Discovery of Novel, Selective Prostaglandin EP4 Receptor Antagonists with Efficacy in Cancer Models.

Prostaglandin E2 (PGE2) receptor 4 (EP4) is one of four EP receptors commonly upregulated in the tumor microenvironment and plays vital roles in stimulating cell proliferation, invasion, and metastasis. Biochemical blockade of the PGE2-EP4 signaling pathway is a promising strategy for controlling inflammatory and immune related disorders. Recently combination therapies of EP4 antagonists with anti-PD-1 or chemotherapy agents have emerged in clinical studies for lung, breast, colon, and pancreatic cancers. Herein, a novel series of indole-2-carboxamide derivatives were identified as selective EP4 antagonists, and SAR studies led to the discovery of the potent compound 36. Due to favorable pharmacokinetics properties and good oral bioavailability (F = 76%), compound 36 was chosen for in vivo efficacy studies. Compound 36 inhibited tumor growth in a CT-26 colon cancer xenograft better than E7046 and a combination of 36 with capecitabine significantly suppressed tumor growth (TGI up to 94.26%) in mouse models.

High-speed tunable optical absorber based on a coupled photonic crystal slab and monolayer graphene structure.

Reconfigurable metasurfaces have been pursued intensively in recent years for the ability to modulate the light after fabrication. However, the optical performances of these devices are limited by the efficiency, actuation response speed and mechanical control for reconfigurability. In this paper, we propose a fast tunable optical absorber based on the critical coupling of resonance mode to absorptive medium and the plasma dispersion effect of free carriers in semiconductor. The tunable absorber structure includes a single-layer or bi-layer silicon photonic crystal slab (PCS) to induce a high-Q optical resonance, a monolayer graphene as the absorption material, and bottom reflector to remove transmission. By modulating the refractive index of PCS via the plasma dispersion of the free carrier, the critical coupling condition is shifted in spectrum, and the device acquires tuning capability between perfect absorption and total reflection of the incident monochromatic light beam. Simulation results show that, with silicon index change of 0.015, the tunable absorption of light can achieve the reflection/absorption switching, and full range of reflection phase control is feasible in the over coupling region. The proposed reconfigurable structure has potential applications in remote sensing, free-space communications, LiDAR, and imaging.

Impacts of metabolic disorders on short- and long-term mortality after coronary artery surgery in the elderly.

BACKGROUND: Elderly patients undergoing cardiac operation often suffer various metabolic comorbidities, such as diabetes mellitus (DM) and obesity. The metabolic disorders in these individuals are widely considered to be possible predisposing factors for unfavourable prognosis. This retrospective study was aimed to determine the association of metabolic diseases with the mortality of elderly patients after coronary artery bypass grafting (CABG) and to identify the protective or risk factors related to their short- and long-term survival. METHODS: Totally 684 patients aged 75 years or above undergoing isolated CABG were evaluated retrospectively. There were two groups depending on the body mass index (BMI): an overweight and obesity group (n = 354) and a normal weight and lean group (n = 330). Propensity score matching (PSM) was performed to adjust baseline clinical characteristics, which reduced confounding bias. The short-term postoperative mortality was tested via logistic regression. Kaplan-Meier and Cox regression analyses were done to compute the overall survival in each group and to identify relevant variables associated with all-cause mortality, respectively. RESULTS: The prevalence rates of metabolic comorbidities in the total cohort were: diabetes mellitus (32.5%), overweight or obesity (51.8%) and hypertension (72.8%). The 30-day postoperative mortality was 5.1% and the long-term mortality was 15.25% at a median 46.2-month follow-up (1.0-178.6 months). The 30-day postoperative mortality was relevant to DM, diseased coronary arteries, New York Heart Association class, intra-aortic balloon pump and emergency surgery. The long-term mortality was negatively associated with overweight and obesity. Univariate and multivariate logistic regression recognized DM as an adverse factor related with 30-day postoperative mortality whether before or after PSM. The long-term mortality was not significantly relevant with DM (HR = 0.753, 95% CI 0.402-1.411). Overweight or obesity was not the risk factor of 30-day postoperative mortality (OR = 1.284, 95% CI 0.426-3.868), but was the protective factor of long-term survival (HR = 0.512, 95% CI 0.279-0.939). CONCLUSIONS: The "obesity paradox" exists regarding the prognosis of individuals aged ≥ 75, which was presented as lower long-term mortality no matter from all cause or cardio-cerebrovascular cause in patients with BMI ≥ 24. Trial registration ChiCTR2200061869 (05/07/2022).

