical treatment on other limited-stage SCLC. Although more advanced diagnostic methods are now used for the diagnosis and classification of SCLC, the selection of surgical candidates is still arbitrary. METHODS: Data were collected from patients with SCLC who underwent surgery at the First Affiliated Hospital of Zhengzhou University from January 2011 to January 2021. Kaplan-Meier method was used to calculate cumulative survival curves, and log-rank test was used to evaluate differences among different subgroups. The Cox proportional hazard regression model was used to assess the predictive power of the variables for prognosis and survival. RESULTS: Smoking index, surgical resection method, TNM stage of postoperative pathology, and postoperative chemotherapy were significantly correlated with postoperative survival (P<0.05), which were independent predictors for postoperative survival. Patients with a smoking index >800 had a higher risk of death after surgery [hazard ratio (HR): 7.050, 95% confidence interval (CI): 3.079-16.143, P<0.001]. Compared with patients who underwent pulmonary lobectomy, those who underwent other pneumoresections (e.g., wedge resection, segmental resection, sleeve resection) had an increased risk of death (HR: 2.822, 95% CI: 1.030-7.734, P=0.044). Compared with stage I patients, stage II and stage III patients had an increased risk of death, with HRs of 6.039 and 3.145, respectively. Compared with those who received ≤4 courses of postoperative chemotherapy, those who received >4 courses of postoperative chemotherapy had reduced postoperative mortality risk (HR: 0.211, 95% CI: 0.097-0.459, P<0.001). CONCLUSIONS: A high smoking index suggests worse prognosis; therefore, patients who smoke should be advised to quit smoking. Compared with stage II and stage III patients, surgical treatment is recommended for stage I SCLC patients. TNM staging, especially N staging, should be evaluated prior to surgery. Pulmonary lobectomy with mediastinal lymph node dissection should be the preferred surgical treatment for patients with SCLC. Patients should receive at least 5 courses of adjuvant chemotherapy after surgery.

SOX2-Upregulated microRNA-30e Promotes the Progression of Esophageal Cancer via Regulation of the USP4/SMAD4/CK2 Axis.

Esophageal cancer (EC) is a highly aggressive disease, and its progression involves a complex gene regulation network. Transcription factor SOX2 is amplified in various cancers including EC. A pathway involving SOX2 regulation of microRNAs (miRNAs) and their target genes has been previously revealed. This study aims to delineate the ability of SOX2 to influence the EC progression, with the involvement of miR-30e/USP4/SMAD4/CK2 axis. SOX2 expression was first examined in the clinical tissue samples from 30 EC patients. Effects of SOX2 on proliferation, migration, and invasion alongside tumorigenicity of transfected cells were examined by means of gain- and loss-of-function experiments. EC tissues and cells exhibited high expression of SOX2, miR-30e, and CK2 and poor expression of USP4 and SMAD4. Mechanistically, SOX2 was positively correlated with miR-30e and upregulated the expression of miR-30e. miR-30e specifically targeted USP4, which induced deubiquitination of SMAD4 and promoted its expression. Meanwhile, SMAD4 was enriched in the CK2 promoter region and thus inhibited its expression. SOX2 stimulated EC cell proliferative, invasive, and migratory capacities in vitro and tumor growth in vivo by regulating the miR-30e/USP4/SMAD4/CK2 axis. Collectively, our work reveals a novel SOX2-mediated regulatory network in EC that may be a viable target for EC treatment.

Mechano-Responsive, Tough, and Antibacterial Zwitterionic Hydrogels with Controllable Drug Release for Wound Healing Applications.

Acute wounds subject to frequent deformations are difficult to be treated because the healing process was easily interfered by external mechanical forces. Traditional wound dressings have limited efficacy because of their poor mechanical properties and skin adhesiveness and difficulty in the delivery of therapeutic drugs effectively. As such, tough and skin-adhesive wound dressings with sustainable and stimuli-responsive drug release properties for treatment of those wounds are highly desirable. For this purpose, we have developed a mechano-responsive poly(sulfobetaine methacrylate) hydrogel which aims to control the delivery of antibiotic drug upon application of mechanical forces. Diacrylated Pluronic F127 micelles were used as a macro-cross-linker of the hydrogel and loaded with hydrophobic antimicrobial drugs. The micelle-cross-linked hydrogel has excellent mechanical properties, with the ultimate tensile strength and tensile strain of up to 112 kPa and 1420%, respectively, and compressive stress of up to 1.41 MPa. Adhesiveness of the hydrogel to the skin tissue was ∼6 kPa, and it did not decrease significantly after repetitive adhesion cycles. Protein adsorption on the hydrogel was significantly inhibited compared to that on commercial wound dressings. Because of the mechano-responsive deformation of micelles, the release of drug from the hydrogel could be precisely controlled by the extent and cycles of mechanical loading and unloading, endowing the hydrogel with superior antibacterial property against both Gram-positive and Gram-negative bacteria. In addition, drug penetration into the skin tissue was enhanced by mechanical stress applied to the hydrogel. The micelle-cross-linked zwitterionic hydrogel also showed good cell biocompatibility, negligible skin irritation, and healing capacity to acute skin wounds in mice. Such a tough mechano-responsive hydrogel holds great promise as wound dressings for acute wounds subjected to frequent movements.

MicroRNA let-7i Inhibits Histone Lysine Demethylase KDM5B to Halt Esophageal Cancer Progression.

