GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are prevalent birth defects. Although pathogenic CAKUT genes are known, they are insufficient to reveal the causes for all patients. Our previous studies indicated GEN1 as a pathogenic gene of CAKUT in mice, and this study further investigated the correlation between GEN1 and human CAKUT. METHODS: In this study, DNA from 910 individuals with CAKUT was collected; 26 GEN1 rare variants were identified, and two GEN1 (missense) variants in a non-CAKUT group were found. Mainly due to the stability results of the predicted mutant on the website, in vitro, 10 variants (eight CAKUT, two non-CAKUT) were selected to verify mutant protein stability. In addition, mainly based on the division of the mutation site located in the functional region of the GEN1 protein, 8 variants (six CAKUT, two non-CAKUT) were selected to verify enzymatic hydrolysis, and the splice variant GEN1 (c.1071 + 3(IVS10) A > G) was selected to verify shear ability. Based on the results of in vitro experiments and higher frequency, three sites with the most significant functional change were selected to build mouse models. RESULTS: Protein stability changed in six variants in the CAKUT group. Based on electrophoretic mobility shift assay of eight variants (six CAKUT, two non-CAKUT), the enzymatic hydrolysis and DNA-binding abilities of mutant proteins were impaired in the CAKUT group. The most serious functional damage was observed in the Gen1 variant that produced a truncated protein. A mini-gene splicing assay showed that the variant GEN1 (c.1071 + 3(IVS10) A > G) in the CAKUT group significantly affected splicing function. An abnormal exon10 was detected in the mini-gene splicing assay. Point-mutant mouse strains were constructed (Gen1: c.1068 + 3 A > G, p.R400X, and p.T105R) based on the variant frequency in the CAKUT group and functional impairment in vitro study and CAKUT phenotypes were replicated in each. CONCLUSION: Overall, our findings indicated GEN1 as a risk factor for human CAKUT.

Gestational diabetes mellitus induces congenital anomalies of the kidney and urinary tract in mice by altering RET/MAPK/ERK pathway.

Gestational diabetes mellitus (GDM) presents a substantial population health concern. Previous studies have revealed that GDM can ultimately influence nephron endowment. In this study, we established a GDM mouse model to investigate the embryological alterations and molecular mechanisms underlying the development of congenital anomalies of the kidney and urinary tract (CAKUT) affected by GDM. Our study highlights that GDM could contribute to the manifestation of CAKUT, with prevalent phenotypes characterized by isolated hydronephrosis and duplex kidney complicated with hydronephrosis in mice. Ectopic ureteric buds (UBs) and extended length of common nephric ducts (CNDs) were noted in the metanephric development stage. The expression of Ret and downstream p-ERK activity were enhanced in UBs, which indicated the alteration of RET/MAPK/ERK pathway may be one of the mechanisms contributing to the increased occurrence of CAKUT associated with GDM.

HER3 receptor and its role in the therapeutic management of metastatic breast cancer.

Metastatic breast cancer (mBC) poses a significant threat to women's health and is a major cause of malignant neoplasms in women. Human epidermal growth factor receptor (HER)3, an integral member of the ErbB/HER receptor tyrosine kinase family, is a crucial activator of the phosphoinositide-3 kinase/protein kinase B signaling pathway. HER3 overexpression significantly contributes to the development of resistance to drugs targeting other HER receptors, such as HER2 and epidermal growth factor receptors, and plays a crucial role in the onset and progression of mBC. Recently, numerous HER3-targeted therapeutic agents, such as monoclonal antibodies (mAbs), bispecific antibodies (bAbs), and antibody-drug conjugates (ADCs), have emerged. However, the efficacy of HER3-targeted mAbs and bAbs is limited when used individually, and their combination may result in toxic adverse effects. On the other hand, ADCs are cytotoxic to cancer cells and can bind to target cells through antibodies, which highlights their use in targeted HER3 therapy for mBC. This review provides an overview of recent advancements in HER3 research, historical initiatives, and innovative approaches in targeted HER3 therapy for metastatic breast cancer. Evaluating the advantages and disadvantages of current methods may yield valuable insights and lessons.

Preparation and Reactivity of Core-Shell Al@CL-20 Composites Embedded with Graphene-Based Complexes as Catalysts.

