Discovery and preclinical evaluations of GST-HG131, a novel HBV antigen inhibitor for the treatment of chronic hepatitis B infection.

Chronic hepatitis B (CHB) remains a significant health challenge worldwide. The current treatments for CHB achieve less than 10% cure rates, majority of the patients are on therapy for life. Therefore, cure of CHB is a high unmet medical need. HBV surface antigen (HBsAg) loss and seroconversion are considered as the key for the cure. RG7834 is a novel, orally bioavailable small molecule reported to reduce HBV antigens. Based on RG7834 chemistry, we designed and discovered a series of dihydrobenzopyridooxazepine (DBP) series of HBV antigen inhibitors. Extensive SAR studies led us to GST-HG131 with excellent reduction of HBV antigens (both HBsAg and HBeAg) in vitro and in vivo. GST-HG131 improved safety in rat toxicology studies over RG7834. The promising inhibitory activity, together with animal safety enhancement, merited GST-HG131 progressed into clinical development in 2020 (NCT04499443).

Investigation of dosimetric variations of liver radiotherapy using deformable registration of planning CT and cone-beam CT.

Many patients with technically unresectable or medically inoperable hepatocellular carcinoma (HCC) had hepatic anatomy variations as a result of interfraction deformation during fractionated radiotherapy. We conducted this retrospective study to investigate interfractional normal liver dosimetric consequences via reconstructing weekly dose in HCC patients. Twenty-three patients with HCC received conventional fractionated three-dimensional conformal radiation therapy (3DCRT) were enrolled in this retrospective investigation. Among them, seven patients had been diagnosed of radiation-induced liver disease (RILD) and the other 16 patients had good prognosis after treatment course. The cone-beam CT (CBCT) scans were acquired once weekly for each patient throughout the treatment, deformable image registration (DIR) of planning CT (pCT) and CBCT was performed to acquire modified CBCT (mCBCT), and the structural contours were propagated by the DIR. The same plan was applied to mCBCT to perform dose calculation. Weekly dose distribution was displayed on the pCT dose space and compared using dose difference, target coverage, and dose volume histograms. Statistical analysis was performed to identify the significant dosimetric variations. Among the 23 patients, the three weekly normal liver D50 increased by 0.2 Gy, 4.2 Gy, and 4.7 Gy, respectively, for patients with RILD, and 1.0 Gy, 2.7 Gy, and 3.1 Gy, respectively, for patients without RILD. Mean dose to the normal liver (Dmean) increased by 0.5 Gy, 2.6 Gy, and 4.0 Gy, respectively, for patients with RILD, and 0.4 Gy, 3.1 Gy, and 3.4 Gy, respectively, for patients without RILD. Regarding patients with RILD, the average values of the third weekly D50 and Dmean were both over hepatic radiation tolerance, while the values of patients without RILD were below. The dosimetric consequence showed that the liver dose between patients with and without RILD were different relative to the planned dose, and the RILD patients suffered from liver dose over hepatic radiation tolerance. Evaluation of routinely acquired CBCT images during radiation therapy provides biological information on the organs at risk, and dose estimation based on mCBCT could potentially form the basis for personalized response adaptive therapy.

Prevention of Frey Syndrome With Temporal Fascia Flap in Parotidectomy.

The objective of this study was to evaluate a total parotidectomy performed through a face-lift incision integrated with a temporal fascia flap. We have accomplished a group of 40 cases of total parotidectomy from July 2008 to May 2013. Twenty-two cases accepted a modified performance which combined rhytidectomy incision with temporal fascia flap. The other 18 cases were fulfilled by Blair incision and no reconstruction of parotid bed as control. The patients were followed up every 6 months. In the interviews, the assessment of the operation from patients was recorded. The cosmetic gratification, presence or absence of gustatory flushing or sweating, and functional reversion of facial nerve and great auricular nerve were surveyed by 3 investigators. The criteria that integrated the subjective with objective items were stipulated for evaluation. Gustatory sweating had been identified in 0% and 44% of patients of the testing and control group, respectively. The average scale of the experimental and control group postoperatively was 7.89 and 5.93 individually. The difference of the average scale between testing and control group presented statistical significance. The author's technique is either aesthetically satisfying or efficacious to prevention of gustatory sweating in total parotidectomy.

[Exploration of cross-cultivar group characteristics of a new cultivar of Prunus mume 'Zhizhang Guhong Chongcui'].