A Portable Micro-Gas Chromatography with Integrated Photonic Crystal Slab Sensors on Chip.

The miniaturization of gas chromatography (GC) systems has made it possible to utilize the analytical technique in various on-site applications to rapidly analyze complex gas samples. Various types of miniaturized sensors have been developed for micro-gas chromatography (µGC). However, the integration of an appropriate detector in µGC systems still faces a significant challenge. We present a solution to the problem through integration of µGC with photonic crystal slab (PCS) sensors using transfer printing technology. This integration offers an opportunity to utilize the advantages of optical sensors, such as high sensitivity and rapid response time, and at the same time, compensate for the lack of detection specificity from which label-free optical sensors suffer. We transfer printed a 2D defect free PCS on a borofloat glass, bonded it to a silicon microfluidic gas cell or directly to a microfabricated GC column, and then coated it with a gas responsive polymer. Realtime spectral shift in Fano resonance of the PCS sensor was used to quantitatively detect analytes over a mass range of three orders. The integrated µGC-PCS system was used to demonstrate separation and detection of a complex mixture of 10 chemicals. Fast separation and detection (4 min) and a low detection limit (ng) was demonstrated.

Bioresorbable Multilayer Photonic Cavities as Temporary Implants for Tether-Free Measurements of Regional Tissue Temperatures.

Objective and Impact Statement. Real-time monitoring of the temperatures of regional tissue microenvironments can serve as the diagnostic basis for treating various health conditions and diseases. Introduction. Traditional thermal sensors allow measurements at surfaces or at near-surface regions of the skin or of certain body cavities. Evaluations at depth require implanted devices connected to external readout electronics via physical interfaces that lead to risks for infection and movement constraints for the patient. Also, surgical extraction procedures after a period of need can introduce additional risks and costs. Methods. Here, we report a wireless, bioresorbable class of temperature sensor that exploits multilayer photonic cavities, for continuous optical measurements of regional, deep-tissue microenvironments over a timeframe of interest followed by complete clearance via natural body processes. Results. The designs decouple the influence of detection angle from temperature on the reflection spectra, to enable high accuracy in sensing, as supported by in vitro experiments and optical simulations. Studies with devices implanted into subcutaneous tissues of both awake, freely moving and asleep animal models illustrate the applicability of this technology for in vivo measurements. Conclusion. The results demonstrate the use of bioresorbable materials in advanced photonic structures with unique capabilities in tracking of thermal signatures of tissue microenvironments, with potential relevance to human healthcare.

Epigenetic induction of tumor stemness via the lipopolysaccharide-TET3-HOXB2 signaling axis in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell cancer (ESCC) is one kind of frequent digestive tumor. The inflammatory environment plays an important role in the tumorigenesis and development of ESCC. Cancer stem cells are a small group of tumor cells with stem cell characteristics, which can potentially hinder the tumor management and treatment. METHODS: ELISA was performed to detect the lipopolysaccharide concentration in cancer tissues. qPCR, Western blot, FACS, Immunohistochemistry, Immunofluorescence and Dot blot were applied to detect target genes expression. CCK-8, Colony-formation, Transwell, Sphere and Xenograft were conducted to investigate the function of cells, influenced by risk factors. The survival curve was drawn with the Kaplan-Meier product limit estimator. Nano-hmC-Seal-seq was utilized to detect the downstream target of TET3. ChIP-qPCR was adopted to demonstrate the transcriptional regulation of stem cell-associated genes by HOXB2. RESULTS: Lipopolysaccharide concentration was significantly up-regulated in ESCC. High concentration of lipopolysaccharide stimulation induced the stemness of ESCC cells. TET3 expression was elevated with lipopolysaccharide stimulation via p38/ERK-MAPK pathway in ESCC and negatively correlated with patients' survival. TET3 induced the stemness of ESCC cells. Nano-hmC-Seal-seq showed that TET3 overexpression led to a significant increase in 5hmC levels of HOXB2 gene region, which was thus identified as the downstream target of TET3. The binding of HOXB2 to NANOG and cMYC was verified by ChIP-qPCR. CONCLUSIONS: Lipopolysaccharide served as a tumor promotor in ESCC by inducing cancer cell stemness through the activation of a LPS-TET3-HOXB2 signaling axis, which might provide a novel therapeutic strategy for ESCC. Video Abstract.

Clinical characteristics, diagnosis, treatment, and prognostic factors of pulmonary mucosa-associated lymphoid tissue-derived lymphoma.

