Management and treatment of terminal metastatic castration-resistant prostate cancer (mCRPC) remains heavily debated. We sought to investigate the efficacy of programmed cell death 1 (PD-1) inhibitor plus anlotinib as a potential solution for terminal mCRPC and further evaluate the association of genomic characteristics with efficacy outcomes. We conducted a retrospective real-world study of 25 mCRPC patients who received PD-1 inhibitor plus anlotinib after the progression to standard treatments. The clinical information was extracted from the electronic medical records and 22 patients had targeted circulating tumor DNA (ctDNA) next-generation sequencing. Statistical analysis showed that 6 (24.0%) patients experienced prostate-specific antigen (PSA) response and 11 (44.0%) patients experienced PSA reduction. The relationship between ctDNA findings and outcomes was also analyzed. DNA-damage repair (DDR) pathways and homologous recombination repair (HRR) pathway defects indicated a comparatively longer PSA-progression-free survival (PSA-PFS; 2.5 months vs 1.2 months, P = 0.027; 3.3 months vs 1.2 months, P = 0.017; respectively). This study introduces the PD-1 inhibitor plus anlotinib as a late-line therapeutic strategy for terminal mCRPC. PD-1 inhibitor plus anlotinib may be a new treatment choice for terminal mCRPC patients with DDR or HRR pathway defects and requires further investigation.
Male ; Humans ; Prostate-Specific Antigen ; Treatment Outcome ; Prostatic Neoplasms, Castration-Resistant/drug therapy* ; Immune Checkpoint Inhibitors/therapeutic use* ; Retrospective Studies

HMGB1's role in tumors is complex and diverse,and it exerts its biological function by combining with different receptors.One of the receptors is called RAGE,which is localized to the cell membrane and binds to HMGB1 released outside the cell.The HMGB1/RAGE axis promotes tumor development,moreover,tumor development and its drug resistance are closely related to inflammation.This article mainly reviews the molecular mechanism of HMGB1/RAGE axis in pro-inflammatory and protumor effects in pancreatic,colorectal and liver cancers.We also summarize the research progress of papaverine and its derivatives for the treatment of HMGB1/RAGE axis in tumor inflammation,with aims of providing new ideas for exploring the molecular mechanism of action in tumor inflammation,and providing a new theoretical basis for the research of HMGB1/RAGE axis therapeutics.

This study aims to identify the active components and the mechanism of Jingqi Yukui Capsules(JQYK) in the treatment of gastric ulcer based on network pharmacology, and verify some key targets and signaling pathways through animal experiment. To be specific, first, the active components and targets of JQYK were retrieved from a Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine(BATMAN-TCM) and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), and the targets of gastric ulcer from GeneCards and Online Mendelian Inheritance in Man(OMIM) with the search term "gastric ulcer". The common targets of the two were the potential targets of the prescription for the treatment of the di-sease. Then, protein-protein interaction(PPI) network of key targets were constructed based on STRING and Cytoscape 3.7.2, followed by Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment by matescape database and pathway visualization by Omicshare. For the animal experiment, the improved method of Okabe was used to induce gastric ulcer in rats, and the model rats were classified into the model group, JQYK high-dose(JQYK-H), medium-dose(JQYK-M), and low-dose(JQYK-L) groups, Anweiyang Capsules(WYA) group, and Rabeprazole Sodium Enteric Capsules(RBPZ) group. Normal rats were included in the blank group. Rats in the blank group and model group were given distilled water and those in the administration groups received corresponding drugs. Then gastric ulcer healing in rats was observed. The changes of the gastric histomorphology in rats were evaluated based on hematoxylin-eosin(HE) staining, and the content of inducible nitric oxide synthase(iNOS) in rat gastric tissue was detected with Coomassie brilliant blue method. The mRNA and protein levels of some proteins in rat gastric tissue were determined by real-time quantitative polymerase chain reaction(RT-qPCR) and Western blot(WB) to further validate some key targets and signaling pathways. A total of 206 active components and 535 targets of JQYK, 1 305 targets of gastric ulcer, and 166 common targets of the disease and the drug were yielded. According to PPI analysis and KEGG pathway enrichment analysis, multiple key targets, such as interleukin-6(IL-6), tumor necrosis factor(TNF), mitogen-activated protein kinase 1(MAPK1), MAPK3, and MAPK14, as well as nuclear factor kappa-B(NF-κB) signaling pathway, IL-17 signaling pathway, and leukocyte transendothelial migration in the top 20 key signaling pathways were closely related to inflammation. The key protein p38 MAPK and NF-κB signaling pathway were selected for further verification by animal experiment. The gastric ulcer in the JQYK-H group recovered nearly to the level in the blank group, with significant decrease in the content of iNOS in rat gastric tissue and significant reduction in the mRNA and phosphorylation levels of p38 MAPK and the mRNA and protein levels of NF-κB p65 in rat gastric tissue. The results indicated that JQYK can inhibit the phosphorylation of the key protein p38 MAPK and the expression of NF-κB p65 in the NF-κB signaling pathway, thereby exerting the anti-inflammatory effect and effectively improving the quality of gastric ulcer healing in rats. Thus, the animal experiment result verifies some predictions of network pharmacology.
Animal Experimentation ; Animals ; Capsules ; Gastric Mucosa/metabolism* ; Humans ; Network Pharmacology ; Rats ; Stomach Ulcer/genetics*

