A Novel Maternally Inherited GNAS Variant in a Family With Hyperphagia and Obesity: 3 Cases.

GNAS variants were recently described in 1% of patients not known to have pseudohypoparathyroidism/inactivating PTH/PTHrP signalling disorder 2 in the UK Genetics of Obesity Study. We describe a new missense GNAS variant, c.791A > C, p.(Asp264Thr), in a family with obesity, hyperphagia and mild PTH resistance. A 6-year-old female (body mass index +4.3 SD score [SDS], height +1.9 SDS) presented with hyperphagia and obesity from age 3 years. She had subtle brachydactyly, macrocephaly, and mildly delayed development. The 12-year-old brother (height +2.1 SDS, body mass index +2.9 SDS) had hyperphagia, obesity, mildly delayed development, and autism. He had subtle brachydactyly, as did the affected mother. We assessed the functional effect of the mutant, measuring cAMP production in cells transfected with wild type and mutant GNAS after ligand stimulation. Cells with the mutant GNAS showed impaired cAMP generation through melanocortin receptor 4, GH releasing hormone receptor, and PTH receptor. These cases demonstrate the clinical heterogeneity of monogenic disease, suggesting a need to test for PHP1A in children with obesity even without classical signs of PHP1A.

The Tandem VR™ protocol: Synchronized nature-based and other outdoor experiences in virtual reality for hospice patients and their caregivers.

Background: Nature-based and other outdoor virtual reality (VR) experiences in head-mounted displays (HMDs) offer powerful, non-pharmacological tools for hospice teams to help patients undergoing end-of-life (EOL) transitions. However, the psychological distress of the patient-caregiver dyad is interconnected and highlights the interdependence and responsiveness to distress as a unit. Hospice care services and healthcare need strategies to help patients and informal caregivers with EOL transitions. Methods: Our study uses the synchronized Tandem VR TM approach where patient-caregiver dyads experience immersive nature-based and other outdoor VR content. This mixed methods study will recruit 20 patient-caregiver dyads (N = 40) enrolled in home hospice services nearing EOL. Dyads will experience a personalized nature-based and other outdoor VR experience lasting 5-15 min. Self-reported questionnaires and semi-structured interviews will be collected pre/post the VR intervention to identify the impacts of Tandem VR TM experiences on the QOL, pain, and fear of death in patient-caregiver dyads enrolled with hospice services. Additionally, this protocol will determine the acceptance of Tandem VR TM experiences by dyads as a non-pharmacological modality for addressing patient and caregiver needs. Acceptance will be quantified by the number of dyads accepting or declining the VR experience during recruitment. Discussion: Using personalized, nature-based and other outdoor VR content, the patient-caregiver dyads can simultaneously engage in an immersive encounter may help alleviate symptoms associated with declining health and EOL phases for the patient and the often overburdened caregiver. This protocol focuses on meeting the need for person-centered, non-pharmacological interventions to reduce physical, psychological, and spiritual distress. Trial registration: NCT06186960.

[Effect of preoperative immune checkpoint inhibitors on reducing residual lymph node metastases in patients with gastric cancer: a retrospective study].

