The Double Antibody Drug Conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma.

BACKGROUND: The antibody-drug conjugates sacituzumab govitecan (SG) and enfortumab vedotin (EV) are standard monotherapies for metastatic urothelial carcinoma (mUC). Given the different targets and payloads, we evaluated the safety and efficacy of SG + EV in a phase I trial in mUC (NCT04724018). PATIENTS AND METHODS: Patients with mUC and Eastern Cooperative Oncology Group performance status ≤1 who had progressed on platinum and/or immunotherapy were enrolled. SG + EV were administered on days 1 + 8 of a 21-day cycle until progression or unacceptable toxicity. Primary endpoint was the incidence of dose-limiting toxicities during cycle 1. The number of patients treated at each of four pre-specified dose levels (DLs) and the maximum tolerated doses in combination (MTD) were determined using a Bayesian Optimal Interval design. Objective response, progression-free survival, and overall survival were secondary endpoints. RESULTS: Between May 2021 and April 2023, 24 patients were enrolled; 1 patient never started therapy and was excluded from the analysis. Median age was 70 years (range 41-88 years); 11 patients received ≥3 lines of therapy. Seventy-eight percent (18/23) of patients experienced grade ≥3 adverse event (AE) regardless of attribution at any DL, with one grade 5 AE (pneumonitis possibly related to EV). The recommended phase II doses are SG 8 mg/kg with EV 1.25 mg/kg with granulocyte colony-stimulating factor support; MTDs are SG 10 mg/kg with EV 1.25 mg/kg. The objective response rate was 70% (16/23, 95% confidence interval 47% to 87%) with three complete responses; three patients had progressive disease as best response. With a median follow-up of 14 months, 9/23 patients have ongoing response including 6 responses lasting over 12 months. CONCLUSIONS: The combination of SG + EV was assessed at different DLs and a safe dose for phase II was identified. The combination had encouraging activity in patients with mUC with high response rates, including clinically significant complete responses. Additional study of this combination is warranted.

Saturation of Fishbone Instability by Self-Generated Zonal Flows in Tokamak Plasmas.

Gyrokinetic simulations of the fishbone instability in DIII-D tokamak plasmas find that self-generated zonal flows can dominate the nonlinear saturation by preventing coherent structures from persisting or drifting in the energetic particle phase space when the mode frequency down-chirps. Results from the simulation with zonal flows agree quantitatively, for the first time, with experimental measurements of the fishbone saturation amplitude and energetic particle transport. Moreover, the fishbone-induced zonal flows are likely responsible for the formation of an internal transport barrier that was observed after fishbone bursts in this DIII-D experiment. Finally, gyrokinetic simulations of a related ITER baseline scenario show that the fishbone induces insignificant energetic particle redistribution and may enable high performance scenarios in ITER burning plasma experiments.

Development and validation of survival nomograms for patients with differentiated thyroid cancer with distant metastases: a SEER Program-based study.

BACKGROUND: We aimed to develop a nomogram model of overall survival (OS) and cancer-specific survival (CSS) in patients with differentiated thyroid cancer with distant metastases, and to evaluate and validate the nomogram. Also, its prognostic value was compared with that of the 8th edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (AJCC8SS). METHODS: Patients with distant metastatic differentiated thyroid cancer (DMDTC) from 2004 to 2015 were selected from the Surveillance, Epidemiology, and End Results (SEER) Program to extract the clinical variables used for analysis. A total of 906 patients were divided into a training set (n = 634) and validation set (n = 272). OS and CSS were selected as the primary end point and secondary end point. LASSO regression analysis and multivariate Cox regression analysis were applied to screen variables for constructing OS and CSS nomograms for survival probability at 3, 5, and 10 years. Nomograms were evaluated and validated using the consistency index (C-index), time-dependent receiver operator characteristic (ROC) curves, area under the ROC curve, calibration curves, and decision curve analysis (DCA). The predictive survival of the nomogram was compared with that of AJCC8SS. Kaplan-Meier curves and log-rank tests were used to evaluate the risk-stratification ability OS and CSS nomograms. RESULTS: CS and CSS nomograms included six independent predictors: age, marital status, type of surgical procedure, lymphadenectomy, radiotherapy, and T stage. The C-index for the OS nomogram was 0.7474 (95% CI = 0.7199-0.775), and that for the CSS nomogram was 0.7572 (0.7281-0.7862). The nomogram showed good agreement with the "ideal" calibration curve in the training set and validation sets. DCA confirmed that the survival probability predicted by the nomogram had high clinical predictive value. The nomogram could stratify patients more accurately, and showed more robust accuracy and predictive power, than AJCC8SS. CONCLUSIONS: We established and validated prognostic nomograms for patients with DMDTC, which had significant clinical value compared with AJCC8SS.

