BACKGROUND: Oral squamous cell carcinoma (OSCC) is a prevalent type of cancer with a high mortality rate in its late stages. One of the major challenges in OSCC treatment is the resistance to epidermal growth factor receptor (EGFR) inhibitors. Therefore, it is imperative to elucidate the mechanism underlying drug resistance and develop appropriate precision therapy strategies to enhance clinical efficacy. METHODS: To evaluate the efficacy of the combination of the Ca 2+ /calmodulin-dependent protein kinase II (CAMK2) inhibitor KN93 and EGFR inhibitors, we performed in vitro and in vivo experiments using two FAT atypical cadherin 1 ( FAT1 )-deficient (SCC9 and SCC25) and two FAT1 wild-type (SCC47 and HN12) OSCC cell lines. We assessed the effects of EGFR inhibitors (afatinib or cetuximab), KN93, or their combination on the malignant phenotype of OSCC in vivo and in vitro . The alterations in protein expression levels of members of the EGFR signaling pathway and SRY-box transcription factor 2 (SOX2) were analyzed. Changes in the yes-associated protein 1 (YAP1) protein were characterized. Moreover, we analyzed mitochondrial dysfunction. Besides, the effects of combination therapy on mitochondrial dynamics were also evaluated. RESULTS: OSCC with FAT1 mutations exhibited resistance to EGFR inhibitors treatment. The combination of KN93 and EGFR inhibitors significantly inhibited the proliferation, survival, and migration of FAT1 -mutated OSCC cells and suppressed tumor growth in vivo . Mechanistically, combination therapy enhanced the therapeutic sensitivity of FAT1 -mutated OSCC cells to EGFR inhibitors by modulating the EGFR pathway and downregulated tumor stemness-related proteins. Furthermore, combination therapy induced reactive oxygen species (ROS)-mediated mitochondrial dysfunction and disrupted mitochondrial dynamics, ultimately resulting in tumor suppression. CONCLUSION Combination therapy with EGFR inhibitors and KN93 could be a novel precision therapeutic strategy and a potential clinical solution for EGFR-resistant OSCC patients with FAT1 mutations.
Humans ; ErbB Receptors/metabolism* ; Mouth Neoplasms/metabolism* ; Cell Line, Tumor ; Animals ; Drug Resistance, Neoplasm/genetics* ; Cadherins/metabolism* ; Carcinoma, Squamous Cell/metabolism* ; Mice ; Mutation/genetics* ; Mice, Nude ; Protein Kinase Inhibitors/therapeutic use* ; Cetuximab/pharmacology* ; Afatinib/therapeutic use* ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects*

OBJECTIVES: To investigate the molecular epidemiology of children with phenylketonuria (PKU) in Gansu, China, providing foundational data for intervention strategies. METHODS: A retrospective analysis was conducted on 1 159 PKU families who attended Gansu Provincial Maternity and Child Care Hospital from January 2012 to December 2024. Sanger sequencing, multiplex ligation-dependent probe amplification, whole exome sequencing, and deep intronic variant analysis were used to analyze the PAH gene. RESULTS: For the 1 159 children with PKU, 2 295 variants were identified in 2 318 alleles, resulting in a detection rate of 99.01%. The detection rates were 100% (914/914) in 457 classic PKU families, 99.45% (907/912) in 456 mild PKU families, and 96.34% (474/492) in 246 mild hyperphenylalaninemia families. The 2 295 variants detected comprised 208 distinct mutation types, among which c.728G>A (14.95%, 343/2 295) had the highest frequency, followed by c.611A>G (4.88%, 112/2 295) and c.721C>T (4.79%, 110/2 295). The cumulative frequency of the top 23 hotspot variants reached 70.28% (1 613/2 295), and most variant alleles were detected in exon 7 (29.19%, 670/2 295). CONCLUSIONS Deep intronic variant analysis of the PAH gene can improve the genetic diagnostic rate of PKU. The development of targeted detection kits for PAH hotspot variants may enable precision screening programs and enhance preventive strategies for PKU.
Humans ; Phenylketonurias/epidemiology* ; Female ; Male ; Retrospective Studies ; Phenylalanine Hydroxylase/genetics* ; Mutation ; Child, Preschool ; China/epidemiology* ; Child ; Infant