Objective: To investigate the effect of immune checkpoint inhibitors on reducing residual lymph node metastasis in patients with gastric cancer. Methods: The cohort of this retrospective study comprised patients from Nanfang Hospital of Southern Medical University and the First Affiliated Hospital of Xiamen University who had undergone systemic treatment prior to gastrectomy with D2 lymphadenectomy and had achieved Grade 1 primary tumor regression (TRG1) from January 2014 to December 2023. After exclusion of patients who had undergone preoperative radiotherapy, data of 58 patients (Nanfang Hospital: 46; First Affiliated Hospital of Xiamen University: 12) were analyzed. These patients were allocated to preoperative chemotherapy (Chemotherapy group, N=36 cases) and preoperative immunotherapy plus chemotherapy groups (Immunotherapy group, N=22 cases). There were no significant differences between these groups in sex, age, body mass index, diabetes, tumor location, pathological type, Lauren classification, tumor differentiation, pretreatment depth of invasion by primary tumor, pretreatment lymph node stage, pretreatment clinical stage, mismatch repair protein status, number of preoperative treatment cycles, or duration of preoperative treatment (all P>0.05). The primary outcome measure was postoperative lymph node downstaging. Secondary outcomes included postoperative depth of invasion by tumor, number of lymph nodes examined, and factors affecting residual lymph node metastasis status. Results: Lymph node downstaging was achieved significantly more often in the Immunotherapy group than the Chemotherapy group (pN0: 90.9% [20/22] vs. 61.1% [22/36]; pN1: 4.5% [1/22] vs. 36.1% [13/36]; pN2: 4.5% [1/22) vs. 0; pN3: 0 vs. 2.8% [1/36], Z=-2.315, P=0.021). There were no significant difference between the two groups in number of lymph nodes examined (40.5±16.3 vs. 40.8±17.5, t=0.076, P=0.940) or postoperative depth of invasion by primary tumor (pT1a: 50.0% [11/22] vs. 30.6% [11/36]; pT1b: 13.6% [3/22] vs. 19.4% [7/36]; pT2: 13.6% [3/22] vs. 13.9% [5/36]; pT3: 13.6% [3/22] vs. 25.0% [9/36]; pT4a: 9.1% [2/22] vs. 11.1% [4/36], Z=-1.331, P=0.183). Univariate analysis revealed that both preoperative treatment regimens were associated with residual lymph node metastasis status in patients whose primary tumor regression was TRG1 (χ2=6.070, P=0.014). Multivariate analysis incorporated the following factors: pretreatment depth of invasion by primary tumor, pretreatment lymph node stage, pretreatment clinical stage, number of preoperative treatment cycles, and preoperative treatment duration. We found that a combination of immunotherapy and chemotherapy administered preoperatively was an independent protective factor for reducing residual lymph node metastases in study patients whose primary tumor regression was TRG1 (OR=0.147, 95%CI: 0.026-0.828, P=0.030). Conclusion: Compared with preoperative chemotherapy alone, a combination of preoperative immunotherapy and chemotherapy achieved greater reduction of residual lymph node metastases in the study patients who achieved TRG1 tumor regression in their primary lesions.

[Interim efficacy of a multicenter cohort study for China Net Childhood Lymphoma mature B-cell lymphoma 2017 regimen in the treatment of pediatric High-grade-B cell lymphoma].

Objective: To analyze the mid-term efficacy of the China Net Childhood Lymphoma mature B-cell lymphoma 2017 (CNCL-B-NHL-2017) regimen in treating children with high-grade B-cell lymphoma (HGBL). Methods: Clinical and pathological data of HGBL children aged≤18 years admitted to 16 hospitals of the Chinese Children's Lymphoma Collaborative Group (CNCL) from May 2017 to April 2021 were collected retrospectively. They were divided in to high-grade B-cell lymphoma with double hit/triple hit (HGBL-DH/TH) group and high-grade B-cell lymphoma non-specified (HGBL-NOS) group, according to the 2016 version of the World Health Organization (WHO) Hematopoietic and Lymphoid Tissues Cancer Classification. Both groups of patients were treated with stratified chemotherapy by risk according to the CNCL-B-NHL-2017 scheme. The deadline for follow-up was December 31, 2023. All the patients were examined by chromosome fluorescence in situ hybridization (FISH), and the rearrangement of genes MYC, BCL-2 and BCL-6 was confirmed. The clinical and pathological characteristics of patients at disease onset were analyzed, and the therapeutic effects of patients in different clinical stages and risk groups were compared. Survival analysis was drawn by Kaplan Meier method, the log-rank test was used to compare the differences in the cumulative survival rate between different groups, and multivariate Cox regression model was used to identify the prognostic factors. Results: A total of 62 patients were included, with an onset age [M(Q1, Q3)] of 7 (4, 11) years, including 48 males and 14 females. There were 11 (17.7%) patients in stageⅡ, 33(53.2%)patients in stage Ⅲ and 18(29.1%)patients in stage Ⅳ. FISH testing showed that 4 cases (6.5%) were HGBL-DH and 3 (4.8%) were HGBL-TH. The remaining 55 cases (88.7%) were HGBL-NOS, with 18 cases accompanied by MYC rearrangement. There were 7 cases in the HGBL-DH/TH group and 55 cases in the HGBL-NOS group. Thirteen cases (20.9%) were treated with the B1 regimen, 3 cases (4.8%) with B2 regimen, 37 cases (59.6%) with C1 regimen, and 9 cases (14.7%) with the C2 regimen. Forty-eight cases (77.4%) received rituximab therapy at the same time. Five cases (8.0%) progressed during treatment. The follow-up time [M(Q1, Q3)] was 43.5 (36.1, 53.7) months. The complete remission rate was 91.9% (57/62). The 3 year overall survival rate was 93.5% and event-free survival (EFS) rate was 91.9%. The 3-year overall survival rate in the HGBL-NOS group was higher than that in the HGBL-DH/TH group (96.3% vs 71.4%, P=0.011). The 3-year EFS rate of the HGBL-NOS group was higher than that of the HGBL-DH/TH group (94.5% vs 71.4%, P=0.037). In the HGBL-NOS subgroup, the overall survival rate of children with MYC rearrangement was lower (100% vs 88.9%,P=0.039). Multivariate Cox regression analysis showed that central invasion (HR=6.05, 95%CI: 1.96-38.13, P=0.046) was a risk factor for overall survival. Conclusion: CNCL-B-NHL-2017 regimen shows significant effects in the treatment of pediatric HGBL, with a good prognosis.

