Ubiquitin-specific protease 1 (USP1) is one of the deubiquitinating enzymes which has received increasing attention in cancer research. USP1 is overexpressed in many types of cancer cells, and has been found to control tumorigenesis and progression by regulating various proteins associated with tumors, such as SIK2, GSK-3β, and Bcl-2. Knockdown or pharmacological inhibition of USP1 can effectively suppress tumors and is also expected to address the issues of cisplatin and poly ADP-ribose polymerase (PARP) inhibitor resistance. This review describes the structure and function of USP1 and the relationship between USP1 targets and tumors and systematically summarizes the structure-activity relationships of small molecule USP1 inhibitors disclosed from 2013 to 2023. Finally, this review discusses the challenges and opportunities in developing small molecule USP1 inhibitors.

Tinnitus is a clinically refractory disease with a high incidence.LAI's Tongyuan acupuncture method believes that tinnitus is nothing more than the two ends of deficiency and excess.The deficiency is closely related to original spirit,and the excess is related to the pathological factors such as externally-contracted six pathogenic factors,phlegm-damp and blood stasis,and qi stagnation and yang constraint.The Tongyuan acupuncture method is based on original spirit,takes the two vessels of conception vessel(CV)and governor vessel(GV)as the general outline,takes the regulation of yin and yang as the main method,pays attention to the combination of local and overall,and emphasizes the application of tonification and purgation,and has the clinical effect of reinforcing healthy qi and dispelling pathogen,cultivating the vital essence.In clinical application,the method of'unblocking governor vessel and nourishing spirit'is used to play the role of heart and brain nourishing spirit and warming and supporting yang qi.The method of'conducting qi back to its source'has the effect of cultivating the vital essence and regulating qi movement.The treatments should be cooperated according to the syndromes,so that the pathogens can be expelled and healthy qi can be settled.Qi and blood have origins of generation and transformation and normally nourishing in the ear,so as to effectively alleviate the patient's tinnitus symptoms.This paper summarizes and analyzes Professor LAI Xin-Sheng's Experience in the diagnosis and treatment of tinnitus by Tongyuan acupuncture method,and provides a new acupuncture treatment plan for clinical application.

OBJECTIVE: To evaluate the efficacy and safety of Cidan Capsule combined with adjuvant transarterial chemoembolization (TACE) in patients with a high risk of early recurrence after curative resection of hepatocellular carcinoma (HCC). METHODS: A multicenter, randomized controlled trial was conducted in patients with high-risk recurrence factors after curative resection of HCC from 9 medical centers between July 2014 and July 2018. Totally 249 patients were randomly assigned to TACE with or without Cidan Capsule administration groups by stratified block in a 1:1 ratio. Postoperative adjuvant TACE was given 4-5 weeks after hepatic resection in both groups. Additionally, 125 patients in the TACE plus Cidan group were administrated Cidan Capsule (0.27 g/capsule, 5 capsules every time, 4 times a day) for 6 months with a 24-month follow-up. Primary endpoints included disease-free survival (DFS) and tumor recurrence rate (TRR). Secondary endpoint was overall survival (OS). Any drug-related adverse events (AEs) were observed and recorded. RESULTS: As the data cutoff in July 9th, 2018, the median DFS was not reached in the TACE plus Cidan group and 234.0 days in the TACE group (hazard ratio, 0.420, 95% confidence interval, 0.290-0.608; P<0.01). The 1- and 2-year TRR in the TACE plus Cidan and TACE groups were 31.5%, 37.1%, and 60.8%, 63.4%, respectively (P<0.01). Median OS was not reached in both groups. The 1- and 2-year OS rates in TACE plus Cidan and TACE groups were 98.4%, 98.4%, and 89.5%, 87.9%, respectively (P<0.05). The most common grade 3-4 AEs included fatigue, abdominal pain, lumbar pain, and nausea. One serious AE was reported in 1 patient in the TACE plus Cidan group, the death was due to retroperitoneal mass hemorrhage and hemorrhagic shock, and was not related to study drug. CONCLUSIONS Cidan Capsule in combination with TACE can reduce the incidence of early recurrence in HCC patients at high-risk of recurrence after radical hepatectomy and may be an appropriate option in postoperative anti-recurrence treatment. (Registration No. NCT02253511).

