Advanced HCC with amplified mesenchymal epithelial transition factor receptor responds well to savolitinib: a case report

ObjectiveCurrent treatment agents for HCC are mostly immune checkpoint inhibitors (ICIs) plus bevacizumab and multitarget tyrosine kinase inhibitors (TKIs); however, their limited overall response rate and shorter median progression-free survival (PFS) discourage their frequent use. The development of Mesenchymal Epithelial Transition Factor receptor (MET) Tyrosine Kinase Inhibitors (MET-TKI) has transformed the treatment pattern in MET-altered solid tumors and improved their prognosis. However, the benefits of MET-TKIs in MET-amplified hepatocellular carcinoma (HCC) remain unclear.MethodsHere, we present a case of advanced HCC amplified with MET treated with savolitinib, a MET-TKI, after progression from first-line treatment with bevacizumab plus sintilimab.ResultsThe patient achieved a partial response (PR) to savolitinib in the second line setting. The progression-free survival (PFS) of first-line of bevacizumab plus sintilimab and sequential second-line treatment with MET-TKI, savolitinib, are 3 and over 8 months, respectively. furthermore, the patient still had continuous PR status with manageable toxicities.ConclusionsThe present case report provides first-hand evidence that savolitinib may be beneficial for patients with advanced MET-amplified HCC and offers a promising treatment option

Orexin A Affects INS-1 Rat Insulinoma Cell Proliferation via Orexin Receptor 1 and the AKT Signaling Pathway

Our aim is to investigate the role of the AKT/PKB (protein kinase B) signaling pathway acting via orexin receptor 1 (OX1R) and the effects of orexin A (OXA) on cell proliferation in the insulin-secreting beta-cell line (INS-1 cells). Rat INS-1 cells were exposed to different concentrations of OXA in vitro and treated with OX1R antagonist (SB334867), PI3K antagonist (wortmannin), AKT antagonist (PF-04691502), or negative control. INS-1 amount of cell proliferation, viability and apoptosis, insulin secretion, OX1R protein expression, caspase-3 activity, and AKT protein levels were determined. We report that OXA (10-10 to 10-6 M) stimulates INS-1 cell proliferation and viability, reduces the proapoptotic activity of caspase-3 to protect against apoptotic cell death, and increases insulin secretion. Additionally, AKT phosphorylation was stimulated by OXA (10-10 to 10-6 M). However, the OX1R antagonist SB334867 (10-6 M), the PI3K antagonist wortmannin (10-8 M), the AKT antagonist PF-04691502 (10-6 M), or the combination of both abolished the effects of OXA to a certain extent. These results suggest that the upregulation of OXA-OX1R mediated by AKT activation may inhibit cell apoptosis and promote cell proliferation in INS-1 cells. This finding provides functional evidence of the biological actions of OXA in rat insulinoma cells

Derivation and validation of a prognostic model for predicting in-hospital mortality in patients admitted with COVID-19 in Wuhan, China:the PLANS (platelet lymphocyte age neutrophil sex) model

Background Previous published prognostic models for COVID-19 patients have been suggested to be prone to bias due to unrepresentativeness of patient population, lack of external validation, inappropriate statistical analyses, or poor reporting. A high-quality and easy-to-use prognostic model to predict in-hospital mortality for COVID-19 patients could support physicians to make better clinical decisions. Methods Fine-Gray models were used to derive a prognostic model to predict in-hospital mortality (treating discharged alive from hospital as the competing event) in COVID-19 patients using two retrospective cohorts (n = 1008) in Wuhan, China from January 1 to February 10, 2020. The proposed model was internally evaluated by bootstrap approach and externally evaluated in an external cohort (n = 1031). Results The derivation cohort was a case-mix of mild-to-severe hospitalized COVID-19 patients (43.6% females, median age 55). The final model (PLANS), including five predictor variables of platelet count, lymphocyte count, age, neutrophil count, and sex, had an excellent predictive performance (optimism-adjusted C-index: 0.85, 95% CI: 0.83 to 0.87; averaged calibration slope: 0.95, 95% CI: 0.82 to 1.08). Internal validation showed little overfitting. External validation using an independent cohort (47.8% female, median age 63) demonstrated excellent predictive performance (C-index: 0.87, 95% CI: 0.85 to 0.89; calibration slope: 1.02, 95% CI: 0.92 to 1.12). The averaged predicted cumulative incidence curves were close to the observed cumulative incidence curves in patients with different risk profiles. Conclusions The PLANS model based on five routinely collected predictors would assist clinicians in better triaging patients and allocating healthcare resources to reduce COVID-19 fatality

