Lenvatinib, a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer, facing limitations due to drug resistance. Here, we applied a multidimensional, high-throughput screening platform comprising patient-derived resistant liver tumor cells (PDCs), organoids (PDOs), and xenografts (PDXs) to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings. Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment, expediting drug repurposing screens. Pharmacological screening identified romidepsin, YM155, apitolisib, NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models. Notably, romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway. A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models. Collectively, our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer, providing a feasible multidimensional platform for personalized medicine.

Osteoporotic proximal humeral fracture (OPHF) is one of the common osteoporotic fractures in the aged, with an incidence only lower than vertebral compression fracture, hip fracture, and distal radius fracture. OPHF, secondary to osteoporosis and characterized by poor bone quality, comminuted fracture pattern, slow healing, and severely impaired shoulder joint function, poses a big challenge to the current clinical diagnosis and treatment. In the field of diagnosis, treatment, and rehabilitation of OPHF, traditional Chinese and Western medicine have accumulated rich experience and evidence from evidence-based medicine and achieved favorable outcomes. However, there is still a lack of guidance from a relevant consensus as to how to integrate the advantages of the two medical systems and achieve the integrated diagnosis and treatment. To promote the diagnosis and treatment of OPHF with integrated traditional Chinese and Western medicine, relevant experts from Orthopedic Expert Committee of Geriatric Branch of Chinese Association of Gerontology and Geriatrics, Youth Osteoporosis Group of Orthopedic Branch of Chinese Medical Association, Osteoporosis Group of Orthopedic Surgeon Branch of Chinese Medical Doctor Association, and Osteoporosis Committee of Shanghai Association of Integrated Traditional Chinese and Western Medicine have been organized to formulate Expert consensus on the diagnosis and treatment of osteoporotic proximal humeral fracture with integrated traditional Chinese and Western medicine ( version 2024) by searching related literatures and based on the evidences from evidence-based medicine. This consensus consists of 13 recommendations about the diagnosis, treatment and rehabilitation of OPHF with integrated traditional Chinese medicine and Western medicine, aimed at standardizing, systematizing, and personalizing the diagnosis and treatment of OPHF with integrated traditional Chinse and Western medicine to improve the patients ′ function.

Objective The aim of this study is to analyze the prevalence of depression and anxiety symptoms and its relationship with the socio-economic position(SEP)among the elderly people in Dai rural areas of Jinggu County,Yunnan province.Methods A multi-stage stratified random sampling method was used to conduct a questionnaire survey among 1409 people aged 60 and over in Dai rural areas of Jinggu County,Yunnan Province.The individual SEP index was constructed using the principal component analysis.Results The prevalence of anxiety symptoms,depression symptoms,and mixed anxiety-depressive disorder symptoms was 4.8%,52.0%,and 4.2% among them,2.6%,49.4%,and 2.3% among the males,and 6.8%,54.5%,and 6.0% among the females respectively.Females had the higher prevalence of anxiety symptoms and mixed anxiety-depressive disorder symptoms than males(P<0.05).Elderly people with the higher level of education,annual per capita household income and SEP had the lower prevalence of anxiety symptoms and mixed anxiety-depressive disorder symptoms than their counterparts(both P<0.05).The prevalence of depression symptoms increased with age(P<0.01).The difference in the prevelence of depression symptoms among the elderly people with the different numbers of chronic conditions was statistically significant(P<0.01).The results of multivariate logistic regression analysis showed that the elderly people with lower SEP were more likely to suffer from the anxiety symptoms(OR=0.707,95% CI:0.566～0.883),depression symptoms(OR=0.492,95% CI:0.438～0.552),and mixed anxiety-depressive disorder symptoms(OR=0.602,95% CI:0.469～0.773).Conclusion There are significant socio-economic differences in the prevalence of anxiety symptoms and depression symptoms among the elderly people in Dai rural areas of Jinggu County,Yunnan province.Future mental health interventions should more focus on females,elderly people with advanced age,multiple chronic diseases and low SEP,so as to reduce the occurrence of depression symptoms and anxiety symptoms.