Incomplete combustion of Al in solid propellants can be effectively resolved by coating of an oxidizer at the microscale. In this paper, Al@CL-20 composites with polydopamine as the interfacial layer were prepared using this strategy. The structure, heat of reaction, thermal decomposition properties, and combustion performances of these composites under the effects of graphene oxide (GO) and graphene-based carbohydrazide complexes (GO-CHZ-M, M = Co2+, Ni2+) have been comprehensively investigated. The experimental results show that the heat of reaction of Al@CL-20 is 6482 J g-1, which is 561 J g-1 higher than that of the corresponding mechanical mixture. The presence of GO-CHZ-Co can further increase the heat of reaction of Al@CL-20 to 6729 J g-1 with a decreased activation energy by about 54.8%. Under the synergistic effect of interfacial control and GO-CHZ-M, the ignition delay time of Al@CL-20-Co decreases from 5.1 to 4.2 ms. Besides, the D50 of the combustion condensed products (CCPs) decreased from 5.62 to 4.33 µm, indicating the combustion efficiency of Al is greatly improved.

The value of bioimpedance analysis in the assessment of hydration and nutritional status in children on chronic peritoneal dialysis.

Bioimpedance analysis (BIA)-body composition monitoring (BCM) has been used to evaluate the hydration and nutritional status of adults and children on dialysis. However, its clinical application still has challenges, so further exploration is valuable. We used BIA-BCM to evaluate the hydration and nutritional status of children undergoing chronic peritoneal dialysis from 1 July 2021 to 31 December 2022 in the Children's Hospital of Fudan University to explore the clinical value of this method. A total of 84 children on chronic peritoneal dialysis (PD) were included. In the PD group, 16 (19.05%) and 31 (36.90%) had mild and severe overhydration (OH), respectively; 41.27% (26/63) had a low lean tissue index (LTI). In the PD group, patients with relative OH (Re-OH) > 5.6% had significantly higher systolic blood pressure (SBP) and SBP z score (SBPz). Patients with LTI > 12% had significantly higher body mass index (BMI) and BMI z score (BMIz). Canonical correlation analysis indicated a linear relationship (ρ = 0.708) between BIA-BCM hydration and the clinical hydration indicator and a linear relationship (ρ = 0.995) between the BIA-BCM nutritional indicator and the clinical nutritional indicator. A total of 56% of children on chronic peritoneal dialysis had OH, and 41% had a low LTI. In PD patients, SBP and SBPz were correlated with BIA-BCM Re-OH, and BMI and BMIz were correlated with BIA-BCM LTI. BIA-BCM indicators have good clinical value in evaluating hydration and nutrition.

Inhibition of MAPK/ERK pathway activation rescues congenital anomalies of the kidney and urinary tract (CAKUT) in Robo2PB/+ Gen1PB/+ mice.

Congenital anomalies of the kidney and urinary tract (CAKUT) have been attributed to genetic and environmental factors. However, monogenic and copy number variations cannot sufficiently explain the cause of the majority of CAKUT cases. Multiple genes through various modes of inheritance may lead to CAKUT pathogenesis. We previously showed that Robo2 and Gen1 coregulated the germination of ureteral buds (UB), significantly increasing CAKUT incidence. Furthermore, MAPK/ERK pathway activation is the central mechanism of these two genes. Thus, we explored the effect of the MAPK/ERK inhibitor U0126 in the CAKUT phenotype in Robo2PB/+Gen1PB/+ mice. Intraperitoneal injection of U0126 during pregnancy prevented the development of the CAKUT phenotype in Robo2PB/+Gen1PB/+ mice. Additionally, a single dose of 30 mg/kg U0126 on day 10.5 embryos (E10.5) was most effective for reducing CAKUT incidence and ectopic UB outgrowth in Robo2PB/+Gen1PB/+ mice. Furthermore, embryonic kidney mesenchymal levels of p-ERK were significantly decreased on day E11.5 after U0126 treatment, along with decreased cell proliferation index PHH3 and ETV5 expression. Collectively, Gen1 and Robo2 exacerbated the CAKUT phenotype in Robo2PB/+Gen1PB/+ mice through the MAPK/ERK pathway, increasing proliferation and ectopic UB outgrowth.

Graphene Oxide-Intercalated Tetrazole-Based Coordination Polymers: Thermally Stable Hybrid Energetic Crystals with Enhanced Photosensitivity.

