Final analysis of camrelizumab plus chemotherapy for untreated advanced or metastatic esophageal squamous cell carcinoma: The ESCORT-1st trial.

BACKGROUND: The interim analysis of the randomized phase 3 ESCORT-1st study demonstrated significantly longer overall survival (OS) and progression-free survival (PFS) for camrelizumab-chemotherapy than placebo-chemotherapy in untreated advanced/metastatic esophageal squamous cell carcinoma (ESCC). Here, we present the final analysis of this study and investigate potential indicators associated with OS. METHODS: Patients were randomized 1:1 to receive camrelizumab (200 mg) or placebo, both in combination with up to six cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All treatments were administered intravenously every 3 weeks. The co-primary endpoints were OS and PFS assessed by the independent review committee. FINDINGS: As of April 30, 2022, the median OS was significantly longer in the camrelizumab-chemotherapy group compared to the placebo-chemotherapy group (15.6 [95% confidence interval (CI): 14.0-18.4] vs. 12.6 months [95% CI 11.2-13.8]; hazard ratio [HR]: 0.70 [95% CI 0.58-0.84]; one-sided p < 0.0001), with 3-year OS rates of 25.6% and 12.8% in the two groups, respectively. The 2-year PFS rates were 20.4% in the camrelizumab-chemotherapy group and 3.4% in the placebo-chemotherapy group. Adverse events were consistent with those reported in the interim analysis. Higher PD-L1 expression correlated with extended OS, and multivariate analysis identified sex and prior history of radiotherapy as independent indicators of OS. CONCLUSIONS: The sustained and significant improvement in efficacy with camrelizumab-chemotherapy compared to placebo-chemotherapy, along with the absence of accumulating or delayed toxicities, supports the long-term use of camrelizumab-chemotherapy as a standard therapy in untreated advanced/metastatic ESCC. FUNDING: This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Ultra-broadband on-chip power splitters for arbitrary ratios on silicon-on-insulator.

We propose and demonstrate on-chip power splitters based on adiabatic rib waveguide enabling arbitrary splitting ratios on a monolithic silicon photonic platform. The devices are elaborately engineered based on adiabatic directional couplers with a trapezoid-structure in the longitudinal direction in the mode evolution region. The measurement results indicate that the proposed devices can achieve over 150 nm bandwidth for arbitrary splitting ratios of 50%:50%, 70%:30% and 90%:10%. The mode evolution footprint is greatly narrowed to below 79 µm with an insertion loss of less than 0.22 dB. The demonstrated arbitrary ratio power splitters offer a promising application prospect in high-density photonic integrated circuits.

Microbiome: Role in Inflammatory Skin Diseases.

As the body's largest organ, the skin harbors a highly diverse microbiota, playing a crucial role in resisting foreign pathogens, nurturing the immune system, and metabolizing natural products. The dysregulation of human skin microbiota is implicated in immune dysregulation and inflammatory responses. This review delineates the microbial alterations and immune dysregulation features in common Inflammatory Skin Diseases (ISDs) such as psoriasis, rosacea, atopic dermatitis(AD), seborrheic dermatitis(SD), diaper dermatitis(DD), and Malassezia folliculitis(MF).The skin microbiota, a complex and evolving community, undergoes changes in composition and function that can compromise the skin microbial barrier. These alterations induce water loss and abnormal lipid metabolism, contributing to the onset of ISDs. Additionally, microorganisms release toxins, like Staphylococcus aureus secreted α toxins and proteases, which may dissolve the stratum corneum, impairing skin barrier function and allowing entry into the bloodstream. Microbes entering the bloodstream activate molecular signals, leading to immune disorders and subsequent skin inflammatory responses. For instance, Malassezia stimulates dendritic cells(DCs) to release IL-12 and IL-23, differentiating into a Th17 cell population and producing proinflammatory mediators such as IL-17, IL-22, TNF-α, and IFN-α.This review offers new insights into the role of the human skin microbiota in ISDs, paving the way for future skin microbiome-specific targeted therapies.

Association between circHIPK3/miR-378a-3p/HDAC4 axis and osteoporotic fractures: A comprehensive investigation.