Objective To investigate the clinical effect of lithium disilicate glass ceramic cantilever resin-bonded fixed partial dentures(CRBFPDs)on single anterior tooth loss to provide a reference for the selection of restoration methods for single anterior tooth loss.Methods This study was reviewed and approved by the Ethics Committee,and informed consent was obtained from the patients.Forty-two patients with less than two anterior teeth with monomaxillary loss were included in this study.After 6 months,1 year,2 years,and 3 years,the aesthetic and functional effects of the restorations and the periodontal health status were evaluated,and the visual analog scale(VAS)was used to assess pa-tient satisfaction.Results During the observation period,the connector fractured in one case within 3 months.One case had debonded within 2 years.The aesthetic restoration effect of all lithium disilicate glass ceramic CRBFPDs was categorized as Class A.The periodontal health was good,there was no clinical absorption in the soft and hard tissues of the abutment or subbridge,periodontal status according to the evaluation indices was classified as class A,and the total satisfaction rate of the patient was 100%.Conclusion For single anterior tooth loss patients,lithium disilicate glass ceramic cantilever resin-bonded fixed partial denture can achieve the restoration effect of less invasion,better adhesion,aesthetics,comfort and good biocompatibility.With high patient satisfaction,it can be considered an ideal restoration method for replacing a single anterior tooth.

Objective:To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China.Methods:Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed.Results:6 893 patients in CP ( n=6 453, 93.6%) or AP ( n=440, 6.4%) receiving initial imatinib ( n=4 906, 71.2%), nilotinib ( n=1 157, 16.8%), dasatinib ( n=298, 4.3%) or flumatinib ( n=532, 7.2%) -therapy. With the median follow-up of 43 ( IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance ( n=1 055, 15.3%), intolerance ( n=248, 3.6%), pursuit of better efficacy ( n=168, 2.4%), economic or other reasons ( n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph + ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph + ACA, poorer TFS; Ph + ACA, poorer OS. Conclusion:At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

Objective To investigate the effect of erector spinae plane block on ultrasound-based hemodynamic parameters of the arteries of the four limbs and biochemical stress indicators in patients with thoracoscopic lobectomy. Methods A total of 120 patients with thoracoscopic lobectomy were randomly divided into study group and control group, with 60 cases in each group.The study group received erector spinae plane block during surgery, while the control group received conventional anesthesia measures.Pulmonary function indicators[peak expiratory flow rate (PEFR), forced vital capacity (FVC), forced expiratory volume in the first second (FEV₁)], ultrasound-based hemodynamic parameters of the arteries of the four limbs (maximum systolic velocity, minimum diastolic velocity, mean velocity, arterial pulsatility index, and arterial resistance index), stress indicators[cortisol (Cor), norepinephrine (NE), angiotensin Ⅱ(Ang Ⅱ), and adrenocorticotropic hormone (ACTH)], and analgesic effect were compared between the two groups at different time points[before anesthesia induction (T₀), after extubation (T₁), and after drainage tube removal (T₂)]. Results FEV₁, FVC and PEFR in both groups were significantly lower at T₁ and T₂ than at T₀, and FEV₁, FVC and PEFR in the study group were significantly higher than those in the control group at T₁ and T₂(P < 0.05).The maximum systolic velocity and arterial resistance index in both groups were significantly lower at T₁ and T₂ than at T₀, while the minimum diastolic velocity, mean velocity and arterial pulsatility index were significantly higher at T₁ and T₂ than at T₀(P < 0.05).The maximum systolic velocity and arterial resistance index in the study group were significantly higher than those in the control group at T₁ and T₂, but the minimum diastolic velocity, mean velocity and arterial pulsatility index were significantly lower than those in the control group (P < 0.05).Cor, ACTH, Ang Ⅱ and NE in both groups were significantly higher at T₂ than at T₀, and Cor, ACTH, Ang Ⅱ and NE in the study group were significantly lower than those in the control group at T₂(P < 0.05).The Prince-Henry pain score, effective compression times, and actual compression times in the study group were significantly lower than those in the control group (P < 0.05). Conclusion Application of erector spinae plane block in thoracoscopic lobectomy causes smaller fluctuations in hemodynamic parameters of the arteries of four limbs and biochemical stress indicators, with a better anesthetic effect.