[High expression of the stemness-associated molecule Nanog in esophageal squamous cell carcinoma tissues promotes tumor invasion and metastasis by activating the TGF-ß signaling pathway].

OBJECTIVE: To investigate the expression of Nanog and its regulatory relationship with MMP-2/MMP-9 proteins in esophageal squamous cell carcinoma (ESCC). METHODS: We detected Nanog and MMP-2/MMP-9 protein expressions in 127 ESCC tissues and 82 adjacent normal tissues using immunohistochemistry and explored their correlations with the clinicopathological parameters and prognosis of the patients. GEO database was utilized to analyze the pathways enriched with the stemness-related molecules including Nanog, and TIMER online tool was used to analyze the correlations among TßR1, MMP-2, and MMP-9 in esophageal cancer. RESULTS: Nanog and MMP-2/MMP-9 proteins were significantly upregulated in ESCC tissues and positively intercorrelated. Their expression levels were closely correlated with infiltration depth and lymph node metastasis of ESCC but not with age, gender, or tumor differentiation. The patients with high expressions of Nanog and MMP-2/MMP-9 had significantly shorter survival time. Bioinformatics analysis showed enrichment of stemness-associated molecules in the TGF-ß signaling pathway, and the expressions of MMP-2/MMP-9 and TßR1 were positively correlated. In cultured ESCC cells, Nanog knockdown significantly decreased the expression of TßR1, p-Smad2/3, MMP-2, and MMP-9 and strongly inhibited cell migration. CONCLUSION: The high expressions of Nanog, MMP-2, and MMP-9, which are positively correlated, are closely related with invasion depth, lymph node metastasis, and prognosis of ESCC. Nanog regulates the expressions of MMP-2/MMP-9 proteins through the TGF-ß signaling pathway, and its high expression promotes migration of ESCC cells.

[Overexpression of lncRNA FEZF1-AS1 promotes progression of non-small cell lung cancer via the miR-130a-5p/CCND1 axis].

OBJECTIVE: To explore the molecular mechanism by which FEZF1-AS1 overexpression promotes progression of nonsmall cell lung cancer (NSCLC) via the miR-130a-5p/CCND1 axis. METHODS: TCGA database was used to analyze FEZF1-AS1 expression levels in NSCLC. FEZF1-AS1 expression was detected by qRT-PCR in clinical specimens of NSCLC tissues and NSCLC cell lines, and its correlation with clinical features of the patients were analyzed. The binding sites of FEZF1-AS1 with hsa-miR-130a-5p and those of hsa-miR-130a-5p with CCND1 were predicted. CCK8 assay, clone formation assay, scratch assay, and Transwell assay were employed to examine the effects of FEZF1-AS1 knockdown and hsa-miR-130a-5p inhibitor on proliferation, invasion, and migration abilities of lung cancer cell lines. Dual luciferase assay was used to verify the binding of FEZF1-AS1 with hsa-miR-130a-5p and the binding of hsa-miR-130a-5p with CCND1. Western blotting was performed to detect the changes in CCND1 protein expression level in H1299 and H358 cells following FEZF1-AS1 knockdown and treatment with hsa-miR-130a-5p inhibitor. RESULTS: FEZF1-AS1 was highly expressed in NSCLC tissues in close correlation with lymph node metastasis and also in H1299 and H358 cell lines (all P < 0.05). FEZF1-AS1 knockdown obviously reduced proliferation, migration, and invasion abilities of NSCLC cells (P < 0.05). Dual luciferase assay confirmed the binding of hsa-miR-130a-5p with FEZF1-AS1 and CCND1 (P < 0.05), and hsa-miR-130a-5p inhibitor significantly inhibited proliferation, migration, and invasion of NSCLC cells (P < 0.05). FEZF1-AS1 knockdown significantly reduced CCND1 protein expression in NSCLC cells, and this effect was strongly inhibited by treatment with hsa-miR-130a-5p inhibitor (P < 0.05). CONCLUSION: FEZF1-AS1 is highly expressed in NSCLC tissue in close correlation with lymph node metastasis to promote cancer progression through the miR-130a-5p/CCND1 axis.

