Abstract Background Relapsed or refractory Hodgkin's lymphoma is a challenge for medical oncologists because of poor overall survival. We aimed to assess the feasibility, safety, and efficacy of ...CD30-targeting CAR T cells in patients with progressive relapsed or refractory Hodgkin's lymphoma, in which CD30 expression is mostly positive. Methods This open-label, phase 1 study took place at the Chinese PLA General Hospital. Eligible patients (aged 16–80 years) had relapsed or refractory Hodgkin's lymphoma. All patients received a conditioning chemotherapy regimen at the discretion of physician, followed by the infusion of CD30-directed CAR T cells. Using escalating doses to avoid severe toxicity associated with infusion, patients received a starting dose of 3·2 × 105 CAR T cells per kg and then infused by 5-fold increments continuously for 3–5 days. After the dose-escalation infusion, no patients experienced greater than grade 3 toxicity events. We periodically monitored the expression level of CAR transgenes in peripheral blood and biopsied tumour tissues according to assigned protocol by quantitative PCR. Two-way analysis of variance (ANOVA) was used to determine the significance of the differences between means in all experiments. This trial was approved by the Institutional Review Board at the Chinese PLA General Hospital and is registered with ClinicalTrials.gov , number NCT02259556 . All patients gave written informed consent before enrolment. Findings Between Dec 1, 2014, and Mar 1, 2015, 11 patients were enrolled. All of whom had a heavy pretreatment history (15 previous treatments, range 6–24) or multiple tumour lesions (3·3 lymph node regions involved, range 0-7; involvement of one or more extralymphatic organs), or both. The patients received a mean of 1·5×107 CAR-positive T cell per kg (SD 0·25, range 1·2–2·1) in total during infusion. Nine (82%) patients responded to the treatment: one (9%) patient maintained continuous complete remission, five (46%) patients achieved partial response, and three (27%) patients achieved stable disease. All patients experienced tolerable infusion-related febrile syndrome. One (9%) patient had 5 days of self-limiting arthralgia, myalgia, and dual knee swelling 2 weeks after cell infusion. The copy number of CAR transgene in peripheral blood peaked 3–17 days after infusion, which was accompanied by a two-times higher increase in the number of lymphocytes. Analysis of biopsied tissues revealed a highly efficient trafficking of CAR T cells into the targeted sites. Interpretation CD30-directed CAR T-cell therapy was safe, feasible, and efficient in patients with relapsed or refractory Hodgkin's lymphoma and guaranteed a large-scale patients recruitment. Funding Science and Technology Planning Project of Beijing City (No. Z151100003915076) and National Natural Science Foundation of China (Nos. 31270820, 81230061, 81121004, and 81402566).
Objective The purpose of this study was to investigate the impact of chronic hypoxia on the nitric oxide synthase isoenzymes in specific brain structures. Study Design Time-mated pregnant guinea pigs ...were exposed to 10.5% molecular oxygen for 14 days (animals with chronic fetal hypoxia; HPX) or room air (control animals; NMX); L-N6-(1-iminoethyl)-lysine ( L-NIL ; an inducible nitric oxide synthase inhibitor, 1 mg/kg/d) was administered to HPX group for 14 days (L–NIL + HPX). Fetal brains were harvested at term. Multilabeled immunofluorescence was used to generate a brain injury map. Laser capture microdissection and quantitative polymerase chain reaction were applied; cell injury markers, apoptosis activation, neuron loss, total nitric oxide, and the levels of individual nitric oxide synthase isoenzymes were quantified. Results Chronic hypoxia causes selective fetal brain injury rather than global. Injury is associated with differentially affected nitric oxide synthases in both neurons and glial cells, with inducible macrophage-type nitric oxide synthase up-regulated at all injury sites. L-NIL attenuated the injury, despite continued hypoxia. Conclusion These studies demonstrate that chronic hypoxia selectively injures the fetal brain in part by the differential regulation of nitric oxide synthase isoenzymes in an anatomic- and cell-specific manner.
