Mechanosensitive Ion Channel TMEM63A Gangs Up with Local Macrophages to Modulate Chronic Post-amputation Pain / 神经科学通报·英文版

Post-amputation pain causes great suffering to amputees, but still no effective drugs are available due to its elusive mechanisms. Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phantom pain afflicting patients after amputation. This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain (CPAP). However, the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery. In this study, we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infiltrated into the dorsal root ganglion (DRG) neurons worked synergistically to promote CPAP. Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG, and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer (TNT). Behavioral tests showed that the mechanical, heat, and cold sensitivity were not affected in the Tmem63a-/- mice in the naïve state, suggesting the basal pain was not affected. In the inflammatory and post-amputation state, the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a-/- mice. Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG, tibial nerve, residual stump, and the neuroma-like structure of the TNT mouse model, Consistent with this, expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β all increased dramatically in the DRG. Interestingly, the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump. Furthermore, the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model, indicating an interaction between nociceptors and macrophages, and that these two factors gang up together to regulate the formation of CPAP. This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.

Clinical research of less invasive surfactant administration combined with nasal intermittent positive pressure ventilation in preterm infants with respiratory distress syndrome / 中华急诊医学杂志

Objective:To evaluate the efficacy and safety of less invasive surfactant administration (LISA) combined with nasal intermittent positive pressure ventilation (NIPPV) in the treatment of infants with respiratory distress syndrome (RDS).Methods:A prospective study was conducted on preterm infants of gestational age ≤34 weeks with RDS who were admitted to the Neonatal Intensive Care Unit of Xuzhou Central Hospital from October 2019 to November 2021. The infants were randomly assigned into the LISA+NIPPV group and the intubation-surfactant-extubation (INSURE) +nasal continuous positive airway pressure (NCPAP) group. In the LISA+NIPPV group, with the support of NIPPV, a Lisa tube was inserted through the vocal cords under direct vision with direct laryngoscope, and then pulmonary surfactant (PS) was infused into the lung. In the INSURE+NCPAP group, the patients were endotracheally intubated and infused with PS into the lung through endotracheal tube, then extubated and continued to receive NCPAP therapy (INSURE). The blood gas analysis at 1 h and 6 h after PS infusion, the adverse reactions during injection, clinical efficacy, bronchopulmonary dysplasia (BPD) and other related complications were compared between the two groups.Results:A total of 112 preterm infants with RDS were enrolled, including 58 in the LISA+NIPPV group and 54 in the INSURE+NCPAP group. The blood oxygen partial pressure (PaO 2) and PaO 2/FiO 2 (P/F) in the LISA+NIPPV group were significantly higher than those in the INSURE+NCPAP group at 1 h and 6 h after PS infusion, while carbon dioxide partial pressure (PaCO 2) were significantly lower than that in the INSURE+NCPAP group, and the differences were statistically significant (all P<0.05). The rate of tracheal intubation within 72 h (15.5% vs. 33.3%), the duration of non-invasive ventilation [ (7.5 ± 4.3) d vs.(9.9 ± 5.5) d ], total oxygen inhaling [ (10.5 ± 3.5) d vs.(13.3 ± 4.1) d ], failure rate of machine withdrawal (8.6% vs. 31.0% ), the times of apnea [7.0 (3.0-21.0) times vs. 15.0 (4.0-28.0) times ] and re-administration of PS (17.2% vs. 33.3%) in the LISA+NIPPV group were significantly lower than those in the INSURE+NCPAP group, and the differences were statistically significant ( P<0.05). The incidence of regurgitation in the LISA+NIPPV group was lower than that in the INSURE+NCPAP group (13.8% vs. 35.2%), and the difference was statistically significant ( P<0.05). There was no significant difference in the time needed for intubation between the two groups ( P>0.05). The occurrence of BPD in the LISA+NIPPV group was significantly lower than that in the INSURE+NCPAP group (10.3% vs. 25.9%), and there was no significant difference in other related complication between the two groups (all P>0.05). Conclusions:LISA combined with NIPPV in the treatment of preterm infants with RDS can effectively improve oxygenation, reduce carbon dioxide retention, reduce the mechanical ventilation rate, shorten the duration of noninvasive mechanical ventilation, and reduce the incidence of BPD.

