The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

Objective     To explore the causes of conversion to thoracotomy in patients with minimally invasive esophagectomy (MIE) in a surgical team, and to obtain a deeper understanding of the timing of conversion in MIE. Methods     The clinical data of patients who underwent MIE between September 9, 2011 and February 12, 2022 by a single surgical team in the Department of Thoracic Surgery of the Fourth Hospital of Hebei Medical University were retrospectively analyzed. The main influencing factors and perioperative mortality of patients who converted to thoracotomy in this group were analyzed. Results     In the cohort of 791 consecutive patients with MIE, there were 520 males and 271 females, including 29 patients of multiple esophageal cancer, 156 patients of upper thoracic cancer, 524 patients of middle thoracic cancer, and 82 patients of lower thoracic cancer. And 46 patients were converted to thoracotomy for different causes. The main causes for thoracotomy were advanced stage tumor (26 patients), anesthesia-related factors (5 patients), extensive thoracic adhesions (6 patients), and accidental injury of important structures (8 patients). There was a statistical difference in the distribution of tumor locations between patients who converted to thoracotomy and the MIE patients (P<0.05). The proportion of multiple and upper thoracic cancer in patients who converted to thoracotomy was higher than that in the MIE patients, while the proportion of lower thoracic cancer was lower than that in the MIE patients. The perioperative mortality of the thoracotomy patients was not significantly different from that of the MIE patients (P=1.000). Conclusion     In MIE, advanced-stage tumor, anesthesia-related factors,extensive thoracic adhesions, and accidental injury of important structures are the main causes of conversion to thoracotomy. The rate varies at different tumor locations. Intraoperative conversion to thoracotomy does not affect the perioperative mortality of MIE.

Objective:To investigate the clinicopathological characteristics and prognostic factors of patients with esophageal cancer.Methods:The retrospective case-control study was conducted. The clinicopathological data of 447 patients with esophageal cancer who were admitted to the Fourth Hospital of Hebei Medical University from January 1, 2017 to December 31, 2020 were collected. There were 312 males and 135 females, aged 60(range, 37?82)years. Observation indica-tors: (1) clinicopathological characteristics; (2) treatment; (3) follow-up; (4) analysis of prognostic factors for esophageal cancer. Follow-up using telephone interview or outpatient examination was conducted to detect survival of patients up to December 2021. The total survival time was from the surgery date to death or the last follow-up. Patients with duration of follow-up more than 2 years were included for survival and prognostic analysis. Measurement data with normal distribution were represented as Mean± SD, and measurement data with skewed distribution were represented as M(range). Count data were represented as absolute numbers. Kaplan-Meier method was used to draw survival curves and calculate survival rates. Log-Rank test was used for survival analysis. Univariate analysis was conducted using the Log-rank test. Multivariate analysis was conducted using the COX hazard regression model. Results:(1) Clinicopathological characteristics. Of the 447 patients, 69.80%(312/447) were males and 30.20%(135/447) were females, and there were 3, 18, 101, 229, 93, 3 cases aged 30?39 years, 40?49 years, 50?59 years, 60?69 years, 70?79 years, 80?89 years, respectively. About the pathological type, there were 424 cases with squamous carcinoma, 11 cases with small cell carcinoma, 4 cases with adenosquamous carcinoma, 3 cases with sarco-matoid carcinoma, 2 cases with adenocarcinoma, 1 case with neuroendocrine carcinoma, 1 case with undifferentiated carcinoma, and 1 case with adenoid cystic carcinoma. There were 2 cases with tumor located at cervicothoracic segment, 49 cases with tumor located at upper thoracic segment, 273 cases with tumor located at mid-thoracic segment, and 123 cases with tumor located at lower thoracic segment. There were 6, 24, 74, 59, 192, 80, 12 cases in stage pT0, pT1a, pT1b, pT2, pT3, pT4a, pT4b of pathological T staging, respectively. There were 207, 63, 142, 28, 7 cases in stage pN0, pN1, pN2, pN3, pN4 of pathological N staging by Japan Esophagus Society (JES), respectively. There were 207, 128, 76, 36 cases in stage pN0, pN1, pN2, pN3 of pathological N staging by Union for International Cancer Control (UICC), respectively. About TNM staging, there were 25, 53, 127, 174, 68 cases in stage 0, Ⅰ, Ⅱ, Ⅲ, Ⅳa of JES staging, and 16, 9, 53, 35, 108, 96, 45, 85 cases in stage 0, Ⅰa, Ⅰb,Ⅱa, Ⅱb, Ⅲa, Ⅲb, Ⅲc of UICC staging, respectively. (2) Treatment. Of the 447 patients, 63 cases underwent neoadjuvant therapy(12 cases combined with immunotherapy), 384 cases underwent no neoadjuvant therapy. There were 347, 97, 2, 1 cases with surgical approach as right thoracic approach, left thoracotomy approach, cervical abdominal approach, left thoracoabdominal approach, respectively. There were 316, 5, 126 cases with surgical platform as totally endoscopic esophagec-tomy, Hybrid surgery, open surgery, respectively. There were 350 and 97 cases with digestive recons-truction as posterior mediastinal approach and intrathoracic approach, respectively. Surgical margin as R 0, R 1, R 2 resection was detected in 323, 116, 8 cases, respectively. Six of 447 patients died during the hospital stay. (3) Follow-up. All the 447 patients were followed up for 25(range, 2?48)months, including 233 cases with the follow-up more than 2 years. The median survival time of 233 patients was unreached, and the postoperative 2-year survival rate was 76.8%. (4) Analysis of prognostic factors for esophageal cancer. Results of univariate analysis showed that gender, neoadjuvant therapy, surgical margin, pT staging, pN staging by JES, pN staging by UICC, TNM staging by JES, TNM staging by UICC were related factors influencing prognosis of 233 patients with esophageal cancer ( χ2=6.62, 17.81, 32.95, 37.93, 27.06, 35.56, 45.24, 37.84, P<0.05). Results of multivariate analysis showed that gender, surgical margin, TNM staging by JES were independent factors influencing prognosis of 233 patients with esophageal cancer ( hazard ratio=0.48, 1.94, 1.46, 95% confidence intervals as 0.25?0.91, 1.07?3.52, 1.16?1.84, P<0.05). Conclusions:The incidence of esophageal cancer is relatively high in males, with the onset age mainly distribute in 60?69 years and the mainly pathological type as squamous carcinoma. Patients with esophageal cancer have advanced tumor staging, low proportion of neoadjuvant therapy, high R 0 resection rate of surgical treatment. Gender, surgical margin, TNM staging by JES are independent factors influencing prognosis of patients with esophageal cancer.