BACKGROUND: Osteoporotic fractures (OFs) are a significant public health issue, which can lead to pain and impaired mobility. The underlying mechanisms of OFs remain unclear, but recent studies have suggested that the circRNA-miRNA-mRNA pathway may play a crucial role. PURPOSE: This study aimed to investigate the potential involvement of the circHIPK3/miR-378a-3p/HDAC4 pathway in the pathogenesis of OFs. METHODS: We collected tissue and serum samples from 10 patients with OFs and 10 healthy controls. The expression levels of circHIPK3, miR-378a-3p, and HDAC4 were measured by qPCR and WB. Additionally, we quantified the serum levels of bone metabolism-related indicators (ALP, OC, TRAP, OCIF, ODF) using ELISA. RESULTS: Our results revealed significant upregulation of circHIPK3 and HDAC4 in both tissue and serum samples from OF patients compared with controls. Simultaneously, we detected a lower expression level of miR-378a-3p in OF tissues and serum than that in the control group. Furthermore, the serum levels of bone metabolism-related indicators ALP, TRAP, OCIF, and ODF were significantly higher in OF patients than in the control group. Interestingly, the serum level of OCIF was lower in OF patients than in the control group. CONCLUSION: Our study provides important evidence for the involvement of the circHIPK3/miR-378a-3p/HDAC4 pathway in the pathogenesis of OFs. The upregulation of circHIPK3 and HDAC4 and downregulation of miR-378a-3p observed in OF patients suggests their potential regulatory effects on bone metabolism. Meanwhile, abnormal expression of serum bone metabolism-related indicators may contribute to the development of OFs by disrupting the balance of bone remodeling.

X-Intersected Silicon Modulator of Well-Rounded Performance.

In silicon modulator design, implantation is always a key factor, significantly influencing the doping profile and carrier distribution. As waveguide doping is limited by the compact footprint of the modulator rib, three-dimensional complex optimization is a viable option to improve performance. This work proposes an X-intersected modulator based on two inversely slanted junctions using the effective 3D Monte Carlo method for junction generation. The optimized results show that the modulation efficiency of the design is 1.09 V·cm, while the loss is 18 dB/cm, and the 3 dB bandwidth reaches over 35 GHz owing to the decreased resistance and capacitance of the 3D junction. This work demonstrates the benefits of 3D doping design in silicon modulators, contributing to higher efficiency and avoiding additional PN overlap to introduce lower capacitance. The design of 3D doping profiles well balances the DC and AC performance, and provides novel modulator solutions for high-speed datacom.

CLDN18.2 and 4-1BB bispecific antibody givastomig exerts antitumor activity through CLDN18.2-expressing tumor-directed T-cell activation.

BACKGROUND: Claudin18.2 (CLDN18.2) is a tight junction protein that has been identified as a clinically proven target in gastric cancer. Stimulation of 4-1BB with agonistic antibodies is also a promising strategy for immunotherapy and 4-1BB+ T cells were reported to be present within the tumor microenvironment of patients with gastric cancer. However, hepatotoxicity-mediated by 4-1BB activation was observed in clinical trials of agonistic anti-4-1BB monoclonal antibodies. METHODS: To specifically activate the 4-1BB+ T cells in tumor and avoid the on-target liver toxicity, we developed a novel CLDN18.2×4-1BB bispecific antibody (termed 'givastomig' or 'ABL111'; also known as TJ-CD4B or TJ033721) that was designed to activate 4-1BB signaling in a CLDN18.2 engagement-dependent manner. RESULTS: 4-1BB+ T cells were observed to be coexisted with CLDN18.2+ tumor cells in proximity by multiplex immunohistochemical staining of tumor tissues from patients with gastric cancer (n=60). Givastomig/ABL111 could bind to cell lines expressing various levels of CLDN18.2 with a high affinity and induce 4-1BB activation in vitro only in the context of CLDN18.2 binding. The magnitude of T-cell activation by givastomig/ABL111 treatment was closely correlated with the CLDN18.2 expression level of tumor cells from gastric cancer patient-derived xenograft model. Mechanistically, givastomig/ABL111 treatment could upregulate the expression of a panel of pro-inflammatory and interferon-γ-responsive genes in human peripheral blood mononuclear cells when co-cultured with CLDN18.2+ tumor cells. Furthermore, in humanized 4-1BB transgenic mice inoculated with human CLDN18.2-expressing tumor cells, givastomig/ABL111 induced a localized immune activation in tumor as evident by the increased ratio of CD8+/regulatory T cell, leading to the superior antitumor activity and long-lasting memory response against tumor rechallenge. Givastomig/ABL111 was well tolerated, with no systemic immune response and hepatotoxicity in monkeys. CONCLUSIONS: Givastomig/ABL111 is a novel CLDN18.2×4-1BB bispecific antibody which has the potential to treat patients with gastric cancer with a wide range of CLDN18.2 expression level through the restricted activation of 4-1BB+ T cells in tumor microenvironment to avoid the risk of liver toxicity and systemic immune response.