Clinical and molecular characteristics and prognosis of classical hairy cell leukemia and hairy cell leukemia variant / 中华内科杂志

Objective: To evaluate the clinical characteristics, treatment response, and outcomes in patients with classical hairy cell leukemia (cHCL) and HCL variant (HCL-V). Methods: This is a retrospective case series study. Between January 2011 and December 2021, clinical data of 30 patients newly with diagnosed HCL at Peking Union Medical College Hospital were analyzed. The main outcome measures include clinical characteristics, treatment efficacy and survival. The Kaplan-Meier method was used for survival analysis. Results: Twenty-one cases of cHCL and 9 cases of HCL-v were included. The median age at diagnosis was 55.5 (range, 30-86) years, with the ratio of male to female 2.75∶1. The main clinical manifestations included fatigue in 11 cases (36.7%), abdominal distension in 7 cases (23.3%), and infection in 4 cases, while 8 cases were asymptomatic. Splenomegaly was reported in 24 cases (80.0%), including 7 (23.3%) with megalosplenia. The white blood cell count, lymphocyte count, and the proportion of peripheral hairy cells in HCL-v group were significantly higher than those in cHCL group, whereas the development of anemia, thrombocytopenia, and monocytopenia in cHCL group was more remarkable than that in HCL-v group (all P<0.05). The BRAF-V600E gene mutation was detected only in cHCL patients (11/14 vs. 0/9, P<0.001). In terms of immunophenotype, the expression of CD25, CD103, CD123 and CD200 in cHCL group (20/20, 20/20, 4/7, 7/17) were all stronger than those in HCL-v group (3/9, 7/9, 0/4, 2/8). Twenty-two patients were treated, of which 13 cases (12 cases of cHCL and 1 case of HCL-v) with cladribine, and 9 cases (4 cHCL and 5 HCL-v) with interferon. Complete remission rate and overall response rate were comparable between cladribine and interferon treatment groups (both P<0.05). The median follow-up time was 31 (range, 1-125) months, and the median overall survival (OS) of the entire group was 125 months. The 5-year OS rate in HCL-v patients represented a trend of inferior (50.0% vs. 95.0%, P=0.207). Conclusions: The clinical features of HCL are unspecific, which includes fatigue, splenomegaly and recurrent infection. The clinical features, immunophenotype, treatment response and prognosis of HCL-v are different from those of cHCL. BRAF-V600E gene mutation is suggested as a key marker for differential diagnosis. Cladribine is recommended as front-line regimen of cHCL patients with satisfactory efficacy and prognosis. Conversely, response and clinical outcome in HCL-v patients still need to be improved.

The influencing factors of renal response in newly diagnosed multiple myeloma patients with renal impairment / 中华血液学杂志

Objective: To investigate the causative factors of renal function in newly diagnosed multiple myeloma (MM) patients with renal inadequacy. Methods: 181 MM patients with renal impairment from August 2007 to October 2021 at Peking Union Medical College Hospital were recruited, whose baseline chronic kidney disease (CKD) stage was 3-5. Statistical analysis was performed based on laboratory tests, treatment regimens, hematological responses, and survival among various renal function efficacy groups. A logistic regression model was employed in multivariate analysis. Results: A total of 181 patients were recruited, and 277 patients with CKD stages 1-2 were chosen as controls. The majority choose the BCD and VRD regimens. The progression-free survival (PFS) (14.0 months vs 24.8 months, P<0.001) and overall survival (OS) (49.2 months vs 79.7 months, P<0.001) of patients with renal impairment was considerably shorter. Hypercalcemia (P=0.013, OR=5.654) , 1q21 amplification (P=0.018, OR=2.876) , and hematological response over a partial response (P=0.001, OR=4.999) were independent predictive factors for renal function response. After treatment, those with improvement in renal function had a longer PFS than those without (15.6 months vs 10.2 months, P=0.074) , but there was no disparity in OS (56.5 months vs 47.3 months, P=0.665) . Conclusion: Hypercalcemia, 1q21 amplification, and hematologic response were independent predictors of the response of renal function in NDMM patients with renal impairment. MM patients with CKD 3-5 at baseline still have worse survival. Improvement in renal function after treatment is attributed to the improvement in PFS.

Clinical characteristics and progression risk factors for patients with monoclonal gammopathy of undetermined significance / 中华血液学杂志

Objective: To analyze the clinical presentation and progression risk factors of patients with monoclonal gammopathy of undetermined significance (MGUS) in China. Methods: We retrospectively assessed the clinical features and disease progression of 1 037 patients with monoclonal gammopathy of undetermined significance between January 2004 and January 2022 at Peking Union Medical College Hospital. Results: A total of 1 037 patients were recruited in the study, including 636 males (63.6%) , with a median age of 58 (18-94) years. The median concentration of serum monoclonal protein was 2.7 (0-29.4) g/L. The monoclonal immunoglobulin type was IgG in 380 patients (59.7%) , IgA in 143 patients (22.5%) , IgM in 103 patients (16.2%) , IgD in 4 patients (0.6%) , and light chain in 6 patients (0.9%) . 171 patients (31.9%) had an abnormal serum-free light chain ratio (sFLCr) . According to the Mayo Clinic model for risk of progression, the proportion of patients in the low-risk, medium-low-risk, medium-high risk, and high-risk groups were 254 (59.5%) , 126 (29.5%) , 43 (10.1%) , and 4 (0.9%) , respectively. With a median follow-up of 47 (1-204) months, 34 of 795 patients (4.3%) had disease progression, and 22 (2.8%) died. The overall progression rate was 1.06 (0.99-1.13) /100 person-years. Patients with non-IgM MGUS have a markedly higher disease progression rate per 100 person-years than IgM-MGUS (2.87/100 person-years vs 0.99/100 person-years, P=0.002) . The disease progression rate per 100 person-years in non-IgM-MGUS patients of Mayo classification low-risk, medium-low risk and medium-high risk groups were 0.32 (0.25-0.39) /100 person-years, 1.82 (1.55-2.09) /100 person-years, and2.71 (1.93-3.49) /100 person-years, which had statistically difference (P=0.005) . Conclusion: In comparison to non-IgM-MGUS, IgM-MGUS has a greater risk of disease progression. The Mayo Clinic progression risk model applies to non-IgM-MGUS patients in China.