High-energy-density photosensitive pyrotechnics with good thermal stability have been in increasing demand in recent years. In this paper, graphene oxide (GO)-intercalated energetic coordination polymers (ECPs) are prepared with improved thermostability but great photosensitivity by using high nitrogen compounds azotetrazole (AT) and 5,5'-bistetrazole-1,1'-diolate dehydrate (BTO) as ligands. The decomposition activation energy (Ea) of Cu-AT has been increased from 135.7 to 151.9 kJ·mol-1 after intercalating 5 wt% GO, and in the meantime, the exothermic peak temperature (Tp) was increased by 12.6 °C. However, the decomposition Ea of Cu-BTO decreased under the effect of the same amount of GO with little effect on Tp. This confirms that GO has stabilization effects on the Cu-AT crystal, whereas the catalytic effects on Cu-BTO would dominate after dehydration with its crystal lattice collapse. Also, when the content of GO was 3%, the resultant GO0.03-Cu-AT exhibits a higher density (2.88 g·cm-3) and good thermostability (Tp = 293.7 °C). This ECP shows excellent low-energy laser ignition performance, which can be ignited with an energy of less than 1 mJ at a wavelength of 976 nm. Low-energy laser initiation is considered to be a safer but more reliable method than the traditional electrical-based ones.

Stabilization of AlH3 Crystals by the Coating of Hydrophobic PFPE and Resulted Reactivity with Ammonium Perchlorate.

Aluminum hydride (AlH3) is a promising fuel component of solid propellant, but its stabilization is still challenging. Herein, surface functionalization of hydrophobic perfluoropolyether (PFPE) followed by ammonium perchlorate (AP) coating has been implemented. In particular, AlH3@PFPE@xAP (x = 10, 30, 50, or 64.21%) composites (AHFPs) were prepared by a spray-drying technique. The PFPE-functionalized AlH3 with a hydrophobic surface shows an increased water contact angle (WCA) from 51.87° to 113.54°. Compared with pure AlH3, the initial decomposition temperatures of AHFPs were increased by 17 °C, and the decomposition properties of AP in the AHFPs were also enhanced with significantly decreased peak temperature and fairly increased energy output. Moreover, the decomposition induction time of AHFPs-30% was improved by almost 1.82 times that of raw AlH3, which indicates that the coatings of PFPE and AP could improve the stability of AlH3. The maximum flame radiation intensity of AHFPs-30% was 21.6 × 103, which is almost 7.71 times that of pure AlH3 (2.8 × 103).

Integrating Ecosystem Health and Services for Assessing Ecological Risk and its Response to Typical Land-Use Patterns in the Eco-fragile Region, North China.

Changes in land-use patterns may increase the ecological risks faced by Eco-Fragile regions. It is vital for regional ecological restoration and management of Eco-Fragile regions to reasonably assess ecological risk and study its response to typical land-use patterns. Existing study on regional ecological risk largely ignored the internal representation of ecosystem health and ecosystem services to ecological risk, and also ignored the internal relationship between ecological risk and land use patterns. This study developed a regional ecological assessment model by describing the relationship between ecosystem health, ecosystem services and ecological risks. Among them, the ecosystem health assessment used the Net Primary Productivity, landscape index and ecosystem elasticity coefficient based on different land use patterns to build Vigor-Organization-Resilience (VOR) model, and the improved equivalent factor method was used to calculate the ecosystem service value. Taking the Fen River Basin (FRB), a typical Eco-Fragile region of the Loess Plateau, as a study region, spatial auto-correlation analysis was used to reveal the temporal and spatial changes and spatial clustering characteristics of regional ecological risk, and regression analysis was used to study the relationship between typical land use patterns and ecological risks, which was included in the consideration of ecological and environmental risk management strategies. The results show that the regions with high ecological risk are mainly distributed in the middle and southwest of the FRB; the regions with low ecological risk are mainly distributed in the north, east and west of the FRB. Both high-risk and low-risk areas show significant spatial clustering effects. The change of ecological risk in FRB is related to the land use patterns. The ecological risk is negatively related to the expansion of construction land and cultivated land at the county and patch scales. On this basis, the environmental management strategies at different scales are discussed. This study can helpful deepen the understanding of the impact of land use patterns on ecological risk, and can also provide important reference for regional ecological risk management and land use policies.

Disruption of Gen1 causes ectopic budding and kidney hypoplasia in mice.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a family of often-concurrent diseases with various anatomical spectra. Null-mutant Gen1 mice frequently develop multiple urinary phenotypes, most commonly duplex kidneys, and are ideal subjects for research on ectopic budding in CAKUT development. The upper and lower kidney poles of the Gen1PB/PB mouse were examined by histology, immunofluorescence, and immunohistochemistry. The newborn Gen1PB/PB mouse lower poles were significantly more hypoplastic than the corresponding upper poles, with significantly fewer glomeruli. On embryonic day 14.5, immediately before first urine formation, the upper pole kidney was already larger than the lower pole kidney. In vivo and in vitro, embryonic kidney upper poles had more ureteric buds than lower poles. Gen1PB/PB embryos exhibited ectopic ureteric buds, usually near the original budding site, occasionally far away, or, rarely, derived from the primary budding site. Therefore, ectopia of the ureteric buds is the core of CAKUT formation. Further studies will be needed to investigate the regulatory roles of these genes in initial ureteric budding and subsequent ontogenesis during metanephros development.