The regulation of spermatogonial proliferation and apoptosis is of great significance for maintaining spermatogenesis. The single-cell RNA sequencing (scRNA-seq) analysis of the testis was performed to identify genes upregulated in spermatogonia. Using scRNA-seq analysis, we identified the spermatogonia upregulated gene origin recognition complex subunit 6 (Orc6), which is involved in DNA replication and cell cycle regulation; its protein expression in the human and mouse testis was detected by western blot and immunofluorescence. To explore the potential function of Orc6 in spermatogonia, the C18-4 cell line was transfected with control or Orc6 siRNA. Subsequently, 5-ethynyl-2-deoxyuridine (EdU) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, flow cytometry, and western blot were used to evaluate its effects on proliferation and apoptosis. It was revealed that ORC6 could promote proliferation and inhibit apoptosis of C18-4 cells. Bulk RNA sequencing and bioinformatics analysis indicated that Orc6 was involved in the activation of wingless/integrated (Wnt)/ β-catenin signaling. Western blot revealed that the expression of β-catenin protein and its phosphorylation (Ser675) were significantly decreased when silencing the expression of ORC6. Our findings indicated that Orc6 was upregulated in spermatogonia, whereby it regulated proliferation and apoptosis by activating Wnt/β-catenin signaling.

As a natural product with a long history of medicinal use, parthenolide has aroused great interest of chemists and biologists. Existing studies have shown that it has anti-inflammatory, antitumor and other pharmacological activities, and also revealed its action on NF-κB signaling pathway, DNMT1 enzyme and Wnt/β-catenin signaling pathway. But its biological targets remain to be elucidated systematically. Proteolysis Targeting Chimeras (PROTAC) provides a new strategy for target discovery of natural products, which can be used to explore the panorama of protein changes in cells through proteomic investigation, so as to analyze their potential targets. Based on this idea, current study designed and synthesized 20 parthenolide-derived degraders. After measured their antitumor activity in vitro, selected compounds were carried out the proteomic experiment. Finally, 139 down-regulated differentially expressed proteins were identified and the discovery of parthenolide interacting protein was preliminarily explored.

Lateral epicondylitis is a common clinical disease with characteristics of lateral elbow pain, insidious onset and easy recurrence, which can cause forearm pain and decreased wrist strength, seriously affecting patients′ daily life and work. Although there are various treatment methods for lateral epicondylitis with different effects, standard treatments are still lacking nowadays. Platelet-rich plasma (PRP) has good effects on bone and tendon repair, and is now widely used in the treatment of lateral epicondylitis. However, there is a lack of a unified understanding of the technology and specifications of PRP in the treatment of lateral epicondylitis. Therefore, the Sports Medicine Branch of the Chinese Medical Association and Physical Medicine and Rehabilitation Branch of the Chinese Medical Association organized experts in the fields of sports medicine and rehabilitation medicine in China to formulate the "clinical expert consensus on platelet-rich plasma treatment for lateral epicondylitis (2022 version)", and proposed suggestions based on evidence-based medicine mainly from the concept, epidemiology and pathophysiology of lateral epicondylitis, symptoms, signs and imaging manifestations of lateral epicondylitis, PRP concept and application component requirements, quality control of PRP preparation technology, indications and contraindications of PRP in the treatment of lateral epicondylitis, PRP injection in the treatment of lateral epicondylitis, application of PRP in the operation of lateral epicondylitis, related problems after PRP treatment of lateral epicondylitis, evaluation of the results after PRP treatment of lateral epicondylitis, and health and economic evaluation of PRP treatment of lateral epicondylitis, so as to provide guidance for clinical diagnosis and treatment.

Objective:To investigate the quality of rehabilitation medical service in tertiary general hospitals in Gansu Province. Methods:Stratified sampling was used to sample tertiary general hospitals in Gansu Province for on-site surveys in 2017. A quality evaluation index system was established in the view of medical service providers, including 17 indicators, based on Donabedian model and experts' opinions. Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) and Rank-sum Ratio were applied to make a comprehensive evaluation on the overall service quality of the hospital rehabilitation medical service. Results:A total of 27 tertiary general hospitals were sampled, in 13 cities/prefectures of Gansu Province. For the structure quality, the compliance rate of the business operation area and the number of beds in the rehabilitation medicine department were 77.78% and 51.85% respectively; while the compliance rates of the physicians, therapists and nurses were all less than 50%. For the process and results quality, the compliance rates were all more than 85%. For the overall quality of rehabilitation medical service, five hospitals were classified as Good, located in Lanzhou, Tianshui and Jiayuguan; 18 hospitals were classified as Medium, located in Longnan, Longdong, Lanzhou and surround, Linxia and Hexi regions; four hospitals classified as Poor, located in Lanzhou and Tianshui. Conclusion:The overall quality of rehabilitation services in the tertiary general hospitals of Gansu Province needs to be improved, and the development of rehabilitation services is uneven in various regions. Comprehensive evaluation provides an important reference to promote the rational distribution of rehabilitation medical resources and improve the quality of rehabilitation medical services.