LINC01094 promotes human nasal epithelial cell epithelial-to-mesenchymal transition and pyroptosis via upregulating HMGB1.

BACKGROUND: Excessive epithelial-to-mesenchymal transition (EMT) of nasal epithelial cells (NECs) play a prominent role in chronic rhinosinusitis with nasal polyps (CRSwNP) pathogenesis. Long intergenic non-coding RNA 01094 (LINC01094) was previously reported to be overexpressed in CRSwNP, while the regulatory mechanism by which LINC01094 regulates CRSwNP progression remains unclear. Our study aimed to investigate the role of LINC01094 in CRSwNP development. METHODS: hNEC were isolated from tissues of controls and CRSwNP patients and stimulated with interleukin (IL)-13. 3-(4, 5-Dimethylthiazolyl2)-2, 5-diphenyltetrazolium bromide (MTT) assay was employed to analyze hNEC viability. Flow cytometry was employed to analyze pyroptosis. Immunofluorescence was employed to analyze Snail nuclear translocation. The interactions between LINC01094, fused in sarcoma (FUS) and high mobility group box-1 (HMGB1) were analyzed by RNA immunoprecipitation (RIP) and RNA pull-down assays. RESULTS: LINC01094 and EMT-related proteins were markedly upregulated in nasal polyp tissues of CRSwNP. LINC01094 knockdown inhibited IL-13-induced hNEC EMT and pyroptosis. LINC01094 promoted HMGB1 expression in CRSwNP by binding with FUS. HMGB1 promoted Snail nuclear import in GSK-B phosphorylation-dependent manner. CONCLUSION: LINC01094 facilitated hNEC EMT and pyroptosis in CRSwNP by activating the HMGB1/GSK-B Snail axis, which suggested that LINC01094 might serve as a biomarker and therapeutic target in CRSwNP.

[Ultrasonographic features of thyroid carcinoma of different sizes: comparison between medullary thyroid carcinomas and papillary thyroid carcinomas].