Fetal hyperechoic kidney cohort study and a meta-analysis

Objective: To investigate the positive rate of chromosomal and monogenic etiologies and pregnancy outcomes in fetuses with hyperechoic kidney, and to provide more information for genetic counseling and prognosis evaluation.Methods: We performed a retrospective analysis of 25 cases of hyperechoic kidney diagnosed prenatal in the Second Affiliated Hospital of Harbin Medical University and Harbin Red Cross Central Hospital (January 2017–December 2022). Furthermore, we conducted a meta-analysis of a series of hyperechoic kidneys (HEK) in the literature to assess the incidence of chromosomal and monogenic etiologies, mortality, and pooled odds ratio (OR) estimates of the association between the incidence of these outcomes and other associated ultrasound abnormalities.Results: 25 fetuses of HEK were enrolled in the cohort study, including 14 with isolated hyperechoic kidney (IHK) and 11 with non-isolated hyperechoic kidney (NIHK). Chromosomal aneuploidies were detected in 4 of 20 patients (20%). The detection rate of pathogenic or suspected pathogenic copy number variations (CNVs) was 29% (4/14) for IHK and 37% (4/11) for NIHK. Whole exome sequencing (WES) was performed in 5 fetuses, and pathogenic genes were detected in all of them. The rate of termination of pregnancy was 56% in HEK. 21 studies including 1,178 fetuses were included in the meta-analysis. No case of abnormal chromosome karyotype or (intrauterine death)IUD was reported in fetuses with IHK. In contrast, the positive rate of karyotype in NIHK was 22% and that in HEK was 20%, with the ORs of 0.28 (95% CI 0.16–0.51) and 0.25, (95% CI 0.14–0.44), respectively. The positive rate of (chromosome microarray analysis) CMA in IHK was 59% and that in NIHK was 32%, with the ORs of 1.46 (95% CI 1.33–1.62) and 0.48 (95% CI, 0.28–0.85), respectively. The positive rate of monogenic etiologies in IHK was 31%, with the OR of 0.80 (95% CI 0.25–2.63). In IHK, the termination rate was 21% and neonatal mortality was 13%, with the ORs of 0.26 (95% CI, 0.17–0.40), 1.72 (95% CI, 1.59–1.86), and that in NIHK was 63%, 0.15 (95% CI, 0.10–0.24); 11%, 0.12 (95% CI, 0.06–0.26), respectively. The intrauterine mortality in NIHK group was 2%, with the OR of 0.02 (95% CI, 0.01–0.05). HNF1B variant has the highest incidence (26%) in IHK.Conclusion: The positive rate of karyotype was 20% in HEK and 22% in NIHK. The positive rate of CMA was 32% in NIHK and 59% in IHK. The positive rate of IHK monogenic etiologies was 31%. HNF1B gene variation is the most common cause of IHK. The overall fetal mortality rate of NIHK is significantly higher than that of IHK. The amount of amniotic fluid, kidney size and the degree of corticomedullary differentiation have a great impact on the prognosis, these indicators should be taken into consideration to guide clinical consultation and decision-making

SUMOylation of DEC1 Protein Regulates Its Transcriptional Activity and Enhances Its Stability

Differentiated embryo-chondrocyte expressed gene 1 (DEC1, also known as sharp2, stra13, or BHLHB2) is a mammalian basic helix-loop-helix protein that is involved in many aspects of gene regulation through acting as a transcription factor. Changes in DEC1 expression levels have been implicated in the development of cancers. Using COS-7 cell, we showed that DEC1 can be modified by the small ubiquitin-like modifiers, SUMO1, 2 and 3. Two major SUMOylation sites (K159 and K279) were identified in the C-terminal domain of DEC1. Substitution of either K159 or K279 with arginine reduced DEC1 SUMOylation, but substitution of both K159 and K279 abolished SUMOylation, and more protein appeared to be retained in the cytoplasm compared to wild-type DEC1. The expression of DEC1 was up-regulated after serum starvation as previously reported, but at the same time, serum starvation also led to more SUMOylation of DEC1. In MCF-7 cells SUMOylation also stabilized DEC1 through inhibiting its ubiquitination. Moreover, SUMOylation of DEC1 promoted its repression of CLOCK/BMAL1-mediated transcriptional activity through recruitment of histone deacetylase1. These findings suggested that posttranslational modification of DEC1 in the form of SUMOylation may serve as a key factor that regulates the function of DEC1 in vivo