Repeat peroral endoscopic myotomy with simultaneous submucosal and muscle dissection as a salvage option for recurrent achalasia.

BACKGROUND: For recurrent achalasia after initial peroral endoscopic myotomy (POEM) failure, repeat POEM (Re-POEM) has been reported as a treatment option. However, severe esophageal interlayer adhesions caused by previous procedures impede the successful establishment of a submucosal tunnel and lead to aborted Re-POEM procedures. Our team previously described POEM with simultaneous submucosal and muscle dissection (POEM-SSMD) as a feasible solution for achalasia with severe interlayer adhesions. AIM: To investigate the effectiveness and safety of Re-POEM with simultaneous submucosal and muscle dissection (Re-POEM-SSMD). METHODS: A total of 1049 patients with achalasia who underwent successful endoscopic myotomy at the Digestive Endoscopic Center of Chinese PLA General Hospital from December 2014 to May 2022 were reviewed. Patients with recurrent achalasia who experienced initial POEM clinical failure were retrospectively included in this study. The primary endpoint was retreatment clinical success, defined as an Eckardt score ≤ 3 during the postretreatment follow-up and no need for additional treatment. Procedure-related adverse events, changes in manometric lower esophageal sphincter (LES) pressure and reflux complications, as well as procedure-related parameters, were recorded. RESULTS: Sixteen patients underwent Re-POEM (9 patients) or Re-POEM-SSMD (7 patients) successfully at a median of 45.5 mo (range, 4-95 mo) after initial POEM. During a median follow-up period of 31 mo (range, 7-96 mo), clinical success (Eckardt score ≤ 3) was achieved in 8 (88.9%) and 6 (85.7%) patients after Re-POEM and Re-POEM-SSMD, respectively (P = 0.849). The median Eckardt score dropped from 4 (range, 3-8) at preretreatment to 1 (range, 0-5) at postretreatment in the Re-POEM group (P = 0.025) and from 5 (range, 2-8) to 2 (range, 0-4) in the Re-POEM-SSMD group (P < 0.001). The mean manometric LES pressure decreased from 23.78 ± 9.04 mmHg to 11.45 ± 5.37 mmHg after Re-POEM (P < 0.001) and from 26.80 ± 7.48 mmHg to 11.05 ± 4.38 mmHg after Re-POEM-SSMD (P < 0.001). No serious adverse events were recorded in both groups. CONCLUSION: In conclusion, Re-POEM-SSMD appears to be a safe and effective salvage therapy for recurrent achalasia with severe interlayer adhesions.

High-efficiency and CMOS compatible out-of-plane light emission based on a silicon coupler.

Photonic antennas are critical in applications such as spectroscopy, photovoltaics, optical communications, holography, and sensors. Metal antennas are widely used because of their small size, but they are difficult to be compatible with a CMOS. All-dielectric antennas are easier to integrate with Si waveguides, but are generally larger in size. In this paper, we propose the design of a small-sized, high-efficiency semicircular dielectric grating antenna. The antenna's key size is only 2.37µm×4.74µm, and the emission efficiency reaches over 64% in the wavelength range from 1.16 to 1.61 µm. The antenna provides a new, to the best of our knowledge, approach for three-dimensional optical interconnections between different decks of integrated photonic circuits.

High resolution, high channel count silicon arrayed waveguide grating router on-chip.

