[Pedigree Analysis and Molecular Mechanism Study of Hereditary Glanzmann Thrombasthenia Caused by Compound Heterozygous Mutation of the ITGA2B Gene].

Objective: The phenotype and genotype of a pedigree with Glanzmann thrombasthenia caused by compound heterozygous mutation in the ITGA2B gene and its molecular pathogenesis were explored. Methods: The platelet aggregation rate of the proband and his family was detected by using a platelet aggregation test with adenosine diphosphate, collagen, epinephrine, arachidonic acid, and ristocetin. The expression levels of CD41 (αⅡb), CD61 (ß3), and CD42b (GPⅠb) on the platelet surface was detected by flow cytometry. Gene sequencing technology was used for the genetic identification of the family. RT-PCR was used in the detection of mRNA splicing, and qRT-PCR was used in detecting the relative mRNA level of the ITGA2B gene. Bioinformatics analysis was used to evaluate the pathogenicity of mutation sites and their effects on protein structure and function. The expressions of total αⅡb and ß3 in platelets were analyzed by Western blot. Results: Except ristocetin, the other four inducers could not induce platelet aggregation in the proband. Flow cytometry showed that the expression levels of αⅡb and ß3 were only 0.25% and 9.76%, respectively, on the platelet surface of the proband, whereas GPⅠb expression was relatively normal. The expression levels of glycoproteins in the other family members were almost normal. c.480C>G and c.2929C>T mutations were detected in the proband through gene sequencing. The c.480C>G mutation was inherited from his mother, and the c.2929C>T mutation was inherited from his father. The RT-PCR and sequencing results showed that the c.480C>G mutation caused mRNA splicing in the proband and his mother, resulting in the deletion of 99 bases in c.476G-574A (p.S160-S192). qRT-PCR showed that the c.2929C>T variant reduced the mRNA level of the ITGA2B gene in the proband and his father. Bioinformatics analysis suggested that the c.480C>G mutation might form a binding sequence with hnRNP A1 protein and generate the 5'SS splice site. The three-dimensional structural model of the αⅡb subunit showed that the ß-propeller domain of the p.S160-S192 deletion lost two ß-strands and one α-helix in blade 2. The c.2929C>T nonsense mutation caused premature translation termination and produced a truncated protein with the deletion of p.R977-E1039, including the cytoplasmic domain, transmembrane domain, and a ß chain of the extracellular Calf-2 domain. The total αⅡb expression of the proband was absent, and the relative expression of ß3 was 11.36% of the normal level. Conclusion: The compound heterozygous mutation c.480C>G in exon 4 and c.2929C>T in exon 28 of the ITGA2B gene probably underlies Glanzmann thrombasthenia in this pedigree.

[Experimental study on the artificial infection of common freshwater snails with Angiostrongylus cantonensis in Dali Bai Autonomous Prefecture, Yunnan Province].

OBJECTIVE: To evaluate the potential risk of transmission of angiostrongyliasis by common freshwater snails in Dali Bai Autonomous Prefecture, Yunnan Province, so as to provide insights into local surveillance of angiostrongyliasis. METHODS: Common freshwater snails were collected from Dali Bai Autonomous Prefecture, Yunnan Province from March to April, 2020, and identified and bred in laboratory. SD rats were infected with third-stage larvae of Angiostrongylus cantonensis that were isolated from commercially available Pomacea canaliculata snails in Dali Bai Autonomous Prefecture, and freshwater snails were infected with the first-stage larvae of A. cantonensis that were isolated from the feces of SD rats 39 days post-infection at room temperature. The developmental process and morphological characteristics of worms in hosts were observed, and the percentages of A. cantonensis infections in different species of freshwater snails were calculated. Then, SD rats were infected with the third-stage larvae of A. cantonensis that were isolated from A. cantonensis-infected freshwater snails, and the larval development and reproduction was observed. RESULTS: More than 3 000 freshwater snail samples were collected from farmlands, ditches and wetlands around Erhai Lake in Dali Bai Autonomous Prefecture, and Cipangopaludina chinensis, P. canaliculata, Parafossarulus striatulus, Oncomelania hupensis robertsoni, Galba pervia, Physa acuta, Radix swinhoei, Assiminea spp., Tricula spp. and Bellamya spp. were morphologically identified. A total of 105 commercially available P. canaliculata snails were tested for A. cantonensis infections, and 2 P. canaliculata snails were found to be infected with A. cantonensis, in which the third-stage larvae of A. cantonensis were isolated. Ten species of freshwater snails were artificially infected with the third-stage larvae of A. cantonensis, and all 10 species of freshwater snails were found to be infected with A. cantonensis, with the highest positive rate of A. cantonensis infections in Bellamya spp. (62.3%, 137/204), and the lowest in C. chinensis (35.5%, 11/31). After SD rats were infected with the third-stage larvae of A. cantonensis isolated from different species of freshwater snails, mature adult worms of A. cantonensis were yielded. CONCLUSIONS: Multiple species of freshwater snails may serve as intermediate hosts of A. cantonensis under laboratory conditions in Dali Bai Autonomous Prefecture of Yunnan Province. Further investigations on natural infection of A. cantonensis in wild snails in Dali Bai Autonomous Prefecture seem justified.