Interfacial Nucleation Mechanism of Water-Soluble Ag-In-S Quantum Dots at Room Temperature and Their Visible Light Catalytic Performance.

A novel interfacial reaction nucleation mechanism for the preparation of water-soluble Ag-In-S quantum dots (AIS QDs) was proposed in which interfacial acid regulates the concentration of hydroxide ions outside the complex and sulfur sources attack cations at the interface of the complex, covalent bonds between cations and sulfur sources are formed at the interface of the complex, and the nucleation and growth of crystals is finished at room temperature. By bypassing the heating process normally necessary for crystal nucleation and growth, AIS QDs can be produced on a large scale under simple, mild conditions. At the same time, the characteristics of this mechanism enable AIS QDs to be directly synthesized in an organic pollutant solution. This study represents a significant advance in the mechanism of crystal synthesis and contributes to the photocatalytic decomposition of organic pollutants from theory to practice.

Effects of Atractylon on Proliferation and Apoptosis of Intestinal Cancer Cells Through PI3K/AKT/mTOR Signaling Pathway.

The study aimed to explore the effects of atractylon on the proliferation and apoptosis of intestinal cancer cells through the phosphatidylinositol 3-hydroxy kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. The intestinal cancer HT29 cell lines were cultured in vitro, and atractylon at different concentrations (15 and 30 mg/mL) was added. Then cell proliferative activity was detected via cell counting kit-8 (CCK8) assay, and the proportion of positive cells was determined using EdU staining. The content of interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-9 (MMP-9) was detected via enzyme-linked immunosorbent assay (ELISA), and the apoptosis of HT29 cells was detected through terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Moreover, reverse transcription-polymerase chain reaction (RT-PCR) was performed to determine the messenger ribonucleic acid (mRNA) levels of proliferation, apoptosis and PI3K/AKT/mTOR signaling pathway-related genes, and Western blotting was used to analyze the expression of the PI3K/AKT/mTOR signaling pathway. The cell growth status was poorer with a lower density in the 15 mg/mL atractylon group and basically normal morphological structure in the 30 mg/mL atractylon group. The number of cells significantly declined and the proliferative activity was also significantly weakened in the 30 mg/mL atractylon group. There were obviously more apoptotic cells in the 30 mg/mL atractylon group. Besides, INF-γ, TNF-α and MMP-9 were all evidently decreased in the 30 mg/mL atractylon group. Expressions of B-cell lymphoma-2 (Bcl-2), PI3K, AKT and mTOR obviously declined in the 30 mg/mL atractylon group, and they were raised in the NC group, while the expression of Caspase3 showed the opposite trends. Atractylon at an appropriate concentration can inhibit the proliferation and promote the apoptosis of intestinal cancer cells by suppressing the PI3K/AKT/mTOR signaling pathway, which can be used to treat colorectal cancer and other related diseases.

Multi-centre study of the clinical features and gene variant spectrum of Gitelman syndrome in Chinese children.

Based on the Chinese Children Genetic Kidney Disease Database (CCGKDD), we established a pediatric Gitelman syndrome (GS) cohort to explore the phenotype and genotype characteristics. Thirty-two patients with SLC12A3 gene variants were collected. Five cases (16%) were homozygous, 16 (50%) were compound heterozygous, 10 (31%) carried only a single variant, and the other one harbored two de novo variants beyond classification. p.(T60M) was found in eight patients. The average diagnosis age was 7.79 ± 3.54 years. A total of 31% of the patients were asymptomatic. Muscle weakness was the most common symptom, accounting for 50%. Earlier age of onset (4.06 ± 1.17 yr vs. 8.10 ± 3.46 yr vs. 8.61 ± 3.56 yr, p< 0.05) and lower urinary calcium-creatinine ratio (p = 0.024) were found in the homozygous group than those in the heterozygous and compound heterozygous group. Patients with p.(T60M) variant had an earlier age of onset (4.01 ± 2.83 yr vs. 6.92 ± 3.07 yr, p = 0.025) and lower urinary calcium-creatinine ratio (p = 0.056). Thus, more than 30% of GS children have no clinical symptoms. Homozygous variant and the p.(T60M) variant may be associated with earlier onset and lower urinary calcium excretion in Chinese pediatric GS.