[Comparative analysis of the effects of bronchial intubation and bronchial blocker on the outcomes of thoracoscopic surgery in infants and small children].

Objective: To compare the effects of bronchial intubation and blocker on the outcomes of thoracoscopic surgery in infants and small children. Methods: A total of 387 children, including 210 males and 177 females, aged (17.5±8.3) months, who underwent elective thoracoscopic surgery under general anesthesia in Children's Hospital Affiliated to Capital Institute of Pediatrics from January 2019 to August 2023 were retrospectively analyzed. The children were divided into bronchial intubation group and bronchial blocker group according to the intraoperative single-lung ventilation mode. After matching the age factor using the propensity score matching with nearest neighbor matching method, 258 cases were finally included in the bronchial intubation group, and 129 cases were included in the bronchial blocker group. The primary outcome was the incidence of postoperative pulmonary complications in two groups. The secondary outcomes included the incidence of intraoperative hypoxemia, postoperative oxygenation index, postoperative extubation time, the length of postoperative hospitalization and the total medical expenses during hospitalization between the two groups. Results: The incidence of postoperative pulmonary complications in the bronchial intubation group and bronchial blocker group was 15.5% (40/258) and 12.4% (16/129), the incidence of intraoperative hypoxemia was 20.2% (52/258) and 16.3% (21/129), the postoperative oxygen indexes were 306 (269, 323) and 311 (274, 336) mmHg (1 mmHg=0.133 kPa), the extubation time was (9.2±4.5) and (8.9±4.2) min, the length of postoperative hospitalization was (5.5±0.6) and (5.5±0.5) days and the total medical expenses were (34±6) and (35±6) thousand yuan, with no statistically significant differences between the two groups (all P>0.05). Conclusion: Both bronchial intubation and blocker can be used for one lung ventilation in thoracoscopic surgery for infants and small children, without affecting the postoperative outcomes.

[Construction and characterization of a modA gene mutant strain of Klebsiella pneumoniae].

OBJECTIVE: To construct a mutant strain of Klebsiella pneumoniae NTUH- K2044 with modA gene deletion and its complementary strain and explore the role of modA gene in modulating anaerobic nitrate respiratory growth and phenotypes of K. pneumoniae. METHODS: The modA deletion mutant K. pneumoniae strain was constructed by homologous recombination using the suicide vector pKO3-Km. To obtain the complementary strain C-modA, the whole sequence fragment containing the promoter, open reading frame and terminator regions of modA was cloned into pGEM-T-easy and electrically transformed into the modA deletion mutant. The NTUH-K2044 wild-type strain, modA gene deletion mutant and complementary strain were compared by measuring in vitro anaerobic nitrate respiration growth, competitiveness index, biofilm quantification, mucoviscosity assay and morphological measurement using Image J. RESULTS: The modA deletion mutant strain ΔmodA and the complementary strain C-modA were successfully constructed. The modA gene knockout strain showed inhibited anaerobic nitrate respiratory growth compared with the wild- type and C-modA strains with significantly weakened competitiveness, reduced capacity of biofilm synthesis during anaerobiosis, and lowered mucoviscosity under anaerobic conditions. The ΔmodA strain showed a spherical morphology in anaerobic conditions as compared with the normal short rod-like morphology of K. pneumoniae, with also distinctly shorter length than the wild-type and C-modA strains. CONCLUSION: The molybdate transport system encoding gene modA is associated with the pathogenic capacity of K. pneumoniae by modulating its anaerobic nitrate respiration, competitiveness, biofilm formation, hypermucoviscous phenotype and morphology.