[Study of the methotrexate loaded extracellular vesicles in the treatment of experimental periodontitis in mice].

Objective: To investigate the therapeutic effect of methotrexate loaded vesicles on experimental periodontitis in mice. Methods: Extracellular vesicles (EVs) were isolated from human umbilical cord mesenchymal stem cells (hUC-MSC). Methotrexate loaded vesicles (MTX-EVs) were constructed, whose morphology and size were analyzed by using scanning electron microscopy and particle size analyzer. Western blotting was used to identify their surface specific proteins. C57BL/6J male mice of 4-5 weeks (provided by Experimental Animal Center of The Fourth Military Medical University) were selected, among which 8 were randomly selected by blind grasp method without treatment and fed normally as normal group, and others were induced to periodontitis models by local injection of lipopolysaccharide (LPS) into the periodontium. The LPS was injected once every day with a concentration of 2 g/L and a volume of 5 µl, lasting for two weeks. The mice with successfully induced periodontitis were randomly divided into 4 groups by blind grasping method, with 8 mice in each group. The LPS group was with no treatment, and the other three groups were treated with periodontal local injection of MTX, EVs or MTX-EVs, respectively. Two weeks later, enzyme-linked immunosorbent assay (ELISA) was used to detect the expressions of inflammatory cytokine interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α (TNF-α) in gingival tissue. The amount of alveolar bone resorption of four groups was detected by using micro-CT scanning and HE staining. The expression proportion of the inflammatory factor in gingival tissue was analyzed by using flow cytometry. Results: The scanning electron microscopy results showed that EVs and MTX-EVs were circular or elliptical in shape. Dynamic light scattering (DLS) particle size analysis showed that the particle size of EVs was around 200 nm, while that of MTX-EVs was around 300 nm. The ELISA results showed IL-1ß levels in the normal group, LPS group, LPS+MTX group, LPS+EVs group and LPS+MTX-EVs group were (28.86±2.76), (51.50±2.04), (35.26±2.40), (45.49±2.04) and (35.77±3.49) ng/L. That is, the IL-1ß concentrations in the LPS+MTX group, LPS+EVs group and LPS+MTX-EVs group were significantly lower than that in the LPS group (P<0.05); the mass concentration of IL-1ß in the LPS +MTX-EVs group was significantly lower than that in the LPS+EVs group (P<0.05). The concentrations of IL-6 in the normal group, LPS group, LPS+MTX group, LPS+EVs group and LPS+MTX-EVs group were (125.44±4.12), (221.64±10.59), (178.16±16.90), (181.09±18.22) and (170.15±9.04) ng/L, among which the concentration of IL-6 in the last three groups were significantly lower than that in the LPS group (P<0.05). The mass concentration of IL-6 in the LPS+MTX-EVs group was significantly lower than those in the LPS+MTX group and LPS+EVs group (P<0.05). The concentrations of TNF-α in the normal group, LPS group, LPS+MTX group, LPS+EVs group and LPS+MTX-EVs group were (320.27±38.68), (479.62±40.94), (342.18±25.89), (415.88±12.01) and (325.75±30.83) ng/L, among which the concentrations of last three groups were significantly lower than the LPS group (P<0.05); the mass concentration of TNF-α in the LPS+MTX-EVs group was significantly lower than those in the LPS+EVs group and LPS+MTX group (P<0.05). The micro-CT results showed that the distance of cement-enamel junction-alveolar bone crest (CEJ-ABC) of the first molar and root (M1R1) in the normal group, LPS group, LPS+MTX group, LPS+EVs group and LPS+MTX-EVs group of mice were (0.11±0.03), (0.28±0.02), (0.23±0.03), (0.20±0.04), and (0.18±0.03) mm, respectively. Compared with the LPS group, the CEJ-ABC of the M1R1 in the LPS+MTX group, LPS+EVs group and LPS+MTX-EVs group were inhibited to varied degrees with statistically significant differences (P<0.05). Among them, LPS+MTX-EVs group had the best bone resorption inhibitioin effect compared to LPS+MTX group and LPS+EVs group, and the differences were statistically significant (P<0.05). The flow cytometry results indicated that the proportion of interferon-γ (IFN-γ) positive cells was (11.77±1.02)% in the LPS group, (6.87±0.65)% in the LPS+EVs group, and (4.15±0.92)% in the LPS+MTX-EVs group, respectively. The proportions of IFN-γ positive cells in the LPS+EVs group and LPS+MTX-EVs group were significantly lower than that in the LPS group (P<0.05), while the ratio of IFN-γ positive cells in the LPS+MTX-EVs group was found significantly lower than that in the LPS+EVs group (P<0.05). Conclusions: MTX-EVs can effectively alleviate the periodontal local inflammatory environment and reduce bone resorption of alveolar bone in periodontitis model mice.

