Purpose: Combinations of immune checkpoint inhibitors (ICIs) and chemotherapy have become the standard first-line treatment for human epidermal growth factor receptor 2 (HER-2)-negative advanced gastric cancer. However, primary resistance remains a challenge, with no effective biomarkers available for its prediction. This retrospective study explores the relationship between the baseline inflammatory burden index (IBI) and primary resistance in such context. Materials and Methods: We analyzed 62 patients with HER-2-negative advanced gastric cancer who received ICIs and chemotherapy as their first-line treatment. The IBI was calculated as follows: C-reactive protein (mg/L) × neutrophil count (10 3 /mm 3 )/lymphocyte count (10 3 /mm 3 ). Based on disease progression within 6 months, patients were categorized into the primary resistant or the control group. We compared baseline characteristics and IBI scores between the groups and assessed the predictive value of the IBI using the receiver operating characteristic curve. Both univariate and multivariate binary logistic regression analyses were conducted to identify factors influencing primary resistance. Results: Nineteen patients were included in the primary resistance group, and forty-three patients were included in the control group. The IBI was significantly higher in the resistant group compared to the control group (P<0.01). The area under the curve for the IBI was 0.82, indicating a strong predictive value. Multivariate analysis identified the IBI as an independent predictor of primary resistance (P=0.014). Conclusions The baseline IBI holds promise as a predictor of primary resistance to combined ICIs and chemotherapy in patients with HER-2-negative advanced gastric cancer.

Purpose: Combinations of immune checkpoint inhibitors (ICIs) and chemotherapy have become the standard first-line treatment for human epidermal growth factor receptor 2 (HER-2)-negative advanced gastric cancer. However, primary resistance remains a challenge, with no effective biomarkers available for its prediction. This retrospective study explores the relationship between the baseline inflammatory burden index (IBI) and primary resistance in such context. Materials and Methods: We analyzed 62 patients with HER-2-negative advanced gastric cancer who received ICIs and chemotherapy as their first-line treatment. The IBI was calculated as follows: C-reactive protein (mg/L) × neutrophil count (10 3 /mm 3 )/lymphocyte count (10 3 /mm 3 ). Based on disease progression within 6 months, patients were categorized into the primary resistant or the control group. We compared baseline characteristics and IBI scores between the groups and assessed the predictive value of the IBI using the receiver operating characteristic curve. Both univariate and multivariate binary logistic regression analyses were conducted to identify factors influencing primary resistance. Results: Nineteen patients were included in the primary resistance group, and forty-three patients were included in the control group. The IBI was significantly higher in the resistant group compared to the control group (P<0.01). The area under the curve for the IBI was 0.82, indicating a strong predictive value. Multivariate analysis identified the IBI as an independent predictor of primary resistance (P=0.014). Conclusions The baseline IBI holds promise as a predictor of primary resistance to combined ICIs and chemotherapy in patients with HER-2-negative advanced gastric cancer.

Pyroptosis is an identified programmed cell death that has been highly linked to endoplasmic reticulum (ER) dynamics. However, the crucial proteins for modulating dynamic ER membrane curvature change that trigger pyroptosis are currently not well understood. In this study, a biotin-labeled chemical probe of potent pyroptosis inducer α-mangostin (α-MG) was synthesized. Through protein microarray analysis, reticulon-4 (RTN4/Nogo), a crucial regulator of ER membrane curvature, was identified as a target of α-MG. We observed that chemically induced proteasome degradation of RTN4 by α-MG through recruiting E3 ligase UBR5 significantly enhances the pyroptosis phenotype in cancer cells. Interestingly, the downregulation of RTN4 expression significantly facilitated a dynamic remodeling of ER membrane curvature through a transition from tubules to sheets, consequently leading to rapid fusion of the ER with the cell plasma membrane. In particular, the ER-to-plasma membrane fusion process is supported by the observed translocation of several crucial ER markers to the "bubble" structures of pyroptotic cells. Furthermore, α-MG-induced RTN4 knockdown leads to pyruvate kinase M2 (PKM2)-dependent conventional caspase-3/gasdermin E (GSDME) cleavages for pyroptosis progression. In vivo, we observed that chemical or genetic RTN4 knockdown significantly inhibited cancer cells growth, which further exhibited an antitumor immune response with anti-programmed death-1 (anti-PD-1). In translational research, RTN4 high expression was closely correlated with the tumor metastasis and death of patients. Taken together, RTN4 plays a fundamental role in inducing pyroptosis through the modulation of ER membrane curvature remodeling, thus representing a prospective druggable target for anticancer immunotherapy.
Pyroptosis/immunology* ; Humans ; Endoplasmic Reticulum/immunology* ; Animals ; Nogo Proteins/antagonists & inhibitors* ; Mice ; Cell Line, Tumor ; Xanthones/pharmacology* ; Neoplasms/pathology* ; Mice, Nude