Objective: To investigate the ultrasonographic features of medullary thyroid carcinomas (MTCs) of different sizes and supply valid information for separating MTCs from papillary thyroid carcinomas (PTCs). Methods: There were 87 patients with MTC and 220 patients with PTC detected by ultrasonography and confirmed by pathology at Tianjin Medical University Cancer Institute and Hospital from June 2018 to March 2022. Nodules were divided into the large nodule group (the maximum diameter of the tumor was＞1 cm) and the small nodule group (the maximum diameter of the tumor was ≤1 cm). There were 97 cases in the small nodule group, including 28 cases of MTC and 69 cases of PTC. There were 210 cases in the large nodule group, including 59 cases of MTC and 151 cases of PTC. After stratification by thyroid nodules, ultrasonographic features of thyroid nodules and metastatic lymph nodes, preoperative serum calcitonin (CT) and carcinoembryonic antigen (CEA) levels were compared between MTC and PTC patients. Results: In the small nodule group, the proportion of MTCs exhibiting hypoecho, smooth margins, and having blood flow signals was higher than that of PTCs, with statistically significant differences (all P＜0.05). In the large nodule group, the proportion of MTCs showing cystic solidity, hypoecho, smooth margins, blood flow, and the type Ⅳvascular distribution was higher than PTCs, and the difference of calcification type between them was also statistically significant (all P＜0.05). In contrast, the differences in the number of lesions and aspect ratio between MTCs and PTCs were not statistically significant regardless of nodule size (all P＞0.05). In the small nodule group,6 metastatic lymph nodes of medullary thyroid carcinoma (LNM-MTC) and 11 metastatic lymph nodes of papillary thyroid carcinoma (LNM-PTC) were correctly diagnosed by ultrasound, respectively. The diagnostic compliance rate of ultrasound was 78.6% (22/28) and 78.3% (54/69), respectively, with no statistically significant difference (P=0.973). In the large nodule group, 28 LNM-MTC and 11 LNM-PTC were correctly diagnosed by ultrasound, respectively. The diagnostic compliance of ultrasound was 88.1% (52/59) and 73.5% (111/151), respectively, which was statistically significant (P=0.022). Among them, 82.1% of LNM-MTC and 56.6% of LNM-PTC showed abnormal blood flow signals, with a statistically significant difference (P=0.016). There were significant differences in preoperative serum CT and CEA levels of different sizes of MTCs (all P＜0.05). Conclusions: Different sizes of MTCs require diverse demonstrative criteria. Abnormal blood flow signal is of great significance in the diagnosis of LNM-MTC. Within the absence of ultrasonic characteristics, preoperative serum CT test can provide confidence for the diagnosis of MTC.

[Analysis on the ultrasonic characteristics of tonsillar lymphoma].

Objective: To analyze the ultrasonic features of tonsillar lymphoma to improve the diagnostic accuracy. Methods: The clinical, pathological and ultrasonic data of nine patients with tonsillar lymphoma confirmed by pathology at Tianjin Medical University Cancer Institute and Hospital during June 2015 and June 2022 were analyzed retrospectively, and the characteristics of their ultrasonic images were summarized. Results: All 9 cases of tonsil lymphoma were unilateral tonsil disease, including 4 cases on the left side and 5 cases on the right side. The average maximum diameter of tonsil lymphoma in 9 cases was 4.32 cm. There were 3 cases with simultaneous involvement of tonsil and cervical lymph nodes, all of which were ipsilateral lymph nodes. Gray scale ultrasound showed that the lesions were hypoechoic, with clear boundaries in 7 cases and unclear boundaries in 2 cases. The shape was full and irregular in 5 cases and oval in 4 cases. The echo was uniform in 7 cases and uneven in 2 cases. Color Doppler ultrasonography showed abundant internal blood flow signal in 1 case, a little dotted linear internal blood flow signal in 5 cases, and no obvious internal blood flow signal in 3 cases. Conclusions: The ultrasonic features of tonsillar lymphoma include hypoechoic area, clear boundary, full shape, irregular and uniform internal echo, no or low linear signal of internal blood flow. Ultrasonography is of great value in the diagnosis of this disease and can help clinical decision-making.

A remotely-delivered pilot and feasibility program to promote physical and food literacy in adolescents with intellectual disabilities.

BACKGROUND: Youth with intellectual disabilities experience disparities in physical activity and diet quality. Physical and food literacy are hypothesised to support adoption of healthy lifestyles; however, few such interventions have been developed for this population. METHOD: Participants with intellectual disabilities ages 12-16 years were recruited for a 12-week online sports skills and nutrition education intervention. Feasibility, acceptability, and preliminary efficacy were assessed by attendance, satisfaction, and pre-post measures of motor skills, perceived competence and motivation for physical activity, classifying foods, making healthy choices, and food consumption. RESULTS: Six teens participated in the program and attended 87.5% of the sessions. Satisfaction data suggested that the program was well-received by both teens and parents. Trends toward improvements on physical activity and nutrition outcome measures were observed. CONCLUSIONS: Preliminary data from this pilot study suggest that physical and food literacy in youth with intellectual disabilities can be improved, which in turn may contribute to the adoption of healthy lifestyles.