[Efficacy of venetoclax-based induction regimen in newly diagnosed pediatric acute myeloid leukemia].

Objective: To explore the efficacy of venetoclax-based induction regimen for children with newly diagnosed acute myeloid leukemia (AML). Methods: Children with newly diagnosed AML in Beijing Children's Hospital Affiliated to Capital Medical University and Baoding Hospital Affliliated to Capital Medical University from November 2019 and December 2023 were prospectively included. The patients were divided into DAH group (daunorubicin, cytarabine and homoharringtonine) and VAH group (venetoclax, cytarabine and homoharringtonine) according to induction regimen. The clinical data of the children were collected, the clinical characteristics and induced remission rate between the two groups were compared, and multivariate logistic regression was used to analyze the related factors affecting the induced remission rate. Results: A total of 135 patients were enrolled, including 96 cases in the DAH group (54 males and 42 females), aged [M (Q1, Q3)] 6.4 (3.9, 11.6) years and 39 cases in the VAH group (26 males and 13 females), aged 8.0 (6.2, 13.2) years. Among patients initially diagnosed with low-medium risk AML, the morphologic complete remission rates were 94.7% (18/19) in the VAH group and 84.4% (38/45) in the DAH group, respectively, and the negativity conversion rates of minirnal residual disease (MRD) were 57.9% (11/19) and 46.7% (21/45), respectively, with no statistically difference (all P>0.05). Among patients initially diagnoised with high-risk AML, the morphologic complete remission rates in the VAH group was higher than that in the DAH group [95.0% (19/20) vs 70.6% (36/51), P=0.027], and negativity conversion rates of MRD were 45.0% (9/20) and 33.3% (17/51), respectively, with no statistically difference (P=0.359). The induction regimen (venetoclax, cytarabine and homoharringtonin) was beneficial to morphological remission (OR=0.126, 95%CI: 0.025-0.629). FLT3 mutation was not conducive to morphological remission (OR=5.832, 95%CI: 1.778-19.124) and negative MRD (OR=4.166, 95%CI: 1.396-12.433). Conclusion: Venetoclax-based induction regimen is more effective than traditional chemotherapy regimen for newly diagnosed pediatric AML.

[Clinical features and outcomes of digestive tract perforation in pediatric mature B-cell non-Hodgkin lymphoma].

To summarize the clinical features and prognosis of pediatric mature B-cell non-Hodgkin lymphoma (mB-NHL) with digestive tract perforation. The clinical manifestations, laboratory and imaging examinations, treatment and outcomes of mB-NHL children complicated with digestive tract perforation admitted to Beijing Children's Hospital of Capital Medical University from January 2016 to June 2023 were retrospectively analyzed. A total of 12 patients were included, with 11 males and 1 female, aged 0.8-16.0 (7.5±5.4) years. Among them, there were 10 cases of Burkitt lymphoma, 1 case of high-grade B-cell lymphoma (HGBL) and 1 case of diffuse large B-cell lymphoma (DLBCL), respectively. Intestinal involvement was involved in all cases, with St.Jude staging ranging from stage Ⅲ to Ⅳ. Eleven cases had large abdominal mass. In 7 cases, abdominal X-ray examination showed free gas under the diaphragm. Eleven cases experienced digestive tract perforation after chemotherapy, and the time of perforation after initiation of chemotherapy was 2.0-111.0 (41.2±33.6) days. The most common site of perforation was ileum (6 cases), followed by gastric wall (2 cases), jejunum (1 case), colon (1 case) and appendix (1 case). Eight patients underwent surgery, and the time between surgery and re-chemotherapy was 7.0-45.0 (17.6±12.0) days. One case with perforation before chemotherapy died after giving up treatment. The remaining 11 cases received conservative treatment or surgical intervention, followed by regular chemotherapy after symptom and infection control. The follow-up time was 6.0-82.0 (45.0±26.1) months, and all survived.

[The mechanism of SSO regulating SiO(2)-induced lipid metabolism disorders in macrophages was explored based on lipid metabolomics].