19 cinnamamide/ester-triazole compounds were designed, synthesized and evaluated for their anti-Alzheimer's disease (AD) activity. Among them, compound 4f displayed excellent anti-β-amyloid protein (Aβ)-mediated cytotoxicity (EC₅₀ = 2.03 ± 2.45 μmol·L^-1) in APPswe cells and acetylcholinesterase inhibiton (IC₅₀ = 4.88 ± 4.70 μmol·L^-1). Further study indicated that, at dosages of (1, 5 and 25 mg·kg^-1), compound 4f was effective in improving spatial learning and memory deficits in Aβ_1-42-impaired mice, which was achieved by promoting the nonamyloidogenic signaling and inhibiting the amyloidogenic pathway, along with the suppression of Aβ-induced Tau phosphorylation. All animal experiments in this study were approved by the Experimental Animal Care and Use Committee of the Institute of Medicinal Biotechnology (IMB-20220908D701). In conclusion, compound 4f holds promise as a lead candidate for AD treatment, and the present study lays the foundation for its subsequent development.

Purpose: Combinations of immune checkpoint inhibitors (ICIs) and chemotherapy have become the standard first-line treatment for human epidermal growth factor receptor 2 (HER-2)-negative advanced gastric cancer. However, primary resistance remains a challenge, with no effective biomarkers available for its prediction. This retrospective study explores the relationship between the baseline inflammatory burden index (IBI) and primary resistance in such context. Materials and Methods: We analyzed 62 patients with HER-2-negative advanced gastric cancer who received ICIs and chemotherapy as their first-line treatment. The IBI was calculated as follows: C-reactive protein (mg/L) × neutrophil count (10 3 /mm 3 )/lymphocyte count (10 3 /mm 3 ). Based on disease progression within 6 months, patients were categorized into the primary resistant or the control group. We compared baseline characteristics and IBI scores between the groups and assessed the predictive value of the IBI using the receiver operating characteristic curve. Both univariate and multivariate binary logistic regression analyses were conducted to identify factors influencing primary resistance. Results: Nineteen patients were included in the primary resistance group, and forty-three patients were included in the control group. The IBI was significantly higher in the resistant group compared to the control group (P<0.01). The area under the curve for the IBI was 0.82, indicating a strong predictive value. Multivariate analysis identified the IBI as an independent predictor of primary resistance (P=0.014). Conclusions The baseline IBI holds promise as a predictor of primary resistance to combined ICIs and chemotherapy in patients with HER-2-negative advanced gastric cancer.

This article reports a child with cardioaciocutaneous syndrome (CFCS) caused by a rare microdeletion of chromosome 19p13.3, and a literature review is conducted. The child had unusual facies, short stature, delayed mental and motor development, macrocephaly, and cardiac abnormalities. Whole-exome sequencing identified a 1 040 kb heterozygous deletion in the 19p13.3 region of the child, which was rated as a "pathogenic variant". This is the first case of CFCS caused by a loss-of-function mutation reported in China, which enriches the genotype characteristics of CFCS. It is imperative to enhance the understanding of CFCS in children. Early identification based on its clinical manifestations should be pursued, and genetic testing should be performed to facilitate diagnosis.
Humans ; Chromosome Deletion ; Chromosomes, Human, Pair 19/genetics* ; Ectodermal Dysplasia/genetics* ; Facies ; Failure to Thrive/genetics* ; Heart Defects, Congenital/genetics*

OBJECTIVES: To study the effect of prophylactic phenytoin (PHT) or levetiracetam (LEV) on busulfan (BU) blood concentration in children undergoing hematopoietic stem cell transplantation. METHODS: Pediatric patients conditioned with BU plus cyclophosphamide and fludarabine at the First People's Hospital of Chenzhou from September 2023 to February 2025 were retrospectively included. Patients were grouped by prophylactic antiepileptic regimen into PHT (n=24) and LEV (n=26). BU blood concentrations at the end of infusion (0 hour) and at 1, 2, and 4 hours post-infusion were compared between groups. RESULTS: At 0 hour post-infusion, BU blood concentrations did not differ significantly between groups (P>0.05). At 1, 2, and 4 hours post-infusion, BU blood concentrations were higher in the LEV group than in the PHT group (P<0.05). The area under the concentration-time curve from 0 to ∞ (AUC_0-∞) was greater in the LEV group (P<0.001), and the attainment rate of AUC_0-∞ was higher in the LEV group than in the PHT group (73% vs 21%, P<0.001). No significant differences were observed between groups in time to hematopoietic engraftment or in the incidence of BU-related adverse drug reactions (P>0.05). CONCLUSIONS Compared with PHT, LEV prophylaxis is associated with higher BU blood concentration and a higher AUC_0-∞ attainment rate. There is no observed difference in BU efficacy or safety between PHT and LEV.
Humans ; Levetiracetam/therapeutic use* ; Busulfan/pharmacokinetics* ; Hematopoietic Stem Cell Transplantation ; Male ; Female ; Child ; Child, Preschool ; Phenytoin/pharmacology* ; Infant ; Retrospective Studies ; Anticonvulsants/pharmacology* ; Adolescent