Holocarboxylase synthetase deficiency induced by HLCS gene mutations: a rare disease study / 中国当代儿科杂志

A boy, aged 16 months, attended the hospital due to head and facial erythema for 15 months and vulva erythema for 10 months with aggravation for 5 days. The boy developed perioral and periocular erythema in the neonatal period and had erythema and papules with desquamation and erosion in the neck, armpit, and trigone of vulva in infancy. Blood gas analysis showed metabolic acidosis; the analysis of amino acid and acylcarnitine profiles for inherited metabolic diseases and the analysis of organic acid in urine suggested multiple carboxylase deficiency; genetic testing showed a homozygous mutation of c.1522C>T(p.R508W) in the HLCS gene. Finally the boy was diagnosed with holocarboxylase synthetase deficiency and achieved a good clinical outcome after oral biotin treatment. This article analyzes the clinical data of a child with holocarboxylase synthetase deficiency and summarizes the etiology, diagnosis, and treatment of this child, so as to provide ideas for clinicians to diagnose this rare disease.

Study on the Regulation of Chidamide on CD8+T Cells in T-cell Acute Lymphoblastic Leukemia / 中国实验血液学杂志

OBJECTIVE@#To explore the regulatory effect of chidamide on CD8+ T cells in T-cell acute lymphoblastic leukemia.@*METHODS@#The expression levels of CXCL9 and CXCL3 mRNA in Jurkat cells, lymphocytes treated with chidamide and lymphocytes co-cultured with chidamide-treated Jurkat cells were detected by fluorescence quantitative PCR. The proportion of CD8+ T cells in lymphocytes treated with chidamide and lymphocytes co-cultured with chidamide-treated Jurkat cells was determined by flow cytometry.@*RESULTS@#Chidamide upregulated CXCL9 mRNA expression in Jurkat cell line in a dose-dependent manner (r=0.950). The mRNA expression of CXCL9 in chidamide 5 μmol/L group was 164 times higher than that in control group. Chidamide upregulated CXCL9 mRNA expression in lymphocytes, but the up-regulated level was significantly lower than that in Jurkat cell line treated with the same concentration of chidamide. Co-culture with chidamide treated Jurkat cells upregulated the proportion of CD8+ T cells in lymphocytes.@*CONCLUSION@#In T-cell acute lymphoblastic leukemia, chidamide may increase the concentration of CXCL9 in the tumor microenvironment by up-regulating the expression of CXCL9 in tumor cells, leading to an increase in the number of CD8+ T cells.

Progress in surgical treatment of malignant pleural mesothelioma / 中华胸心血管外科杂志

Malignant pleural mesothelioma(MPM) is a kind of rare and aggressive malignant neoplasm. Surgery plays one of the most important roles in the treatment of MPM. However, due to the high morbidity and mortality reported, the survival benefit and indication of surgery are still controversial. This article will review the surgical indications, discuss and compare the roles of extrapleural pneumonectomy(EPP) and pleurectomy / decortication(P/D) which aim to achieve macroscopic complete resection(MCR) in the treatment of MPM. Finally, we summarized the progress of other treatment methods including targeted therapy and immunotherapy.