'Zhizhang Guhong Chongcui' is a new cultivar of Prunus mume with cross-cultivar group characteristics. It has typical characteristics of cinnabar purple cultivar group and green calyx cultivar group. It has green calyx, white flower, and light purple xylem, but the mechanism remains unclear. In order to clarify the causes of its cross-cultivar group traits, the color phenotype, anthocyanin content and the expression levels of genes related to anthocyanin synthesis pathway of 'Zhizhang Guhong Chongcui', 'Yuxi Zhusha' and 'Yuxi Bian Lü'e' were determined. It was found that the red degree of petals, sepals and fresh xylem in branches was positively correlated with the total anthocyanin content. MYBɑ1, MYB1, and bHLH3 were the key transcription factor genes that affected the redness of the three cultivars of flowers and xylem. The transcription factors further promoted the high expression of structural genes F3'H, DFR, ANS and UFGT, thereby promoting the production of red traits. Combined with phenotype, anthocyanin content and qRT-PCR results, it was speculated that the white color of petals of 'Zhizhang Guhong Chongcui' were derived from the high expression of FLS, F3'5'H, LAR and ANR genes in other branches of cyanidin synthesis pathway, and the low expression of GST gene. The green color of sepals might be originated from the relatively low expression of F3'H, DFR and ANS genes. The red color of xylem might be derived from the high expression of ANS and UFGT genes. This study made a preliminary explanation for the characteristics of the cross-cultivar group of 'Zhizhang Guhong Chongcui', and provided a reference for molecular breeding of flower color and xylem color of Prunus mume.

Encapsulation of R. planticola Rs-2 from alginate-starch-bentonite and its controlled release and swelling behavior under simulated soil conditions.

The plant growth-promoting bacteria (PGPR) Raoultella planticola Rs-2 was encapsulated with the various blends of alginate, starch, and bentonite for development of controlled-release formulations. The stability and release characteristics of these different capsule formulations were evaluated. The entrapment efficiency of Rs-2 in the beads (capsules) was more than 99%. The diameter of dry beads ranged from 0.98 to 1.41 mm. The bacteria release efficiency, swelling ratio, and biodegradability of the different bead formulations were enhanced by increasing the starch or alginate contents, but were impeded by higher bentonite content. The release kinetics of viable cells from capsules and the swelling ratio of capsules were studied in simulated soil media of varying temperature, moisture, pH, and salt content. The release of loaded Rs-2 cells and swelling of capsules are greatly affected by moisture, temperature, pH and salt content of the release medium. The release of viable Rs-2 cells from capsules was positively associated with the swelling properties of the capsules. The release of Rs-2 cells occurred through a Case II diffusion mechanism. In summary, this work indicates that alginate-starch-bentonite blends are a viable option for the development of efficient controlled-release formulations of Rs-2 biofertilizer, and which could have a promising application in natural field conditions.

Short-Term Power Prediction of a Photovoltaic Power Station Based on the SSA-CEEMDAN-FCN Model.

Photovoltaic power generation is greatly affected by weather factors. To improve the prediction accuracy of photovoltaic power generation, complete ensemble empirical mode decomposition with an adaptive noise algorithm (CEEMDAN) is proposed to preprocess the power sequence. Then, the full convolutional network (FCN) model optimized based on the sparrow search algorithm (SSA) is used to predict the short-term photovoltaic power. SSA can more reasonably determine the parameters of FCN and improve the prediction performance of FCN. Therefore, the FCN model optimized by the SSA algorithm is used to establish prediction models for subsequences and predict each subsequence, respectively. Finally, the predicted value of each subsequence is superimposed. Taking the actual data of a photovoltaic power station in Jiangsu province of China as an example, by comparing some different common prediction models, it is proved that the proposed method is reasonable and feasible.

Cumulative dose of radiation therapy of hepatocellular carcinoma patients and its deterministic relation to radiation-induced liver disease.

This study aimed to investigate the relationship between dose and radiation-induced liver disease (RILD) in patients with hepatocellular carcinoma (HCC) receiving 3-dimensional conformal radiotherapy (3DCRT). Twenty-three patients with HCC who received conventional fractionated 3DCRT, including 7 who were diagnosed with classic RILD, were enrolled in this retrospective investigation. Cone-beam computed tomography (CBCT) scans were acquired at the time of treatment for each patient. The beams from each patient's treatment plan were applied to each pretreatment CBCT (the modified CBCT or mCBCT) to construct the delivered dose distribution of the day considering inter-treatment anatomy changes. The daily doses were summed together with the help of deformable image registration (DIR) to obtain the adjusted cumulative dose (Dadjusted). The dose changes to the normal liver between the original planned dose (Dplan) and Dadjusted were evaluated by V20, V30, V40, and the mean dose to normal liver (MDTNL). Univariate analysis was performed to identify the significant dose changes. Among the 23 patients, the liver V20, V30, V40, and MDTNL showed significant differences between Dplan and Dadjusted, with average values of these parameters increased by 4.1%, 4.7%, 4.5%, and 3.9 Gy, respectively (p < 0.05). The adjusted liver dose in 21 patients (91%) was higher than the planned value. For patients without and with RILD,the MDTNL was increased on average by 3.5 Gy and 4.7 Gy, and normal tissue complication probability (NTCP) increased on average by 2.8% and 7.5%, respectively. Our study found that the adjusted cumulative dose based on calculations using pretreatment mCBCT differs significantly from planned dose; the use of the dosimetric results of the initial plan was found to be less predictive of RILD as compared with Dadjusted. Determination of a reconstructed Dadjusted using the mCBCT scans are more accurate in predicting RILD and has the potential to reduce the risk of RILD.