OBJECTIVE: To retrospectively analyze the clinical characteristics, prognosis and prognostic factors of patients with light-chain (AL) amyloidosis, so as to provide reference for the diagnosis and treatment of AL amyloidosis. METHODS: Clinical data of 52 patients diagnosed with AL amyloidosis at two hospitals from January 2017 to November 2022 were collected. The clinical characteristics, differences in clinical indexes between the deceased group and the survival group were analyzed. Kaplan-Meier curves were used for overall survival (OS) analysis, and Cox regression models were used to analyze the factors affecting the prognosis. RESULTS: The median age of the 52 patients at diagnosis was 61(41-81) years old, and 63.5% of the patients were male. Heart (69.2%) and kidney (67.3%) were the most involved organs, and 67.3% of the patients had two or more organs involved. Most patients (71.2%) received chemotherapy regimens containing bortezomib, including 5 patients (9.6%) who received treatment with daratumumab in combination with bortezomib. The proportion of male patients (81.0%), the proportion of patients with cardiac involvement (95.2%), and the proportion of patients with Mayo 2012 stage ≥III (95.2%), as well as the levels of hs-cTnI and NT-proBNP in the deceased group were significantly higher than those in the survival group ( P < 0.05). The median OS time of the enrolled patients was 33.4(2.6-60.2) months, with 1-year, 2-year, 3-year and 5-year OS rates of 83.7%, 79.3%, 58.9% and 32.7%, respectively. The Kaplan-Meier survival curve analysis revealed that patients with male gender (P =0.040), NT-proBNP ≥3 600 ng/L ( P < 0.001), Mayo 2012 stage ≥III ( P < 0.001), and cardiac involvement (P =0.008) had poor prognosis and shorter overall survival (OS) time. The multivariate regression analysis showed that Mayo 2012 stage ≥III was an independent risk factor for prognosis. CONCLUSION In recent years, the survival rate of patients with AL amyloidosis has improved significantly, but the 5-year survival rate is still relatively low. Cardiac biomarkers (NT-proBNP and hs-cTnI) and Mayo 2012 stage at diagnosis continue to provide important prognostic information. Bortezomib-based regimens were used as the primary treatment in most patients, and the addition of daratumumab is becoming increasingly common.
Humans ; Retrospective Studies ; Prognosis ; Middle Aged ; Male ; Female ; Aged ; Immunoglobulin Light-chain Amyloidosis/diagnosis* ; Adult ; Aged, 80 and over ; Kaplan-Meier Estimate

BACKGROUND: Early control of low-density lipoprotein cholesterol (LDL-C) is crucial for reducing the progress of cardiovascular disease. However, its additional role to the risk of primary osteoporosis in men with coronary heart disease was inconclusive. Our study aims to determine the association of LDL-C and its trajectories for osteoporosis risk in the middle-aged and aged men of China. METHODS: The retrospective cohort study of 1546 men aged 69.74 ± 11.30 years conducted in Beijing, China from 2015 to 2022. And the incidence of primary osteoporosis was annually recorded. LDL-C trajectories were further identified by latent class growth model using repeated measurements of LDL-C. The association of baseline LDL-C for osteoporosis was estimated using hazard ratio (HR) with 95% CI in Cox proportional hazard model, while mean level and trajectories of LDL-C for osteoporosis were evaluated using odds ratio (OR) with 95% CI in logistic regression model. RESULTS: During the median 6.2-year follow-up period, 70 men developed primary osteoporosis. The higher level of baseline LDL-C (HR = 1.539, 95% CI: 1.012-2.342) and mean LDL-C (OR = 2.190, 95% CI: 1.443-3.324) were associated with higher risk of osteoporosis in men with coronary heart disease after adjusted for covariates. Compared with those in the LDL-C trajectory of low-stable decrease, participants with medium-fluctuant trajectory, whose longitudinal LDL-C started with a medium LDL-C level and appeared an increase and then decrease, were negatively associated with osteoporosis risk (OR = 2.451, 95% CI: 1.152-5.216). And participants with initially high LDL-C level and then a rapid decrease demonstrated a tendency towards reduced risk (OR = 0.718, 95% CI: 0.212-2.437). CONCLUSIONS Elevated LDL-C level and its long-term fluctuation may increase the risk of primary osteoporosis in men. Early controlling a stable level of LDL-C is also essential for bone health.