Objective: To investigate the mechanism of Sulfo-N-succinimidyloleate (SSO) regulating lipid metabolism disorder induced by silicon dioxide (SiO(2)) . Methods: In March 2023, Rat alveolar macrophages NR8383 were cultured in vitro and randomly divided into control group (C), SSO exposure group (SSO), SiO(2) exposure group (SiO(2)) and SiO(2)+SSO exposure group (SiO(2)+SSO). NR8383 cells were exposure separately or jointly by SSO and SiO(2) for 36 h to construct cell models. Immunofluorescence and BODIPY 493/ 503 staining were used to detect cluster of differentiation (CD36) and intracellular lipid levels, the protein expression levels of CD36, liver X receptors (LXR), P-mammalian target of rapamycin (P-mTOR) and cholinephosphotransferase 1 (CHPT1) were detected by Western blot, respectively, and lipid metabolomics was used to screen for different lipid metabolites and enrichment pathways. Single-factor ANOVA was used for multi-group comparison, and LSD test was used for pair-to-group comparison. Results: SiO(2) caused the expression of CD36 and P-mTOR to increase (P=0.012, 0.020), the expression of LXR to decrease (P=0.005), and the intracellular lipid level to increase. After SSO treatment, CD36 expression decreased (P=0.023) and LXR expression increased (P=0.000) in SiO(2)+SSO exposure group compared with SiO(2) exposure group. Metabolomics identified 87 different metabolites in the C group and SiO(2) exposure group, 19 different metabolites in the SiO(2) exposure group and SiO(2)+SSO group, and 5 overlaps of different metabolites in the two comparison groups, they are PS (22∶1/14∶0), DG (O-16∶0/18∶0/0∶0), PGP (i-13∶0/i-20∶0), PC (18∶3/16∶0), and Sphinganine. In addition, the differential metabolites of the two comparison groups were mainly concentrated in the glycerophospholipid metabolism and sphingolipid metabolism pathways. The differential gene CHPT1 in glycerophospholipid metabolic pathway was verified, and the expression of CHPT1 decreased after SiO(2) exposure. Conclusion: SSO may improve SiO(2)-induced lipid metabolism disorders by regulating PS (22∶1/14∶0), DG (O-16∶0/18∶0/0∶0), PGP (i-13∶0/i-20∶0), PC (18∶3/16∶0), SPA, glycerophospholipid metabolism and sphingolipid metabolism pathways.

[Clinical characteristics and prognostic analysis of 34 patients with primary thyroid lymphoma].

Objective: To investigate the clinical characteristics, diagnosis, treatment, and prognosis of primary thyroid lymphoma (PTL) . Methods: A retrospective analysis was conducted on the clinical and pathological data of 34 newly diagnosed PTL patients admitted to Beijing Tongren Hospital from September 2010 to February 2023. The Kaplan-Meier survival curve and Log-rank test were used for survival analysis, and the Cox regression model was applied for univariate analysis of prognostic factors. Results: All 34 PTL patients presented with cervical mass as the initial clinical manifestation. There were 9 males and 25 females. The pathological diagnosis was diffuse large B-cell lymphoma (DLBCL) in 29 patients and mucosa-associated lymphoid tissue (MALT) lymphoma in 5 patients. Among the DLBCL patients, 6 had B symptoms, 17 had an Eastern Cooperative Oncology Group (ECOG) score of ≥2, the Ann Arbor staging was stage Ⅰ-Ⅱ in 21 cases and stage Ⅲ-Ⅳ in 8 cases, the tumor diameter was ≥10 cm in 4 cases, and 14 had concurrent Hashimoto thyroiditis; 27 cases received chemotherapy, with 21 cases achieving complete remission (CR), 2 cases partial remission (PR), and 6 cases of disease progression; the 5-year progression-free survival and overall survival rates were 78.9% and 77.4%, respectively; univariate survival analysis showed that B symptoms, tumor diameter ≥10 cm, and Ann Arbor stage Ⅲ-Ⅳ were significant factors affecting patient prognosis (P<0.05). MALT lymphoma patients were all in stages Ⅰ-Ⅱ, had an ECOG score of 0-1, and were without B symptoms. All patients underwent surgical resection, with 4 cases achieving CR and 1 case PR. Conclusion: PTL is more common in females with concurrent Hashimoto thyroiditis, with the majority of pathological types being B-cell lymphoma. The main treatment is chemotherapy, supplemented by radiotherapy and surgery, and the prognosis is relatively favorable.

[A recombinant adeno-associated virus expressing secretory TGF-ß type â ¡ receptor inhibits triple-negative murine breast cancer 4T1 cell proliferation and lung metastasis in mice].