Objective:To investigate the effects of miR-125b on radiosensitivity of cervical cancer cells and its possible downstream mechanism.Methods:The expression of miR-125b and Foxp3 in cervical cancer tissues and cells was detected by RT-qPCR. The HeLa cells were irradiated with 0, 2, 4 and 6 Gy of X-rays. The expression of miR-125b and Foxp3 in each group was detected by RT-qPCR. After downregulation of miR-125b expression and 6 Gy X-ray irradiation, the proliferation ability of HeLa cells was detected by MTT assay, and the expression of Bax and Bcl-2 proteins were detected by Western blot. The relationship between miR-125b and Foxp3 was detected by Targetscan and Dual luciferin reporter assay. After downregulation of Foxp3 expression and 6 Gy X-ray irradiation, the proliferation ability of HeLa cells was detected by MTT assay, and the expression of Bax and Bcl-2 proteins were detected by Western blot. The effects of miR-125b on radiosensitivity of HeLa cells through Foxp3 were detected. After down-regulation of Foxp3, the contents of IL-10 and TGF-β in supernatant were detected by ELISA.Results:The expression of miR-125b in the tissues and cells of cervical cancer was significantly decreased, while the expression of Foxp3 was significantly increased. The expression of miR-125b in HeLa cells was increased after radiation in a dose dependent manner. The expression of Foxp3 in HeLa cells was decreased after radiation in a dose dependent manner. After 6 Gy X-ray irradiation of HeLa cells, down-regulation of miR-125b increased the cell proliferation capacity, significantly reduced the expression of Bax and increased the expression of Bcl-2. miR-125b targets Foxp3 and negatively regulates Foxp3 expression. After 6 Gy X-ray irradiation of HeLa cells, down-regulation of Foxp3 significantly reduced the proliferation capacity of HeLa cells, increased the expression of Bax and decreased the expression of Bcl-2. Overexpression of miR-125b can enhance radiosensitivity of HeLa cells through Foxp3.After 6 Gy X-ray irradiation, down-regulation of Foxp3 reduced the expression of IL-10 and TGF-β in cells.Conclusions:Upregulation of miR-125b enhances the radiosensitivity of cervical cancer cells by targeting and negatively regulating Foxp3, and the mechanism of that may be related to the down-regulation of Foxp3 to reduce the expression of IL-10 and TGF-β in the cells.