Study on the correlation between telomere dysfunction of human gastric mucosa and chronic atrophic gastritis / 中华消化杂志

Objective:To investigate the correlation between telomere dysfunction of human gastric mucosa and chronic atrophic gastritis (CAG).Methods:From February 12, 2019 to July 10, 2020, at Endoscopy Center, Guang′anmen Hospital, China Academy of Chinese Sciences, 30 patients received endoscopy and pathological diagnosed with CAG (CAG group) were collected, and 30 patients with chronic non-atrophic gastritis (CNAG) were collected at the same time (CNAG group). The relative telomere length was detected by real time fluorescent quantitative polymerase chain reaction. The expression of telomere repeat binding factor (TRF) 1, TRF2 and protection of telomere (POT) 1 at protein level were detected by immunohistochemical staining and semi-quantitative analysis. Spearman analysis was used to analyze the correlation between the relative telomere length of gastric mucosa and the protein expression levels of TRF1, TRF2 and POT1. Mann-Whitney U test and independent sample t test were used for statistical analysis. Results:The relative telomere length of the gastric mucosa in the CAG group was shorter than that in the CNAG group (0.67 (0.51 to 1.17) vs. 1.06(0.69 to 1.37)), and the difference was statistically significant ( U=297.00, P=0.024). The protein expression levels of TRF1, TRF2, and POT1 in the CAG group were all higher than those in the CNAG group, respectively (4.26±2.49 vs. 1.86±1.34, 10.12±2.76 vs. 8.78±2.81, 4.22±2.48 vs. 2.53±1.62), and the differences were statistically significant ( t=8.05, 3.23, 5.39; P<0.001, =0.001, and <0.001). In the CAG group, the protein expression levels of TRF2 and POT1 in gastric mucosa were negatively correlated with the relative telomere length ( r=-0.477 and -0.417, P=0.008 and 0.022). Conclusions:The telomere dysfunction is related to the pathogenesis of CAG. The change of telomere binding protein expression level is involved in the shortening of telomere and pathological process of CAG patients.

Running ahead of evolution - AI based simulation for predicting future high-risk SARS-CoV-2 variants

The never-ending emergence of SARS-CoV-2 variations of concern (VOCs) has challenged the whole world for pandemic control. In order to develop effective drugs and vaccines, one needs to efficiently simulate SARS-CoV-2 spike receptor binding domain (RBD) mutations and identify high-risk variants. We pretrain a large protein language model on approximately 408 million protein sequences and construct a high-throughput screening for the prediction of binding affinity and antibody escape. As the first work on SARS-CoV-2 RBD mutation simulation, we successfully identify mutations in the RBD regions of 5 VOCs and can screen millions of potential variants in seconds. Our workflow scales to 4096 NPUs with 96.5% scalability and 493.9x speedup in mixed precision computing, while achieving a peak performance of 366.8 PFLOPS (reaching 34.9% theoretical peak) on Pengcheng Cloudbrain-II. Our method paves the way for simulating coronavirus evolution in order to prepare for a future pandemic that will inevitably take place. Our models are released at https://github.com/ZhiweiNiepku/SARS-CoV-2_mutation_simulation to facilitate future related work.

Cross-neutralization and viral fitness of SARS-CoV-2 Omicron sublineages

The rapid evolution of SARS-CoV-2 Omicron sublineages mandates a better understanding of viral replication and cross-neutralization among these sublineages. Here we used K18-hACE2 mice and primary human airway cultures to examine the viral fitness and antigenic relationship among Omicron sublineages. In both K18-hACE2 mice and human airway cultures, Omicron sublineages exhibited a replication order of BA.5 [≥] BA.2 [≥] BA.2.12.1 > BA.1; no difference in body weight loss was observed among different sublineage-infected mice. The BA.1-, BA.2-, BA.2.12.1-, and BA.5-infected mice developed distinguisable cross-neutralizations against Omicron sublineages, but exhibited little neutralizations against the index virus (i.e., USA-WA1/2020) or the Delta variant. Surprisingly, the BA.5-infected mice developed higher neutralization activity against heterologous BA.2 and BA.2.12.1 than that against homologous BA.5; serum neutralizing titers did not always correlate with viral replication levels in infected animals. Our results revealed a distinct antigenic cartography of Omicron sublineages and support the bivalent vaccine approach.

Comparative transcriptomic analysis of the super hybrid rice Chaoyouqianhao under salt stress.

BACKGROUND: Soil salinization is a threat to food security. China is rich in saline land resources for potential and current utilization. The cultivation and promotion of salt-tolerant rice varieties can greatly improve the utilization of this saline land. The super hybrid rice Chaoyouqianhao (CY1000) is one of the most salt-tolerant rice varieties and is widely used, but the molecular mechanism underlying its salt tolerance is not clear. RESULTS: In this study, the characteristics of CY1000 and its parents were evaluated in the field and laboratory. The results showed that aboveground parts of CY1000 were barely influenced by salt stress, while the roots were less affected than those of its parents. A comparative transcriptomic strategy was used to analyze the differences in the response to salt stress among the male and female parents of CY1000 at the seedling stage and the model indica rice 93-11. We found that the salt tolerance of CY1000 was mainly inherited from its male parent R900, and its female parent GX24S showed hardly any salt tolerance. To adapt to salt stress, CY1000 and R900 upregulated the expression of genes associated with soluble component synthesis and cell wall synthesis and other related genes and downregulated the expression of most genes related to growth material acquisition and consumption. In CY1000 and R900, the expression of genes encoding some novel key proteins in the ubiquitination pathway was significantly upregulated. After treatment with MG-132, the salt tolerance of CY1000 and R900 was significantly decreased and was almost the same as that of the wild type after salt stress treatment, indicating that ubiquitination played an important role in the salt tolerance mechanism of CY1000. At the same time, we found that some transcription factors were also involved in the salt stress response, with some transcription factors responding only in hybrid CY1000, suggesting that salt tolerance heterosis might be regulated by transcription factors in rice. CONCLUSION: Our results revealed that the ubiquitination pathway is important for salt tolerance in rice, and several novel candidate genes were identified to reveal a novel salt tolerance regulation network. Additionally, our work will help clarify the mechanism of heterosis in rice. Further exploration of the molecular mechanism underlying the salt tolerance of CY1000 can provide a theoretical basis for breeding new salt-tolerant rice varieties.