Transition of Urban Morphology in the Mountainous Areas Since Early-Modern Times from the Perspective of Urban Historic Landscape—A GIS Tools and Historical Map Translation Approach

Regenerating cities must blend modernization and heritage. Both urban morphology and Historic Urban Landscape (HUL) highlight historical processes and may assist in regeneration. Using Chongqing as the study example may further understand mountain cities, which are prevalent worldwide but seldom examined in morphology research. This study explores and organizes the historical modernization of Chongqing’s parent city from early-modern times to the present day using a universal approach established in this research developed by the HUL perspective and research framework, Geographic information system (GIS), Depthmap tool, and historical map translation method. Large-scale modernization occurred prior to the 1980s, followed by more modest rehabilitation projects. The whole procedure is described by the phrase “Construction first, then planning, then transformation,” which entails a “free growth” block structure at the outset, along with planning control. The study contributes the following: (1) Establishing a theoretical framework and research technique for the universal city based on historical sources and modern instruments; (2) Chongqing’s future sustainable development and historical preservation depend in large part on figuring out the city’s complicated modernization history; (3) The study of mountain cities may benefit from understanding the geographical development and spatial dynamic layering of Chongqing. (4) This study bridges the gap in time by going beyond the early modern period covered by the previous ones and into the post-statehood era (1949–2022)

Transition of Urban Morphology in the Mountainous Areas Since Early-Modern Times from the Perspective of Urban Historic Landscape—A GIS Tools and Historical Map Translation Approach

Regenerating cities must blend modernization and heritage. Both urban morphology and Historic Urban Landscape (HUL) highlight historical processes and may assist in regeneration. Using Chongqing as the study example may further understand mountain cities, which are prevalent worldwide but seldom examined in morphology research. This study explores and organizes the historical modernization of Chongqing’s parent city from early-modern times to the present day using a universal approach established in this research developed by the HUL perspective and research framework, Geographic information system (GIS), Depthmap tool, and historical map translation method. Large-scale modernization occurred prior to the 1980s, followed by more modest rehabilitation projects. The whole procedure is described by the phrase “Construction first, then planning, then transformation,” which entails a “free growth” block structure at the outset, along with planning control. The study contributes the following: (1) Establishing a theoretical framework and research technique for the universal city based on historical sources and modern instruments; (2) Chongqing’s future sustainable development and historical preservation depend in large part on figuring out the city’s complicated modernization history; (3) The study of mountain cities may benefit from understanding the geographical development and spatial dynamic layering of Chongqing. (4) This study bridges the gap in time by going beyond the early modern period covered by the previous ones and into the post-statehood era (1949–2022)

Mechanical Properties and Microscopic Mechanism of a Multi-Cementitious System Comprising Cement, Fly Ash, and Steel Slag Powder

The objective of this study was to reduce the stockpile of steel slag, which is a solid waste generated in the steelmaking process, and promote the resource utilization of steel slag powder (SSP) in construction projects. Experimental research was conducted on SSP and fly ash (FA) as supplementary cementitious materials. Composite cement paste samples were prepared to investigate the effects of the water-to-binder ratio and cement-substitution rate on the macroscopic mechanical properties, including the setting time, fluidity, flexural strength, and compressive strength of the prepared paste. The mineral composition in the raw materials was measured using X-ray diffraction (XRD), and a micro-morphological and structural analysis of the hydrated cementitious material samples was performed using scanning electron microscopy (SEM); the SEM and Image Pro Plus (IPP) image analysis techniques were combined for a quantitative analysis of the microstructure. The results showed that the addition of FA and SSP delayed the hydration of cement, thereby improving the flowability of the composite paste. Under the same curing age and cement substitution rate, the sample strength decreased with increasing water-to-binder ratio. Under the same water-to-binder ratio and curing age, the variations in the flexural and compressive strengths of the SSP group samples were inconsistent in the early and later stages, and the sample group with 20% SSP exhibited optimal mechanical strength in the later stage. The microscopic results showed that the needle-like AFt crystals in the hydrated pores decreased in number with the increase in the SSP content. The hydration products of the FA–SSP admixture, such as C–S–H gel and RO phase, acted as pore fillers in alkaline environments. When the water-to-binder ratio was 0.4 and the FA-to-SSP ratio was 1:1 to replace 40% cement, the performance of the hardened cement paste was the best among all the test groups containing both FA and SSP. This study provides a theoretical basis for the practical application of SSP and FA as cementitious materials in construction-related fields