Abstract Background Patients with hepatocellular carcinoma frequently develop multiple anatomically separate liver tumours even at early stages of the disease, thus severely limiting the benefit of ...surgery. Hepatitis B virus is one of the most well recognised carcinogens causing hepatocellular carcinoma in man, and the integration of viral DNA into the host genome might sufficiently induce hepatocyte transformation. The question of whether virus integration has a role in development of multiple hepatocellular carcinomas cannot be answered until the pattern of hepatitis B virus DNA integration is better understood. We aimed to search for a potential link between viral integration and development of multiple hepatocellular carcinoma. Methods We studied a Chinese man (aged 47 years) with multiple hepatocellular carcinomas that were potentially caused by an occult hepatitis B virus infection. We combined advanced liquid-phase hybridisation and capture techniques with single-cell sequencing to analyse viral integration sites in individual cells taken from the patient. The pattern of integration of hepatitis B virus was used as a genetic marker to investigate clonal evolution in hepatocellular carcinomas and hypervascular liver metastases. The study was approved by the institutional review board of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Written informed consent was obtained from the patient before recruitment, according to the regulations of the institutional review board. Findings Hepatitis serology testing showed that the patient was HBsAg negative and HBsAb positive, and hepatitis B virus DNA was undetectable in his serum samples; all of these findings are consistent with the definition of occult hepatitis B virus infection. However, we detected integration of hepatitis B virus into hepatocellular carcinoma, adjacent non-hepatocellular carcinoma tissues, and tumour thrombi from the inflow and outflow hepatic vasculature. By sequencing 270 single cells from six tumour tissues, we identified two integration sites that are recurrent among almost all HBV-integrated cells—the intergenic region of MED30–EXT1 on chromosome 8 and the intragenic region of CSMD2 on chromosome 1. The preferred integration hot spots were located in the core protein-coding gene (for MED30–EXT1 ) and the DR1 region on the HBX gene (for CSMD2 ). Additionally, the DR1 region of HBX has a preference of integrating into the intronic region of CSMD2 , resulting in a truncated HBX gene, which might alter the oncogenic transforming ability of hepatocytes. Interpretation Our findings lend support to the hypothesis that multifocal hepatocellular carcinomas are monoclonal in origin and are formed in the absence of hepatitis B virus replication. Furthermore, the sites of oncogenic viral integration are not random and occur in genes that might have important roles in carcinogenesis and metastasis. Funding Major and Special Program of National Science and Technology in Twelfth Five-year Plan of China (2012ZX10002016-004 to X-PC), Major Science Foundation of the Ministry of Health of China (201302009 to X-PC), the National Natural Science Foundation of China (31200666 and 81471612 to QC; 81202300 to H-FL, and 81372495 to X-PC), the National Basic Research Program of China (973 Program; No.2011CB809203), Chinese 863 Program (2012AA02A502, 2012AA02A201), Guangdong Innovative Research Team Program (2009010016), the Guangdong Enterprise Key Laboratory of Human Disease Genomics, and the Shenzhen Municipal Government of China (CXB201108250094A, CXB201108250096A).
An AD8 cut-off score of ≥4 has been reported to successfully detect 90% of dementia cases in elderly patients aged 75 years and above.
We investigated the benefits of a pilot clinical service ...conducted in primary care that used the AD8 to identify patients with dementia in an at-risk population.
Patients ≥75 years of age were recruited from a primary health care center in Singapore. Trained nurses administered the AD8 to informants of eligible patients. Patients screened positive (AD8 score ≥4) were referred to specialist memory clinics by primary health care physicians for further evaluation.
