Objective:This study investigated the efficacy and safety of denosumab (DENOS) versus zoledronic acid (ZOL) in the bone disease treatment of newly diagnosed multiple myeloma.Methods:The clinical data of 80 patients with myeloma bone disease (MBD) at the Fifth Medical Center of PLA General Hospital between March 1, 2021 and June 30, 2023 were retrospectively reviewed. Eighteen patients with severe renal impairment (SRI, endogenous creatinine clearance rate<30 ml/min) were treated with DENOS, and 62 non-SRI patients were divided into DENOS (30 patients) and ZOL group (32 patients) .Results:Hypocalcemia was observed in 26 (33%) patients, and 22 patients developed hypocalcemia during the first treatment course. The incidence of hypocalcemia in the non-SRI patients of DENOS group was higher than that in the ZOL group [20% (6/30) vs 13% (4/32), P=0.028]. The incidence of hypocalcemia in SRI was 89% (16/18). Multivariate logistic regression analysis revealed that endogenous creatinine clearance rate<30 ml/min was significantly associated with hypocalcemia after DENOS administration ( P<0.001). After 1 month of antiresorptive (AR) drug application, the decrease in the serum β-C-terminal cross-linked carboxy-telopeptide of collagen type I concentrations of SRI and non-SRI patients in the DENOS group were significantly higher than that in the ZOL group (68% vs 59% vs 27%, P<0.001). The increase in serum procollagen type Ⅰ N-terminal propeptide concentrations of patients with or without SRI in the DENOS group were significantly higher than that in the ZOL group (34% vs 20% vs 11%, P<0.05). The level of intact parathyroid hormone in each group increased after AR drug treatment. None of the patients developed osteonecrosis of the jaw and renal adverse events, and no statistically significant differences in the overall response rate, complete remission and stringent complete remission rates were found among the groups ( P>0.05), and the median PFS and OS time were not reached ( P>0.05) . Conclusions:In the treatment of MBD, DENOS minimizes nephrotoxicity and has strong AR effect. Hypocalcemia is a common adverse event but is usually mild or moderate and manageable.

Objective:To explore the independent risk factors of portal vein thrombosis (PVT) in liver cirrhosis, and to establish and evaluate a risk prediction model for PVT in patients with cirrhosis.Methods:A total of 295 cases of cirrhosis hospitalized in Renmin Hospital of Wuhan University from December 2019 to October 2021 were divided into a modeling set ( n=207) and an internal validation set ( n=88) by the random number table. In addition, patients with cirrhosis hospitalized in Yichang Central People's Hospital, Wuhan Puren Hospital, No.2 People's Hospital of Fuyang City and People's Hospital of China Three Gorges University during the same period were collected as an external validation set ( n=92). The modeling set was divided into PVT group ( n=56) and non-PVT group ( n=151). Univariate analysis was used to preliminarily screen the related indicators of PVT, and then multivariate logistic regression analysis with forward stepwise regression was used to determine independent risk factors for PVT. A nomogram prediction model was constructed based on the independent risk factors obtained. The internal and external validation set were used to verify the predictive ability of the model. Distinction degree was used to evaluate the ability of the model to distinguish patients with or without PVT. Hosmer-Lemeshow goodness-of-fit test was used to evaluate the consistency between predicted risk and the actual risk of the model. Results:Univariate analysis showed that smoking, history of splenectomy, trans-jugular intrahepatic portosystemic shunt (TIPS), gastrointestinal bleeding and endoscopic variceal treatment, and levels of hemoglobin, alanine aminotransferase, aspartate aminotransferase and D-dimer were significantly different between the PVT group and the non-PVT group ( P<0.05). Multivariate logistic regression analysis found that smoking ( P=0.020, OR=31.21, 95% CI: 1.71-569.40), levels of D-dimer ( P=0.003, OR=1.12, 95% CI: 1.04-1.20) and hemoglobin ( P=0.039, OR=0.99, 95% CI: 0.97-1.00), history of TIPS ( P=0.011, OR=18.04, 95% CI: 1.92-169.90) and endoscopic variceal treatment ( P=0.001, OR=3.21, 95% CI: 1.59-6.50) were independent risk factors for PVT in patients with liver cirrhosis. Receiver operator characteristic (ROC) curve analysis showed that the area under the ROC curve (AUC) for the internal validation set was 0.802 (95% CI: 0.709-0.895) ( P<0.001), and the AUC for the external validation set was 0.811 (95% CI: 0.722-0.900) ( P<0.001). Both AUC were larger than 0.75. The calibration curve of Hosmer-Lemeshow goodness-of-fit test showed that the P values of both internal validation set ( χ2=3.602, P=0.891) and the external validation set ( χ2=11.025, P=0.200) were larger than 0.05. Conclusion:Smoking, history of TIPS or endoscopic variceal treatment, levels of D-dimer and hemoglobin are independent risk factors for PVT in patients with liver cirrhosis. The prediction nomogram model based on the above factors has strong predictive ability.