A 32×32 100 GHz silicon photonic integrated arrayed waveguide grating router (AWGR) is experimentally demonstrated for dense wavelength division multiplexing (DWDM) applications. The dimension of the AWGR is 2.57 mm×1.09 mm with a core size of 1.31 mm×0.64 mm. It exhibits 6.07 dB maximum channel loss non-uniformity with -1.66 dB best-case insertion loss and average channel crosstalk of -15.74 dB. In addition, in the case of 25 Gb/s signals, the device successfully realizes high-speed data routing. The AWG router provides clear optical eye diagrams and low power penalty at bit-error-rates of 10-9.

Linked color imaging vs Lugol chromoendoscopy for esophageal squamous cell cancer and precancerous lesion screening: A noninferiority study.

BACKGROUND: Lugol chromoendoscopy (LCE) has served as a standard screening technique in high-risk patients with esophageal cancer. Nevertheless, LCE is not suitable for general population screening given its side effects. Linked color imaging (LCI) is a novel image-enhanced endoscopic technique that can distinguish subtle diff-erences in mucosal color. AIM: To compare the diagnostic performance of LCI with LCE in detecting esophageal squamous cell cancer and precancerous lesions and to evaluate whether LCE can be replaced by LCI in detecting esophageal neoplastic lesions. METHODS: In this prospective study, we enrolled 543 patients who underwent white light imaging (WLI), LCI and LCE successively. We compared the sensitivity and specificity of LCI and LCE in the detection of esophageal neoplastic lesions. Clinicopathological features and color analysis of lesions were assessed. RESULTS: In total, 43 patients (45 neoplastic lesions) were analyzed. Among them, 36 patients (38 neoplastic lesions) were diagnosed with LCI, and 39 patients (41 neoplastic lesions) were diagnosed with LCE. The sensitivity of LCI was similar to that of LCE (83.7% vs 90.7%, P = 0.520), whereas the specificity of LCI was greater than that of LCE (92.4% vs 87.0%, P = 0.007). The LCI procedure time in the esophageal examination was significantly shorter than that of LCE [42 (34, 50) s vs 160 (130, 189) s, P < 0.001]. The color difference between the lesion and surrounding mucosa in LCI was significantly greater than that observed with WLI. However, the color difference in LCI was similar in different pathological types of esophageal squamous cell cancer. CONCLUSION: LCI offers greater specificity than LCE in the detection of esophageal squamous cell cancer and precancerous lesions, and LCI represents a promising screening strategy for general populations.

Compact, ultrabroadband and temperature-insensitive arbitrary ratio power splitter based on adiabatic rib waveguides.

We propose a compact, ultrabroadband and temperature-insensitive adiabatic directional coupler based on rib silicon waveguide-enabling arbitrary splitting ratios. Simulation results show that the device can achieve arbitrary splitting ratios from 1400 to 1600 nm, equal to 50%:50%, 60%:40%, 70%:30%, 80%:20%, and 90%:10% for the fundamental transverse electric mode. The designed device has an excess loss of less than 0.19 dB on the operational waveband. Furthermore, the proposed device shows a great robustness to fabrication imperfection, with a waveguide width deviation of 50 nm and ambient temperature change from 0°C to 200°C. These properties make the design a potential candidate for ultrahigh-density photonic integration chips.

Intra-brachial ergonovine, not acetylcholine, is associated with radial artery vasospasm in patients with coronary vasospasm.

BACKGROUND: The intracoronary provocation test is expensive and may cause complications. Therefore, we investigated the sensitivity, specificity and safety of different drug- and dose-peripheral artery provocation tests in the diagnosis of coronary artery spasm (CAS). METHODS: The patients who had repeated chest pain as well as both coronary and radial stenoses <50% were selected. These patients were divided into CAS group (n = 24) and control group (n = 33) after the intracoronary ergonovine provocation test. All patients underwent radial artery provocation tests at different dose-acetylcholine (200 µg, 400 µg and 800 µg) and ergonovine (60 µg, 100 µg and 160 µg). The predictive values of radial provocation tests for CAS diagnosis were analysed using receiver operator characteristic (ROC) curves. RESULTS: In radial acetylcholine provocation tests, 200 µg of acetylcholine failed to induce radial artery spasm, and the radial artery stenosis degree was not significantly different between the CAS group and control group at 400 µg and 800 µg of acetylcholine (all p > 0.05). In the radial artery ergonovine provocation tests, the radial artery stenosis degree was all significantly higher in the CAS group than in the control group at the three different doses (all p < 0.05). The specificity and sensitivity of radial ergonovine provocation tests were 90.91% and 50.00% at 60 µg, 96.97% and 66.67% at 100 µg, and 90.91% and 95.83% at 160 µg. Only the radial 160 µg-ergonovine provocation test caused CAS in one case. CONCLUSION: The radial acetylcholine provocation test has no diagnostic value for CAS. The radial 160 µg-ergonovine provocation test has higher sensitivity and specificity for CAS diagnosis, but its safety should be paid attention to.