[The effects and mechanisms of Gefitinib on airway inflammation and airway remodeling in C57BL/6 mice with asthma].

Objective: To investigate the effects of the epidermal growth factor receptor(EGFR) inhibitor Gefitinib on airway inflammation and airway remodelling in asthmatic C57BL/6 mice, and to analyze its possible mechanisms. Methods: Male C57BL/6 mice, aged 6-8 weeks, were randomly assigned into five groups: Group A (control group), Group B (asthma group), Group C (asthma+20 mg/kg gefitinib group), Group D (asthma+40 mg/kg gefitinib group), and Group E (40 mg/kg gefitinib group), with seven mice per group. Mice were sensitized by intraperitoneal injection of a mixture of 0.2 ml solution containing OVA and Al(OH)3 [20 µg OVA+2 mg Al(OH)3 dissolved in 0.2 ml of physiological saline] at Day 0 and 14. Starting from Day 25 to 31, Group B, C, and D were challenged with nebulization of 1% OVA solution (8 ml) to induce asthma, once a day for approximately 40 minutes, with continuous aerosolization for 7 days. Group C and D were given 0.2 ml of Gefitinib dissolved in 0.5% carboxymethylcellulose sodium (CMCNa) by gavage half an hour before challenging, and Group E was simultaneously given with 0.2 ml of Gefitinib dissolved in 0.5% CMCNa only. Group A and B were given an equivalent volume of 0.5% CMCNa by gavage. After 24 h of final challenge, the bronchoalveolar lavage fluid (BALF) was prepared for the determination of total cell count and eosinophil count. The levels of total immune globulin E (IgE) in serum and interleukin (IL)-4, IL-5 and IL-13 in BALF and lung tissue homogenates were measured by ELISA. The mRNA expression levels of IL-4, IL-5, IL-13 in lung were measured. Immunohistochemistry and Western blot experiments were used to detect the expression levels of EGFR in lung tissues. Results: In Group B, the level of total IgE in serum, total cell count, eosinophil count, the levels of IL-4, IL-5, IL-13 in BALF and the phosphorylation of EGFR and its downstream activation in lung were higher than those in Group A (all P<0.05). The levels of total IgE in serum [(261.32±44.38) ng/ml, (194.09±52.39) ng/ml vs (1 023.70±105.51) ng/ml], total cell count [(23.70±4.08)×105/ml, (14.92±4.06)×105/ml vs (35.36±6.30)×105/ml], eosinophil count [(108.00±13.69)×104/ml, (67.00±17.28)×104/ml vs (147.86±20.06)×104/ml], IL-4 [(36.42±4.48) pg/ml, (30.45±8.12) pg/ml vs (58.72±7.17) pg/ml], IL-5 [(16.20±4.62) pg/ml, (13.38±5.14) pg/ml vs (23.46±5.38) pg/ml], IL-13 [(18.45±7.28) pg/ml, (14.33±7.70) pg/ml vs (104.12±24.66) pg/ml] in BALF of Group C and D were lower than those in Group B (all P<0.05). The levels of IL-4, IL-5, and IL-13 as well as their mRNA levels in the lung tissue of Group C and D were lower than those in Group B (all P<0.05). In Group C and D, the positive expression rate of phosphorylated epidermal growth factor receptor (p-EGFR) in lung tissue [(40.53±6.80)%, (23.60±4.42)% vs (70.78±5.36)%], p-EGFR/EGFR (61.68±7.48, 51.13±5.19 vs 105.90±11.66), phosphorylated extracellular regulated protein kinase (p-Erk)/extracellular regulated protein kinase (Erk) (75.28±7.11, 47.54±4.83 vs 98.76±4.71), and phosphorylated protein kinase B (p-Akt)/protein kinase B (Akt) (96.24±5.40, 68.52±2.73 vs 103.30±4.52) was lower than those of Group B (all P<0.05). There was no statistically significant difference in the relevant indicators between Group A and E (all P>0.05). Conclusion: Gefitinib may alleviate airway inflammation and airway remodeling in asthmatic mice by inhibiting EGFR phosphorylation and affecting the activation of downstream Erk and Akt.

Retraction Note: BNIP1 inhibits cell proliferation, migration and invasion, and promotes apoptosis by mTOR in cervical cancer cells.