OBJECTIVE: To investigate the effects of an adeno-associated virus (AAV2) vector expressing secretory transforming growth factor-ß (TGF-ß) type Ⅱ receptor (sTßRⅡ) extracellular domain-IgG2a Fc fusion protein (sTßRⅡ-Fc) on proliferation and migration of triple-negative murine breast cancer 4T1 cells in mice. METHODS: The pAAV-sTßRⅡ-Fc vector expressing sTßRⅡ-Fc fusion protein constructed by molecular cloning, the capsid protein-expressing vector pAAV2 and the helper vector were co-transfected into HEK 293T cells to prepare the recombinant AAV2-sTßRⅡ virus, which was purified by density gradient centrifugation with iodixanol. Western blotting was used to examine the effects of AAV-sTßRⅡ virus on Smad2/3 phosphorylation in 4T1 cells and on expression levels of E-cadherin, vimentin and p-Smad2/3 in 4T1 cell xenografts in mice. BALB/c mice bearing subcutaneous xenografts of luciferase-expressing 4T1 cells received intravenous injections of AAV-sTßRⅡ virus, AAV-GFP virus or PBS (n=6) through the tail vein, and the proliferation and migration of 4T1 cells were analyzed with in vivo imaging. Ki67 expression in the tumor tissues and sTßRⅡ protein expressions in mouse livers were detected with immunohistochemistry and immunofluorescence staining, and tumor metastases in the vital organs were examined with HE staining. RESULTS: The recombinant pAAV-sTßRⅡ-Fc vector successfully expressed sTßRⅡ in HEK 293T cells. Infection with AAV2-sTßRⅡ virus significantly reduced TGF-ß1-induced Smad2/3 phosphorylation in 4T1 cells and effectively inhibited proliferation and lung metastasis of 4T1 xenografts in mice (P<0.05). In the tumor-bearing mice, intravenous injection of AAV-sTßRⅡ virus significantly increased E-cadherin expression, reduced vimentin and Ki67 protein expressions and Smad2/3 phosphorylation level in the tumor tissues (P<0.05 or 0.01), and induced liver-specific sTßRⅡ expression without causing body weight loss or heart, liver, spleen or kidney pathologies. CONCLUSION: The recombinant AVV2 vector encoding sTßRⅡ extracellular domain is capable of blocking the TGF-ß signaling pathway to inhibit the proliferation and lung metastasis of 4T1 cells in mice.

[High expression of ATP5A1 in gastric carcinoma is correlated with a poor prognosis and enhanced glucose metabolism in tumor cells].

OBJECTIVE: To analyze the expression level of ATP5A1 in gastric carcinoma and its influence on the prognosis of the patients and glucose metabolism in the tumor cells. METHODS: We retrospectively analyzed the data of 115 patients undergoing radical resection of gastric carcinoma in our hospital from February, 2013 to November, 2016. ATP5A1 expression in the surgical specimens were detected using immunohistochemistry, and the long-term prognosis of the patients with high (n=58) and low ATP5A1 expression (n=57) were analyzed. In gastric carcinoma MGC803 cells, the effects of lentivirus-mediated ATP5A1 knockdown or overexpression on glucose metabolism were investigated. We also observed the growth and glucose metabolism of xenografts derived from MGC803 cells with ATP5A1 knockdown or overexpression in nude mice. RESULTS: ATP5A1 was significantly overexpressed in gastric carcinoma tissues in close correlation with blood CEA and CA19-9 levels, pathological grade, T stage and N stage (P < 0.05). ATP5A1 overexpression was an independent risk factor for a significantly lowered 5-year survival rate of patients with gastric carcinoma (P < 0.05). ROC curve analysis demonstrated the predictive value of high ATP5A1 expression for the patients'prognosis (P < 0.001). In MGC803 cells, ATP5A1 overexpression significantly upregulated cellular glucose uptake and lactate production and increased the protein levels of HK2, PFK1, and LDHA (P < 0.05), while ATP5A1 knockdown produced the opposite changes (P < 0.05). In the tumor-bearing mice, overexpression of ATP5A1 increased glucose metabolism of the tumor cells and promoted tumor growth (P < 0.05). Overexpression of ATP5A1 promoted the expressions of p-JNK and p-JUN in MGC803 cells (P < 0.05), and the JNK inhibitor SP600125 significantly inhibited the enhancement of cellular glucose metabolism induced by ATP5A1 overexpression (P < 0.05). CONCLUSION: High ATP5A1 expression in gastric cancer is associated a poor long-term prognosis of the patients, and its effect is mediated at least partly by promoting glucose metabolism of the cells through the JNK/JUN pathway.

[Syphilis infection and related factors among HIV-infected patients in Zhejiang Province].