Of the 551 eligible patients in the primary health care center, 168 (30.5%) consented and the AD8 was administered to their informants. Among the recruited patients, 23 (13.7%) were screened positive and 7 (30.4%) of them accepted referrals to specialist memory clinics. The clinical diagnoses for these patients were as follows: no cognitive impairment (NCI) (n = 1), cognitive impairment no dementia (CIND) (n = 5), and dementia (n = 1). Most of the (98.8%) nurses found AD8 user-friendly and could track functional decline. Eighteen of the 23 (78.3%) primary health care physicians who referred patients to specialist memory clinics considered the AD8 useful for facilitating referrals. The remaining physicians (21.7%) preferred performance-based tests.
The AD8 is easily administered by nurses and useful to a majority of primary health care physicians to generate referrals. However, physician preference for performance-based tests and a lower prevalence of dementia in the at-risk population may indicate the need to consider a "2-pronged assessment approach" that combines both performance-based and informant-based brief tests to reduce false positive rates and better detect dementia.
Objective The objective of the study was to examine the relevance of the soluble form c-Met (sMet) with the clinical risk for severe preeclampsia. Study Design This prospective case-control study was ...performed by using plasma derived from 44 preeclamptic and 51 uncomplicated pregnant women. Plasma concentration of sMet was measured with specific enzyme-linked immunosorbent assay, and the predictive values were determined based on the receiver-operating characteristic (ROC) curves analysis. Results Plasma s-Met level in normal pregnant women changed in a gestation-dependent manner, peaking at weeks 19-24. In women with severe preeclampsia, the circulating sMet level was significantly lower than that in the gestational stage-matched controls during gestational weeks 15-30. The ROC curve analysis revealed a significant correlation between plasma sMet level and the risk of developing severe preeclampsia. Conclusion Plasma sMet could serve as a potential biomarker for predicting severe preeclampia at early second trimester of pregnancy.
Abstract The aim of this study is to investigate the effects of electroacupuncturing (EA) zusanli points on levels of basic hemodynamics, lactate, and cytokines in dogs with hemorrhagic shock. Thirty ...healthy dogs were randomly divided into 5 groups: sham hemorrhagic shocked group, hemorrhagic shocked group, EA group, nonacupuncturing group, and EA after vagotomy group. Zusanli points were electroacupunctured with constant voltage (10-15 V, 30 Hz) for 30 minutes immediately after the shock models were established. Before the stimulation, a blood pressure transducer was implanted into the right femoral artery for continuous recording of mean arterial pressure (MAP), and a 5F Swan-Ganz pediatric catheter was implanted into the pulmonary artery. The levels of serum tumor necrosis factor α (TNF- α ) in the femoral artery were detected at 0, 120, and 180 minutes after hemorrhage. The levels of serum lactate in the femoral artery were detected before hemorrhage (−45 minutes), at 0 minute, and at 180 minutes. In the hemorrhagic shocked group, the levels of MAP, cardiac output, cardiac index, central venous pressure, and pulmonary arterial wedge pressure decreased significantly; at the same time, the levels of serum TNF- α and serum lactate increased significantly. There were no differences between these groups and the hemorrhagic group, but they were different from the sham hemorrhagic shocked group. In the EA group, the levels of MAP, cardiac output, cardiac index, central venous pressure, and pulmonary arterial wedge pressure gradually increased, but the content of serum TNF- α and lactate obviously decreased. The results suggested that EA zusanli points produce a protective effect on hemorrhagic shock in dogs.