[Study on the mechanism of cross-linked hyaluronic acid-dexamethasone hydrogelin post-traumatic osteoarthritis].

Objective: To explore the mechanism of cross-linked hyaluronic acid-dexamethasone hydrogel (cHA-Dex) in inhibiting chondrocyte apoptosis and alleviating early post-traumatic osteoarthritis (PTOA). Methods: To generate PTOA model, anterior cruciate ligament transection (ACLT)was performed on SD rats (n=70), and the sham surgery group (n=70) was set as control. The changes in inflammatory indicators such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), matrix metalloproteinase-3 (MMP-3), and matrix metalloproteinase-13 (MMP-13) in the joint lavage fluid were measured at different time points (1-14 days, 5 rats at each time point) after surgery. The cHA-Dex (0.5 mg/ml) hydrogel (experimental group, n=70) and ordinary low-molecular-weight hyaluronic acid (HA) hydrogel premixed with Dex, that was, HA-Dex (0.5 mg/ml) hydrogel (control group, n=70) were injected into the joint cavity of PTOA rats, and the release amount and cumulative release amount of Dex in the joint fluid of rats at each time point(1-14 days, 5 rats at each time point) were detected to reveal the release mechanism of cHA-Dex hydrogel. The cartilage of knee joint of patients with osteoarthritis (OA) who underwent knee arthroplasty in the Second Hospital of Shanxi Medical University from January 2020 to December 2022 was taken for in vitro tissue block culture (Outbridge score=1 or 2,n=18). After the cartilage tissue block was treated with cHA-Dex hydrogel premixed with 0.1, 0.2, and 0.5 mg/ml Dex, the mRNA expression levels of IL-1ß, IL-6, TNF-α, MMP-3, and MMP-13 in the articular cartilage tissue block were detected. OA chondrocytes were isolated from cartilage samples using enzymatic hydrolysis and cultured in vitro (n=18). Chondrocytes were divided into 4 groups: saline, cHA hydrogel, Dex (0.5 mg/ml), and cHA-Dex (0.5 mg/ml) hydrogel group. The effects of different interventions on chondrocyte proliferation and apoptosis were tested. Results: The Osteoarthritis Research Society International (OARSI) score of safranine O-solid green staining in PTOA group was 3.34±0.35, and it was 1.17±0.21 in Sham group(P=0.010). The Meachim score of knee joint osteophytes in PTOA rats was significantly higher than that in the Sham group (2.66±0.41 vs 0.22±0.17, P=0.010), indicating PTOA model in rat was established successfully. The cHA-Dex hydrogel, which corresponded to the peak changes of inflammatory factors in the joints of PTOA rats in the early stage, was also released in the early stage and sustained-released in the late stage. After the OA articular cartilage tissue block was treated with cHA-Dex hydrogel premixed with 0.1, 0.2, and 0.5 mg/ml Dex, the mRNA expression levels of IL-1 ß, IL-6, TNF-α, MMP-3, and MMP-13 in the tissue block were reduced significantly (all P<0.05) and in a dose-dependent manner. Compared with Dex (0.5 mg/ml) alone group, the apoptosis rate of cHA-Dex (0.5 mg/ml) hydrogel group was significantly reduced (0.60±0.07 vs 6.63±0.98, P=0.010).Compared with the normal saline or the cHA hydrogel alone group, the cHA-Dex (0.5 mg/ml) hydrogel group had significant cell proliferation, and the difference at each time point were all significant statistically (all P<0.05). Conclusion: For the early inflammation of PTOA, cHA-Dex hydrogel can not only inhibit cartilage inflammation, but also reverse the increased apoptosis and decreased proliferation rate of chondrocytes caused by Dex, and finally alleviate the progress of PTOA by releasing Dex.

[Research progress on global health competency and its models].