Objective To design an assisted patient conveying and vibration damping system to solve the problems of operator fatigue and patient bump during casualty evacuation.Methods The assisted patient conveying and vibration damping system was composed of several conveying straps and a vibration damping mechanism.The conveying straps were made up of a waist strap,two shoulder straps,a chest strap,adhesive straps and joint components,and the joint components included adjusting buckles,big buckles,small buckles,connecting buckles and hook mechanisms;the vibration damping mechanism adopted the technical form of extension handle combined with vibration absorber,in which the extension handle was made of rigid material and the vibration absorber was equipped with a scissor guiding mechanism.Tests were carried out on the system to record the operating time of the operators and to analyze the system's vibration damping characteristics.Results The system developed extended the operating time of the stretcher conveyers while reduced the vibration during casualty transport,with a maximum vibration reduction of 71.73％.Conclusion The system developed gains advantages in low vibration and low workload,and can be used for casualty conveying in poor road conditions.[Chinese Medical Equipment Journal,2024,45(1):15-24]

Vascular cognitive impairment (VCI) encompasses a wide spectrum of cognitive disorders, ranging from mild cognitive impairment to vascular dementia. Its diagnosis relies on thorough clinical evaluations and neuroimaging. VCI predominately arises from vascular risk factors (VRFs) and cerebrovascular disease, either independently or in conjunction with neurodegeneration. Growing evidence underscores the prevalence of VRFs, highlighting their potential for early prediction of cognitive impairment and dementia in later life. The precise mechanisms linking vascular pathologies to cognitive deficits remain elusive. Chronic cerebrovascular pathology is the most common neuropathological feature of VCI, often interacting synergistically with neurodegenerative processes. Current research efforts are focused on developing and validating reliable biomarkers to unravel the etiology of vascular brain changes in VCI. The collaborative integration of these biomarkers into clinical practice, alongside routine incorporation into neuropathological assessments, presents a promising strategy for predicting and stratifying VCI. The cornerstone of VCI prevention remains the control of VRFs, which includes multi-domain lifestyle modifications. Identifying appropriate pharmacological approaches is also of paramount importance. In this review, we synthesize recent advancements in the field of VCI, including its definition, determinants of vascular risk, pathophysiology, neuroimaging and fluid-correlated biomarkers, predictive methodologies, and current intervention strategies. Increasingly evident is the notion that more rigorous research for VCI, which arises from a complex interplay of physiological events, is still needed to pave the way for better clinical outcomes and enhanced quality of life for affected individuals.
Humans ; Cognitive Dysfunction/diagnosis* ; Dementia, Vascular/therapy* ; Risk Factors ; Biomarkers ; Cerebrovascular Disorders/diagnosis*

Eleven monoterpenes including seven new chemical structures or new natural products covering two pairs of scalemic enantiomers, together with four known analogues, were isolated from an aqueous extract of the Angelica sinensis root head (Guitou) by separation techniques of column chromatography over macroporous adsorbent resin, MCI resin, silica gel, Sephadex LH-20, and Toyopearl HW-40C, together with preparative thin-layer chromatography as well as reversed phase and chiral HPLC. Their structures were determined by spectroscopic data analysis, combined with theoretic calculation of electronic circular dichroism (ECD) spectra and single crystal X-ray diffraction. The new structures or new natural products named (+)-/(-)-angelinones A and B [(+)-/(-)-1 and (+)-/(-)-2], angelinones C and D (3 and 4), and angelinol A (5), respectively, while the known analogues were 6β,9-dihydroxy-(+)-α-pinene (6), 1,1,5-trimethyl-2-hydroxymethyl-cyclohexa-2,5-dien-4-one (7), jasminol E (8), and (+)-trans-sobrerol (9). All the isolates were reported in this plant for the first time, except for the previously reported 6 from an ethanol extract of the aerial parts of A. sinensis, of which the structure was confirmed by X-ray crystallography in this study.