Objective: Using propensity score matching method (PSM) to investigate the clinical effect of postoperative adjuvant radiotherapy and postoperative concurrent chemoradiotherapy for locally advanced hypopharyngeal squamous cell carcinoma. Methods: From July 2007 to July 2018,174 postoperative patients with locally advanced hypopharyngeal squamous cell carcinoma were enrolled in pre-PSM cohort, including 168 males and 6 females, the median age was 60 years old (ranged from 37 to 79 years old).Loco-regional control (LRC),progression-free survival (PFS) and overall survival (OS) were compared and analyzed between the patients treated with postoperative adjuvant radiotherapy and postoperative concurrent chemoradiotherapy (cisplatin was given in a dose of 80 mg/m² on days 1, 22, and 43). After the propensity score matching (PSM), 61 sub-pairs of 122 patients were generated in post-PSM cohort. Survival rate were assessed with Kaplan-Meier method and Log-rank test. Results: After the propensity score matching(PSM), 61 sub-pairs of 122 patients were generated in post-PSM cohort.The patients were followed up for 3-135 months, the median follow-up was 42 months. No significant differences in 3-year and 5-year LRC, PFS, OS were observed between the two groups (P>0.05) . For postoperative patients who had high-risk factors (extracapsular extension of nodal disease, and/or vascular embolism, and/or lymph node metastasis≥2, and/or positive surgical margin, and/or perineural infiltration),there were significant differences between the two groups in 3-year PFS (60.99% vs 84.49%,P<0.05), 5-year PFS (35.47% vs 56.97%,P<0.05) and 5-year LRC (41.02% vs 68.50%, P<0.05), but no significant difference was found in OS between the two groups (P>0.05). Conclusion Postoperative concurrent chemoradiotherapy was more efficacious than postoperative radiotherapy alone in terms of loco-regional control and PFS for high-risk postoperative patients with locally advanced hypopharyngeal squamous cell carcinoma.

Objective: To compare the treatment outcomes for locally advanced hypopharyngeal carcinoma between surgery plus radio(chemo) therapy(SRT) and non-surgery chemoradiotherapy(CRT). Methods: A total of 119 patients diagnosed with advanced hypopharyngeal carcinoma without distant metastases between 2010 and 2014 were identified in the Chinese People′s Liberation Army General Hospital, and they were divided into 2 groups: 42 cases in SRT group and 77 cases in CRT group. Patients′ clinical information was collected. Survival rates and prognostic factors were analyzed by the Kaplan-Meier method with SPSS 23.0 software. The survival rates, laryngeal preservation rates and complication rates were compared between the two groups using the chi-square test.Among the 119 patients, 112 were males and 7 were females. Age ranged from 27 to 78 years, with an average age of 57 years. Results: There were no significant difference between the SRT and CRT group for five-year disease-free survival (DFS, 53.9% vs. 45.1%, χ²=1.251, P=0.263) and overall survival (OS, 54.9% vs. 45.6%, χ²=1.749, P=0.186). Compared to SRT group, CRT group did not showed the significant increase of treatment complications (χ²=0.858, P=0.354), with a higher laryngeal preservation rate (50.0% vs. 71.4%, χ²=6.493, P=0.011). Conclusions Advanced hypopharyngeal carcinoma is of high malignancy and poor prognosis. Combined modality treatment is a main approach for advanced hypopharyngeal cancer. SRT offers disease-free survival and overall survival rates equivalent to CRT, but with a higher laryngeal preservation rate.

Four new phenolic glycosides, including two flavonoid glycosides (and) and two lignan glycosides (and), were isolated from the traditional Chinese medicine formula, Baoyuan decoction. Their structures were established by detailed analysis of the NMR and HR-ESI-MS spectroscopic data and their absolute configurations were determined by the experimental electronic circular dichroism data as well as chemical methods. Furthermore, the sources of the four new compounds were determined by the UPLC-Qtrap-MS method, which proved thatandare originated from, andandare from.