Diagnostic and clinical utility of genetic testing in children with kidney failure.

BACKGROUND: Genetic kidney disease is well established as an important cause of pediatric kidney failure, and genetic testing might increase diagnostic accuracy, but evidence is limited. This study was conducted to determine the diagnostic yield and clinical impact of genetic testing for children with kidney failure. METHODS: Patients who were diagnosed with kidney failure before 19 years of age at Children's Hospital of Fudan University from 2009 to 2018 and received next-generation sequencing (NGS) were enrolled. The results for likely pathogenic variants in genes known to cause chronic kidney disease (CKD) were analyzed. RESULTS: A molecular diagnosis was identified in 39.9% (75/188) of children with kidney failure. Specific subtype of clinical category was discerned in 54 (72.0%) patients, kidney disease was reclassified in 7 (9.3%) patients, the unknown etiology of 5 (6.7%) patients was molecularly diagnosed, and the clinical diagnoses of the other 9 (12.0%) patients were confirmed. In addition, genetic diagnosis was considered to have contributed to clinical management, including negating the need for kidney biopsy (26/75, 34.7%), avoiding immunosuppressive therapy (24/75, 32.0%), changing surveillance (48/75, 64.0%), guiding specific treatment (21/75, 28.0%), and guiding peri-transplant management and options for kidney transplantation (12/75, 16.0%). Furthermore, cascade testing was subsequently offered to 34.7% (26/75) of families. CONCLUSIONS: Genetic testing identified a molecular diagnosis in nearly 40% of children with kidney failure. Our results confirm that in children with kidney failure, genetic testing can not only establish a specific molecular diagnosis, but has a significant impact on clinical management.

Intrauterine low-protein diet aggravates developmental abnormalities of the urinary system via the Akt/Creb3 pathway in Robo2 mutant mice.

The offspring of Robo2 mutant mice usually present with variable phenotypes of congenital anomalies of the kidney and urinary tract (CAKUT). An intrauterine low-protein diet can also cause CAKUT in offspring, dominated by the duplicated collecting system phenotype. A single genetic or environment factor can only partially explain the pathogenesis of CAKUT. The present study aimed to establish an intrauterine low-protein diet roundabout 2 (Robo2) mutant mouse model and found that the intrauterine low-protein diet led to significantly increased CAKUT phenotypes in Robo2PB/+ mice offspring, dominant by a duplicated collecting system. At the same time, more ectopic and lower located ureteric buds (UBs) were observed in the intrauterine low-protein diet-fed Robo2 mutant mouse model, and the number of UB branches was reduced in the serum-free culture. During UB protrusion, intrauterine low-protein diet reduced the expression of Slit2/Robo2 in Robo2 mutant mice and affected the expression of glial cell-derived neurotrophic factor/Ret, which is a key molecule for metanephric development, with increasing phospho-Akt and phospho-cAMP responsive element-binding protein 3 activity and a reduction of apoptotic cells in embryonic day 11.5 UB tissues. The mechanism by which an intrauterine low-protein diet aggravates CAKUT in Robo2 mutant mice may be related to the disruption of Akt/cAMP responsive element-binding protein 3 signaling and a reduction in apoptosis in UB tissue.

Intrauterine low-protein diet disturbs metanephric gene expression and induces urinary tract developmental abnormalities in mice.

Intrauterine low-protein diet can affect kidney development and hence final nephron number. In this study, we reported that intrauterine low-protein diet can cause congenital anomalies of the kidney and urinary tract (CAKUT) phenotypes, which was dominated by the duplicated collecting system phenotype. At the same time, ectopic ureteric buds were increased under intrauterine low-protein diet and the number of UB branches was reduced in the serum-free culture. Intrauterine low-protein diet can change metanephric gene expression. Slit2/Robo2 and Spry1 expression levels were decreased, Ret expression was increased, and downstream p-Akt activity enhanced with apoptosis abnormal in ureteric bud tissue, which may be the mechanisms that intrauterine low-protein diet causes increased incidence of CAKUT in offspring. Thus, we showed correlation between intrauterine low-protein diet and CAKUT in offspring.

Separation of misalignment aberrations in interferometric testing for the surface measurement of the frustum of a cone.