Objective To analyze the clinical characteristics,treatment regimens and influencing factors of prognosis of patients with mantle cell lymphoma(MCL).Methods The clinical data of 41 patients with MCL was collected.These patients were initially diagnosed and treated in the Fifth Medical Center of Chinese PLA General Hospital between August 2004 and December 2019.The clinical features,therapeutic efficacy and prognosis-related factors were clarified.Results The median duration of follow-up was 68(1-165)months.The 3-year progression free survival(PFS)and overall survival(OS)were 37.29%and 62.75%respectively.Based on univariate analysis,B symptoms,Eastern Cooperative Oncology Group(ECOG)scores,the mantle cell lymphoma international prognostic index(MIPI),relapse and refractory state and the therapeutic effect were statistically significant for progression free survival.B symptoms,R-chemotherapy and therapeutic effect were statistically significant for overall survival.In multivariate analysis,B symptoms and the MIPI were statistically significant for progression free survival.B symptoms,R-chemotherapy and therapeutic effect were statistically significant for overall survival.There were statistically significant differences in 3-year OS between patients with different MIPI and MIPI-C scores.Conclusion Mantle cell lymphoma mostly occurs in elder males,and is more likely to be detected in late the stage.B symptoms,R-chemotherapy and therapeutic effect are independent prognostic factors for patients with MCL.The MIPI and MIPI-C scores have clinical guidance significance for patient survival.

Objective:To analyze the characteristics of child cases admitted to accidental injury and provide reliable basis for the prevention of accidental injury.Methods:The clinical data of children admitted to Hunan Children′s Hospital aged 0-18 due to accidental injuries from January 1, 2018 to December 31, 2021 were retrospectively analyzed. The type of accidental injury and characteristic factors such as prognosis, gender, age, time, and location of the child were analyzed.Results:A total of 9 049 children with accidental injury were admitted, accounting for 3.72%(9 049/33 697) of the total number of hospitalized children. The top three types of accidental injuries were falls/drop (3 695 cases), foreign bodies/suffocation (2 639 cases) and traffic accidents (1 165 cases), accounting for 82.87%(7 499/9 049). There were 8 760 cases (96.81%) of improvement and recovery, 178 cases (1.97%) of disability, and 111 cases (1.23%) of unhealed/dead. Among the accidental injuries, 5 833 cases (64.46%) were boys and 3 216 cases (35.54%) were girls, and the incidence ratio was 1.81∶1. There was significant difference between boys and girls in the composition ratio of the type of accidental injury such as falls/falls, foreign bodies/suffocation, poisoning, sharp object injury, drowning ( χ2 values were 3.90-20.56, all P<0.05). Among the accidental injuries, the children aged 1 to<3 years had higher accidental injuries than the other age groups (3 263 cases, accounting for 36.06%), and the composition ratio of accidental injuries in different age groups was different ( χ2 values were 12.98-573.97, all P<0.05). Among the accidental injuries, the accidental injuries occurred in the second quarter and the third quarter were higher than those in the other two quarters (4 892 cases, accounting for 54.06%), and the composition ratio of accidental injuries such as falls/falls, foreign bodies/suffocation, burn and scald, drowning occurred in different quarters was different ( χ2 values were 10.79-18.88, all P<0.05). In the case of accidental injuries, the family was the most likely place of accidental injury, with different types of accidental injuries occurring in different places ( χ2 values were 10.08-2 186.54, all P<0.05). Conclusions:Children′s unintentional injuries are most likely to occur in boys aged 1-<3 years, and fall/fall is the main injury type. Traffic accidents are the most important unintentional injury type leading to children′s unhealed/dead. Different injury types were related to child gender, age, quarter, and place of occurrence.Due to the differences in the occurrence mechanism and injury mode of accidental injuries in different countries and regions, and the majority of accidental injuries can be prevented, targeted preventive measures should be taken according to the characteristics of children′s accidental injuries in different regions, and a comprehensive prevention system for children′s accidental injuries should be constructed to ensure children′s safety.