Summary Background The aim of this study was to investigate the effect of alpha lipoic acid (α-LA) on a porcine in-stent restenosis (ISR) model. Methods In protocol 1, porcine vascular smooth muscle ...cells (PVSMC) were stimulated by granulocyte-colony stimulating factor (G-CSF) in the presence or absence of α-LA. MTT (3-4,5-dimethylthiazole-2-yl 2,5-diphenyl tetrazolium bromide) assay and western blotting were used to determine the cell growth inhibitory rate and anti-inflammatory effect associated with nuclear factor-κb (NF-κb) and extracellular signal-regulated kinase (ERK). In protocol 2, 28 days after balloon overdilation injuries, 24 bare metal stents were placed in coronary artery of 12 pigs. The pigs were randomly divided to receive control diet with or without α-LA (100 mg/kg). In protocol 3, 8 control stents and 8 α-LA coated stents were randomly implanted in 2 coronary arteries of 8 pigs and follow-up coronary angiogram and histopathologic assessment were performed 4 weeks after stenting. Results Protocol 1. The proliferation of PVSMC was inhibited and protein expression of NF-κb and ERK were attenuated by α-LA pretreatment. Protocol 2. On histopathologic analysis, the neointimal area (4.0 ± 1.0 mm2 vs. 1.5 ± 0.7 mm2 , p < 0.001) and histopathologic area of stenosis (66.7 ± 10.7% vs. 24.2 ± 9.7%, p < 0.001) were reduced in the α-LA feeding group compared to controls. Protocol 3. On histopathologic analysis, the neointimal area (3.9 ± 0.8 mm2 vs. 1.0 ± 0.4 mm2 , p < 0.001), and the histopathologic area of stenosis (67.1 ± 8.8% vs. 17.4 ± 10.0%, p < 0.001) were reduced in the α-LA coated stent group compared to the control stent group. Conclusions α-LA feeding and α-LA coated stents inhibit neointimal hyperplasia in porcine ISR, possibly through inhibiting the activation of NF-κb pathway and proliferation of PVSMC.
Abstract Purpose Vocal fold leukoplakia is a premalignant precursor of squamous cell carcinoma. Although many efforts have been contributed to therapy of this disease, none exhibits a satisfactory ...result. The aims of this study were to investigate the effectiveness and feasibility of andrographolide therapy in vocal fold leukoplakia and to explore the preliminary mechanism underlying. Materials and Methods Forty-one eligible patients were enrolled in the study. The patients were treated for 10-minute exposures of 5 ml (25 mg/ml) andrographolide injection aerosols twice a day, and 2 weeks was considered as one treatment course. Electronic laryngoscope was used to observe the condition of vocal fold leukoplakia during the treatment. Every patient received one or two treatment courses, and the follow-up was carried out for 12 months. Toxic reactions of treatments were evaluated on the basis of the standards of the United States MD Anderson Cancer Center. Moreover, laryngeal carcinoma cell line Hep2 was applied to explore the mechanism of effect of andrographolide. Anti-proliferative effect on Hep2, cell nuclear morphology, express of mitogen-activated protein kinases (MAPK) and pro-apoptotic protein were detected after andrographolide treatment. Results We found that andrographolide exhibited significant curative effects on treatments, which were accompanied by thinning of the lesion of leukoplakia, reduction in the whitish surface area, and return of pink or red epithelium. A complete response up to 85% was observed, and no toxic side effect events occurred during the study. No patient with a complete response had a recurrence in the follow-up. Moreover, cellular experiments in Hep2 indicated that andrographolide activated MAPK pathway and caspase cascade, and finally induced apoptosis in laryngeal carcinoma cell. Conclusions The advantages of andrographolide are connected with minimally invasive and localized character of the treatment and no damage of collagenous tissue structures, which are more convenient and less painful for patients. These results suggest that andrographolide treatment is a viable strategy for curing vocal fold leukoplakia.
Abstract From individual randomized studies, it is not clear whether a closed suction drainage should be used after total knee arthroplasty. Our meta-analysis compares the clinical outcomes of closed ...suction drainage with nondrainage after total knee arthroplasty in randomized controlled trials reported between January 1966 and May 2010. Fifteen eligible trials involving 1361 knee incisions (686 knees with closed suction drainage and 675 knees without drainage) satisfied the inclusion criteria for our meta-analysis. The result of the meta-analysis indicates that closed suction drainage reduces the incidence of soft tissue ecchymosis and requirement for dressing reinforcement, but increases the rate of homologous blood transfusion. No significant difference between drainage and nondrainage was observed in the incidence of infection, deep venous thrombosis, or postoperative range of motion.
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