Primary pulmonary mucosa-associated lymphoid tissue-derived (MALT) lymphoma is a rare disease with a favorable prognosis. However, its clinical characteristics, diagnosis, treatment, and prognoses remain unclear. We retrospectively analyzed 80 patients with pathologically confirmed MALT lymphoma from 2006 to 2018. The clinical characteristics, diagnosis, treatments, and prognoses of all the 80 patients were recorded. Patients were stratified into surgery and biopsy groups, respectively, to evaluate the role of surgery in the diagnosis and treatment of MALT lymphoma. The prognoses were compared between different clinical characteristics and treatments. Pathological diagnoses were confirmed by surgery, bronchoscopy, and percutaneous biopsy. Thirty patients were treated by surgery. While MALT lymphoma was only diagnosed by bronchofiberoscopy or bercutaneous biopsy in four of 18 patients in the surgery group who underwent the procedure. Six patients received adjuvant chemotherapy and one patient received involved-field radiotherapy in surgery group. Thirty-one patients were treated with chemotherapy alone, one patient was treated with radiotherapy, one patient received only symptomatic and supportive treatment, and waiting and watching without treatment were recommended in 17 patients in biopsy group. Eight patients died during follow-up and the 5-year survival rate was 87.1%. Tumor number, treatment, and age were prognostic factors for overall survival (OS), but age was the only independent prognostic factor according to multivariate analysis. While, tumor number was the only prognostic factor in the analysis about progression-free survival (PFS). No significant difference was found in OS or PFS between patients treated with and without surgical resection. MALT lymphoma is an indolent disease with favorable treatment outcome. Tumor number is associated with PFS and age is the only significant prognostic factor for pulmonary MALT lymphoma patients because of its indolent nature, but surgery still plays an important role in the diagnosis and treatment of MALT lymphoma.

TEX9 and eIF3b functionally synergize to promote the progression of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignant digestive tumors around the world. We previously demonstrated that eIF3b could promote the progression of ESCC. The exact mechanisms underlying these effects remained unknown. METHODS: Quantitative proteomics was applied to detect the potential targets of Eukaryotic translation initiation factor 3 subunit b (eIF3b). RT-qPCR and Western blot were performed to detect the expression of targeted gene and pathway related genes. RNA-immunoprecipitation was applied to verify the binding of eIF3b with targeted gene. Moreover, CCK-8 assay, colony-formation assay, transwell assay, flow cytometry for cell apoptosis and tumor xenograft assay were performed to analyze the regulation of the targeted gene on the bio-function of ESCC cells. RESULTS: Quantitative proteomics data showed that Testis-expressed protein 9 (TEX9) expression was positively associated with eIF3b expression. RT-qPCR and Western blot results confirmed the quantitative proteomics data and demonstrated that TEX9 expression was positively correlated with TNM stage in ESCC. Furtherly, RNA-immunoprecipitation confirmed that eIF3b binding to TEX9 mRNA. The bio-function related assay demonstrated that TEX9 and eIF3b functionally synergized to promote the proliferation and migration, and inhibited the apoptosis of ESCC cells. In the analysis of mechanism, we revealed that TEX9 and eIF3b promoted the progression of ESCC through the activation of AKT signaling pathway. CONCLUSIONS: The synergized promoting role of TEX9 and eIF3b in the progression of ESCC may provide a novel mechanism for exploring viable therapeutic strategies for ESCC.

Bioresorbable photonic devices for the spectroscopic characterization of physiological status and neural activity.

Capabilities in real-time monitoring of internal physiological processes could inform pharmacological drug-delivery schedules, surgical intervention procedures and the management of recovery and rehabilitation. Current methods rely on external imaging techniques or implantable sensors, without the ability to provide continuous information over clinically relevant timescales, and/or with requirements in surgical procedures with associated costs and risks. Here, we describe injectable classes of photonic devices, made entirely of materials that naturally resorb and undergo clearance from the body after a controlled operational lifetime, for the spectroscopic characterization of targeted tissues and biofluids. As an example application, we show that the devices can be used for the continuous monitoring of cerebral temperature, oxygenation and neural activity in freely moving mice. These types of devices should prove useful in fundamental studies of disease pathology, in neuroscience research, in surgical procedures and in monitoring of recovery from injury or illness.

Bioresorbable optical sensor systems for monitoring of intracranial pressure and temperature.