At present, the research on Global Health Competencies is mainly conducted in the field of the establishment of competency models and application of indicators. This review summarizes the research progress of the Global Health Competency and its models, and focuses on cutting-edge research from the aspects of target audience, purpose, content, classical model, methods and future development. The competency model is suggested to be adjusted and updated according to the practices of different countries and regions. The research and funding of the competency model in the field of public health is suggested to be strengthened, and the global health and diplomacy are suggested to be combined to enrich and improve the competency model. Finally, this review aims to promote Global Health Competencies research in China, especially to improve the global health talent training system and relevant policies in further research.

[Application of PRAME immunohistochemistry in the differential diagnosis of primary endometrial and endocervical adenocarcinomas].

Objective: To investigate the diagnostic value of preferentially expressed antigen in melanoma (PRAME) immunohistochemical staining in differential diagnosis of primary endometrial and endocervical adenocarcinomas. Methods: Eighty-seven cases of endometrial adenocarcinoma and sixty-three cases of cervical adenocarcinoma were collected from May 2018 to November 2023 in the Department of Pathology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School and all the cases were subject to PRAME immunohistochemical staining. The difference of PRAME expression between endometrial and endocervical adenocarcinomas was analyzed. Results: In 87 cases of endometrial adenocarcinoma, patients' age ranged from 35 to 71 years (average 59 years, median 59 years); in 63 cases of cervical adenocarcinoma patients' age ranged from 28 to 80 years (average 49 years, median 47 years). Seventy-eight cases (78/87, 89.7%) of endometrial adenocarcinoma; 2 cases (2/63, 3.2%) of cervical adenocarcinoma showed positive PRAME staining, and both cases of cervical adenocarcinoma were clear cell carcinoma. The sensitivity and specificity of PRAME in distinguishing between endometrial and cervical adenocarcinoma in the cohort were 89.7% and 96.8%, while those in differentiating non-clear cell carcinoma of the uterus from that of the cervix reached up to 91% and 100%, respectively. Conclusions: Immunohistochemical staining for PRAME demonstrates statistically significant differences between endometrial and cervical carcinomas, making it a useful auxiliary diagnostic marker for differentiating cervical and endometrial adenocarcinoma, especially non-clear cell carcinoma.

Fibro-Adipogenic Progenitors: Versatile keepers of skeletal muscle homeostasis, beyond the response to myotrauma.

While Fibro-Adipogenic Progenitors (FAPs) have been originally identified as muscle-interstitial mesenchymal cells activated in response to muscle injury and endowed with inducible fibrogenic and adipogenic potential, subsequent studies have expanded their phenotypic and functional repertoire and revealed their contribution to skeletal muscle response to a vast range of perturbations. Here we review the emerging contribution of FAPs to skeletal muscle responses to motor neuron injuries and to systemic physiological (e.g., exercise) or pathological metabolic (e.g., diabetes) perturbations. We also provide an initial blueprint of discrete sub-clusters of FAPs that are activated by specific perturbations and discuss their role in muscle adaptation to these conditions.

Giant magnon spin conductivity in ultrathin yttrium iron garnet films.

Conductivities are key material parameters that govern various types of transport (electronic charge, spin, heat and so on) driven by thermodynamic forces. Magnons, the elementary excitations of the magnetic order, flow under the gradient of a magnon chemical potential1-3 in proportion to a magnon (spin) conductivity. The magnetic insulator yttrium iron garnet is the material of choice for efficient magnon spin transport. Here we report a giant magnon conductivity in thin yttrium iron garnet films with thicknesses down to 3.7 nm when the number of occupied two-dimensional subbands is reduced from a large number to a few, which corresponds to a transition from three-dimensional to two-dimensional magnon transport. We extract a two-dimensional magnon spin conductivity around 1 S at room temperature, comparable to the (electronic) conductivity of the high-mobility two-dimensional electron gas in GaAs quantum wells at millikelvin temperatures4. Such high conductivities offer opportunities to develop low-dissipation magnon-based spintronic devices.

Activation of Nrf2 signaling by 4-octyl itaconate attenuates the cartilaginous endplate degeneration by inhibiting E3 ubiquitin ligase ZNF598.