Silicon modulator based on omni junctions by effective 3D Monte-Carlo method.

3D doping structure has significant advantages in modulation efficiency and loss compared with 2D modulator doping profiles. However, to the best of our knowledge, previous work on 3D simulation methods for interdigitated doping designs applied simplified models, which prohibited complex 3D doping. In this work, innovative omni junctions, based on the effective 3D Monte-Carlo method, are believed to be the first proposed for high-performance modulators. Simulation results show that the modulation efficiency reaches 0.88 V·cm, while the loss is only 16 dB/cm, with capacitance below 0.42 pF/mm. This work provides a modulator design with superior modulation efficiency and serviceability for high-speed datacom.

Likelihood ratio test for genetic association study with case-control data under Probit model.

Probit and Logit models are the most popular for binary disease statusing in genetic association studies. They are equally used and nearly exchangeable in the analysis of prospectively collected data. However, no strong inferences were made based on Probit models for the retrospectively collected case-control data, especially in the presence of random effects. This paper systematically investigates the performance of Probit mixed-effects models for case-control data. We find that the retrospective likelihood has a closed-form, which motivates the development of likelihood ratio tests for genetic association. Specifically, we developed four likelihood ratio tests based on whether the disease prevalence is completely unavailable, partly available, or completely available. We show that their limiting distribution without a genetic effect is an equal mixture of two chi-square distributions with degrees of freedom 1 and 2, respectively. Our simulations indicate that they can have a remarkable power gain against the popular Logit-model-based score tests, and the disease prevalence information can enhance the power of the likelihood ratio tests. After analyzing a Kenya malaria data, we found out that the proposed test produces a significant result on the association of the gene ABO with malaria, whereas the commonly used competitors fail.

Prospective single-center feasible study of innovative autorelease bile duct supporter to delay adverse events after endoscopic papillectomy.

BACKGROUND: Conventional endoscopic papillectomy (EP) is safe and effective for the treatment of small papilla adenoma to even large laterally spreading tumors of duodenum lesions. As reported by some existing studies, temporarily placing a prophylactic stent in the pancreatic and bile duct can lower the risk of this perioperative complication. AIM: To evaluate the usefulness, convenience, safety, and short-term results of a novel autorelease bile duct supporter after EP procedure, especially the effectiveness in preventing EP. METHODS: A single-center comparison study was conducted to verify the feasibility of the novel method. After EP, a metallic endoclip and human fibrin sealant kit were applied for protection. The autorelease bile duct supporter fell into the duct segment and the intestinal segment. Specifically, the intestinal segment was extended by nearly 5 cm as a bent coil. The bile was isolated from the pancreatic juice using an autorelease bile duct supporter, which protected the wound surface. The autorelease bile duct supporter fell off naturally and arrived in colon nearly 10 d after the operation. RESULTS: En bloc endoscopic resection was performed in 6/8 patients (75%), and piecemeal resection was performed in 2/8 of patients (25%). None of the above patients were positive for neoplastic lymph nodes or distant metastasis. No cases of mortality, hemorrhage, delayed perforation, pancreatitis, cholangitis or duct stenosis with the conventional medical treatment were reported. The autorelease bile duct supporter in 7 of 8 patients fell off naturally and arrived in colon 10 d after the operation. One autorelease bile duct supporter was successfully removed using forceps or snare under endoscopy. No recurrence was identified during the 8-mo (ranging from 6-9 mo) follow-up period. CONCLUSION: In brief, it was found that the autorelease bile duct supporter could decrease the frequency of procedure-associated complications without second endoscopic retraction. Secure closure of the resection wound with clips and fibrin glue were indicated to be promising and important for the use of autorelease bile duct supporters. Well-designed larger-scale comparative studies are required to confirm the findings of this study.