Continuous measurements of pressure and temperature within the intracranial, intraocular, and intravascular spaces provide essential diagnostic information for the treatment of traumatic brain injury, glaucoma, and cardiovascular diseases, respectively. Optical sensors are attractive because of their inherent compatibility with magnetic resonance imaging (MRI). Existing implantable optical components use permanent, nonresorbable materials that must be surgically extracted after use. Bioresorbable alternatives, introduced here, bypass this requirement, thereby eliminating the costs and risks of surgeries. Here, millimeter-scale bioresorbable Fabry-Perot interferometers and two dimensional photonic crystal structures enable precise, continuous measurements of pressure and temperature. Combined mechanical and optical simulations reveal the fundamental sensing mechanisms. In vitro studies and histopathological evaluations quantify the measurement accuracies, operational lifetimes, and biocompatibility of these systems. In vivo demonstrations establish clinically relevant performance attributes. The materials, device designs, and fabrication approaches outlined here establish broad foundational capabilities for diverse classes of bioresorbable optical sensors.

Calpain-2 Enhances Non-Small Cell Lung Cancer Progression and Chemoresistance to Paclitaxel via EGFR-pAKT Pathway.

Lung cancer is one of the most frequent malignant tumors, with the top morbidity and mortality, in China. Calpain family regulates cellular processes including migration and invasion. However, the role of Calpain-2 in non-small cell lung cancer (NSCLC) remains unclear. This study aims to explore the bio-function of Calpain-2 on NSCLC and chemoresistance to paclitaxel. In this study, Immunohistochemistry, RT-qPCR and Western blot were performed to detect the Calpain-2 expression and related pathway protein in NSCLC. The Kaplan-Meier product limit estimator and Cox regression were conducted for survival analysis. CCK-8, Transwell, colony-formation, apoptosis and tumor xenograft assays were performed to analyze tumor-promoting role of Calpain-2, and the chemoresistance to paclitaxel. Our data showed that Calpain-2 was up-regulated in NSCLC. Notably, Calpain-2 level positively correlated with differentiation grade and negatively correlated with the 5-year overall survival, which served as an independent prognostic predictor. Knockdown of Calpain-2 inhibited cell proliferation and migration, while promoted apoptosis in vitro. In vivo, Calpain-2-knockdowned cells formed smaller subcutaneous tumors. Meanwhile, knockdown of Calpain-2 down-regulated EGFR and pAKT expression, which weakened the chemoresistance of NSCLC cells to paclitaxel by suppressing cell proliferation and inducing apoptosis, and even enhanced the paclitaxel-mediated downregulation of EGFR and pAKT level. To conclude, Calpain-2 might activate EGFR/pAKT pathway to promote NSCLC progression and contributes to the chemoresistance to paclitaxel, which might be a therapeutic target to prevent or postpone the progression of NSCLC.

Flexible Transient Optical Waveguides and Surface-Wave Biosensors Constructed from Monocrystalline Silicon.

Optical technologies offer important capabilities in both biological research and clinical care. Recent interest is in implantable devices that provide intimate optical coupling to biological tissues for a finite time period and then undergo full bioresorption into benign products, thereby serving as temporary implants for diagnosis and/or therapy. The results presented here establish a silicon-based, bioresorbable photonic platform that relies on thin filaments of monocrystalline silicon encapsulated by polymers as flexible, transient optical waveguides for accurate light delivery and sensing at targeted sites in biological systems. Comprehensive studies of the mechanical and optical properties associated with bending and unfurling the waveguides from wafer-scale sources of materials establish general guidelines in fabrication and design. Monitoring biochemical species such as glucose and tracking physiological parameters such as oxygen saturation using near-infrared spectroscopic methods demonstrate modes of utility in biomedicine. These concepts provide versatile capabilities in biomedical diagnosis, therapy, deep-tissue imaging, and surgery, and suggest a broad range of opportunities for silicon photonics in bioresorbable technologies.

Flos Puerariae Extract Ameliorates Cognitive Impairment in Streptozotocin-Induced Diabetic Mice.

Objective. The effects of Flos Puerariae extract (FPE) on cognitive impairment associated with diabetes were assessed in C57BL/6J mice. Methods. Experimental diabetic mice model was induced by one injection of 50 mg/kg streptozotocin (STZ) for 5 days consecutively. FPE was orally administrated at the dosages of 50, 100, or 200 mg/kg/day, respectively. The learning and memory ability was assessed by Morris water maze test. Body weight, blood glucose, free fatty acid (FFA) and total cholesterol (TCH) in serum, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and acetylcholinesterase (AChE) activities in cerebral cortex and hippocampus were also measured. Results. Oral administration of FPE significantly improved cognitive deficits in STZ-induced diabetic mice. FPE treatment also maintained body weight and ameliorated hyperglycemia and dyslipidemia in diabetic mice. Additionally, decreased MDA level, enhanced CAT, and GSH-Px activities in cerebral cortex or hippocampus, as well as alleviated AChE activity in cerebral cortex, were found in diabetic mice supplemented with FPE. Conclusion. This study suggests that FPE ameliorates memory deficits in experimental diabetic mice, at least partly through the normalization of metabolic abnormalities, ameliorated oxidative stress, and AChE activity in brain.

