Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 (DNAH10) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C > T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10-knockin mice harboring missense variants and Dnah10-knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.
Humans ; Male ; Animals ; Mice ; Semen/metabolism* ; Dyneins/metabolism* ; Cilia/metabolism* ; Mutation ; Ciliary Motility Disorders/genetics*

Objective:To evaluate the safety and efficacy of radiofrequency ablation guided by CT hepatic arteriography (CTHA) in the treatment of multiple nodular liver metastases of colorectal cancer.Methods:Clinical data of 32 patients with liver metastasis of colorectal cancer who underwent femoral arterial catheterization and percutaneous radiofrequency ablation guided by CT hepatic arteriography (CTHA) at the Affiliated Cancer Hospital of Zhengzhou University from March 2020 to September 2021 were retrospectively analyzed, including 21 males and 11 females, aged (53.2±9.9) years old. Before ablation, the angiography catheter were placed in the common or proper hepatic artery under the digital subtraction angiography (DSA). The patients were then transferred to a CT operating room. Under general anesthesia, contrast agent was injected into the indwelling angiography catheter and percutaneous radiofrequency ablation guided by CTHA was performed. The presentation of lesions, the dosage of contrast agent and complications during ablation were analyzed, and the treatment outcome was followed up outpatient or inpatient review.Results:All 32 patients uneventfully underwent DSA-guided angiography catheter placement, and CTHA-guided radiofrequency ablation was successfully performed in 97 lesions, with a technical success rate of 100% (97/97). The difference between CT values at the lesion enhancement site and peri-tumor hepatic parenchyma were greater than 25 HU. The total amount of contrast agent used during the procedure was 63.9±14.7 ml. All ablation-related complications were graded as A or B according to the Society of Interventional Radiology classification system. The complete ablation rate assessed by CTHA after the ablation was 100% (97/97). The rate of lesion necrosis was 100% evaluated by MRI one month after ablation. All patients were followed up and no recurrence was observed in 97 ablated lesions by the end of follow-up period.Conclusion:Radiofrequency ablation guided by CTHA is safe and feasible for the treatment of multiple nodular liver metastases of colorectal cancer, which could reduce the local recurrence of lesions after ablation.

Humans ; Nephrectomy ; Hemostatics/therapeutic use* ; Laparoscopy ; Kidney Neoplasms/surgery* ; Minimally Invasive Surgical Procedures

Bacterial antitumor therapy has great application potential given its unique characteristics, including genetic manipulation, tumor targeting specificity and immune system modulation. However, the nonnegligible side effects and limited efficacy of clinical treatment limit their biomedical applications. Engineered bacteria for therapeutic applications ideally need to avoid their accumulation in normal organs and possess potent antitumor activity. Here, we show that macrophage-mediated tumor-targeted delivery of Salmonella typhimurium VNP20009 can effectively reduce the toxicity caused by administrating VNP20009 alone in a melanoma mouse model. This benefits from tumor-induced chemotaxis for macrophages combined with their slow release of loaded strains. Inspired by changes in the tumor microenvironment, including a decrease in intratumoral dysfunctional CD8⁺ T cells and an increase in PDL1 on the tumor cell surface, macrophages were loaded with the engineered strain VNP-PD1nb, which can express and secrete anti-PD1 nanoantibodies after they are released from macrophages. This novel triple-combined immunotherapy significantly inhibited melanoma tumors by reactivating the tumor microenvironment by increasing immune cell infiltration, inhibiting tumor cell proliferation, remodeling TAMs to an M1-like phenotype and prominently activating CD8⁺ T cells. These data suggest that novel combination immunotherapy is expected to be a breakthrough relative to single immunotherapy.