The article "BNIP1 inhibits cell proliferation, migration and invasion, and promotes apoptosis by mTOR in cervical cancer cells", by F.-H. Li, L. Xiang, L. Ran, S. Zhou, Z. Huang, M. Chen, W.-F. Yu, published in Eur Rev Med Pharmacol Sci 2019; 23 (4): 1397-1407-DOI: 10.26355/eurrev_201902_17096-PMID: 30840260 has been retracted by the Editor in Chief for the following reasons. Following some concerns raised on PubPeer regarding a possible overlap in Figure 2A, the Editor in Chief has started an investigation to assess the validity of the results as well as possible figure manipulation. The journal investigation revealed a duplication in Figure 2A between BNIP1 panels, migration and invasion, respectively and in Control and invasion panels. Consequently, the Editor in Chief mistrusts the results presented and has decided to withdraw the article. The authors have been informed about the journal's investigation but remained unresponsive. https://www.europeanreview.org/article/17096 This article has been retracted. The Publisher apologizes for any inconvenience this may cause.

[Treatment status of tyrosine kinase inhibitor for newly-diagnosed chronic myeloid leukemia: a domestic multi-centre retrospective real-world study].

Objective: To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China. Methods: Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed. Results: 6 893 patients in CP (n=6 453, 93.6%) or AP (n=440, 6.4%) receiving initial imatinib (n=4 906, 71.2%), nilotinib (n=1 157, 16.8%), dasatinib (n=298, 4.3%) or flumatinib (n=532, 7.2%) -therapy. With the median follow-up of 43 (IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance (n=1 055, 15.3%), intolerance (n=248, 3.6%), pursuit of better efficacy (n=168, 2.4%), economic or other reasons (n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph(+) ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph(+) ACA, poorer TFS; Ph(+) ACA, poorer OS. Conclusion: At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

[Progress in lipoarabinomannan antigen detection for tuberculosis diagnosis in people living with HIV/AIDS].

Tuberculosis (TB) is the leading cause of death among people living with HIV/AIDS (PLWHA), posing a significant disease burden. Early TB screening in PLWHA is a key intervention to reduce transmission and control disease progression. ​Lipoarabinomannan (LAM) is a glycolipid of Mycobacterium tuberculosis (MTB) that can be detected in the urine of tuberculosis patients. LAM is useful for the rapid and accurate diagnosis of tuberculosis. This article reviews LAM and its application and limitations in the diagnosis of PLWHA, hoping to provide a reference for the diagnosis of tuberculosis in PLWHA.

Polygenic Risk Score Reveals Genetic Heterogeneity of Alzheimer's Disease between the Chinese and European Populations.

BACKGROUND: The polygenic risk score (PRS) aggregates the effects of numerous genetic variants associated with a condition across the human genome and may help to predict late-onset Alzheimer's disease (LOAD). Most of the current PRS studies on Alzheimer's disease (AD) have been conducted in Caucasian ancestry populations, while it is less studied in Chinese. OBJECTIVE: To establish and examine the validity of Chinese PRS, and explore its racial heterogeneity. DESIGN: We constructed a PRS using both discovery (N = 2012) and independent validation samples (N = 1008) from Chinese population. The associations between PRS and age at onset of LOAD or cerebrospinal fluid (CSF) biomarkers were assessed. We also replicated the PRS in an independent replication cohort with CSF data and constructed an alternative PRS using European weights. SETTING: Multi-center genetics study. PARTICIPANTS: A total of 3020 subjects were included in the study. MEASUREMENTS: PRS was calculated using genome-wide association studies data and evaluated the performance alone (PRSnoAPOE) and with other predictors (full model: LOAD ~ PRSnoAPOE + APOE+ sex + age) by measuring the area under the receiver operating curve (AUC). RESULTS: PRS of the full model achieved the highest AUC of 84.0% (95% CI = 81.4-86.5) with pT< 0.5, compared with the model containing APOE alone (61.0%). The AUC of PRS with pT<5e-8 was 77.8% in the PRSnoAPOE model, 81.5% in the full model, and only ranged from 67.5% to 75.1% in the PRS with the European weights model. A higher PRS was significantly associated with an earlier age at onset (P <0.001). The PRS also performed well in the replication cohort of the full model (AUC=83.1%, 95% CI = 74.3-92.0). The CSF biomarkers of Aß42 and the ratio of Aß42/Aß40 were significantly inversely associated with the PRS, while p-Tau181 showed a positive association. CONCLUSIONS: This finding suggests that PRS reveal genetic heterogeneity and higher prediction accuracy of the PRS for AD can be achieved using a base dataset and validation within the same ethnicity. The effective PRS model has the clinical potential to predict individuals at risk of developing LOAD at a given age and with abnormal levels of CSF biomarkers in the Chinese population.

