Whole-Exome Sequencing and Experimental Validation Unveil the Roles of TMEM229A Q200del Mutation in Lung Adenocarcinoma.

INTRODUCTION: Lung adenocarcinoma (LUAD) is one of the major histopathological types of non-small cell lung cancer (NSCLC), including solid, acinar, lepidic, papillary and micropapillary subtypes. Increasing evidence has shown that micropapillary LUAD is positively associated with a higher percentage of driver gene mutations, a higher incidence of metastasis and a poorer prognosis, while lepidic LUAD has a relatively better prognosis. However, the novel genetic change and its underlying mechanism in the progression of micropapillary LUAD have not been exactly determined. METHODS: A total of 181 patients with LUAD who underwent surgery at the First Affiliated Hospital of Huzhou University from January 2020 to December 2022 were enrolled. Three predominant lepidic and three predominant micropapillary LUAD tissue samples were carried out using whole-exome sequencing. Comprehensive analysis of genomic variations and the difference between lepidic and micropapillary LUAD was performed. In addition, the TMEM229A Q200del mutation was verified using our cohort and TCGA-LUAD datasets. The correlations between the TMEM229A Q200del mutation and the clinicopathological characteristics of patients with LUAD were further analyzed. The functions and mechanisms of TMEM229A Q200del on NSCLC cell proliferation and migration were also determined. RESULTS: The frequency of genomic changes in patients with micropapillary LUAD was higher than that in patients with lepidic LUAD. Mutations in EGFR, ATXN2, C14orf180, MUC12, NOTCH1, and PKD1L2 were concomitantly detected in three predominant micropapillary and three predominant lepidic LUAD cases. The TMEM229A Q200del mutation was only mutated in lepidic LUAD. Additionally, the TMEM229A Q200del mutation had occurred in 16 (8.8%) patients, and not found TMEM229A R76H and M346T mutations in our cohort, while TMEM229A mutations (R76H, M346T, and Q200del) occurred only in 1.0% of the TCGA-LUAD cohort. Further correlation analysis between the TMEM229A Q200del mutation and clinicopathological characteristics suggested that a lower frequency of the Q200del mutation was significantly associated with positive lymph node metastasis, advanced TNM stage, positive cancer thrombus, and pathological features. Finally, overexpression of TMEM229A Q200del suppressed NSCLC cell proliferation and migration in vitro. Mechanistically, overexpression of TMEM229A and TMEM229A Q200del both reduced the expression level of phosphorylated (p)-ERK and p-AKT (Ser473), and the reduced protein level of p-ERK in the TMEM229A Q200del group was more pronounced compared to the TMEM229A group. CONCLUSION: Our results demonstrated that the TMEM229A Q200del mutant may play a protective role in the progression of LUAD via inactivating ERK pathway, providing a potential therapeutic target in LUAD.

Application of hospital-community-home linkage management model in patients with type 2 diabetic nephropathy.

OBJECTIVE: To explore the effect of the hospital-community-home (HCH) linkage management mode in patients with type 2 diabetic nephropathy (DN). METHOD: A total of 80 patients with type 2 DN hospitalised in the Department of Nephrology of our hospital between July 2021 and June 2022 were recruited and subsequently divided into the observation group and the control group using the random number table method, with 40 patients in each group. The control group received routine health education and discharge guidance. The HCH linkage management model was implemented for the observation group based on routine care. The improvements in compliance behaviour, biochemical parameters of renal function, blood glucose level and self-management ability were compared before the intervention and at 3 and 6 months after the intervention. RESULTS: After the intervention, the scores for compliance behaviour of the observation group were better than those of the control group, with a statistically significant difference (P < 0.05). The biochemical indicators of renal function and blood glucose level were significantly lower in the observation group compared with in the control group, with a statistically significant difference (P < 0.05). After the intervention, the observation group showed a great improvement in self-management ability and cognition of the disease, with significant differences (P < 0.05). CONCLUSION: The HCH linkage management mode can improve the compliance behaviour of patients with type 2 DN, effectively improve the renal function and blood sugar level of patients, enhance the self-management ability and cognition of the disease and delay the development of the disease.

Successful application of PD-1 knockdown CLL-1 CAR-T therapy in two AML patients with post-transplant relapse and failure of anti-CD38 CAR-T cell treatment.