Objective: To explore the effect of perioperative chemotherapy on the prognosis of gastric cancer patients under real-world condition. Methods: A retrospective cohort study was carried out. Real world data of gastric cancer patients receiving perioperative chemotherapy and surgery + adjuvant chemotherapy in 33 domestic hospitals from January 1, 2014 to January 31, 2016 were collected. Inclusion criteria: (1) gastric adenocarcinoma was confirmed by histopathology, and clinical stage was cT2-4aN0-3M0 (AJCC 8th edition); (2) D2 radical gastric cancer surgery was performed; (3) at least one cycle of neoadjuvant chemotherapy (NAC) was completed; (4) at least 4 cycles of adjuvant chemotherapy (AC) [SOX (S-1+oxaliplatin) or CapeOX (capecitabine + oxaliplatin)] were completed. Exclusion criteria: (1) complicated with other malignant tumors; (2) radiotherapy received; (3) patients with incomplete data. The enrolled patients who received neoadjuvant chemotherapy and adjuvant chemotherapy were included in the perioperative chemotherapy group, and those who received only postoperative adjuvant chemotherapy were included in the surgery + adjuvant chemotherapy group. Propensity score matching (PSM) method was used to control selection bias. The primary outcome were overall survival (OS) and progression-free survival (PFS) after PSM. OS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the last effective follow-up or death. PFS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the first imaging diagnosis of tumor progression or death. The Kaplan-Meier method was used to estimate the survival rate, and the Cox proportional hazards model was used to evaluate the independent effect of perioperative chemo therapy on OS and PFS. Results: 2 045 cases were included, including 1 293 cases in the surgery+adjuvant chemotherapy group and 752 cases in the perioperative chemotherapy group. After PSM, 492 pairs were included in the analysis. There were no statistically significant differences in gender, age, body mass index, tumor stage before treatment, and tumor location between the two groups (all P>0.05). Compared with the surgery + adjuvant chemotherapy group, patients in the perioperative chemotherapy group had higher proportion of total gastrectomy (χ(2)=40.526, P<0.001), smaller maximum tumor diameter (t=3.969, P<0.001), less number of metastatic lymph nodes (t=1.343, P<0.001), lower ratio of vessel invasion (χ(2)=11.897, P=0.001) and nerve invasion (χ(2)=12.338, P<0.001). In the perioperative chemotherapy group and surgery + adjuvant chemotherapy group, 24 cases (4.9%) and 17 cases (3.4%) developed postoperative complications, respectively, and no significant difference was found between two groups (χ(2)=0.815, P=0.367). The median OS of the perioperative chemotherapy group was longer than that of the surgery + adjuvant chemotherapy group (65 months vs. 45 months, HR: 0.74, 95% CI: 0.62-0.89, P=0.001); the median PFS of the perioperative chemotherapy group was also longer than that of the surgery+adjuvant chemotherapy group (56 months vs. 36 months, HR=0.72, 95% CI:0.61-0.85, P<0.001). The forest plot results of subgroup analysis showed that both men and women could benefit from perioperative chemotherapy (all P<0.05); patients over 45 years of age (P<0.05) and with normal body mass (P<0.01) could benefit significantly; patients with cTNM stage II and III presented a trend of benefit or could benefit significantly (P<0.05); patients with signet ring cell carcinoma benefited little (P>0.05); tumors in the gastric body and gastric antrum benefited more significantly (P<0.05). Conclusion: Perioperative chemotherapy can improve the prognosis of gastric cancer patients.
Chemotherapy, Adjuvant ; Female ; Gastrectomy ; Humans ; Male ; Neoadjuvant Therapy ; Neoplasm Staging ; Prognosis ; Retrospective Studies ; Stomach Neoplasms/surgery*