OBJECTIVE: Cartilaginous endplate (CEP) degeneration is the main early manifestations of intervertebral disc degeneration (IVDD), and is closely related to the oxidative stress. Nrf2 (nuclear factor E2-related factor 2, NFE2L2) is a vital transcriptional factor of cellular antioxidant and anti-inflammatory responses. We aimed to illustrate whether the Nrf2 which was increased in expression by 4-octyl itaconate (4OI) could attenuate intervertebral disc degeneration through suppressing macrophage associated inflammation and catabolism of cartilaginous endplate. METHODS: Firstly, we detected the expression of Nrf2 in human degenerative CEPs. Then, we performed in vitro, ex vivo and in vivo (a rat-tail puncture model) experiments to explore the role of 4OI in IVDD. Also, by cell co-culture experiments, we demonstrated 4OI restrained the macrophage-associated inflammatory responses. Finally, through western blotting and immunoprecipitation (IP) assay, we clarified the ZNF598-mediated ubiquitination of Nrf2. RESULTS: We found decreased expression of Nrf2 in human degenerative CEPs. Using a rat IVDD model(n = 6), 4OI significantly ameliorated the progression of IVDD by MR images and histological analysis. Immunofluorescence results reveal that catabolism of CEPs and macrophage-associated inflammation are suppressed by 4OI treatment. Mechanistically, the 4OI increases Nrf2 expression and inhibits the secretion of inflammatory factors (IL-1ß) by Lipopolysaccharide (LPS)-induced macrophages, thus preventing the inflammatory-related CEP degeneration. Meanwhile, 4OI suppresses the reactive oxygen species (ROS) production and catabolism of LPS-induced rat CEP cells. In addition, 4OI inhibits the ZNF598-dependent ubiquitination of Nrf2 in LPS-induced rat CEP cells. CONCLUSIONS: 4OI may alleviate IVDD by suppressing CEP degeneration and macrophage-associated inflammation. 4OI may be an alternative therapy for degenerative CEPs/IVDs.

A comparative study of pilomatricoma and epidermoid cyst with ultrasound.

AIM: To explore and compare the ultrasonic (US) features of pilomatricoma (PM) and epidermoid cyst (EC) in the differential diagnosis and improve the accuracy of US diagnosis of PM. MATERIALS AND METHODS: Three hundred and nine patients who underwent US examination before surgery with a histopathological diagnosis of PM or EC after surgery were analysed retrospectively. The patients were categorised into the training and validation sets according to the inspection times. Univariate analysis was undertaken on the US and clinical features of PM and statistically significant variables (p<0.05) were included in the multivariate logistic regression model to establish a diagnostic model. RESULTS: The results demonstrated that the multivariate logistic regression model for PM was statistically significant (p<0.001). The risk factors included posterior echo attenuation and hypoechoic halos (odds ratio [OR] = 9.277, 10.254) and the protective factors included age, diameter thickness, and posterior echo enhancement (OR=0.936, 0.302, 0.156). The performance of the diagnostic model was tested using the training set (area under the receiver operating characteristic curve [AUC] = 0.974, 95% confidence interval [CI] = 0.955-0.994) and the validation set (AUC = 0.967, 95% CI = 0.926-1.000), which demonstrated good discriminant ability. CONCLUSIONS: The diagnostic accuracy for PM was higher than that for EC when the nodule is characterised by posterior echo attenuation, hypoechoic halos, smaller thickness, and younger age. The US diagnostic model developed may be used to guide the diagnosis of PM.

Multidetector CT-derived tricuspid annulus measurements predict tricuspid regurgitation reduction after transcatheter aortic valve replacement.