Patients with relapsed/refractory acute myeloid leukemia (R/R AML) often show resistance to chemotherapy and have dismal outcomes. Therefore, it is urgent to develop new treatment strategies to address this problem. With tremendous achievement of chimeric antigen receptor T cells (CAR-T) therapy against B-cell malignancies, many efforts have been devoted to developing CAR-T therapy for R/R AML but with limited success, in part owing to a lack of specific targets. C-type lectin-like molecule-1 (CLL-1) is highly expressed on AML blasts with no expression on normal hematopoietic stem cells, which makes it an ideal target of immunotherapy for AML. Here, we report 2 R/R AML patients who relapsed after allogeneic stem cell transplantation and failed multiline salvage therapies including anti-CD38 CAR-T therapy, but were successfully treated with PD-1 silenced anti-CLL-1 CAR-T therapy. Both patients achieved molecular complete remission with incomplete hematologic recovery at 28 days of evaluation after CLL-1 CAR-T cell infusion. Cytokine release syndrome in cases 1 and 2 were grade 1 and 2, respectively. At the last follow-up, cases 1 and 2 had maintained continuous remission for 8 and 3 months, respectively. Our results demonstrated that CLL-1 CAR-T cells might be an effective and safe salvage therapy for AML patients with posttransplant relapse.

Haploidentical CD7 CAR T-cells induced remission in a patient with TP53 mutated relapsed and refractory early T-cell precursor lymphoblastic leukemia/lymphoma.

Patients with relapsed/refractory early T-cell precursor lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) respond poorly to traditional therapy and have dismal prognosis. CD7 is a promising therapeutic targets for chimeric antigen receptor modified T cell therapy (CART) due to its widely expression in almost all T-cell malignancies. Here we present the anti-CD7 CART therapy in a 11-year-old male with TP53 mutated relapsed/refractory ETP-ALL/LBL. The patient suffered second relapse after haploidentical hematopoietic stem cell transplantation, showing resistance to 4 lines salvage therapies including venetoclax. Nanobody derived CD7-CART cells were manufactured by co-transducing CAR-T cells with a CD7 protein expression blocker. 70.5% of blasts (CD7 expression: 92.6%) and extensive extramedullary disease (mediastinal mass, enlarged lymph nodes and spleen) were observed prior to CD7-CART-cell therapy. A total of 5 × 106/kg donor-derived CD7-CART-cells were infused. Hematological and extramedullary remission were both achieved, with persistence of CD7-CART-cells be detected until the last followup at 96th days after the infusion. Reversible adverse effects including grade 3 cytokine release syndrome and macrophage activation syndrome were observed. This case demonstrated that CD7-CART was a potent and safe salvage therapy in relapsed/refractory ETP-ALL/LBL patient with high tumor burden.Trial registration: ClinicalTrials. gov, NCT04785833 , Registered on March 8, 2021, prospectively registered.

Interaction effects of asthma and rhinitis control on work productivity and activity impairment: A cross-sectional study.

Background: Symptomatic asthma and rhinitis negatively impact patients' work productivity and activity. However, little is known about the potential interaction effect of both asthma and rhinitis control on work productivity and activity impairment. Objective: This study aimed to explore whether there are interaction effects of asthma and rhinitis control on work productivity and activity impairment in patients with asthma and with rhinitis. Methods: A total of 206 adult patients were prospectively recruited and were divided into four groups: both poorly controlled (BPC) n = 53), poorly controlled asthma (PCA) with controlled rhinitis (CR) (n = 38), well controlled asthma with uncontrolled rhinitis (n = 43), and both well controlled (BWC) (n = 72) based on the symptom control status of asthma and rhinitis. Work productivity loss and activity impairment, asthma control, and rhinitis control were assessed by using work productivity and activity impairment questionnaire: general health, the asthma control test, and the rhinitis control assessment test, respectively. General linear regression models were used to study the contribution of asthma control, rhinitis control, and the interaction effect on work productivity and activity impairment. Results: Work productivity loss was most frequently reported in patients in the BPC group. Compared with the patients in the BWC group, the patients in the PCA-CR group had significantly higher activity impairment and worse asthma-related quality of life (both p < 0.001). There were significant interaction effects of asthma and rhinitis control, which accounted for the increase in presenteeism, work productivity loss, and activity impairment (all p < 0.001). Although differences in absenteeism were not significant among the groups, there was a significant interaction effect of control levels accounted for absenteeism (p = 0.035). Conclusion: Distinct interaction effects of asthma and rhinitis control reflected a link between upper and lower airways, which indicated that rhinitis control and the interaction effects of asthma and rhinitis control cannot be neglected during asthma management.