Objective:This study aimed to evaluate the efficacy and safety of daratumumab as a maintenance treatment after autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with newly diagnosed multiple myeloma (NDMM) .Methods:The clinical data, hematological and renal response, and safety of 15 post-transplant patients with NDMM who had received daratumumab maintenance between May 1, 2022 and June 30, 2023 were retrospectively analyzed.Results:Fifteen patients (11 males and 4 females) with a median age of 58 (41-72) years were included. Thirteen patients did not receive daratumumab during induction therapy and auto-HSCT, 6 patients had renal impairment, and nine patients had high-risk cytogenetics. The median infusion of daratumumab was 12 (6-17) times, and the median duration of maintenance was 6 (1.5-12) months. The treatment efficacy was evaluated in all 15 patients, and daratumumab maintenance therapy increased the rate of stringent complete response from 40% to 60%. The renal response rate and median estimated glomerular filtration rate of six patients with RI-NDMM were also improved. During daratumumab maintenance therapy, the most common hematological grade 3 adverse event (AE) was lymphopenia [4 of 15 patients (26.67%) ], whereas the most common nonhematologic AEs were infusion-related reactions [7 of 15 patients (46.67%) ] and grade 3 pneumonia [5 of 15 patients (33.33%) ]. The five patients with pneumonia were daratumumab naive [5 of 13 patients (38.46%) ], with a median of 8 (6-10) infusions. Among them, the chest computed tomography of three patients showed interstitial infiltrates, and treatment with methylprednisolone was effective. With a median follow-up of 12 months, the 1-year overall survival rate was 93.33%, and only one patient died (which was not related to daratumumab treatment) .Conclusions:Daratumumab was safe and effective as a maintenance agent for post-auto-HSCT patients with NDMM, and AEs were controllable. The most common nonhematologic AE was grade 3 pneumonia, and a less dose-intense maintenance regimen for the first 8 weeks could reduce the incidence of pneumonia.

In vitro studies have established the prevalent theory that the mitochondrial kinase PINK1 protects neurodegeneration by removing damaged mitochondria in Parkinson's disease (PD). However, difficulty in detecting endogenous PINK1 protein in rodent brains and cell lines has prevented the rigorous investigation of the in vivo role of PINK1. Here we report that PINK1 kinase form is selectively expressed in the human and monkey brains. CRISPR/Cas9-mediated deficiency of PINK1 causes similar neurodegeneration in the brains of fetal and adult monkeys as well as cultured monkey neurons without affecting mitochondrial protein expression and morphology. Importantly, PINK1 mutations in the primate brain and human cells reduce protein phosphorylation that is important for neuronal function and survival. Our findings suggest that PINK1 kinase activity rather than its mitochondrial function is essential for the neuronal survival in the primate brains and that its kinase dysfunction could be involved in the pathogenesis of PD.

Huntington's disease (HD) is an autosomal dominantly-inherited neurodegenerative disease, which is caused by CAG trinucleotide expansion in exon 1 of the Huntingtin (HTT) gene. Although HD is a rare disease, its monogenic nature makes it an ideal model in which to understand pathogenic mechanisms and to develop therapeutic strategies for neurodegenerative diseases. Clustered regularly-interspaced short palindromic repeats (CRISPR) is the latest technology for genome editing. Being simple to use and highly efficient, CRISPR-based genome-editing tools are rapidly gaining popularity in biomedical research and opening up new avenues for disease treatment. Here, we review the development of CRISPR-based genome-editing tools and their applications in HD research to offer a translational perspective on advancing the genome-editing technology to HD treatment.
Humans ; Gene Editing ; Huntington Disease/therapy* ; CRISPR-Cas Systems/genetics* ; Neurodegenerative Diseases

