The clinical practice and dosimetric outcome of the manual adaptive planning during definitive radiotherapy for cervical cancer.

PROPOSE: To evaluate the advantage of the manual adaptive plans comparing to the scheduled plans, and explored clinical factors predicting patients suitable for adaptive strategy. METHODS AND MATERIALS: Eighty two patients with weekly online cone-beam computed tomography (CBCT) were enrolled. The re-CT simulation was performed after 15 fractions and a manual adaptive plan was developed if a significant deviation of the planning target volume (PTV) was found. To evaluate the dosimetric benefit, D98, homogeneity index (HI) and conformity index (CI) for the planning target volume (PTV), as well as D2cc of the bowel, bladder, sigmoid and rectum were compared between manual adaptive plans and scheduled ones. The clinical factors influencing target motion during radiotherapy were analyzed by chi-square test and logistic regression analysis. RESULTS: The CI and HI of the manual adaptive plans were significantly superior to the scheduled ones (P = 0.0002, 0.003, respectively), demonstrating a better dose coverage of the target volume. Compared to the scheduled plans, D98 of the manual adaptive plans increased by 3.3% (P = 0.0002), the average of D2cc to the rectum, bladder decreased 0.358 Gy (P = 0.000034) and 0.240 Gy (P = 0.03), respectively. In addition, the chi-square test demonstrated that age, primary tumor volume, and parametrial infiltration were the clinical factors influencing target motion during radiotherapy. Multivariate analysis further identified the large tumor volume (≥ 50cm3, OR = 3.254, P = 0.039) and parametrial infiltration (OR = 3.376, P = 0.018) as the independent risk factors. CONCLUSION: We found the most significant organ motion happened after 15 fractions during treatment. The manual adaptive plans improved the dose coverage and decreased the OAR doses. Patients with bulky mass or with parametrial infiltration were highly suggested to adaptive strategy during definitive radiotherapy due to the significant organ motion.

Long-term efficacy of a recombinant hepatitis E vaccine in adults: 10-year results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Hepatitis E virus (HEV) is a frequently overlooked causative agent of acute hepatitis. Evaluating the long-term durability of hepatitis E vaccine efficacy holds crucial importance. METHODS: This study was an extension to a randomised, double-blind, placebo-controlled, phase-3 clinical trial of the hepatitis E vaccine conducted in Dontai County, Jiangsu, China. Participants were recruited from 11 townships in Dongtai County. In the initial trial, a total of 112 604 healthy adults aged 16-65 years were enrolled, stratified according to age and sex, and randomly assigned in a 1:1 ratio to receive three doses of hepatitis E vaccine or placebo intramuscularly at month 0, month 1, and month 6. A sensitive hepatitis E surveillance system including 205 clinical sentinels, covering the entire study region, was established and maintained for 10 years after vaccination. The primary outcome was the per-protocol efficacy of hepatitis E virus vaccine to prevent confirmed hepatitis E occurring at least 30 days after administration of the third dose. Throughout the study, the participants, site investigators, and laboratory staff remained blinded to the treatment assignments. This study is registered with ClinicalTrials.gov (NCT01014845). FINDINGS: During the 10-year study period from Aug 22, 2007, to Oct 31, 2017, 90 people with hepatitis E were identified; 13 in the vaccine group (0·2 per 10 000 person-years) and 77 in the placebo group (1·4 per 10 000 person-years), corresponding to a vaccine efficacy of 83·1% (95% CI 69·4-91·4) in the modified intention-to-treat analysis and 86·6% (73·0 to 94·1) in the per-protocol analysis. In the subsets of participants assessed for immunogenicity persistence, of those who were seronegative at baseline and received three doses of hepatitis E vaccine, 254 (87·3%) of 291 vaccinees in Qindong at the 8·5-year mark and 1270 (73·0%) of 1740 vaccinees in Anfeng at the 7·5-year mark maintained detectable concentrations of antibodies. INTERPRETATION: Immunisation with this hepatitis E vaccine offers durable protection against hepatitis E for up to 10 years, with vaccine-induced antibodies against HEV persisting for at least 8·5 years. FUNDING: National Natural Science Foundation of China, Fujian Provincial Natural Science Foundation, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and the Fundamental Research Funds for the Central Universities.

Evaluation of the efficacy and safety of artemether emulsion on localized senile pruritus: A randomized pilot study.