[Adsorption Properties of Sludge-hydrochar for Methylene Blue].

A low-cost and efficient adsorbent, based on sewage sludge, was prepared by hydrothermal carbonization. The sludge-hydrochar was prepared at different temperatures (160, 190, 220, and 250℃) and different reaction times (1, 4, 8, and 16 h). It was applied to the adsorption of methylene blue (MB) in water. This study analyzed the structure and physicochemical properties of hydrochar by BET, FT-IR, and zero charge points. In addition, we investigated the optimum hydrothermal conditions for the preparation of adsorbents and adsorption properties for MB by experiments. Studies have shown that 190℃ and 4 h were the best hydrothermal conditions for the preparation of adsorbent (SS190-4). SS190-4 has the largest specific surface area (11.916 m2·g-1) and the best removal rate (96.44%) for methylene blue (MB). The adsorption of MB is more favorable when the solution is alkaline. The adsorption conforms to the Langmuir isotherm equation, and the maximum model adsorption capacity for MB is 400 mg·g-1. When the concentration of hydrochar is 0.5 g·L-1, it is more economical and reasonable. When there are coexisting ions in the solution, the adsorption capacity of hydrochar to MB is inhibited. The adsorption process of MB by hydrochar conforms to the quasi-secondary kinetic model, which is a spontaneous exothermic reaction.

[Strenthening entry-exit supervision for protecting natural resources of traditional Chinese medicine].

China is highly rich of medicinal plants. Traditional Chinese medicine(TCM) has a long history and is important traditional resources in China. As one of the important strategic resources and the link among all the countries along the ancient "Silk Road", TCM has played important role in economy, politics, society and ecology. With the initiative of the "Belt and Road" in recent years, many natural resources of TCM now are facing the risk of extinction due to more and more frequent trade between China and other countries, also the increase of export has influenced to the stock of TCM. In order to prevent the loss of the resources, strengthen the protection and sustainable use of TCM, our study provided the strategies to the natural resources of TCM's entry-exit supervision from nine aspects, like law and regulation system, based on the analysis of current supervision status quo.

Clinical Features of Chronic Graft-Versus-Host Disease Following Haploidentical Transplantation Combined with Infusion of a Cord Blood.

Our previous studies demonstrated promising outcomes after haploidentical donor transplant combined with unrelated umbilical cord blood (haplo-cord- hematopoietic stem cell transplantation [HSCT]) for hematological disorders. However, clinical profiling regarding chronic graft-versus-host disease (cGVHD) has not yet been fully described under this protocol. This study analyzed the clinical characteristics of cGVHD among 300 patients with hematological malignancies who received haplo-cord-HSCT between January 2012 and July 2016 at our center. During the follow-up, the 5-year cumulative incidence of cGVHD based on the National Institutes of Health (NIH) consensus criteria was 32.2% (95% confidence interval [CI], 28.7-35.7); the 5-year cumulative incidence of moderate to severe cGVHD was 11.4% (95% CI, 9.4-13.4). After the multivariate analysis, the GVHD overall survival (GOS) was associated with relapse, thrombocytopenia, bronchiolitis obliterans syndrome, and steroid-refractory cGVHD. The infused CD34+ cells (≥3.46 × 106/kg) from haploidentical grafts were a protective factor affecting GOS. This study proposed a nomogram for predicting GOS using the aforementioned five variables. The concordance index was 0.877 (95% CI, 0.859-0.895) for the accuracy evaluation of the nomogram. Our results suggested that the 5-year cumulative incidence of NIH-defined cGVHD after haplo-cord-HSCT was 32.2%, and this nomogram may help clinicians select reasonable treatment strategies.

[Analysis of Heterogeneous Biological Characteristics and Prognosis-Related Factors in AL Patients with Mistranslation-Expressed Lymphoid and Myeloid-Related Antigen].