Objective: To investigate syphilis infection and related factors among HIV-infected patients being followed up for more than one year in Zhejiang Province. Methods: Data were collected from the China Disease Control and Prevention Information System, and information such as demographic characteristics, viral load levels, and syphilis serologic test results was collected from HIV-infected persons who were diagnosed with HIV more than 1 year, aged ≥15 years with a current address in Zhejiang Province through December 31, 2022. The logistic regression model analyzed the prevalence of syphilis and the related factors. The SPSS 19.0 software was used for statistical analysis. Results: A total of 33 734 HIV-infected patients, with the prevalence of syphilis was 5.6% (1 879/33 734). Among the syphilis cases, the prevalence of syphilis was 6.4% (1 774/27 934) of males, 7.5% (640/8 543) of 25-34 years old age group, 7.6% (1 025/13 423) of unmarried, 8.3% (1 239/14 862) of homosexual transmission, 6.9% (214/3 080) with a non-local registered residence and 9.6% (602/6 267) with a history of STD before the HIV diagnosis. Multivariate Logistic regression analysis showed that participants who were male (aOR=2.19, 95%CI:1.77-2.72), 25-34 years old age group (aOR=1.80, 95%CI:1.47-2.20), homosexual transmission (aOR=1.67, 95%CI:1.49-1.88), with other provinces registered residence (aOR=1.26, 95%CI:1.09-1.47), and with a history of sexually transmitted disease (STD) before the HIV diagnosis (aOR=1.98, 95%CI:1.78-2.20) were associated with increased risk of syphilis. Being married (aOR=0.79, 95%CI:0.68-0.92) was associated with a decreased risk of syphilis. Conclusions: Syphilis infections were high in HIV-infected patients followed up more than one year in Zhejiang Province. It is recommended that syphilis surveillance and screening frequency should be strengthened among HIV-infected persons with characteristics such as male, homosexual transmission, and STD history.

Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Author Correction: Intravenous N-acetylcysteine in respiratory disease with abnormal mucus secretion.

Eur Rev Med Pharmacol Sci 2023; 27 (11): 5119-5127-DOI: 10.26355/eurrev_202306_32628-PMID: 37318485, published online on June 13, 2023. After publication, the authors have found some mistakes. This erratum corrects the following: In Figure 1, "4 withdrawal" has been corrected into "7 withdrawal" and "95 completed study" has been corrected into "97 corrected study" In the "Efficacy" paragraph at page 5123, "1.0 in the placebo group" has been corrected into "-1.0 in the placebo group". The legend of Table V has been corrected as follows: Table V. Published clinical studies of the mucolytic and expectorant efficacy of IV NAC in respiratory diseases. In Table V, the data regarding the Treatment groups (duration) by Grassi et al5 have been corrected as follows: NAC oral 200 mg TID NAC IM 300 mg BID NAC IV 500 mg OD (6 days) In Table V, the data regarding the Treatment groups (duration) by Henneghien et al8 have been corrected as follows: NAC oral 200 mg TID NAC IV 300 mg TID (3-10 days) NAC IV 500 mg BID (12 days) There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/32628.

[Differential analysis of aqueous humor metabolomics between presenile cataract and senile cataract].

Objective: To explore the differences in metabolites and metabolic pathways in the aqueous humor between patients with presenile cataracts and senile cataracts. Methods: This metabolomic study was conducted at Tianjin Medical University Eye Hospital from August 2020 to September 2022. Eight patients with presenile cataracts (8 eyes) and 8 patients with senile cataracts (9 eyes) were included. Data were collected, including age, gender, preoperative uncorrected visual acuity, intraocular pressure, lens dysfunction index, and axial length. Aqueous humor and anterior capsule tissue samples were obtained during cataract surgery. Metabolites in the aqueous humor were detected using Liquid Chromatography-Mass Spectrometry in a non-targeted approach. The principal component analysis, differential analysis, clustering analysis, and correlation analysis were performed to identify differentially expressed metabolites. These metabolites were ranked based on the fold change (FC). The receiver operating characteristic (ROC) curve analysis and metabolic enrichment analysis were used to identify differential pathways and potential biomarkers for presenile cataracts. Immunohistochemistry was conducted on anterior capsule tissues, and pyruvate levels were measured by colorimetry to validate metabolomic results. Results: Patients with presenile cataracts included 7 males and 1 female, with a mean age of (37.50±4.90) years. Patients with senile cataracts were 7 males and 1 female, with a mean age of (73.44±5.22) years. Except for age, there were no significant differences in baseline data (P>0.05). A total of 347 differential metabolites were identified, 10 of which were potential biomarkers for presenile cataract according to the ROC curve analysis (all P<0.05), including propoxycaine (log2FC=7.26), 2-methyl-2, 3, 4, 5-tetrahydro-1, 5-benzodiazepine-4-ketone (log2FC=6.35), l-pyroglutamic acid (log2FC=-1.72), leanly-proline (log2FC=-0.77), and choline (log2FC=-0.56) in the positive ion mode, and N-phenylacetyl glutamine (log2FC=-1.84), pyruvate (log2FC=1.07), ascorbic acid (log2FC=0.92), pseudouracil nucleoside (log2FC=-0.68), and palmitic acid (log2FC=-0.51) in the negative ion mode. The metabolic enrichment analysis identified 72 differential pathways (32 cationic and 40 anionic), with significant differences in glutathione metabolism, cysteine and methionine metabolism, glycolysis or gluconeogenesis, pyruvate metabolism, and the citric acid cycle (P<0.05). The experimental validation showed reduced lactate dehydrogenase and increased pyruvate levels in patients with presenile cataracts (P<0.05). Conclusions: Pyruvate and nine other metabolites may serve as potential biomarkers for presenile cataracts. Pathways involving glutathione metabolism, cysteine and methionine metabolism, glycolysis or gluconeogenesis, pyruvate metabolism, and the citric acid cycle are notably dysregulated in patients with presenile cataracts.