Time-resolved fluorescence immunochromatographic assay for the detection of mycoplasma pneumoniae IgM and IgG / 中华核医学与分子影像杂志

Objective:To establish time-resolved fluorescence immunochromatographic assay (TFICA) for rapid and quantitative detection of mycoplasma pneumoniae (MP) immunoglobulin (Ig)M and IgG.Methods:Based on capillary effect and europium nanospheres, rapid TFICA for MP-IgM and IgG detections were developed with the optimized parameters (coupling rates of antigens or antibodies to microspheres, dilution of labeled nanospheres, fixture concentrations on test line and serum dilutions). The methodological performances were estimated such as sensitivity, specificity, stability. By testing 55 healthy control samples, the reference values of TFICA were obtained. The reliability was evaluated by Kappa test from detecting sera of 88 cases (33 patients and 55 healthy controls) using TFICA and commercial kits by chemiluminescence immunoassays (CLA). Results:After screening the assay conditions, the mass ratios of mouse anti-human IgG and MP antigen with nanospheres were 1∶20 and 1∶100 respectively; the work dilutions of nanobeads conjugated with anti-human IgG and MP antigen were 1∶200 and 1∶100 respectively; the spraying concentrations of MP antigen and goat anti-human IgM were 0.5 and 1.0 g/L on the test line respectively, and the working dilutions of serum sample were both 1∶300. In the MP-IgM and IgG detections, the linear working ranges were (0.78-70.00)×10 3 relative unit (RU)/L and (0.17-200.00)×10 3 RU/L, while the sensitivities of the assays were 0.78×10 3 and 0.17×10 3 RU/L, respectively. No cross reactions were found with antithyroid peroxidase antibody, anticardiolipin antibody or thyroglobulin antibody. In these MP-IgM and IgG assays, the relative standard deviations were 3.7%-14.8% and 2.9%-14.0%, the average reduction rates of fluorescence were 13.7% and 14.2% respectively after incubation at 37 ℃ for 5 d. The reference values of MP-IgM and IgG were 3.33×10 3 and 2.61×10 3 RU/L, while the Kappa values between TFICA and CLA were 0.79 and 0.76, respectively. Conclusion:TFICA is a simple, sensitive, specific and quantitative method for detecting MP-IgM and IgG antibodies, and may show great promise for future clinical use.

MYC and BCL-2 protein co-expression and prognosis of patients with diffuse large B-cell lymphoma: a propensity score matching analysis / 中华血液学杂志

Objective: We investigated the impact of MYC/BCL-2 protein co-expression on the prognosis of diffuse large B-cell lymphoma (DLBCL) patients and observed whether double expression (DE) remains an independent poor prognostic factor in DLBCL after the addition of therapeutic factors such as DA-EPOCH-R, central prophylaxis, and transplantation. Methods: Available pathological findings were retrospectively collected from 223 DLBCL patients at the Peking Union Medical College Hospital from 2015 to 2018. Seventy-five patients with high MYC/BCL-2 expression were categorized as the DE group. From the 148 non-DE patients, 75 DLBCL patients were selected as the control group, using a 1∶1 matching on propensity scores for age, international prognostic index score, treatment choice, and etc. The differences in overall survival (OS) and progression-free survival (PFS) between the two groups were compared. Results: The 3-year OS was (69.8±5.5) % for the DE group and (77.0±4.9) % for the non-DE group (P=0.225) , while the 3-year PFS was (60.7±5.8) % and (65.3±5.5) % , respectively (P=0.390) . Subgroup analysis in patients treated with the R-CHOP regimen revealed that for the DE and non-DE patients, the 3-year OS was (61.3±7.5) % and (77.2±5.6) % (P=0.027) , and the 3-year PFS was (52.1±7.5) % and (70.6±6.0) % (P=0.040) , respectively. Multivariate analysis showed that age, stage of Ann Arbor, COO staging, whether central prophylaxis was performed, and whether transplantation was performed were significant independent risk factors of the prognosis of DLBCL patients (P<0.05) . On the other hand, MYC/BCL-2 protein double expression was not significantly associated with prognostic outcomes. Conclusion: MYC/BCL-2 protein double expression was significantly associated with poor prognosis under R-CHOP regimen treatment, but the poor prognostic impact of DE on DLBCL was eliminated under intensive regimens such as DA-EPOCH-R and transplantation.