Objective: To analyze the clinical and genetic characteristics of 33 children with congenital lipoid adrenal hyperplasia (CLAH) caused by StAR gene defects. Methods: The clinical, biochemical, genetic, and follow-up (until December 2021) data of 33 children diagnosed with CLAH from 2006 to 2021 were retrospectively analyzed in Xinhua Hospital, Shanghai Jiao Tong University School of Medicine. Results: Of the 33 children with CLAH, 17 had a karyotype of 46, XX and 16 had a karyotype of 46, XY; 31 were female and 2 were male by social gender. Classic type and non-classic type were found in 30 and 3 children respectively. The age at diagnosis was 9.0 (3.0, 34.5) months. All the 30 cases with classic CLAH presented within the first year of life with skin hyperpigmentation (28 cases, 93%), vomiting and(or) diarrhea (19 cases, 63%), no increase in body weight (8 cases, 27%), elevated adrenocorticotropic hormone levels (21cases (70%)>275 pmol/L), decreased cortisol levels (47 (31,126) nmol/L), hyponatremia ((126±13) mmol/L), hyperkalemia ((5.7±1.1) mmol/L), and normal 17α-hydroxyprogesterone levels (30 cases, 100%). All these with classic CLAH exhibited female external genitalia. Three children with non-classic CLAH (including 2 cases of 46, XY and 1 case of 46, XX) also showed signs and symptoms of adrenal insufficiency, but 2 of them had an age of onset later than 1 year of age, including 1 case of 46, XY with male external genitalia and 1 case of 46, XX with female external genitalia. The other 46, XY patient with non-classic CLAH presented with adrenal insufficiency at 2 months of age, showing micropenis and hypospadias. In the 17 females with 46, XX, 4 older than 10 years of age showed spontaneous pubertal development. A total of 25 StAR gene pathogenic variants were identified in 33 patients, with p.Q258* (18/66, 27%), p.K236Tfs*47 (8/66, 12%) and p.Q77* (6/66, 9%) being the common variantion. Six novel variants were found, including c.358T>G, c.713_714del, c.125del, c.745-1G>A, c.179-2A>C, and exon 1 deletion. Conclusions: Patients with classic CLAH typically present with signs and symptoms of primary adrenal insufficiency in the early infancy period and female external genitalia. p.Q258*, p.K236Tfs*47 and p.Q77* are common variants in CLAH patients.
Adrenal Hyperplasia, Congenital/genetics* ; Adrenal Insufficiency ; Adrenocorticotropic Hormone ; Child, Preschool ; China ; Disorder of Sex Development, 46,XY ; Female ; Humans ; Hydrocortisone ; Hydroxyprogesterones ; Hyperplasia ; Infant ; Male ; Mutation ; Phosphoproteins/genetics* ; Retrospective Studies