Animal models are essential for investigating the pathogenesis and developing the treatment of human diseases. Identification of genetic mutations responsible for neurodegenerative diseases has enabled the creation of a large number of small animal models that mimic genetic defects found in the affected individuals. Of the current animal models, rodents with genetic modifications are the most commonly used animal models and provided important insights into pathogenesis. However, most of genetically modified rodent models lack overt neurodegeneration, imposing challenges and obstacles in utilizing them to rigorously test the therapeutic effects on neurodegeneration. Recent studies that used CRISPR/Cas9-targeted large animal (pigs and monkeys) have uncovered important pathological events that resemble neurodegeneration in the patient's brain but could not be produced in small animal models. Here we highlight the unique nature of large animals to model neurodegenerative diseases as well as the limitations and challenges in establishing large animal models of neurodegenerative diseases, with focus on Huntington disease, Amyotrophic lateral sclerosis, and Parkinson diseases. We also discuss how to use the important pathogenic insights from large animal models to make rodent models more capable of recapitulating important pathological features of neurodegenerative diseases.
Amyotrophic Lateral Sclerosis/genetics* ; Animals ; Brain/pathology* ; Disease Models, Animal ; Gene Editing ; Neurodegenerative Diseases/pathology* ; Swine

Objective:To analyze the metabolic status of forest encephalitis patients, research the effect of forest encephalitis on lipid metabolism, and clarify the possible pathogenesis.Methods:Based on liquid chromatography-mass spectrometry (LC-MS), lipidomics analysis was performed in 50 patients with tick-borne encephalitis and 39 healthy samples from Hulunbuir region. The patients′ serum samples were analyzed by utilizing the multivariate statistical analysis method such as principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA).Results:A total of 465 peaks were detected in the samples, and metabolites such as phospholipids and glycerides were identified. To identify the significant differential metabolites ( P<0.01, VIP>1, FC>2), a total of 26 biomarkers were screened, which phospholipids tend to be upregulated[log 2(Fold change)>0], such as phosphatidylcholine (PC) and phosphatidylethanolamine (PE); while glycerides tend to be decreased[log 2(Fold change)<0], such as diacylglycerol (DAG) and triacylglycerol (TAG), and those metabolites were closely related to anti-inflammatory and other metabolic pathways. The AUC value of potential biomarkers obtained was 0.999, which could be used for diagnosis of disease group and healthy group. Conclusions:The study showed that phospholipid metabolism and glyceride metabolism pathways would have some change after human infected by virus, and the differential metabolites could be used as potential markers for the diagnosis of tick-borne encephalitis, which provide a theoretical basis for disease research.

Objective:To investigate the protective effect and mechanism of microRNA-210 agonist (agomiR-210) on kidney in diabetic kidney disease (DKD) rats.Methods:Thirty-six 5-week-old male SD rats were divided into normal control (NC) group, agomiR-NC control group, agomiR-210 control group, DKD model group, DKD+agomiR-NC group and DKD+agomiR-210 group, with 6 rats in each group. Diabetic rats were established by a high-fat diet combined with intraperitoneal injection of streptozotocin (STZ), then were fed for 12 consecutive weeks to construct DKD model rats. During 2nd-4th week of continuous feeding, the rats in DKD+agomiR-210 group were injected with 20 nmol/kg agomiR-210 via tail vein twice a week. Blood glucose levels, 24 h urine albumin (Alb) and 24 h urine microalbumin (MAU) contents were measured regularly. At the end of the 12th week, the rats were sacrificed, and renal tissues were collected. The renal histopathological changes were assessed by HE, PAS and Masson staining methods. The mRNA and protein expression levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in renal tissues were detected by RT-qPCR and Western blot. The distributions and expressions of α-smooth muscle actin (α-SMA), typeⅠ collagen (Col-Ⅰ), type Ⅳ collagen (Col-Ⅳ) and fibronectin (FN) in renal tissues were detected by immunohistochemical method. The protein expression levels of phospho(p)-Smad3 and p-NF-κB p65 in renal tissues were detected by Western blot and immunohistochemical methods.Results:Compared with DKD model group, the renal pathological damages in DKD+agomiR-210 group were improved, the blood glucose level, glycogen deposition and collagen accumulation were significantly decreased (all P<0.05), the urinary excretions of Alb and MAU were significantly reduced (all P<0.01), and the expressions of TNF-α, IL-1β, IL-6, α-SMA, Col-Ⅰ, Col-Ⅳ, FN, p-Smad3 and p-NF-κB p65 in renal tissues were significantly decreased (all P<0.01). Conclusion:AgomiR-210 can alleviate renal pathological changes and urinary Alb and MAU excretion in rats with DKD, which may be related to its inhibition of Smad3 and NF-κB activity.