BACKGROUND: Localized senile pruritus is a continued health problem for the elderly. This study aimed to evaluate the efficacy and safety of artemether emulsion on localized senile pruritus. METHODS: Sixty patients diagnosed with senile pruritus were randomized into the artemether emulsion (1%) group or emulsion base group in a 1:1 ratio (the artemether group vs the control group). The patients used artemether emulsion or emulsion base for pruritus twice daily for 2 weeks. The pruritus visual analog scale (VAS) and the rate of adverse events were evaluated in week 0 and week 2. RESULTS: The VAS scores in week 2 after treatment decreased significantly compared with those before treatment in both groups (P < .05). After treatment, patients receiving the artemether emulsion had significantly lower mean VAS scores compared to those who received the emulsion base (1.21 ±â€…1.64 vs 3.67 ±â€…2.97, P < .05). When the VAS scores were compared between the 2 groups before treatment, the effective rate of the artemether group was significantly higher than that of the control group (χ2 = 55, P < .05) in week 2 after treatment. Besides, no adverse events occurred in both groups. CONCLUSIONS: Both artemether emulsion and emulsion base were effective in treating localized senile pruritus, and artemether emulsion was superior to emulsion base.

Low-dose intralesional injection of 5-fluorouracil and triamcinolone reduces tissue resident memory T cells in chronic eczema.

BACKGROUND: Tissue resident memory T (TRM) cells have been reported to play a significant role in the pathogenesis and relapse of chronic eczema. AIM: To compare the efficacy and safety of the intralesional injection of 5-fluorouracil (5-FU) and triamcinolone (TA) with those associated with TA alone for the treatment of chronic eczema. METHODS: A total of 168 patients were randomized to 5-FU+TA or TA groups and received a one-time intralesional injection of 5-FU+TA or TA only. Biopsies were collected before and 2 wk after treatment for evaluation of histopathological changes. All patients were followed up monthly for up to 1 year. RESULTS: No serious adverse event was observed in either group. Although the mean atopic dermatitis severity index scores and effective rates were comparable between the two groups after 2 wk of treatment, the relapse rate was significantly lower in the 5-FU+TA group than in the TA group. Histological examination showed significantly fewer CD8+ and CD103+ T cells but not CD4+ T cells in the 5-FU+TA group. CONCLUSION: One-time intralesional injection of 5-FU+TA is effective and safe for chronic eczema treatment and can further reduce the retention of TRM cells in the lesional skin and the relapse rate of chronic eczema.

Lentiviral vector with a radiation-inducible promoter, carrying the ING4 gene, mediates radiosensitization controlled by radiotherapy in cervical cancer cells.

The presence of hypoxia in solid tumors is considered one of the major factors that contribute to radiation resistance. The aim of the present study was to establish a therapeutic system, which can be controlled by radiation itself, to enhance radiosensitivity. For this purpose, a lentiviral gene therapy vector containing the human inhibitor of growth 4 (ING4) and its upstream promoter, human early growth response factor-1 (EGR1), which possesses the radiation-inducible characteristics to activate the transcription of its downstream genes, was constructed. Downstream fluorescence proteins were investigated to ensure that the EGR1 promoter was induced by irradiation. Furthermore, ING4 open reading frame (ORF) expression was detected by western blotting. The cell cycle was analyzed by fluorescence-activated cell sorting analysis 48 h after the cells were exposed to X-rays ranging between 0 and 8 Gy. In cells stably and transiently transfected with reporter plasmids, the EGR1-driver gene was sensitive to ionizing irradiation. Furthermore, irradiation-induced ING4 gene expression was observed. The enhanced ING4 expression increased the number of cells in the G2/M phase and decreased the proportion of cells in the G1/S phase. Therefore, ING4 expression inhibited cell proliferation and was associated with less colonies being formed. Furthermore, ING4 suppressed hypoxia-inducible factor 1α expression under hypoxic conditions and promoted cell apoptosis. Overall, these results revealed that combining the EGR1 promoter and ING4 ORF using a lentivirus system may be a promising therapeutic strategy with which to enhance radiosensitivity controlled by radiation. However, further studies using in vivo models are required to confirm these findings.

Efficacy and safety of artemether emulsion for the treatment of mild-to-moderate acne vulgaris: a randomized pilot study.

OBJECTIVE: To evaluate the efficacy and safety of artemether emulsion treating patients with mild-to-moderate acne vulgaris. METHODS: A total of 73 (randomized 1:1) patients were externally administered either artemether emulsion (1%) or fusidic acid emulsion (5g: 0.1g) twice daily for 12 weeks. Efficacy and safety evaluations were performed at weeks 0 and 12 by Global acne Grading System (GAGS), the number of acne and papule, as well as the rate of clinical respond. RESULTS: After 12 weeks, patients randomized to the artemether emulsion group received artemether emulsion had significantly lower GAGS scores (5.08 ± 1.99 versus 13.75 ± 4.87, p < .001) compared to patients who received fusidic acid emulsion. Patients in the artemether emulsion group had comparable baseline acne scores (11.11 ± 3.73 versus 10.75 ± 4.66, p = .626) and papule score (16.11 ± 5.58 versus 17.03 ± 6.34, p = .356), but significantly lower acne score (3.00 ± 1.55 versus 9.08 ± 4.90, p < .001) and comparable papule score (2.81 ± 1.61 versus 12.69 ± 5.45, p < .001) compared to the fusidic acid emulsion group at 12 weeks. No major adverse events were noted in either treatment group through 12 weeks. CONCLUSIONS: Artemether emulsion had better effect in improving mild-to-moderate AV compared to fusidic acid emulsion with barely AEs.