Comparison between endoscopic submucosal tunnel dissection and endoscopic submucosal dissection for superficial neoplasia at esophagogastric junction: a case-matched controlled study of a single center from China.

BACKGROUND: So far, little evidence is available for the comprehensive comparison of endoscopic submucosal tunnel dissection (ESTD) with endoscopic submucosal dissection (ESD) for the treatment of superficial neoplasia at esophagogastric junction (EGJ). METHODS: EGJ superficial neoplasia patients with ESTD treatment between January, 2021 and August, 2020 were retrospectively reviewed and individually matched at 1:1 ratio with those with ESD treatment according to lesion size, specimen area and lesion location, forming ESTD and ESD group, respectively. A sample size of 17 patients was collected for each group. Treatment outcomes including resection time, specimen area, and resection speed as well as occurrence of complications were evaluated. RESULTS: Compared with ESD group, ESTD group got shorter resection time (111.00 ± 11.70 min for ESD group vs. 71.59 ± 6.18 min for ESTD group, p = 0.008) and faster section speed (0.23 ± 0.03 cm2/min for ESD group vs. 0.37 ± 0.06 cm2/min for ESTD group, p = 0.012). No complication was found to occur in ESTD group, while 1 patient with MP damage and 1 with delayed bleeding was found in ESD group. CONCLUSION: For the treatment of EGJ superficial neoplasia, ESTD is a safer and more effective and reliable endoscopic technique compared with ESD.

Comparative efficiency and safety of insulin degludec/aspart with insulin glargine in type 2 diabetes: a meta-analysis of randomized controlled trials.

Recent studies have found compared with insulin glargine (IGlar), insulin degludec/aspart (IDeg/Asp) may provide adequate glycemic control and prevent hypoglycemia events in type 2 diabetes mellitus (T2DM). Consequently, we performed a meta-analysis to appraise and compare the efficiency and safety of IDeg/Asp and IGlar in the treatment of T2DM. We sought the databases including PubMed, Embase, Scopus, Cochrane library to confirm related articles which inspected the effect of IDeg/Asp versus IGlar for the treatment of T2DM until May 2021. Finally, six randomized controlled trials (RCTs) of 1,346 patients were included. The results showed that IDeg/Asp significantly decreased the mean hemoglobin A1c (HbA1c) level but was prone to serious adverse events, and IGlar increased the nocturnal confirmed hypoglycemia events. Besides, there were no significant changes in other indicators, including mean fasting plasma glucose (FPG) level, nine-point self-measured plasma glucose (SMPG) level, and adverse events. What's more, we found that there was no significant difference in the occurrence of hypoglycemia overall, but our subgroup analysis of confirmed hypoglycemia revealed the population in this subgroup (duration of diabetes ≤11 years) might has its particularity effecting the hypoglycemia outcome. Concerning efficiency, IDeg/Asp may have advantages in controlling the mean HbA1c level. Regarding safety, IGlar might increase the risk of nocturnal confirmed hypoglycemia. Further evidence is needed to compare better the efficiency and safety of IDeg/Asp versus IGlar therapy.

Effects of dapagliflozin in the progression of atherosclerosis in patients with type 2 diabetes: a meta-analysis of randomized controlled trials.