[The Miao medicine Sidaxue alleviates rheumatoid arthritis in rats possibly by downregulating matrix metalloproteinases].

OBJECTIVE: To explore the inhibitory effect of Sidaxue, a traditional Miao herbal medicine formula, on articular bone and cartilage destruction and synovial neovascularization in rats with collagen-induced arthritis (CIA). METHODS: In a SD rat model of CIA, we tested the effects of daily gavage of Sidaxue at low, moderate and high doses (10, 20, and 40 g/kg, respectively) for 21 days, with Tripterygium glycosides (GTW) as the positive control, on swelling in the hind limb plantar regions by arthritis index scoring. Pathologies in joint synovial membrane of the rats were observed with HE staining, and serum TNF-α and IL-1ß levels were detected with ELISA. The expressions of NF-κB p65, matrix metalloproteinase 1 (MMP1), MMP2 and MMP9 at the mRNA and protein levels in the synovial tissues were detected using real-time PCR and Western blotting. Network pharmacology analysis was conducted to identify the important target proteins in the pathways correlated with the therapeutic effects of topical Sidaxue treatment for RA, and the core target proteins were screened by topological analysis. RESULTS: Treatment with GTW and Sidaxue at the 3 doses all significantly alleviated plantar swelling, lowered arthritis index scores, improved cartilage and bone damage and reduced neovascularization in CIA rats (P<0.05), and the effects of Sidaxue showed a dose dependence. Both GTW and Sidaxue treatments significantly lowered TNF-α, IL-1ß, NF-κB p65, MMP1, MMP2, and MMP9 mRNA and protein expressions in the synovial tissues of CIA rats (P<0.05). Network pharmacological analysis identified MMPs as the core proteins associated with topical Sidaxue treatment of RA. CONCLUSION: Sidaxue alleviates articular bone and cartilage damages and reduces synovial neovascularization in CIA rats possibly by downregulating MMPs via the TNF-α/IL-1ß/NF-κB-MMP1, 2, 9 signaling pathway, and MMPs probably plays a key role in mediating the effect of Sidaxue though the therapeutic pathways other than oral administration.

Impact of preoperative balance training on postoperative functional recovery of patients after total knee arthroplasty: a systematic review and meta-analysis.

OBJECTIVE: Previous studies' results on the impact of preoperative balance training on postoperative functional recovery after total knee arthroplasty (TKA) appeared to be ambiguous. Thus, this systematic review and meta-analysis were performed to investigate the effects of preoperative balance training on walking ability, balance-specific performance, and other functional indicators in elderly patients post-TKA. MATERIALS AND METHODS: Patient data were obtained from databases including PubMed, Physiotherapy Evidence Database (PEDro), CINAHL, SPORTDiscus, and Scopus. The inclusion criteria followed the Population-Intervention-Comparison-Outcome (PICO) principle. The assessment process involved meticulous screening, judicious data extraction, and rigorous evaluation of trial method quality, conducted by two independent researchers. Based on standardized mean differences and 95% confidence intervals, meta-analysis was performed employing a random-effects model or fixed-effects model. RESULTS: Preoperative balance training appears to be a potentially effective intervention for enhancing the knee osteoarthritis (KOA) patients' knee joint function (RR = 1.16, 95% CI: -2.58, 4.91), isometric knee flexion (RR = 2.49, 95% CI: -2.53, 7.50), knee extension (RR = -0.13, 95% CI: -0.45, 0.18), knee society score (KSS) (RR = 2.18, 95% CI: -1.51, 5.88), stair test (RR = -0.73, 95% CI: -1.84, 0.37), and timed up and go (RR = -1.18, 95% CI: -1.60, -0.76). CONCLUSIONS: Compared to interventions with less emphasis on balance training, rehabilitation programs highly emphasizing balance training significantly enhance the walking ability, balance specificity, and functional indicators of elderly patients post-TKA. This includes rehabilitation programs for senior TKA patients, with a focus on activities meant to improve the sensory system, balance in particular.