Evaluation of the efficacy and tolerance of artemether emulsion for the treatment of papulopustular rosacea: a randomized pilot study.

Objective: To assess the efficacy and safety of artemether emulsion in patients with papulopustular rosacea. Methods: A total of 130 (randomized 1:1) were externally administered either artemether emulsion (1%) or metronidazole emulsion (3%) twice daily for 4 weeks with an open-label 8-week follow-up. The primary endpoints included the proportion of patients who achieved clinical effective responses, as well as erythema and papule and pustule score at week 4. Results: Numerically more patients achieved an effective response at week 4 with artemether emulsion (87.1%) than metronidazole emulsion (80.0%) (p > .05). Patients with artemether emulsion had comparable baseline erythema score (2.45 ± 0.67 versus 2.42 ± 0.70, p = .809) and papule and pustule score (2.11 ± 0.96 versus 2.32 ± 0.83, p = .264), but significantly lower papule and pustule score (0.21 ± 0.52 versus 0.42 ± 0.83, p = .001) and comparable erythema score (0.53 ± 0.88 versus 0.62 ± 0.88, p = .999) compared to patients with metronidazole emulsion at week 4. There was a significantly higher proportion of patients with metronidazole emulsion relapse compared to metronidazole emulsion during the open-label 8-week follow-up period (21.6% versus 2.4%, p < .01). Conclusions: Artemether emulsion improved papulopustular rosacea in the metronidazole emulsion group as early as 4 weeks, but its beneficial effect was maintained through the 8-week follow-up period compared to metronidazole emulsion.

Comparison of hyper- and hypofractionated radiation schemes with IMRT technique in small cell lung cancer: Clinical outcomes and the introduction of extended LQ and TCP models.

PURPOSE: To evaluate the outcomes of 45 Gy/15 fractions/once-daily and 45 Gy/30 fractions/twice-daily radiation schemes utilizing intensity-modulated radiation therapy (IMRT) in extensive stage small cell lung cancer (SCLC), and to build up a new radiobiological model for tumor control probability (TCP) considering multiple biological effects. METHODS: Fifty-eight consecutive patients diagnosed with extensive stage SCLC, treated with chemotherapy and chest irradiation, were retrospectively reviewed. Thirty-seven received hyperfractionated IMRT (Hyper-IMRT, 45 Gy/30 fractions/twice-daily) and 21 received hypofractionated IMRT (Hypo-IMRT, 45 Gy/15 fractions/once-daily). Local progression-free survival (LPFS) and overall survival (OS) were calculated and compared. An extended linear-quadratic (LQ) model, LQRG, incorporating cell repair, redistribution, reoxygenation, regrowth and Gompertzian tumor growth was created based on the clinical data. The TCP model was reformulated to predict LPFS. The classical LQ and TCP models were compared with the new models. Akaike information criterion (AIC) was used to assess the quality of the models. RESULTS: The 2-year LPFS (34.1% vs 27.9%, p = 0.44) and OS (76.9% vs 76.9%, p = 0.26) were similar between Hyper- and Hypo-IMRT patients. According to the LQRG model, the α/ß calculated was 9.2 (95% confidence interval: 8.7-9.9) Gy after optimization. The average absolute and relative fitting errors for LPFS were 9.1% and 18.7% for Hyper-IMRT, and 8.8% and 16.2% for Hypo-IMRT of the new TCP model, compared with 29.1% and 62.3% for Hyper-IMRT, and 30.7% and 65.3% for Hypo-IMRT of the classical model. CONCLUSIONS: Hypo- and Hyper-IMRT resulted in comparable local control in the chest irradiation of extensive stage SCLC. The LQRG model has better performance in predicting the TCP (or LPFS) of the two schemes.

[Expression, purification and immunogenicity analysis of HPV type 18 virus-like particles from Escherichia coli].