[Efficacy analysis of chemotherapy and endocrine therapy combined with targeted drugs after progression on cyclin-dependent kinase 4/6 inhibitor treatment in hormone receptor positive/human epidermal growth factor receptor 2-low metastatic breast cancer].

Objective: To evaluate the efficacy of chemotherapy and endocrine therapy combined with targeted drugs after progression on cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment in hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer. Methods: Patients with metastatic breast cancer diagnosed with HR positive/HER2 low expression at the Fifth Medical Center of PLA General Hospital from October 1, 2018 to September 30, 2023 were retrospectively included. All patients received sequential chemotherapy or sequential endocrine therapy combined with targeted drugs after progression on CDK4/6 inhibitor treatment.The median follow-up was 9 months, and the follow-up ended on October 31, 2023. The patients were divided into chemotherapy group (receiving sequential chemotherapy) and endocrine therapy group (receiving sequential endocrine therapy combined with targeted drugs), according to the treatment plan. Information on demographic data, clinical and pathological diagnosis, treatment regimen, and efficacy evaluation was collected. The basic conditions of patients who may affect the curative effect of different treatment schemes were preset as stratified subgroups, including age, progesterone receptor (PR) status, HER2 status, disease-free survival, number of previous endocrine therapy and chemotherapy, and visceral metastasis. The primary endpoint was progression-free survival (PFS), the secondary endpoints were objective response rate (ORR), clinical benefit rate(CBR) and PFS based on stratification factors. The survival curve was plotted by Kaplan-Meier method, the comparison of PFS between groups was performed by log-rank test, and the comparison of ORR and CBR between groups were performed by χ2 test. Results: A total of 188 patients were included, including 126 patients in the chemotherapy group [all females, aged 29-74 (51±10) years] and 62 patients in the endocrine therapy group [1 male and 61 female, aged 29-77 (51±12) years]. ORR of chemotherapy group was 23.0% (29/126), higher than that of endocrine treatment group [3.2% (2/62)] (P<0.001); The CBR of chemotherapy group and endocrine therapy group were 46.8% (59/126) and 33.9% (21/62), respectively, with no statistical significance (P=0.091). The median PFS of chemotherapy group and endocrine therapy group were 5.0 (95%CI: 4.3-5.7) and 4.0 (95%CI: 1.6-6.4) months, respectively, with no statistical significance (P=0.484). In the preset stratified subgroups, the median PFS of chemotherapy [6.0 (95%CI: 5.4-6.6) months] was longer than that of endocrine combined with targeted therapy [2.0 (95%CI: 1.8-2.2) months] (P<0.001) in PR negative patients; In patients who had progressed on over 2 previous endocrine treatments, the median PFS of chemotherapy [5.0 (95%CI: 3.8-6.2) months] was longer than that of endocrine combined with targeted therapy [2.0 (95%CI: 0.6-3.4) months] (P=0.045). Conclusions: After progression on treatment with CDK4/6 inhibitors for HR-positive/HER2-low expression metastatic breast cancer, both chemotherapy and endocrine therpy combined with targeted drugs are viable treatment options. However, for patients with PR negative or ≥2 lines of endocrine therapy previously, priority should be accorded to chemotherapy.

[The predictive value of dynamic changes of neutrophil/lymphocyte ratio (NLR) combined with the model of end-stage liver disease (MELD) score in patients with acute-on-chronic hepatitis B liver failure].