Efficacy and safety of daratumumab in the treatment of advanced light chain amyloidosis / 中华血液学杂志

Objective: The study investigated the efficacy and safety of daratumumab in the treatment of cardiac light chain (AL) amyloidosis. Methods: We retrospectively analyzed the clinical characteristics, hematologic response, organ response, long-term survival, and adverse events of 20 patients with newly diagnosed or relapsed/refractory cardiac AL amyloidosis treated with daratumumab in Peking Union Medical College Hospitalo from January 2017 to March 2021. Results: The overall median age of 20 patients was 62 (range, 45-73) yeas, with a male to female ratio of 2.3:1. Nine patients were newly diagnosed, while 11 patients had relapsed or refractory disease. Based on Mayo 2004 cardiac AL staging system, stages Ⅱ and Ⅲ diseases were present in 20 patients respectively. Four patients died during the first cycle of daratumumab, and the remaining 16 patients completed a median of 3 (range, 1-10) cycles of treatment. Overall hematologic response rates were 80% each at 1, 3, and 6 months after treatment initiation, and 45% , 60% , and 60% of the patients achieved at least a very good partial response at 1, 3, and 6 months respectively. The median duration to hematologic response was 13 (range, 6-28) days. At 3, 6, and 12 months, 20% , 30% , and 40% of the patients respectively achieved a cardiac response, and the median days to response was 91 (range, 30-216) days. As of the last follow-up, 9 (45% ) patients died. The 1-month mortality rate of all the patients and stage IIIb patients was 25% and 40% , respectively. The 1-year overall survival rate was 48.4% . Lymphocytopenia was the most common hematological adverse event (above grade 3) . Non-hematological adverse events were mainly infusion-related reactions and infections. Conclusion: Daratumumab could induce deep and rapid hematologic response in newly diagnosed and previously treated cardiac AL amyloidosis patients. However, daratumumab was not effective in preventing the high and early mortality rate in stage Ⅲb patients.

Trends in clinicopathological characteristics of surgically-treated lung cancer: sex-based heterogeneity / 中华胸心血管外科杂志

Objective:To explore the sex-based heterogeneity in demographic and pathological trends of lung cancer during the past 30 years.Methods:Patients with primary lung cancer who received surgical treatment in the Department of thoracic surgery, Shanghai Pulmonary Hospital Tongji University from 1989 to 2018 were retrospectively analyzed. The differences between male and female patients in age, smoking history, pathological stage and type were compared. Mann- Kendall trend test was performed for trend analysis. Results:A total of 58 433 patients were included in this study, encompassing 30 729(52.6%) men and 27 , 704(47.4%) women. Compared with male patients, female patients were younger(56.0 years old vs. 59.7 years old), and had a higher proportion of non-smokers(98.3% vs. 52.3%), stage Ⅰ lung cancers(60.6% vs. 49.3%), and adenocarcinoma(93.7% vs. 56.1%, all P-values <0.001). Trend analyses revealed that the proportion of female patients increased year by year, and surpassed males in 2015, with the current ratio of male to female being 1∶1.5. After 2013, the age of onset in females was getting younger, and the average age decreased from 58.7 years old to 54.7 years old( P=0.02). The decrease in the proportion of smoking patients was mainly reflected by male patients(from 68.5% to 31.1%, P<0.01). Stage Ⅰ lung cancers in male and females outnumbered advanced stage in 2012 and 2010, respectively, with a much higher proportion in female patients. Among male patients, adenocarcinoma has replaced squamous cell carcinoma as the most common pathological type since 2012, while in female patients adenocarcinoma remained the most common pathological type of lung cancer, and its proportion continued to increase reaching over 98%. Conclusion:A dramatic change in gender distribution was noticed during the past 30 years. Female patients became the primary population in surgically-treated lung cancers, with a trend of getting younger. The proportion of smokers and squamous cell carcinoma decreased significantly in male patients, and adenocarcinoma has become the most common pathological type of lung cancer. The proportion of stage Ⅰ lung cancers was on a dramatic rise, with the popularization of CT screening for lung cancer.