Objective To investigate the treatment outcome,laryngeal preservation and side-effect in locally advanced hypopharyngeal carcinoma treated with combined Hilical tomotherapy (HT) or intensitymodulated radiotherapy (IMRT) and chemotherapy and/or EGFR inhibitor (Cetuximab or Nimotuzumab).Methods A total of 68 patients (20 cases with T1-2N1-3M0 and 48 cases with T3-4N1-3M0) with locally advanced hypopharyngeal cancer were treated individualy with non-surgical combined modality treatments including induction chemotherapy followed by concurrent chemoradiotherapy,induction chemotherapy followed by concurrent radiotherapy and EGFR inhibitor,concurrent chemoradiotherapy and EGFR inhibitor,and concurrent radiotherapy and EGFR inhibitor.HT was used in 40 patients and IMRT in 28 patients.Side-effects were evaluated with the established Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria.Results The average follow-up time was 25.7 months (range 3-69 months).All patients completed the planned radiotherapy without treatment breaks,and 66 (97.0％) of 68 patients completed the planned chemotherapy.The 2-year and 3-year overall survival rates were 78.8％ and 64.7％ respectively,with an organ preservation rate of 84.2％.The most common side-effect greater than or equal to grade 3 was oropharyngeal mucositis.No patient dependent on a percutaneous gastrostomy and tracheostomy tube.Conclusion Hypopharyngeal carcinoma can be treated with non-surgical combined modality treatment including HT or IMRT,with a high laryngeal organ preservation rate and minimal toxicities.

OBJECTIVE: To compare the postoperative survival rate of laryngeal carcinoma patient at stage III or IV whom accepted partial laryngectomy and total laryngectomy. METHOD: We performed a retrospective cohort follow-up study of 126 patients of stage III or IV who underwent operation for laryngeal carcinoma in Chinese PLA General Hospital between January, 2005 and December, 2009. Survival rates were calculated by product-limit method. RESULT: There were 80 patients at stage III and 46 patient at stage IV. Sixty five patients underwent partial laryngectomy and 61 patients underwent total laryngectomy. There were 24 patients in whole group died in the 5 years, 15 of them underwent partial and 9 accepted total laryngectomy. The 5-years survival rate of partial and total group were 62.58% and 68.74% respectively. The survival curve of both groups had no significant difference (P < 0.05). CONCLUSION For laryngeal carcinoma patients at later stage, with suitable operative indication, the partial laryngectomy could achieve an acceptable effect as well as total laryngectomy.
Carcinoma, Squamous Cell ; mortality ; Humans ; Laryngeal Neoplasms ; mortality ; Laryngectomy ; methods ; mortality ; Neoplasm Staging ; Postoperative Period ; Retrospective Studies ; Survival Rate ; Treatment Outcome

OBJECTIVE: To explore and compare the effect of clinical characters on quality of life (QOL) of laryngeal carcinoma postoperative patients. METHOD: We performed a retrospective cohort follow up study of 303 patients who underwent operation for laryngeal carcinoma. The Chinese version of the general and the head and neck specific quality of life questionnaires of the European Organization for the Research and Treatment of Cancer (EORTC QLQ-C30 and EORTC QLQ-H&H35) were used to measure the quality of life of those patients in the cohort, to study the relationship between QOL and clinical factors. RESULT: In the 303 cases, there were 78 cases retaining the permanent tracheostomies (59 total laryngectomy and 19 partial laryngectomy); 4 patient retain the nasal feed pipe. Female patients were worse than male patients in the domain of physical function and global QOL (P<0.05). Older patients were worse than younger patients in the domain of physical function and speech (P<0.05). Patients with glottic tumors experience better global QOL than their peers with under glottic or supraglottic tumors. The patients with supraglottic tumor have more problem with swallowings (P<0.05). Earlier stage patients have better suitation in many domains than later stage patients, but III stage have more difficulty with swallowing than IV stage. Patients who accepted minimally invasive operation and laryngofissure have better QOL than those accepted partial laryngectomy or total laryngectomy; total laryngectomee have more problems with physical, emotion function, global QOL, sense, speech, cough and morbid feeling than patients with partial laryngectomy, but less problem with fatigue, pain, dyspnea, swollowing and dry mouth; Patients with partial horizontal laryngectomy have more difficulty with swallowing. In the multivariable analysis, the operation mode was an independent factor to speech problem. Patients who accepted neck dissction have more negative outcomes than patients without neck dissection. In the univariable analysis, the permanent tracheostomy was a notable factor which affected many domains in the quality of life; multivariable analysis showed that permanent tracheostomy was an important factor which worked on global quality of life. CONCLUSION The quality of life was affected by many clinical factors. The operation mode was an independent factor which affect speech problem. Decannulation after partial laryngectomy was very important to keep the quality of life.
Female ; Humans ; Laryngeal Neoplasms ; psychology ; surgery ; Laryngectomy ; psychology ; Male ; Postoperative Period ; Quality of Life ; Retrospective Studies ; Surveys and Questionnaires