BACKGROUND: Human infections with zoonotic coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, have raised great public health concern globally. Here, we report a novel bat-origin CoV causing severe and fatal pneumonia in humans. METHODS: We collected clinical data and bronchoalveolar lavage (BAL) specimens from five patients with severe pneumonia from Wuhan Jinyintan Hospital, Hubei province, China. Nucleic acids of the BAL were extracted and subjected to next-generation sequencing. Virus isolation was carried out, and maximum-likelihood phylogenetic trees were constructed. RESULTS: Five patients hospitalized from December 18 to December 29, 2019 presented with fever, cough, and dyspnea accompanied by complications of acute respiratory distress syndrome. Chest radiography revealed diffuse opacities and consolidation. One of these patients died. Sequence results revealed the presence of a previously unknown β-CoV strain in all five patients, with 99.8% to 99.9% nucleotide identities among the isolates. These isolates showed 79.0% nucleotide identity with the sequence of SARS-CoV (GenBank NC_004718) and 51.8% identity with the sequence of MERS-CoV (GenBank NC_019843). The virus is phylogenetically closest to a bat SARS-like CoV (SL-ZC45, GenBank MG772933) with 87.6% to 87.7% nucleotide identity, but is in a separate clade. Moreover, these viruses have a single intact open reading frame gene 8, as a further indicator of bat-origin CoVs. However, the amino acid sequence of the tentative receptor-binding domain resembles that of SARS-CoV, indicating that these viruses might use the same receptor. CONCLUSION A novel bat-borne CoV was identified that is associated with severe and fatal respiratory disease in humans.
Adult ; Aged ; Betacoronavirus ; genetics ; isolation & purification ; Coronavirus Infections ; diagnostic imaging ; therapy ; virology ; Female ; Humans ; Male ; Middle Aged ; Pandemics ; Pneumonia, Viral ; diagnostic imaging ; therapy ; virology ; Tomography, X-Ray ; Treatment Outcome

OBJECTIVE: To explore the expression of Blimp1, ATF4 and CHOP in bone marrow mononuclear cells from patients with multiple myeloma as well as the effect of aspirin on their expression. METHODS: Sixty untreated patients with multiple myeloma and 30 patients with relatively normal bone marrow were selected. Mononuclear cells from the bone marrow fluid were separated using Ficoll separation solution. CD138 plasma cells were sorted by immunomagnetic beads method. RT-PCR was used to detect the expression levels of Blimp1, ATF4 and CHOP mRNA in U266 cells cultured in vitro. The cells were divided into blank control group, negative control group (no-loaded virus transfection) and positive experimental group [LV-Blimp1-RNAi (40051-2) transfection] by lentivirus transfection. RT-PCR was used to detect the expression of Blimp1, ATF4 and CHOP mRNA in cells of different groups. U266 cells were stimulated in vitro with different concentrations of aspirin solution (0, 0.5 mmol/L, 2.5 mmol/L, 5.0 mmol/L) for 24, 48 h and 72 h, respectively. The ability of cell proliferation in different groups was measured by CCK-8. U266 cells were stimulated with different concentrations of aspirin for 48 hours. And the mRNA expression of Blimp1, ATF4 and CHOP was detected by RT-PCR. RESULTS: Compared with plasma cells in normal group, the expression of Blimp1 mRNA in CD138 plasma cells of MM patients significantly increased (8.040±1.878), and the mRNA expression levels of ATF4 and CHOP significantly decreased (0.735±0.089; 0.837±0.062) (P＜0.05). U266 cells were cultured in vitro. Compared with the blank control group and the negative control group, the mRNA expression level of Blimp in the positive experimental group was significantly down-regulated after infection with LV-Blimp1-RNAi (40051-2) lentiviral expression vector (0.637±0.021). ATF4 and CHOP mRNA expression levels were significantly increased (1.452 ± 0.027; 1.721 ± 0.038) (P＜0.05). The proliferation of U266 cells decreased after stimulation with aspirin. In the range of (0.5-5) mmol/L, aspirin could significantly inhibit the proliferation of U266 cells. The inhibition effect of aspirin was increased along with prolongation of time and increase of concentrations. After aspirin stimulation of different concentrations for 48 hours, the expression level of Blimp1 in U266 cells decreased with increasing of drug concentration, while the expression levels of ATF4 and CHOP increased with increasing of drug concentration. CONCLUSION Inhibition of Blimp1 expression in multiple myeloma cells can promote the expression of ATF4 and CHOP. Aspirin can inhibit the proliferation activity of myeloma cells by down-regulating Blimp1 expression in myeloma cells and up-regulating ATF4 and CHOP expression, therefore plays an anti-tumor rote.