AIMS: At present, an increasing number of studies are trying to determine whether dapagliflozin has a significant effect on the occurrence and development of atherosclerosis in patients with type 2 diabetes mellitus (T2DM), but there is no consensus. In addition, the former meta-analyses, relying on only a few previous studies and a minimal number of research indicators, have not been able to draw sufficient conclusions simultaneously. Consequently, we conducted a meta-analysis to evaluate the effectiveness of dapagliflozin in the occurrence and development of atherosclerosis in patients with T2DM. METHODS: We searched electronic databases (PubMed, Embase, Cochrane, and Scopus) and reference lists in relevant papers for articles published in 2011-2021. We selected studies that evaluated the effects of dapagliflozin on the risk factors related to the occurrence or development of atherosclerosis in patients with T2DM. A fixed or random-effect model calculated the weighted average difference of dapagliflozin on efficacy, and the factors affecting heterogeneity were determined by Meta-regression analysis. RESULTS: Twelve randomized controlled trials (18,758 patients) were incorporated in our meta-analysis. In contrast with placebo, dapagliflozin was associated with a significantly increase in high density lipoprotein-cholesterol (HDL-C) [MD = 1.39; 95% CI (0.77, 2.01); P < 0.0001], Δflow-mediated vasodilatation (ΔFMD) [MD = 1.22; 95% CI (0.38, 2.06); P = 0.005] and estimated Glomerular Filtration Rate(eGFR) [MD = 1.94; 95% CI (1.38, 2.51); P < 0.00001]. Furthermore, dapagliflozin had a tremendous advantage in controlling triglycerides (TG) in subgroups whose baseline eGFR < 83 ml/min/1.73m2 [MD = - 10.38; 95% CI (- 13.15, - 7.60); P < 0.00001], systolic blood pressure (SBP) [MD = - 2.82; 95% CI (- 3.22, - 2.42); P < 0.00001], HbA1c, BMI, body weight and waist circumference. However, dapagliflozin has an adverse effect on increasing total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C). Besides, there were no significant changes in other indicators, including adiponectin and C-peptide immunoreactivity. CONCLUSIONS: Our pooled analysis suggested that dapagliflozin has a terrifically better influence over HDL-C, ΔFMD, and eGFR, and it concurrently had a tremendous advantage in controlling TG, SBP, DBP, HbA1c, BMI, body weight, and waist circumference, but it also harms increasing TC and LDL-C. Furthermore, this study found that the effect of dapagliflozin that decreases plasma levels of TG is only apparent in subgroups of baseline eGFR < 83 ml/min/1.73m2, while the subgroup of baseline eGFR ≥ 83 ml/min/1.73m2 does not. Finally, the above results summarize that dapagliflozin could be a therapeutic option for the progression of atherosclerosis in patients with T2DM. Systematic review registration PROSPERO CRD42021278939.

Broadband and CMOS compatible polarization splitter-rotator based on a bi-level taper.

A silicon-on-insulator polarization diversity scheme is proposed. Based on an asymmetrical evanescent coupler, a broadband and compact polarization splitter-rotator comprising mode conversion tapers and mode sorting asymmetric Y junctions is optimized with silicon dioxide upper cladding and a silicon nitride waveguide. The simulation results show mode conversion loss is less than 0.2 dB, and the extinction ratio is lower than -17dB in the wavelength range of 1.48µm to 1.67µm.

Probing Synergistic Targets by Natural Compounds for Hepatocellular Carcinoma.

BACKGROUND: Designing combination drugs for malignant cancers has been restricted due to the scarcity of synergy-medicated targets, while some natural compounds have demonstrated potential to enhance anticancer effects. METHODS: We here explored the feasibility of probing synergy-mediated targets by Berberine (BER) and Evodiamine (EVO) in hepatocellular carcinoma (HCC). Using the genomics-derived HCC signaling networks of compound treatment, NF-κB and c-JUN were inferred as key responding elements with transcriptional activity coinhibited during the synergistic cytotoxicity induction in BEL-7402 cells. Then, selective coinhibitors of NF-κB and c-JUN were tested demonstrating similar synergistic antiproliferation activity. RESULTS: Consistent with in vivo experiments of zebrafish, coinhibitors were found to significantly reduce tumor growth by 79% and metastasis by 96% compared to blank control, accompanied by anti-angiogenic activity. In an analysis of 365 HCC individuals, the low expression group showed significantly lower malignancies and better prognosis, with the median survival time increased from 67 to 213%, compared to the rest of the groups. CONCLUSION: Together, NF-κB and c-JUN were identified as promising synergistic inducers in developing anti-HCC therapies. Also, our method may provide a feasible strategy to explore new targeting space from natural compounds, opening opportunities for the rational design of combinational formulations in combatting malignant cancers.