Ten dimeric phthalide racemates (1-10) were isolated from an aqueous extract of the Angelica sinensis root head (Guitou) by separation techniques of column chromatography over macroporous adsorbent resin, MCI resin, silica gel, and Sephadex LH-20, together with preparative thin-layer chromatography and reversed phase HPLC. The racemates were further separated into (+)-/(-)-1-(+)-/(-)-10 with chiral HPLC. Their structures including absolute configurations were elucidated by comprehensive analysis of spectroscopic data, combined with electronic circular dichroism (ECD) and NMR calculations as well as single crystal X-ray diffractions. Compounds (+)-/(-)-1-(+)-/(-)-10 are either new structure or new natural product, named (+)-/(-)-angelidipthalidic acids A-H [(+)-/(-)-1-(+)-/(-)-8] and (+)-/(-)-angelidipthalidols A and B [(+)-/(-)-9 and (+)-/(-)-10], respectively. Meanwhile, dimeric phthalide mono- and bis-lactone derivatives with 3.3′a,8.6′- and 3.6′,8.3′a-coupling patterns as well as determination of their relative configurations are discussed.

Objectives: To investigated the safety and efficacy of treating patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) and elevated levels of N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) with levosimendan within 24 hours of first medical contact (FMC). Methods: This multicenter, open-label, block-randomized controlled trial (NCT03189901) investigated the safety and efficacy of levosimendan as an early management strategy of acute heart failure (EMS-AHF) for patients with NSTEMI and high NT-proBNP levels. This study included 255 patients with NSTEMI and elevated NT-proBNP levels, including 142 males and 113 females with a median age of 65 (58-70) years, and were admitted in the emergency or outpatient departments at 14 medical centers in China between October 2017 and October 2021. The patients were randomly divided into a levosimendan group (n=129) and a control group (n=126). The primary outcome measure was NT-proBNP levels on day 3 of treatment and changes in the NT-proBNP levels from baseline on day 5 after randomization. The secondary outcome measures included the proportion of patients with more than 30% reduction in NT-proBNP levels from baseline, major adverse cardiovascular events (MACE) during hospitalization and at 6 months after hospitalization, safety during the treatment, and health economics indices. The measurement data parameters between groups were compared using the t-test or the non-parametric test. The count data parameters were compared between groups using the χ² test. Results: On day 3, the NT-proBNP levels in the levosimendan group were lower than the control group but were statistically insignificant [866 (455, 1 960) vs. 1 118 (459, 2 417) ng/L, Z=-1.25,P=0.21]. However, on day 5, changes in the NT-proBNP levels from baseline in the levosimendan group were significantly higher than the control group [67.6% (33.8%,82.5%)vs.54.8% (7.3%,77.9%), Z=-2.14, P=0.03]. There were no significant differences in the proportion of patients with more than 30% reduction in the NT-proBNP levels on day 5 between the levosimendan and the control groups [77.5% (100/129) vs. 69.0% (87/126), χ²=2.34, P=0.13]. Furthermore, incidences of MACE did not show any significant differences between the two groups during hospitalization [4.7% (6/129) vs. 7.1% (9/126), χ²=0.72, P=0.40] and at 6 months [14.7% (19/129) vs. 12.7% (16/126), χ²=0.22, P=0.64]. Four cardiac deaths were reported in the control group during hospitalization [0 (0/129) vs. 3.2% (4/126), P=0.06]. However, 6-month survival rates were comparable between the two groups (log-rank test, P=0.18). Moreover, adverse events or serious adverse events such as shock, ventricular fibrillation, and ventricular tachycardia were not reported in both the groups during levosimendan treatment (days 0-1). The total cost of hospitalization [34 591.00(15 527.46,59 324.80) vs. 37 144.65(16 066.90,63 919.00)yuan, Z=-0.26, P=0.80] and the total length of hospitalization [9 (8, 12) vs. 10 (7, 13) days, Z=0.72, P=0.72] were lower for patients in the levosimendan group compared to those in the control group, but did not show statistically significant differences. Conclusions: Early administration of levosimendan reduced NT-proBNP levels in NSTEMI patients with elevated NT-proBNP and did not increase the total cost and length of hospitalization, but did not significantly improve MACE during hospitalization or at 6 months.
Male ; Female ; Humans ; Aged ; Natriuretic Peptide, Brain ; Simendan/therapeutic use* ; Non-ST Elevated Myocardial Infarction ; Heart Failure/drug therapy* ; Peptide Fragments ; Arrhythmias, Cardiac ; Biomarkers ; Prognosis