Analysis and therapeutic schedule of the postoperative recurrence of bone tuberculosis.

OBJECTIVE: The present study aims to analyze the main reasons that lead to the failure of bone tuberculosis (TB) surgery and the efficacy of reoperation. METHODS: A total of 3,000 cases of bone TB patients were examined retrospectively. Of these, 180 cases had recurrence, including 135 cases of spinal TB and 45 cases of limb TB. Preoperative indicators of duration of anti-TB chemotherapy, nutritional conditions, temperature conditions and erythrocyte sedimentation rate, and medication time of postoperative and recurrence were statistically analyzed. RESULTS: Of all 180 cases with reoperation, 176 cases were cured, and four paralyzed patients were symptomatically improved. The causes of postoperative recurrence of bone TB were relatively complex. Efficacy of reoperation was evaluated. Shorter chemotherapy duration, long-term illness, poor health, a higher body temperature, and an accelerated ESR are likely to increase the risk of recurrence. CONCLUSIONS: Given the operation failure, careful analysis of the failure reasons and the targeted reoperation can obtain satisfactory results, thereby avoiding the failure of the initial surgery.

Effect of ß­globin MAR characteristic elements on transgene expression.

The aim of the present study was to investigate the effect of the characteristic elements of matrix attachment region (MAR) on transgene expression. Human ß­globin MAR was obtained by PCR amplification. A splicing MAR fragment containing all the characteristic elements of ß­globin MAR was artificially synthesized and then cloned into the eukaryotic expression vector. Following digestion and sequence identification, we transfected Chinese hamster ovary (CHO) cells with the two vectors, and then screened for the transformation of stable cells. The transgene expression level was analyzed by ELISA, and the copy numbers of the CAT gene were analyzed by real­time fluorescent quantitative PCR. ß­globin MAR enhanced CAT reporter gene expression by 2.1489­fold, whereas the ß­globin MAR characteristic elements did not enhance this expression. The real­time fluorescent quantitative PCR analysis demonstrated that the relative copy numbers of the CAT gene of the ß­globin MAR expression vector were 1.2­fold higher compared with those of the non­MAR expression vector. MAR was able to improve the transgene expression level to a certain extent. The MAR characteristic elements did not improve the transgene expression alone. The transgenic expression levels were not linear with the transgene copy number; however, the enhancement of transgenic expression was relative to the increase in the gene copy number.

Effects of resveratrol on vascular endothelial growth factor expression in osteosarcoma cells and cell proliferation.

The aim of the current study was to investigate the effects of resveratrol (Res) on vascular endothelial growth factor (VEGF) expression and cell proliferation in the human osteosarcoma cell line U20S. U20S cells were treated with Res at various concentrations (0, 10, 20 and 40 µmol/l) for various times (24, 48 and 72 h). The inhibitory effect of Res on U20S proliferation was observed using methyl thiazolyl tetrazolium (MTT) colorimetry. VEGF expression was determined using real-time polymerase chain reaction (RT-PCR) and western blot analysis. The inhibitory effect of Res on U20S proliferation increased as the concentration of Res increased. The inhibitory effect also increased with time. Res had an inhibitory effect on VEGF expression and significantly inhibited U20S cell proliferation. Res may exert an anti-osteosarcoma effect by inhibiting VEGF expression in tumor cells.

Transmission resonances of compound metallic gratings with two subwavelength slits in each period.

Based on the finite-difference time-domain method, we investigate the transmission resonances of compound metallic gratings with two subwavelength slits filled with different dielectrics inside each period in the visible and near infrared regions. The results show that the transmission spectrum is almost a compound of that of two corresponding simple gratings expect for the transmission feature at a certain resonant wavelength, where the Fabry-Pérot (FP)-like phenomena have been found both inside the two slits, but the orders of the FP-like modes are different. If the order of the FP-like mode inside one slit is one bigger than inside the other, the intensity of the transmission will be significantly weakened. We attribute this phenomenon to the phase resonance because the phases at the exits of the two slits are opposite to each other.