Here, we presented a method to bacterially express the major structural protein L1 of Human Papillomavirus type 18 (HPV18) as soluble form. We found that the purified L1 could self-assemble to virus-like particles (VLPs). Further, we investigated the immunogenicity and the induced level of neutralizing antibody using these VLPs. First, the genome of HPV18 was cloned from a patient in Xiamen. It was used as template for PCR amplification of HPV18 L1 gene. The resultant DNA fragment was inserted into expression vector pTrxFus and expressed in Escherichia coli GI724. Second, L1 protein was purified by ammonium sulfate precipitation, ion-exchange chromatography and hydrophobic interaction chromatography; and the purified L1 was subjected to self-assembly to form VLPs with the removal of premixed reductant DTT. Finally, the size and morphology of these VLPs was investigated by Dynamic Light Scattering and Transmission Electronic Microscopy as 29.34 nm in hydrated radius and globular particles similar with native HPV18. The half effective dosage (ED50) and maximum level of neutralizing antibody elicitation were measured by vaccinations on mice, rabbit and goat using pseudovirus neutralization cell model. The results showed that the ED50 of HPV18 VLPs is 0.006 microg in mice, and the maximum titer of neutralizing antibody elicited in rabbit and goat is up to 10(7). As a conclusion, we can provide HPV18 VLPs with highly immunogenicity from prokaryote expression system, which may pave a new way for research and development of prophylactic vaccine for HPV18.

[Production of human papillomavirus type 16 virus-like particles and its immunogenicity].

HPV16 L1 gene was amplified from HPV16 positive vaginal secretion sample by PCR, and inserted into pTO-T7 to obtain the recombinant expression vector pTO-T7-HPV16-L1. Then, the pTO-T7-HPV16-L1 was transformed into E. coil strain ER2566 and the recombinant protein HPV16 L1 was expressed in soluble form. After purification by ammonium sulfate precipitation, ion-exchange chromatography, and hydrophobic interaction chromatography, the recombinant protein HPV16 L1 had a purity of more than 98%. By removing DTT, purified HPV16 L1 proteins self-assembled in vitro into VLPs with the diameter of 50 nm. The vaccination experiments on experimental animals showed the VLPs could elicit high titer of neutralizing antibodies against HPV 16. HPV16 VLPs with high immunogenicity and high purity can be produced easily and effectively from an E. coli expression system in the study, and thus can be used in structure investigation and HPV16 vaccine development.

Ethyl 2-(4-chloro-2-oxo-2,3-dihydro-1,3-benzothia-zol-3-yl)acetate.

In the mol-ecule of the title compound, C(11)H(10)ClNO(3)S, the benzene and thia-zole rings are oriented at a dihedral angle of 1.25 (3)°. Intra-molecular C-H⋯O and C-H⋯Cl inter-actions result in the formation of two five-membered rings which both adopt envelope conformations.

[Establishment and application of human papillomavirus type 16 pseudovirions neutralization assay].

Human papillomaviruses (HPV) are causally associated with cervical cancer and genital warts. Lack of permissive and productive cell cultures for HPV has hindered the study of HPV and evaluation of virus-neutralizing antibodies. So generation of infectious virions in vitro is highly desirable. In this report, we got high titer infectious HPV16 pseudovirions by calcium phosphate co-transfection of codon optimized HPV16 capsid genes L1 and L2 and reporter plasmids into 293FT cell line. Electron micrograph indicated that the pseudovirions were morphologically similar with the intact HPV16 virions. To evaluate the feasibility of using the pseudovirions to identify neutralizing monoclonal antibodies (mAbs), pseudovirions were incubated with 2-fold gradient dilution of the well identified mAbs V5, E70, U4 and D9 and then used to infect 293FT cells preplated in 96-well tissue culture plate. The infection of pseudovirions could be inhibited by neutralizing mAbs V5, E70 and U4 that recognize surface conformational epitopes on L1 VLP, but not by mAb D9 that is reactive to a linear epitope buried in VLP, which indicated that the pseudovirions could be used to evaluate the neutralization efficiency of mono- and polyclonal antibodies. The pseudovirions were then employed to identify neutralizing mAbs from 18 mAbs generated previously in our lab, 8 of which were conformational and 10 were linear. PD1 and 3D10, both of which recognized conformational epitopes on L1 VLP, had obviously strong neutralizing efficiency, with the neutralizing titer reached 81,920 and 20,480 respectively, while none of the linear mAbs were neutralizing, which reflected that rare linear mAbs have neutralization activity. The mechanism of PD1 and 3D10 block the infection of HPV16 pseudovirions need to be further studied. The technologies about generation of HPV16 pseudovirions and screening neutralizing mAb in our report are economical and efficient, can be easily used in large scale. They pave the way for rapid and precise evaluation of the protection efficiency of our prophylactic HPV vaccine being developed now.