Objective:To investigate the feasibility of CT hepatic arteriography(CTHA) guided percutaneous radiofrequency ablation of hepatocellular carcinoma (HCC).Methods:Forty-four patients diagnosed with hepatocellular carcinomas were enrolled in this prospective study from September 2019 to May 2021 in Henan Cancer Hospital. Thirty-three out of the 44 patients were treatment naive, 8 cases recurred after radiofrequency ablation, and the other 3 patients recurred after surgery. The mean size of HCC nodules was 5-44(17±8)mm measured on enhanced MRI images. Each patient was implanted a 5-French Cobra catheter or a 5-French RH angiographic catheter, then was catheterized into common hepatic artery or proper hepatic artery, under DSA monitoring via right femoral artery. Then the patient was transferred to CT operation room. Percutaneous radiofrequency ablation was performed by CTHA guidance using contrast agent injected via the catheter indwelled in hepatic artery. The endpoint of a complete ablation was a non-enhancing ablation necrosis zone in the target tumor and the target tumor margin at least 5 mm on CTHA. At the end of the procedure, the probe was retracted using tract ablation, and the arterial catheter and sheath were removed. The number of HCC lesions showed on the enhanced MRI and CTHA imaging were compared using Wilcoxon rank-sum test. The technical success rate and volume of contrast agent used during the CTHA ablation procedures were summarized.Results:Additional tumors were founded in 13 out of the 44 patients during the CT hepatic arteriography compared with enhanced MRI. The tumors founded by enhanced MRI and CTHA were 64 and 91 respectively, with statistical significance ( Z=-3.24, P=0.001). One patient dropped out of the study after palliative ablation and was transferred to transaterial chemoembolization treatment because the number of lesions showed by CTHA scan was more than 5. The other 43 patients got complete ablation verified by immediate postoperative assessment using CTHA. The technical success rate was 100%. The average volume of contrast agent used in CTHA guided radiofrequency ablation was 30-80(42±14)ml. There was no complications occurred related to the CTHA guided percutaneous radiofrequency ablation procedures. Conclusions:CTHA can demonstrate additional lesions that can not be detected by the enhanced MRI images, which improves the lesion conspicuity and verifies the optimal position of radiofrequency probe. The complete tumor ablation can be verified by CTHA performed immediately after ablation.

Objective To investigate the effect of embolization with ethanol-soaked gelatin sponge for the treatment of arterioportal shunting (APS) in patients with hepatocellular carcinoma (HCC). Methods From January 2016 to June 2017, a total of 78 patients with unresectable HCC were enrolled in this study. These patients were randomly divided into two groups by digital random method. The experimental group (n=39) received transarterial embolization of the shunt with ethanol-soaked gelatin sponge, while the control group (n=39) received only gelatin sponge shunt. Both of the two groups underwent transarterial chemoembolization if available. Changes in APS, tumor response (according to modified response evaluation criteria in solid tumor), changes in Eastern Cooperative Oncology Group (ECOG), and haemodynamics changes of the portal vein were analyzed. χ2 test and t test were used to compare the differences of qualitative and quantitative parameters between two groups. The APS grades were compared between the two groups before treatment and 2 months after treatment using rank sum test. Results Six patients were lost during the 2-month follow-up, and 72 patients were followed up, which include 38 patients in the experimental group and 34 patients in the control group. Compared to (14/34), the experimental group (25/38) has higher The APS improvement rates of the experimental group and the control group were 65.8％(25/38) and 41.2％(14/34), and there was significant difference (χ2=4.379, P<0.05). Of the 72 patients, 66 cases were conform to modified response evaluation criteria in solid tumor, which include 35 patients in the experimental group and 31 patients in the control group. Tumor response at 2 months of the experimental group and the control group were 57.1％(20/35) and 32.3％(10/31), and there was significant difference (χ2=4.106, P<0.05). The ECOG score was significantly decreased from 2 points to ≤1 point in 19 cases in the experimental group, while 12 cases in the control group (χ2=6.894, P<0.05). Compared with the control group, the diameter of the portal vein dropped significantly (t=2.082, P<0.05), while the blood flow velocity of portal vein increased (t=2.219, P<0.05) obviously in the experimental group 1 month after treatment. Conclusion Tansarterial embolization with ethanol-soaked gelatin sponge can effectively improve APS improvement rate, and quality of life of patients with unresectable HCC accompanied with APS.

Objective? To explore the application effect of cognition-belief-behavior oriented intervention model in patients with cerebral aneurysm embolism. Methods? By convenience sampling, a total of 200 patients with cerebral aneurysm embolism admitted in People's Hospital of Cangnan from January of 2016 to August of 2018 were selected as the research objects and divided into the study group (n=100) and control group (n=100) based on the random number table. The control group was given the traditional nursing intervention and the cognition-belief-behaviour oriented intervention was carried out in the study group. The effect of intervention was evaluated by Health Education Content Mastery Questionnaire and Quality Of Life Scale. Results? After intervention, the mastery of health related education content in the study group was better than that in the control group, with statistical significance (P＜0.05). After the intervention, the scores of each dimension of Quality of Life Scale in the study group were higher than those in the control group, and the differences were statistically significant (P＜ 0.05). Conclusions? The application of cognitive-belief-behavior-oriented interventions in patients with cerebral aneurysm embolism can improve their mastery of health related education knowledge and improve their quality of life.

OBJECTIVETo analyze the clinical features and pathological mutations in 44 families affected with hearing loss from southern Zhejiang, and to provide genetic counseling and prenatal diagnosis for 6 of the families.

METHODSMicroarray was employed to detect c.35delG, c.176del16, c.235delC and c.299-300delAT mutations of the GJB2 gene among 228 patients. For those carrying a single heterozygous mutation, the whole coding region of the GJB2 gene was analyzed by Sanger sequencing. For prenatal diagnosis, maternal DNA contamination was excluded by application of STR analysis.