Objective: To determine the predictive value of dynamic changes of neutrophil/lymphocyte ratio (NLR) combined with the model of end-stage liver disease (MELD) score in patients with acute-on-chronic hepatitis B liver failure. Methods: Patients with acute-on-chronic hepatitis B liver failure who were hospitalized in the Department of Hepatology of Qilu Hospital of Shandong University from January 2010 to July 2023 were retrospectively enrolled. According to the clinical outcomes of patients within 30 days of admission, they were divided into the survival group and the death group. The dynamic changes in NLR and initial values on day 3, 5, 8, and 12 in two groups were analyzed for the diagnostic value of 30-day prognosis in patients with acute-on-chronic hepatitis B liver failure. Logistic regression analysis and machine learning XGBoost algorithm were used to evaluate the risk factors influencing the prognosis of patients at 30 days. Receiver operating characteristic(ROC) curve was used to evaluate the diagnostic value of NLR and initial value change combined with MELD score on day 12 of admission in patients with chronic acute hepatitis B liver failure. Results: A total of 243 patients were enrolled in the study, including 145 patients in the survival group [115 males, 30 females, aged 25-74 (47±11)] and 98 patients in the death group [80 males, 18 females, aged 22-80 (49±13) ]. The median initial NLR of survival group and death group were 3.5 (2.1, 5.3) and 4.9 (2.9, 8.3), respectively, and the difference was statistically significant (P=0.003). The variation of NLR from the initial value on day 3, 5, 8, and 12 in the survival group [1.6 (0, 4.3), 1.9 (-0.2, 4.1), 2.0 (-0.1, 4.3) and 2.9 (0.3, 7.0), respectively] were lower than that in the death group [3.2 (0.9, 7.5), 5.1 (1.8, 7.6), 5.8 (2.0, 10.6) and 9.6 (3.5, 16.4), respectively] (all P<0.001). Logistic regression multivariate analysis showed that the changes in NLR on the 12th day and initial value (OR=1.07,95%CI:1.01-1.14, P=0.014), the changes in NLR on the 3rd day and initial value (OR=2.71, 95%CI: 1.32-5.55, P=0.007), the initial value of NLR (OR=1.18,95%CI:1.01-1.37,P=0.035) and fibrinogen (OR=0.21,95%CI:0.05-0.96,P=0.044) were related factors for death within 30 days. Machine learning XGBoost algorithm showed that the weight of the change between the NLR on the 12th day and the initial value was the highest. The area under the ROC curve of the combined MELD score was 0.812 (95%CI: 0.728-0.895), the specificity was 67.78%, and the sensitivity was 82.35%. Conclusion: Dynamic change of NLR combined with MELD score has high predictive value for the short-term prognosis of patients with acute-on-chronic hepatitis B liver failure.

Machine learning framework develops neutrophil extracellular traps model for clinical outcome and immunotherapy response in lung adenocarcinoma.

Neutrophil extracellular traps (NETs) are novel inflammatory cell death in neutrophils. Emerging studies demonstrated NETs contributed to cancer progression and metastases in multiple ways. This study intends to provide a prognostic NETs signature and therapeutic target for lung adenocarcinoma (LUAD) patients. Consensus cluster analysis performed by 38 reported NET-related genes in TCGA-LUAD cohorts. Then, WGCNA network was conducted to investigate characteristics genes in clusters. Seven machine learning algorithms were assessed for training of the model, the optimal model was picked by C-index and 1-, 3-, 5-year ROC value. Then, we constructed a NETs signature to predict the overall survival of LUAD patients. Moreover, multi-omics validation was performed based on NETs signature. Finally, we constructed stable knockdown critical gene LUAD cell lines to verify biological functions of Phospholipid Scramblase 1 (PLSCR1) in vitro and in vivo. Two NETs-related clusters were identified in LUAD patients. Among them, C2 cluster was provided as "hot" tumor phenotype and exhibited a better prognosis. Then, WGCNA network identified 643 characteristic genes in C2 cluster. Then, Coxboost algorithm proved its optimal performance and provided a prognostic NETs signature. Multi-omics revealed that NETs signature was involved in an immunosuppressive microenvironment and predicted immunotherapy efficacy. In vitro and in vivo experiments demonstrated that knockdown of PLSCR1 inhibited tumor growth and EMT ability. Besides, cocultural assay indicated that the knockdown of PLSCR1 impaired the ability of neutrophils to generate NETs. Finally, tissue microarray (TMA) for LUAD patients verified the prognostic value of PLSCR1 expression. In this study, we focus on emerging hot topic NETs in LUAD. We provide a prognostic NETs signature and identify PLSCR1 with multiple roles in LUAD. This work can contribute to risk stratification and screen novel therapeutic targets for LUAD patients.