Scutellarin alleviates lipopolysaccharide-induced renal injury via mediating cysteine-rich protein 61-connective tissue growth factor-nephroblastoma overexpressed gene 1 expression to inhibit nuclear factor-κB signaling pathway / 中华危重病急救医学

Objective:To explore the protective effect and mechanism of scutellarin (Scu) on sepsis associated-acute kidney injury (SA-AKI).Methods:① In vivo experiment: 36 male C57BL/6 mice were divided into normal saline (NS) control group, lipopolysaccharide (LPS) induced SA-AKI model group (LPS group), 20 mg/kg Scu control group (Scu 20 control group), and 5, 10, 20 mg/kg Scu pretreatment groups by random number table with 6 mice in each group. The SA-AKI model was reproduced by intraperitoneal injection of 10 mg/kg LPS. The NS control group was injected with NS intraperitoneally. The Scu pretreatment groups were intraperitoneally injected with different doses of Scu every day before LPS injection for 1 week. Scu 20 control group was injected with 20 mg/kg Scu for 1 week. After 24 hours of LPS treatment, mice in each group were sacrificed, kidney tissues were collected, and kidney injury was detected by hematoxylin-eosin (HE) staining. Western blotting was used to detect the protein expression levels of nuclear factor-κB (NF-κB) signaling pathway related molecules, apoptosis-related proteins and cysteine-rich protein 61-connective tissue growth factor-nephroblastoma overexpressed gene 1 (CCN1). ② In vitro experiment: human renal tubular epithelial cell line HK-2 was cultured in vitro and used for experiment when the cells fused to 80%. In the cells without LPS treatment and after 100 g/L LPS treatment, pcDNA3.1-CCN1 and small interfering RNA (siRNA) CCN1 sequence were transfected to overexpress and inhibit CCN1 expression, respectively, to observe whether CCN1 was involved in NF-κB signaling pathway activation and apoptosis. In addition, 100g/L LPS and 20 μmol/L Scu were added into HK-2 cells transfected with and without CCN1 siRNA to investigate the mechanism of protective effect of Scu on LPS-induced HK-2 cells injury. Results:① The results of in vivo experiment: the renal function of SA-AKI mice induced by LPS was significantly decreased, and had kidney histological damage and severely damaged renal tubules. Scu could alleviate renal function and histological damage in a dose-dependent manner. Western blotting results showed Scu could reduce the protein expression of NF-κB signaling pathway related molecules and CCN1 in the renal tissue, and had a significant alleviating effect on apoptosis, indicating that CCN1 was involved in NF-κB signaling pathway activation and apoptosis. ② The results of in vitro experiment: in HK-2 cells not treated with LPS, CCN1 overexpression had no effect on apoptosis related protein and pro-inflammatory factors of NF-κB signaling pathway. In HK-2 cells treated with LPS, overexpression of CCN1 significantly inhibited the mRNA expressions of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1), with significant differences as compared with cells stimulated only by LPS [IL-1β mRNA (2 -ΔΔCT): 3.20±0.57 vs. 4.88±0.69, TNF-α mRNA (2 -ΔΔCT): 2.99±0.44 vs. 5.00±0.81, MCP-1 mRNA (2 -ΔΔCT): 2.81±0.50 vs. 5.41±0.75, all P < 0.05], and the apoptosis-related protein was significantly down-regulated. However, when siRNA was used to inhibit the expression of CCN1, the mRNA expressions of pro-inflammatory factors were significantly increased as compared with cells stimulated only by LPS [IL-1β mRNA (2 -ΔΔCT): 6.01±1.13 vs. 4.88±0.69, TNF-α mRNA (2 -ΔΔCT): 5.15±0.86 vs. 5.00±0.81, all P < 0.05], and apoptosis-related protein was significantly up-regulated. In the LPS-induced HK-2 cells, the mRNA expressions of pro-inflammatory factors were significantly down-regulated after Scu treatment as compared with cells stimulated only by LPS [IL-1β mRNA (2 -ΔΔCT) : 2.55±0.50 vs. 6.15±1.04, TNF-α mRNA (2 -ΔΔCT): 2.58±0.40 vs. 3.95±0.52, MCP-1 mRNA (2 -ΔΔCT): 2.64±0.44 vs. 6.21±0.96, all P < 0.05], and apoptosis-related protein was also significantly reduced. When the expression of CCN1 was inhibited by siRNA, the protective effect of Scu on cells was weakened, which showed that the mRNA expressions of pro-inflammatory factors in cells was significantly up-regulated compared with the cells without inhibition of CCN1 expression [IL-1β mRNA (2 -ΔΔCT): 5.34±0.76 vs. 2.55±0.50, TNF-α mRNA (2 -ΔΔCT): 3.66±0.54 vs. 2.58±0.40, MCP-1 mRNA (2 -ΔΔCT): 5.15±0.79 vs. 2.64±0.44, all P < 0.05], and the expression of apoptosis related protein was also significantly up-regulated. Conclusions:Scu could protect the renal function in SA-AKI mice, and the protective effect is associated with NF-κB signaling pathway and CCN1. Thus, Scu could alleviate LPS-induced kidney injury by regulating the NF-κB signaling pathway.