The separation of misalignment aberrations is a crucial step in interferometric testing for the acquisition of the real surface. In this paper, a Fizeau interference system and a conical mirror with a certain angle were used to achieve the shape measurement of the inner surface of the frustum of a cone. Based on the ray-tracing method, the relationship between the adjustment errors and misalignment aberrations was established, and the misalignment aberrations could be removed by using the error separation model that accords with the least-square algorithm theory. The simulation and practical measurement results indicate that the approach proposed is valid and feasible.

Treatment Advances in Lung Cancer with Leptomeningeal Metastasis.

Leptomeningeal metastasis (LM) is a serious and often fatal complication in patients with advanced lung cancer, resulting in significant neurological deficits, decreased quality of life, and a poor prognosis. This article summarizes current research advances in treating lung cancer with meningeal metastases, discusses clinical challenges, and explores treatment strategies. Through an extensive review of relevant clinical trial reports and screening of recent conference abstracts, we collected clinical data on treating patients with lung cancer with meningeal metastases to provide an overview of the current research progress. Exciting progress has been made by focusing on specific mutations within lung cancer, including the use of EGFR tyrosine kinase inhibitors or inhibitors for anaplastic lymphoma kinase gene rearrangement, such as osimertinib, alectinib, and lorlatinib. These targeted therapies have shown impressive results in penetrating the central nervous system (CNS). Regarding whole-brain radiotherapy, there is currently some controversy among investigators regarding its effect on survival. Additionally, immune checkpoint inhibitors (ICIs) have demonstrated reliable clinical benefits due to their ability to retain anticancer activity in CNS metastases. Moreover, combination therapy shows promise in providing further treatment possibilities. Considerable progress has been made in the clinical research of lung cancer with LM. However, the sample size of prospective clinical trials investigating LM for lung cancer is still limited, with most reports being retrospective. Developing more effective management protocols for metastatic LM in lung cancer remains an ongoing challenge for the future.

Clinical efficacy of Camrelizumab combined with first-line chemotherapy in extensive-stage small-cell lung cancer.

Objective: Exploring the clinical efficacy of camrelizumab in combination with first-line chemotherapy in patients with extensive-stage small-cell lung cancer (ES-SCLC). Methods: The clinical data of 35 patients with ES-SCLC who received camrelizumab combined with EC or EP regimen in First Teaching Hospital of Tianjin University of Traditional Chinese Medicine from January 2020 to January 2023 were retrospectively analyzed. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were OS, ORR and DCR. SPSS 25.0 software was used for statistical analysis, Kaplan-Meier curve and Log-Rank test analysis, and survival curve was drawn. Results: The median PFS of 35 patients with SCLC was 7.4 months (95 % CI 6.75-9.81 months), .and the median OS was 12.5 months (95% CI,11.71-16.90 months). The ORR and DCR were 65.7 % and 74.3 %, respectively. Adverse events (AEs) were mainly concentrated in grade 1-2, and the probability of occurrence of grade 3 or above was low. Reactive Cutaneous Capillary Endothelial Proliferation (RCCEP) was the most common, followed by nausea &vomit and anemia. The other common AEs included abnormal thyroid function, decreased neutrophil count, skin rash and leucopenia. Conclusion: Camrelizumab in combination with first-line chemotherapy regimens prolonged OS and PFS in SCLC patients and showed efficacy and safety in real-world data.

Identification of 6-Fluorine-Substituted Coumarin Analogues as POLRMT Inhibitors with High Potency and Safety for Treatment of Pancreatic Cancer.

Increasing evidence has demonstrated that oxidative phosphorylation (OXPHOS) is closely associated with the progression of pancreatic cancer (PC). Given its central role in mitochondrial transcription, the human mitochondrial RNA polymerase (POLRMT) is a promising target for developing PC treatments. Herein, structure-activity relationship exploration led to the identification of compound S7, which was the first reported POLRMT inhibitor possessing single-digit nanomolar potency of inhibiting PC cells proliferation. Mechanistic studies showed that compound S7 exerted antiproliferative effects without affecting the cell cycle, apoptosis, mitochondrial membrane potential (MMP), or intracellular reactive oxygen species (ROS) levels specifically in MIA PaCa-2 cells. Notably, compound S7 inhibited tumor growth in MIA PaCa-2 xenograft tumor model with a tumor growth inhibition (TGI) rate of 64.52% demonstrating significant improvement compared to the positive control (44.80%). In conclusion, this work enriched SARs of POLRMT inhibitors, and compound S7 deserved further investigations of drug-likeness as a candidate for PC treatment.