Photo-induced structural dynamics of o-nitrophenol by ultrafast electron diffraction.

The photo-induced dynamics of o-nitrophenol, particularly its photolysis, has garnered significant scientific interest as a potential source of nitrous acid in the atmosphere. Although the photolysis products and preceding photo-induced electronic structure dynamics have been investigated extensively, the nuclear dynamics accompanying the non-radiative relaxation of o-nitrophenol on the ultrafast timescale, which include an intramolecular proton transfer step, have not been experimentally resolved. Herein, we present a direct observation of the ultrafast nuclear motions mediating photo-relaxation using ultrafast electron diffraction. This work spatiotemporally resolves the loss of planarity which enables access to a conical intersection between the first excited state and the ground state after the proton transfer step, on the femtosecond timescale and with sub-Angstrom resolution. Our observations, supported by ab initio multiple spawning simulations, provide new insights into the proton transfer mediated relaxation mechanism in o-nitrophenol.

Relationship between pericoronary fat-attenuation values quantified by coronary computed tomography angiography and coronary artery disease severity.

AIM: To explore the relationship between pericoronary fat-attenuation index (FAI) values and coronary artery disease (CAD) severity measured using coronary computed tomography angiography (CCTA). MATERIALS AND METHODS: This study retrospectively included 428 patients with CAD who were eligible and underwent CCTA at our hospital. CAD severity on CCTA images including obstructive stenosis and extensive lesions, and segment stenosis and involvement score (SSS, SIS), and CAD-RADS classification were assessed. FAI values for left anterior descending (LAD), left circumflex (LCX) branches, and right coronary artery (RCA) were quantified using fully automated software. The relationship between FAI values and CAD severity was assessed using univariate and multivariate regression models. RESULTS: Univariate analyses showed that sex and current smoking were associated with elevated FAILAD and FAILCX values (all P<0.05), whereas CAD severity was not relevant (all P>0.05). Not only clinical factors such as sex, current smoking, and hypertension were associated with elevated FAIRCA, but also indicators to assess CAD severity including obstructive stenosis, SIS, and SSS were related to it (all P<0.05). Multivariate analysis demonstrated that after correcting for the effects of other conventional cardiovascular risk factors and CCTA imaging features, current smoking was an independent risk factor for elevated FAI values (odds ratio [OR] = 0.569, 0.458, and 0.517; all P<0.05), whereas that SSS (OR=1.041, P=0.027) for elevated FAIRCA values. CONCLUSION: Following correction for conventional cardiovascular risk factors and imaging characteristics, current smoking was an independent clinical risk factor for elevated FAI values, and SSS was an independent risk factor for elevated FAIRCA values.

Deep learning-based fully automatic screening of carotid artery plaques in computed tomography angiography: a multicenter study.

AIM: To develop and validate a deep learning (DL) algorithm for the automated detection and classification of carotid artery plaques (CAPs) on computed tomography angiography (CTA) images. MATERIALS AND METHODS: This retrospective study enrolled 400 patients (300 in the Center Ⅰ and 100 in Ⅱ). Three radiologists co-labeled CAPs, and their revised calcification status (noncalcified, mixed, and calcified) was regarded as ground truth. Center Ⅰ patients were randomly divided into training and internal validation datasets, while Center Ⅱ patients served as the external validation dataset. Carotid artery regions were segmented using a modified 3D-UNet network, followed by CAPs detection and classification using a ResUNet-based architecture in a two-step DL system. The DL model's detection and classification performance were evaluated on the validation dataset using precision-recall curve, free-response receiver operating characteristic (fROC) curve, Cohen's kappa, and ROC curve analysis. RESULTS: The DL model had achieved 83.4% sensitivity at 3.0 false positives (FPs)/CTA scan in internal validation and 78.9% in external validation. F1-scores were 0.764 and 0.769 at the optimal threshold, and area under fROC curves were 0.756 and 0.738, respectively, indicating good overall accuracy for CAP detection. The DL model also showed good performance for the ternary classification of CAPs, with Cohen's kappa achieved 0.728 and 0.703 in both validation datasets. CONCLUSION: This study demonstrated the feasibility of using a fully automated DL-based algorithm for the detection and ternary classification of CAPs, which could be helpful for the workloads of radiologists.