An integrated strategy of biological and physical constraints in biological optimization for cervical carcinoma.

BACKGROUND: For cervical carcinoma cases, this study aimed to evaluate the quality of intensity-modulated radiation therapy (IMRT) plans optimized by biological constraints. Furthermore, a new integrated strategy in biological planning module was proposed and verified. METHODS: Twenty patients of advanced stage cervical carcinoma were enrolled in this study. For each patient, dose volume optimization (DVO), biological model optimization (BMO) and integrated strategy optimization (ISO) plans were created using same treatment parameters. Different biological models were also used for organ at risk (OAR) in BMO plans, which include the LKB and Poisson models. Next, BMO plans were compared with their corresponding DVO plans, in order to evaluate BMO plan quality. ISO plans were also compared with DVO and BMO plans, in order to verify the performance of the integrated strategy. RESULTS: BMO plans produced slightly inhomogeneity and less coverage of planning target volume (PTV) (V95=96.79, HI = 0.10: p < 0.01). However, the tumor control probability (TCP) value, both from DVO and BMO plans, were comparable. For the OARs, BMO plans produced lower normal tissue complication probability (NTCP) of rectum (NTCP = 0.11) and bladder (NTCP = 0.14) than in the corresponding DVO plans (NTCP = 0.19 and 0.18 for rectum and bladder; p < 0.01 for rectum and p = 0.03 for bladder). V95, D98, CI and HI values that were produced by ISO plans (V95 = 98.31, D98 = 54.18Gy, CI = 0.76, HI = 0.09) were greatly better than BMO plans (V95 = 96.79, D98 = 53.42Gy, CI = 0.71, HI = 0.10) with significant differences. Furthermore, ISO plans produced lower NTCP values of rectum (NTCP = 0.14) and bladder (NTCP = 0.16) than DVO plans (NTCP = 0.19 and 0.18 for rectum and bladder, respectively) with significant differences. CONCLUSIONS: BMO plans produced lower NTCP values of OARs compared to DVO plans for cervical carcinoma cases, and resulted in slightly less target coverage and homogeneity. The integrated strategy, proposed in this study, could improve the coverage, conformity and homogeneity of PTV greater than the BMO plans, as well as reduce the NTCP values of OARs greater than the DVO plans.

[Study on lingual mucosa carcinogenesis of C57BL/6 mice induced by 4-nitroquinoline 1-oxide].

OBJECTIVE: This study aimed to induce carcinogenesis of lingual mucosa in C57BL/6 mice by feeding them 4-nitroquinoline 1-oxide (4NQO) solution. METHODS: A total of 85 C57BL/6 mice were randomly divided into distilled water control group (DD group, n=5), 1,2-propylene glycol control group (PG group, n=5), and experimental group (EP group, n= 75). The mice in the experimental group were medially fed in 15 cages. By contrast, the mice in DD, EP, and PG groups were watered with distilled water, 50 mg.L-1 4NQO solution, and 1,2-propylene glycol solution. The mice in EP group were executed every two weeks from week 0, and the mice in the control groups were sacrificed at the 28th week. The mice were weighed. Mucosal lesions were measured by macroscopic observation and histopathologic detection. RESULTS: One mouse in EP group died of unknown reason. The weight of the mice in EP group presented weight loss compared with the mice in DD and PG groups after the 24th week. Seventy-nine macroscopic lesions were observed in the lingual mucosa, oral floor, and upper palatal and buccal mucosa. A total of 70 macroscopic lesions (88.6%) were located in the lingual mucosa. Mucosal lesions changed from simple hyperplasia to squamous cell carcinomas. Well-differentiated squamous cell carcinomas were observed in all mice of EP group by pathological section at the 28th week. No lesion was found in the mice of DD and PG groups. CONCLUSION: The animal model of lingual squamous cell carcinomas was successfully established. The periods from 12th to 16th week and 20th to 28th week were the ideal times for the research on pathogenesis of early and medial-advanced stage during carcinogenesis of squamous cell carcinomas.