It is difficult to insert long-term dialysis catheters after severe stenosis or occlusion of the internal jugular vein and innominate vein. We used REcanalisation and balloon-oriented puncture for Re-insertion of dialysis catheter in nonpatent central veins (REBORN) in seven patients with severe central venous lesions, and all patients were inserted with long-term dialysis catheters successfully. None had severe complications such as pneumothorax, hemothorax, or pulmonary embolism during operation. All catheters functioned well after postoperative follow-up of 2 months. REBORN provides a novel approach to establish difficult dialysis pathways.
Humans ; Catheterization, Central Venous/adverse effects* ; Catheters, Indwelling ; Renal Dialysis ; Jugular Veins ; Punctures

Objective: The relationship between serum uric acid (SUA) levels and glycemic indices, including plasma glucose (FPG), 2-hour postload glucose (2h-PG), and glycated hemoglobin (HbA1c), remains inconclusive. We aimed to explore the associations between glycemic indices and SUA levels in the general Chinese population. Methods: The current study was a cross-sectional analysis using the first follow-up survey data from The China Cardiometabolic Disease and Cancer Cohort Study. A total of 105,922 community-dwelling adults aged ≥ 40 years underwent the oral glucose tolerance test and uric acid assessment. The nonlinear relationships between glycemic indices and SUA levels were explored using generalized additive models. Results: A total of 30,941 men and 62,361 women were eligible for the current analysis. Generalized additive models verified the inverted U-shaped association between glycemic indices and SUA levels, but with different inflection points in men and women. The thresholds for FPG, 2h-PG, and HbA1c for men and women were 6.5/8.0 mmol/L, 11.0/14.0 mmol/L, and 6.1/6.5, respectively (SUA levels increased with increasing glycemic indices before the inflection points and then eventually decreased with further increases in the glycemic indices). Conclusion An inverted U-shaped association was observed between major glycemic indices and uric acid levels in both sexes, while the inflection points were reached earlier in men than in women.
Aged ; Asian Continental Ancestry Group ; Blood Glucose/analysis* ; China/epidemiology* ; Cohort Studies ; Diabetes Mellitus/blood* ; Female ; Glucose Tolerance Test ; Glycated Hemoglobin A/analysis* ; Glycemic Index ; Humans ; Male ; Middle Aged ; Uric Acid/blood*

A 56-year-old female was admitted to Department of Gastroenterology at Peking Union Medical College Hospital with diarrhea for seven months, and abnormal liver function for six months. She had a history of type 1 diabetes. The main clinical manifestations were recurrent fatty diarrhea and abnormal liver function, accompanied by abdominal and retroperitoneal lymphadenopathy, elevated CA19-9 and CEA. Progressive impairment of hepatic synthetic function and shrinkage of liver developed in a short period of time. The pathology of liver biopsy suggested that nodular regeneration of hepatocytes was followed by hyperplasia of thin bile ducts after submassive necrosis. Intestinal mucosa biopsies were performed twice. The pathology showed that the intestinal villi were completely blunt, accompanied with crypt hyperplasia. Goblet cells disappeared with reduced mucin. Paneth cells were barely seen without intraepithelial infiltration of lymphocytes. Rifaximin was not effective, while glucocorticoids improved clinical situation. The diagnosis of autoimmune enteropathy was finally confirmed by multidisciplinary team including departments of gastroenterology, pathology, endocrinology, hematology, infectious diseases, and rheumatology. With the administration of glucocorticoid and sirolimus, diarrhea relieved and liver function returned to normal.