Objective: To investigate the clinical features of children with chronic nonbacterial osteomyelitis (CNO), and raise awareness among clinicians. Methods: In this retrospective study, 18 patients with CNO who were diagnosed in Children's Hospital of Fudan University from January 2015 to December 2021 were included. Results: Eighteen children with CNO (12 males, 6 females) were identified. Their age at onset was 9 (5, 11) years, the delay in diagnosis was 2 (1, 6) months, and follow-up-was 17 (8, 34) months. The most common symptoms were fever in 14 children, as well as bone pain and (or) arthralgia in 14 children. In terms of laboratory results, normal white blood cell counts were observed at onset in 17 patients; increased erythrocyte sedimentation rate (ESR) in all patients; increased C reactive protein (CRP) over the normal value in 14 patients. Of the 18 patients, 2 had positive antinuclear antibodies, while none had positive human leukocyte antigen-B27 or rheumatoid factor. Imaging examination revealed that all the patients had symmetrical and multifocal skeletal lesions. The number of structural lesions detected by imaging investigation was 8 (6, 11). The most frequently affected bones were tibia in 18 patients and femur in 17 patients. Bone biopsy was conducted in 14 patients and acute or chronic osteomyelitis manifested with inflammatory cells infiltration were detected. Magnetic resonance imaging (MRI) found bone lesions in all the patients and bone scintigraphy were positive in 13 patients. All the patients were treated with nonsteroidal anti-inflammatory drugs, among whom 10 cases also treated with oral glucocorticoids, 9 cases with traditional disease modifying anti-rheumatic drugs, 8 cases with bisphosphonates and 6 cases with tumor necrosis factor inhibitors. The pediatric chronic nonbacterial osteomyelitis disease activity score, increased by 70% or more in 13 patients within the initial 6-month follow-up. Conclusions: The clinical manifestations of CNO are lack of specificity. The first symptom of CNO is fever, with or without bone pain and (or) arthralgia, with normal peripheral blood leukocytes, elevated CRP and (or) ESR. Whole body bone scanning combined with MRI can early detect osteomyelitis at subclinical sites, and improve the diagnostic rate of CNO.
Female ; Male ; Humans ; Child ; Retrospective Studies ; Osteomyelitis/drug therapy* ; Arthralgia ; Diphosphonates ; Fever ; Graft vs Host Disease