Recent studies have suggested that microRNA let-7i is a tumor suppressor in human cancers, including esophageal cancer, but its underlying mechanism is not yet fully understood. We investigated the role and mechanisms of let-7i in the progression of esophageal cancer. We first showed that let-7i was downregulated in esophageal cancer tissues and cells and then linked its low expression to cancer progression. Bioinformatic analysis predicted KDM5B as a target gene of let-7i, which was confirmed by a dual-luciferase reporter assay. Loss- and gain-of function approaches were adopted to examine the interactions of let-7i, KDM5B, SOX17, and GREB1 in vitro and in vivo. Overexpression of let-7i suppressed esophageal cancer cell proliferation and invasion and promoted apoptosis. Mechanistic investigation showed that let-7i targeted and inhibited KDM5B expression, whereas KDM5B enhanced H3K4me3 at the SOX17 promoter region. Overexpression of let-7i suppressed the expression of GREB1 in esophageal cancer cells by regulating the KDM5B/SOX17 axis in vivo and in vitro. Taken together, our findings reveal the tumor-suppressive properties of let-7i in esophageal cancer in association with an apparent KDM5B-dependent SOX17/GREB1 axis. This study offers a potential prognostic marker and therapeutic target for esophageal cancer.

Change in Convection Mixing Properties with Salinity and Temperature: CO2 Storage Application.

In this study, we visualised CO2-brine, density-driven convection in a Hele-Shaw cell. Several experiments were conducted to analyse the effects of the salinity and temperature. The salinity and temperature of fluids were selected according to the storage site. By using charge coupled device (CCD) technology, convection finger formation and development were obtained through direct imaging and processing. The process can be divided into three stages: diffusion-dominated, convection-dominated and shutdown stages. Fingers were formed along the boundary at the onset time, reflecting the startup of convection mixing. Fingers formed, moved and aggregated with adjacent fingers during the convection-dominated stage. The relative migration of brine-saturated CO2 and brine enhanced the mass transfer. The effects of salinity and temperature on finger formation, number, and migration were analysed. Increasing the salinity accelerated finger formation but suppressed finger movement, and the onset time was inversely related to the salinity. However, the effect of temperature on convection is complex. The dissolved CO2 mass was investigated by calculating the CO2 mass fraction in brine during convection mixing. The results show that convection mixing greatly enhanced mass transfer. The study has implications for predicting the CO2 dissolution trapping time and accumulation for the geological storage of CO2.

Human umbilical cord mesenchymal stem cells-derived exosomes deliver microRNA-375 to downregulate ENAH and thus retard esophageal squamous cell carcinoma progression.

BACKGROUND: Exosomal microRNAs (miRNAs or miRs) from bone marrow-derived mesenchymal stem cells (UCMSCs) have emerged as promising therapeutic strategies for cancer treatment. The current study aimed to elucidate the underlying mechanism of human umbilical cord mesenchymal stem cells (hUCMSCs)-derived exosomal miR-375 in esophageal squamous cell carcinoma (ESCC). METHODS: After determining the expression of miR-375 and its putative target enabled homolog (ENAH) in ESCC tissues and cells, we tested effects of their altered expression on ESCC proliferation, invasion, migration, and tumorsphere formation was subsequently measured. Transfected hUCMSCs-derived exosomes (hUCMSCs-exo) were isolated and co-cultured with ESCC cells to measure the effects of miR-375 delivered by hUCMSCs-exo on ESCC development. Finally, we investigated the effect of miR-375 on tumor growth in vivo. RESULTS: The expression of miR-375 was reduced, while the expression of ENAH was elevated in ESCC. ENAH was identified as a target gene of miR-375. Elevated miR-375 or depleted ENAH expression inhibited ESCC cell proliferation, invasion, migration, tumorsphere formation, and promoted apoptosis. Moreover, miR-375 delivered by hUCMSCs-exo could suppress ESCC cell proliferation, invasion, migration, tumorsphere formation, but promoted apoptosis in vitro, as well as inhibiting tumor growth in vivo. CONCLUSIONS: Taken together, hUCMSCs-exo can deliver miR-375 to suppress ENAH expression and subsequently inhibit the initiation and progression of ESCC.

Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach.

The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein, we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement factor D inhibitor and exhibited submicromolar FXIa activity and an encouraging absorption, distribution, metabolism, and excretion (ADME) profile while being devoid of a peptidomimetic architecture. Optimization of interactions in the S1, S1ß, and S1' pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with subnanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a preclinical pharmacokinetics (PK) profile consistent with bid dosing in patients.

microRNA-10b confers cisplatin resistance by activating AKT/mTOR/P70S6K signaling via targeting PPARγ in esophageal cancer.

It is well known that the acquisition of chemoresistance is a major obstacle for the effective treatment of human cancers. It is reported that microRNAs (miRNAs) are implicated in chemotherapy resistance of various malignancies. miR-10b was previously proved as an oncogene in multiple malignancies, including esophageal cancer. However, its biological significance in regulating cisplatin (DDP) resistance in esophageal cancer is still elusive. Here, we observed that miR-10b expression was upregulated and peroxisome proliferator-activated receptor-γ (PPARγ) expression was downregulated in esophageal cancer tumor tissues and cells. PPARγ was proved as a functional target of miR-10b. Moreover, suppression of miR-10b enhanced the chemosensitivity of esophageal cancer cells to DDP in vitro and in vivo. In addition, PPARγ-mediated DDP sensitivity was weakened by miR-10b overexpression. Furthermore, miR-10b-activated AKT/mTOR/p70S6K signaling pathway through targeting PPARγ. Inactivation of AKT/mTOR/p70S6K by AKT inhibitor (GSK690693) attenuated miR-10b-induced DDP resistance in esophageal cancer cells. Taken together these observation, miRNA-10b-mediated PPARγ inhibition enhanced DDP resistance by activating the AKT/mTOR/P70S6K signaling in esophageal cancer, suggesting a potential target to improve therapeutic response of patients with esophageal cancer to DDP.