RESULTSThe microarray assay has detected 49 patients with GJB2 mutations, which included 24 homozygous c.235delC mutations, 5 compound heterozygous c.235delC/c.176del16 mutations, 2 compound heterozygous c.235delC/c.299-300delAT mutations. Respectively, 16, 1 and 1 patients have carried single heterozygous c.235delC, c.176del16, and c.299-300delAT mutation. For the 16 patients, 7, 1, 1, 2, and 3 were detected by Sanger sequencing with a second heterozygous mutation of c.109G>A (2 of which were in conjunction with heterozygous c.176del16 and c.299-300delAT mutations), c.230G>A, c.427C>T, c.508-511 dupAACG, 79G>A+341A>G, respectively. Prenatal diagnosis revealed a compound heterozygous mutation in a fetus, heterozygous mutations in 4 fetuses, and no mutation of the GJB2 gene in 1 fetus.

CONCLUSIONThe proportion of carriers for GJB2 gene mutations in patients with hearing loss from southern Zhejiang has reached 21.5%. The c.235delC, c.176del16, and compound c.299-300delAT and c.109G>A mutations can cause moderate to severe hearing loss. In most affected families, Heterozygous mutations may be identified by sequencing the whole coding region of the GJB2 gene. Genetic analysis and prenatal diagnosis can prevent birth of further affected children.

Connexins ; genetics ; Female ; Genetic Testing ; methods ; Hearing Loss ; genetics ; Heterozygote ; Humans ; Male ; Mutation ; genetics ; Phenotype

OBJECTIVETo carry out mutation analysis and prenatal diagnosis for 12 families affected with hearing loss and enlarged vestibular aqueduct from southern Zhejiang province.

METHODSClinical data and peripheral venous blood samples of 38 members from the 12 families were obtained. Mutations of 4 genes, namely SLC26A4, GJB2, c.538C to T and c.547G to A of GJB3, m.1555A to G and m.1494C to T of 12S rRNA, were detected by PCR and Sanger sequencing. Maternal contamination was excluded by application of STR detection during prenatal diagnosis.

RESULTSAmong the probands from the 12 families, 11 were found to be compound heterozygotes or homozygotes and 25 were heterozygotes. All of the families were detected with IVS7-2A to G mutations, and 4 had a second heterozygous mutation (c.2168A to G of the SLC26A4 gene). Four rare pathogenic mutations, namely IVS5-1G to A, c.946G to T, c.1607A to G and c.2167C to G, were detected in another four families. In addition, the partner of proband from pedigree 3 was identified with compound heterozygous mutations of c.235delC and c.299-300delAT, and proband of pedigree 5 has carried a mutation of c.109G to A in GJB2. For SLC26A4 gene, prenatal diagnostic testing has revealed heterozygous mutations in 6 fetuses and compound heterozygous mutations in 2 fetuses.

CONCLUSIONIVS7-2A to G and c.2168A to G of the SLC26A4 gene were the most common mutations in southern Zhejiang. Such mutations can be found in most families affected with hearing loss and enlarged vestibular aqueduct, which may facilitate genetic counseling and prenatal diagnosis for such families.

Adolescent ; Adult ; Base Sequence ; Child ; Child, Preschool ; DNA Mutational Analysis ; Female ; Fetal Diseases ; diagnosis ; genetics ; Hearing Loss ; diagnosis ; embryology ; genetics ; Hearing Loss, Sensorineural ; diagnosis ; embryology ; genetics ; Humans ; Male ; Molecular Sequence Data ; Pedigree ; Pregnancy ; Prenatal Diagnosis ; Vestibular Aqueduct ; abnormalities ; embryology ; Young Adult

Objective To study the risk factors of the biochemical remission of pituitary tumor patients with acromegaly treated by the endoscopic endonasal surgery. Methods A retrospective analysis of clinical data was conducted on 61 cases acromegaly patients underwent endoscopic endonasal surgery between August 2013- November 2016.Endocrinology tests were performed in all patients,including the fasting/random GH(growth hormone,GH)level, Nadir GH during OGTT(oral glucose tolerance test, OGTT), and IGF-1(insulin-like growth factor-1,IGF-1). The clinical data included gender, age, preoperative GH value, preoperative IGF-1 value, tumor invasion of the inferface space of internal carotid artery(ICA),tumor surrounding angle of internal carotid artery(≥/<135°),Knosp grade, Hardy grade, and tumor volume. Univariate analysis and multivariate Logistic retrospective analysis were used to analyze the association between above-mentioned factors and the occurrence of biochemical remission. Results There were 52.5% (32/61)patients achieving biochemical remission.Univariate analysis showed significant differences between patients with and without biochemical remission in preoperative GH value, tumor surrounding angle of internal carotid artery(