Objective To compare laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy for the treatment of obese patients with type 2 diabetes mellitus.Methods A retrospective analysis of T2DM patients with LRYGB (28 cases) and LSG (35 cases) was enrolled from Jan 2010 to Jun 2013.Results The indicator such as BMI,fasting glucose,fasting insulin,HbA1c,and insulin resistance were significantly lower in 1 year,3 years and 5 years after operation [LRYGB group:(37.3 ±3.7) kg/m2 to (32.3 ± 3.4) kg/m2 to (28.8 ± 3.0) kg/m2 to (25.5 ± 2.8) kg/m2,t =13.670,15.499,21.710,P=0.000,0.000,0.000;(8.2 ± 1.8) mmol/L to (6.0 ± 1.3) mmol/L to (5.2 ±0.9) mmol/L to (4.7±0.5) mmol/L,t =6.664,8.723,10.282,P=0.000,0.000,0.000;(32.2±17.0) μ IU/ml to (16.1 ± 12.1) μIU/ml to (8.6 ±5.2) μ IU/ml to (5.2 ±2.8) μIU/ml,t =7.453,8.218,8.687,P =0.000,0.000,0.000;(7.4％ ±0.6％) to (6.2％ ±0.7％) to (5.7％ ±0.7％) to (5.1％ ±0.6％),t =11.362,18.771,21.186,P=0.000,0.000,0.000;(12.0±7.3) to (4.6±4.3) to (2.1 ±1.7) to (1.1 ±0.7),t =6.455,7.667,8.050,P=0.000,0.000,0.000;LSG group:(39.2±5.2) kg/m2 to (34.1 ±4.5) kg/m2to (29.3±4.0) kg/m2to (25.1 ±2.3) kg/m2,t=11.676,13.680,19.161,P=0.000,0.000,0.000;(8.0±2.9) mmol/L to (5.8±1.5) mmol/L to (5.1 ±0.9) mmol/L to (4.6 ±0.5) mmoL/L,t=5.467,6.921,7.741,P=0.000,0.000,0.000;(29.1 ±25.2) μIU/ml to (16.4±10.6) μ IU/ml to (8.8±5.5) μ IU/ml to (5.5 ±2.0) μIU/ml,t =3.512,5.232,5.702,P=0.001,0.000,0.000;(7.7％ ±1.3％) to (6.3％ ±0.6％) to (5.8％ ±0.6％) to (5.2％ ±0.6％),t=8.001,10.106,11.922,P =0.000,0.000,0.000;(9.8 ±9.6) to (3.9 ±2.2) to (1.9 ±1.0) to (1.1 ± 0.4),t =3.733,4.972,5.404,P =0.001,0.000,0.000].There was no significant difference between the two groups in 1 year,3 year and 5 year post-operation (DM remission:71％ to 69％,89％ to 80％,93％ to 89％) (P ＞ 0.05).Conclusion LRYGB and LSG have the same long-term efficacy for T2DM patients.

Two clinical ablation protocols,2C3L and stepwise,have been routinely used in our group to treat atrial fibrillation (AF),but with a less than 60％ long-term arrhythmia-free outcome achieved in patients.The goal of this study was to examine the underlying mechanism of low success in clinical outcome.MRI images from one patient were used to reconstruct a human atrial anatomical model,and fibrotic tissue was manually added to represent the arrhythmia substrate.AF was induced with standard protocols used in clinical practice.2C3L and stepwise were then used to test the efficacy of arrhythmia termination in our model.The results showed that re-entries induced in our model could not be terminated by using either 2C3L or the stepwise protocol.Although some of the induced re-entries were terminated,others emerged in new areas.Ablation using only the 2C3L or stepwise method was not sufficient to terminate all re-entries in our model,which may partially explain the poor long-term arrhythmiafree outcomes in clinical practice.Our findings also suggest that computational heart modelling is an important tool to assist in the establishment of optimal ablation strategies.

To observe the effect of processed Polygonum multiflorum on mRNA expression levels of five subtypes of CYP450 enzymes in rat liver. SD rats were randomly divided into the normal control group, processed P. multiflorum high dose and low dose groups (5.40 g•kg⁻¹ and 1.08 g•kg⁻¹). The rats in administration groups were continuously given with processed P. mutiflorum for 7 days by ig administration, and the rats in normal control group were given with the same volume of distilled water. After successive administration of 7 days, the serum biochemical indications were detected, and Real-time quantitative PCR technology was used to detect the mRNA expression levels of five subtypes of CYP450 enzymes in rat liver. Experimental results showed that AST was decreased significantly in both low and high dose groups. ALT was significantly decreased in low dose group and significantly increased in high dose group. The mRNA expression levels of five subtypes of CYP450 enzymes in rat liver were decreased in high dose and low dose groups in a dose-dependent manner. Especially the high dose processed P. multiflorum could significantly inhibit CYP1A2 and CYP2E1 mRNA expression levels in rats. The study showed that high dose P. multiflorum water extract had hepatotoxicity, and the degree of liver damage was increased with the increase of dose. It shall be noted that 5.40 g•kg⁻¹ water extract of P. multiflorum could significantly inhibit CYP1A2 and CYP2E1 mRNA expression levels in the liver of rats.