OBJECTIVE: To analyze the heterogeneous biological characteristics of acute leukemia (AL) patients with mistranslation expressed lymphoid and myeloid-related antigens, and it's prognosis-related factors. METHODS: Two hundred and fourteen AL patiens with mistranslation expressed lymphoid and myeloid-related antigens were grouped according to immunophenotypes, and the heterogeneous biologic charecteristics and prognosis related factors were analyzed, moreover the survival curves were drawn to analyze the survival of patiens. RESULTS: The immunophenotype in 214 cases was mainly cross-expression of myeloid and B lineage antigen (118 cases), followed by cross-expression of myeloid antigen and T lineage (88 cases), while the cross-expression of myeloid, T and B lineages, was less (only 8 cases). In ALL patiens with cross-expression of myeloid antigen, the CD33 was main type; while in AML patients with cross-expression of lymphoid antigen, CD7 was main type of lineage antigen, CD19 was main type of B lineage antigen. Among 214 AL patients, the cross-expression of CD55 and myeloid antigen was found in 30 cases, the cross-expression of CD7, CD19 and CD74 was observed in 6 cases, the cross-expressions of CD7, CD34 and CD56 was detected in 4 cases. Among AML patients with lymphoid antigen expression, the recurrent chromosmal abnormalities were found in 16 cases; among ALL patients with myeloid antigen expression, the recurrent chromosomal abnormalities were observed in 10 cases. The mistranslation antigen expression existed in 26 patients with recurrent chromosomal abnormalities, the mistranslated CD33 and CD13 in ALL patients with myeloid antigen expression was common, while the mistranslated CD2, CD56 and CD19 in AML patients with lymphoid antigen expression was common. As compared with patients without lymphoid antigen expression, the survival rate decreased significantly in patients with mistranslated CD7(+) and CD34(+) (both P<0.05). The logistic regression analysis showed that CD7, CD34 were main influencing factors for prognosis of AL patients (both P<0.05). CONCLUSION: The AL with mistranslation expressed lymphoid and myeloid antigens is a special kind of leukemia which possesses the heterogencous biological characteristcs and unique prognostic features, thus the immunophemotype of AL patients should be detected by flow cytometry. The existance of mistranlation-expressed differatiation antigens such as CD7 and CD34 is mainly influencing factors for the prognosis of AL patiens.

Giant conductance anisotropy in black phosphorene tuned by external electric field.

Based on the non-equilibrium Green's function method, the conductance anisotropy of black phosphorene has been studied under chemical potential and/or external electric field. The direction and magnitude of the conductance anisotropy strongly depend on the chemical potential, which are in good agreement with experimental observations. Furthermore, the magnitude of conductance anisotropy can be largely modulated by external electric field, which is one order of magnitude larger than previously reported. The directions of the maximum and minimum conductance can be reversed by external electric field, which shows that the former jumps from 24° to 90° and the latter jumps from 90° to 0° respectively. The results are fundamentally interesting and technologically promising in nano-electronics.

[Spatial heterogeneity and influencing factors of soil phosphorus concentration in a mid-subtropical Choerospondias axillaris deciduous broad-leaved forest, China.] / ä¸­äºšçƒ­å¸¦å—é ¸æž£è½å¶é˜”å¶æž—åœŸå£¤ç£·ç´ ç©ºé—´å˜å¼‚åŠå ¶å½±å“å› ç´ .

In order to investigate spatial variations in soil phosphorus (P) concentration and the influencing factors, one permanent plot of 1 hm2 was established and stand structure was surveyed in Choerospondias axillaries deciduous broadleaved forest in Dashanchong Forest Park in Changsha County, Hunan Province, China. Soil samples were collected with equidistant grid point sampling method and soil P concentration and its spatial variation were analyzed by using geo-statistics and geographical information system (GIS) techniques. The results showed that the variations of total P and available P concentrations in humus layer and in the soil profile at depth of 0-10, 10-20 and 20-30 cm were moderate and the available P showed higher variability in a specific soil layer compared with total P. Concentrations of total P and available P in soil decreased, while the variations increased with the increase in soil depth. The total P and available P showed high spatial autocorrelation, primarily resulted from the structural factors. The spatial heterogeneity of available P was stronger than that of total P, and the spatial autocorrelation ranges of total P and available P varied from 92.80 to 168.90 m and from 79.43 to 106.20 m in different soil layers, respectively. At the same soil depth, fractal dimensions of total P were higher than that of available P, with more complex spatial pattern, while available P showed stronger spatial correlation with stronger spatial structure. In humus layer and soil depths of 0-10, 10-20 and 20-30 cm, the spatial variation pattern of total P and available P concentrations showed an apparent belt-shaped and spot massive gradient change. The high value appeared at low elevation and valley position, and the low value appeared in the high elevation and ridge area. The total P and available P concentrations showed significantly negative correlation with elevation and litter, but the relationship with convexity, species, numbers and soil pH was not significant. The total P and available P exhibited significant positive correlations with soil organic carbon (SOC), total nitrogen concentration, indicating the leaching characteristics of soil P. Its spatial variability was affected by many interactive factors.