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

BACKGROUND: Low-density computed tomography (LDCT) improved early lung cancer diagnosis but introduces an excess of false-positive pulmonary nodules data. Hence, accurate diagnosis of early-stage lung cancer remains challenging. The purpose of the study was to assess the feasibility of using circulating tumour cells (CTCs) to differentiate malignant from benign pulmonary nodules. METHODS: 122 patients with suspected malignant pulmonary nodules detected on chest CT in preparation for surgery were prospectively recruited. Peripheral blood samples were collected before surgery, and CTCs were identified upon isolation by size of epithelial tumour cells and morphological analysis. Laser capture microdissection, MALBAC amplification, and whole-exome sequencing were performed on 8 samples. The diagnostic efficacy of CTCs counting, and the genomic variation profile of benign and malignant CTCs samples were analysed. RESULTS: Using 2.5 cells/5 mL as the cut-off value, the area under the receiver operating characteristic curve was of 0.651 (95% confidence interval: 0.538-0.764), with a sensitivity and specificity of 0.526 and 0.800, respectively, and positive and negative predictive values of 91.1% and 30.3%, respectively. Distinct sequence variations differences in DNA damage repair-related and driver genes were observed in benign and malignant samples. TP53 mutations were identified in CTCs of four malignant cases; in particular, g.7578115T>C, g.7578645C>T, and g.7579472G>C were exclusively detected in all four malignant samples. CONCLUSIONS CTCs play an ancillary role in the diagnosis of pulmonary nodules. TP53 mutations in CTCs might be used to identify benign and malignant pulmonary nodules.
Humans ; Lung Neoplasms ; Exome Sequencing ; Multiple Pulmonary Nodules ; Carcinoma ; DNA Repair

Periarticular fracture of the shoulder is a common type of fractures in the elderly. Postoperative adverse events such as internal fixation failure, humeral head ischemic necrosis and upper limb dysfunction occur frequently, which seriously endangers the exercise and health of the elderly. Compared with the fracture with normal bone mass, the osteoporotic periarticular fracture of the shoulder is complicated with slow healing and poor rehabilitation, so the clinical management becomes more difficult. At present, there is no targeted guideline or consensus for this type of fracture in China. In such context, experts from Youth Osteoporosis Group of Chinese Orthopedic Association, Orthopedic Expert Committee of Geriatrics Branch of Chinese Association of Gerontology and Geriatrics, Osteoporosis Group of Youth Committee of Chinese Association of Orthopedic Surgeons and Osteoporosis Committee of Shanghai Association of Chinese Integrative Medicine developed the Chinese expert consensus on the diagnosis and treatment of osteoporotic periarticular fracture of the shoulder in the elderly ( version 2023). Nine recommendations were put forward from the aspects of diagnosis, treatment strategies and rehabilitation of osteoporotic periarticular fracture of the shoulder, hoping to promote the standardized, systematic and personalized diagnosis and treatment concept and improve functional outcomes and quality of life in elderly patients with osteoporotic periarticular fracture of the shoulder.

As the National Health Commission changes the management of novel corona virus infection, the situation and preventive policies for controlling the epidemic have also entered a new stage in China. Perioperative care strategies for orthopedic trauma such as designated isolation and nucleic acid test screening have also been adjusted in the new stage. Based on the perioperative work experiences in the new stage of epidemic from the frontline anti-epidemic staff of orthopedics in domestic hospitals and combined with the literature and relevant evidence-based medical data in perioperative care of orthopedic trauma patients under the current anti-epidemic policies at home and abroad, Chinese Orthopedic Association and Chinese Society of Traumatology organized relevant experts to formulate the Guideline for clinical perioperative care of orthopedic trauma patients in the new stage of novel corona virus infection ( version 2023). The guideline summarized 16 recommendations from the aspects of preoperative diagnosis and treatment, infection prevention, emergency operation and postoperative management to systematically standardize the perioperative clinical pathways, diagnosis and treatment processes of orthopedic trauma in the new stage of novel corona virus infection, so as to provide a guidance and reference for hospitals at all levels to carry out relevant work in current epidemic control policies.