Objective To investigate the effect of FTO gene on laparoscopic Roux-en-Y gastric bypass for type 2 diabetes.Methods From Jan 2014 to 2015 Jun,32 T2DM patients received LRYGB in Beijing Shijitan Hospital.According to single nucleotide polymorphism of FTO rs9939609 gene,patients were divided into TF genotype (20 cases),and AT/AA genotype (12 cases).Results Following the degression of BMI from (36.4 ±3.3) kg/m2 to (28.1 ±2.8) kg/m2,fasting blood glucose and HbA1c in group A significantly improved [(8.9 ± 1.6) mmol/L vs.(5.6 ± 1.2) mmol/L,t =8.274,P =0.000;(8.5％ ± 1.9％) vs.(6.2％ ± 0.8％),t =5.032,P =0.000].Following the degression of BMI from (39.5 ±5.6) kg/m2 to (29.7 ± 5.1) kg/m2,fasting blood glucose and HbA1c in group B significantly improved [(10.8 ± 2.8) mmol/L vs.(4.9 ± 0.6) mmol/L,t =7.589,P =0.000;(9.0％ ± 1.8％) vs.(6.1％ ±0.9％),t =5.324,P =0.000].Insulin resistance index in both groups significantly improved [(12.6±10.7) vs.(4.9±5.6),t=5.402,P=0.000;(16.0±5.6) vs.(1.7±1.3),t=9.025,P=0.000].Fasting blood glucose and the insulin resistance index in group B patients was significantly lower than that in group A patients (P ＜ 0.05).Conclusion T2DM patients with FTO rs9939609 gene phenotype AT/AA have better prognosis than those with TT in postoperative diabetes improvement.

OBJECTIVETo report on 5 patients with maternal 3-methylcrotonyl coenzyme A carboxylase deficiency (MCCD) and to confirm the clinical diagnosis through mutation analysis.

METHODSFive neonates with higher blood 3-hydroxy isovalerylcarnitine (C5-OH) concentration detected upon newborn screening with tandem mass spectrometry and their mothers were recruited. Urinary organic acids were analyzed with gas chromatography mass spectrometry. Gene mutation and protein function analysis were performed by PCR direct sequencing and PolyPhen-2 software.

RESULTSHigher blood C5-OH concentrations (5.11-21.77 μmol/L) and abnormal 3-hydroxy isovalerate and 3-methylcrotonyl glycine in urine were detected in the five asymptomatic mothers, who were diagnosed as benign MCCD. Higher C5-OH concentration was also detected in their neonates by tandem mass spectrometry, which had gradually decreased to normal levels in three neonates. Four new variations, i.e., c.ins1680A(25%), c.203C > T (p.A68V), c.572T > C (p.L191P) and c.639+5G > T were detected in the MCCC1 gene, in addition with 2 mutations [c.1406G > T (p.R469L, novel variation) and c.592C > T (p.Q198X)]. The novel variations were predicted to have affected protein structure and function.

CONCLUSIONFor neonates with higher C5-OH concentration detected upon neonatal screening, their mothers should be also tested to rule out MCCD. Mutations in MCCC1 gene are quite common.

Adult ; Amino Acid Sequence ; Base Sequence ; Carbon-Carbon Ligases ; blood ; deficiency ; genetics ; Carnitine ; analogs & derivatives ; blood ; DNA Mutational Analysis ; Female ; Genomic Imprinting ; Humans ; Infant, Newborn ; Male ; Molecular Sequence Data ; Mutation ; Neonatal Screening ; Sex Factors ; Tandem Mass Spectrometry ; Urea Cycle Disorders, Inborn ; blood ; diagnosis ; enzymology ; genetics