MiR-322-5p Alleviates Cell Injury and Impairment of Cognitive Function in Vascular Dementia by Targeting TSPAN5

Purpose@#As the population ages, the incidence of clinical dementia has been rising around the world. It has been reported that microRNAs act as key diagnostic biomarkers and targets for various neurological conditions, including dementia. MiR-322-5p has been revealed to play an important role in multiple diseases. In this study, we aimed to investigate the role and regulatory mechanism of miR-322-5p in vascular dementia. @*Materials and Methods@#In this study, neonatal rat neurons (NRNs) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to induce cell injury. The animals were subjected to permanent bilateral occlusion of the carotid arteries (2-vessel occlusion, 2VO) to induce the model of chronic brain hypoperfusion. @*Results@#MiR-322-5p expression was significantly downregulated in the neurons exposed to OGD/R and the hippocampi of 2VO rats. Overexpression of miR-322-5p ameliorated cell apoptosis and the inflammatory response in vitro. In a mechanistic study, miR-322-5p was confirmed to directly target and negatively regulate tetraspanin 5 (TSPAN5) in cultured NRNs. Moreover, overexpression of TSPAN5 could counteract the effects of miR-322-5p overexpression on cell apoptosis and the inflammatory response in OGD/Rtreated neurons. More importantly, miR-322-5p improved cognitive ability and inhibited inflammatory production in 2VO rats. @*Conclusion@#Overall, the results suggest that miR-322-5p alleviates vascular dementia development by targeting TSPAN5. This discovery may provide a potential therapeutic target for dementia.

Chinese Herbal Medicine Adjusting Brain Microenvironment via Mediating Central Nervous System Lymphatic Drainage in Alzheimer's Disease / 中国结合医学杂志

Due to its complex pathogenesis and lack of effective therapeutic methods, Alzheimer's disease (AD) has become a severe public health problem worldwide. Recent studies have discovered the function of central nervous system lymphatic drainage, which provides a new strategy for the treatment of AD. Chinese herbal medicine (CHM) has been considered as a cure for AD for hundreds of years in China, and its effect on scavenging β-amyloid protein in the brain of AD patients has been confirmed. In this review, the mechanism of central nervous system lymphatic drainage and the regulatory functions of CHM on correlation factors were briefly summarized. The advances in our understanding regarding the treatment of AD via regulating the central lymphatic system with CHM will promote the clinical application of CHM in AD patients and the discovery of new therapeutic drugs.

Design and application of arterial blood gas analysis assisted by electronic computation: analysis of two cases attached / 中国小儿急救医学

Objective:To make Excel spreadsheet of arterial blood gas analysis to judge the types of acid-base imbalance quickly and accurately, and guide the clinical treatment of acid-base disorders.Methods:According to the Henderson-Hasselbalch equation, the compensation formula of acid-base imbalance prediction, the theory of acid-base balance and the related research progress, the analysis process of acid-base balance disorder was settled, and the IF function in Microsoft Office Excel 2003 was used to edit the formula to make Excel spreadsheet for arterial blood gas analysis.Once the pH value, artery blood carbon dioxide pressure (PaCO 2), actual bicarbonate (HCO 3-), sodiumion (Na + ), chlorineion (Cl -) and compensatory time-limited parameters were input, the types of acid-base imbalance can be shown.Arterial blood gas analysis of 185 cases from intensive care unit at Xuzhou Central Hospital was determined by Excel spreadsheet group and manual group respectively, the results and time of judging the type of acid-base imbalance were compared between two groups for statistical analysis. Results:The results of acid-base imbalance between two groups were compared, and 42 cases were normal and simple acid-base and the consistent rate was 100%, double acid-base imbalances of 107 cases with the consistent rate of 97.20%, triple acid-base imbalances of 36 cases with the consistent rate of 91.67%.After Kappa consistency test (Kappa value=0.944) and Pair chi-square Test (McNemar-Bowker Test)( P=0.223), the results of two groups were consistent.It took less time to judge the results of normal or simple acid-base imbalance[(32.32±4.26)s vs.(75.88±19.22)s], double acid-base imbalance[(31.28±5.31)s vs.(137.56±37.64)s] and triple acid-base imbalance[(32.98±4.23)s vs.(315.09±89.37)s] by the Excel spreadsheet group compared with the manual group, and the differences were statistically significant ( P<0.01). Conclusion:The automatic judging of Excel spreadsheet for arterial blood gas analysis can quickly and accurately determine the types of acid-base imbalance in arterial blood gas analysis and has more advantages for triple acid and base imbalance especially with simple interface and simple operation.And it can avoid the missing judgment of acid and base imbalance when pH is 7.35 to 7.45.