AIM: To use multidetector row computed tomography (MDCT)-derived tricuspid annulus (TA) measurements to identify predictors for tricuspid regurgitation (TR) reduction after transcatheter aortic valve replacement (TAVR), and to investigate the impact of TR change on prognosis. MATERIALS AND METHODS: A retrospective, single-centre study was conducted on consecutive patients who underwent TAVR with concomitant baseline mild or more severe TR from April 2012 to April 2022. TA parameters were measured using MDCT. RESULTS: The study comprised 266 patients (mean age 74.2 ± 7.6 years, 147 men) and 45.1% had more than one grade of TR reduction at follow-up. Independent predictors of TR reduction at follow-up were distance between TA centroid and antero-septal commissure (odd ratio [OR] 0.776; 95% confidence interval [CI]: 0.672-0.896, p=0.001), baseline TR of moderate or worse (OR 4.599; 95% CI: 2.193-9.648, p<0.001), systolic pulmonary artery pressure (OR 1.018; 95% CI: 1.002-1.035, p=0.027), age (OR 0.955; 95% CI: 0.920-0.993, p=0.019), and pre-existing atrial fibrillation (OR 0.209; 95% CI: 0.101-0.433, p<0.001). Patients without TR reduction had higher rates of rehospitalisation (hazard ratio [HR] 0.642; 95% CI: 0.413-0.998, p=0.049). CONCLUSIONS: The MDCT-derived TA parameter was predictive of TR reduction after TAVR. Persistent TR after TAVR was associated with higher rates of rehospitalisation.

[Establishment of a novel co-cultured liver cancer model based on tumor microenvironment].

Objective: To construct a new co-cultured liver cancer research model composed of activated hepatic stellate cells (aHSC) and liver cancer cells, explore the efficacy difference between it and traditional model, so as to establish a liver cancer research model in vitro and in vivo that can reflect the real clinical efficacy. Methods: A new co-culture model of liver cancer consisting of aHSC and liver cancer cells was constructed. The differences in efficacy between the new co-culture model and the traditional single cell model were compared by cytotoxicity test, cell migration test, drug retention test and in vivo tumor inhibition test. Western blot was used to detect the drug-resistant protein P-gp and epithelial-mesenchymal transition-related proteins. Masson staining was used to observe the deposition of collagen fibers in tumor tissues of tumor-bearing mice. CD31 immunohistochemical staining was used to observe the microvessel density in tumor tissues of tumor-bearing mice. Results: The cytotoxicity of single cell model and co-culture model was dose-dependent. With the increase of curcumin (CUR) concentration, the cell viability decreased, but the cell viability of single cell model decreased faster than that of co-culture model. When the concentration of CUR was 10 µg/ml, the cell viability of the co-culture model was 62.3% and the migration rate was (28.05±3.68)%, which were higher than those of the single cell model [38.5% and (14.91±5.92)%, both P<0.05]. Western blot analysis showed that the expressions of P-gp and vimentin were up-regulated in the co-culture model, which were 1.55 and 2.04 fold changes of the single cell model, respectively. The expression of E-cadherin was down-regulated, and the expression level of E-cadherin in the single cell model was 1.17 fold changes of the co-culture model. Drug retention experiment showed that the co-culture model could promote drug efflux and reduce drug retention. In vivo tumor inhibition experiment showed that the m-HSC+ H22 co-transplantation model had faster tumor growth and larger tumor volume than those of the H22 single cell transplantation model. After CUR treatment, the tumor growths of m-HSC+ H22 co-transplantation model and H22 single cell transplantation model were inhibited. Masson staining showed that the deposition of collagen fibers in tumor tissues of m-HSC+ H22 co-transplantation model mice was more than that of H22 single cell transplantation model. CD31 immunohistochemical staining showed that the microvessel density in tumor tissue of m-HSC+ H22 co-transplantation model was higher than that of H22 single cell transplantation model. Conclusions: The aHSC+ liver cancer cell co-culture model has strong proliferation and metastasis ability and is easy to be resistant to drugs. It is a new type of liver cancer treatment research model superior to the traditional single cell model.

[Efficacy and safety analysis of umbilical cord blood combined with haploid hematopoietic stem cell transplantation in the treatment of malignant hematological malignancies].

Objective: To investigate the efficacy and safety of umbilical cord blood combined with haploid HSCT (haplo-cord HSCT) in the treatment of hematological malignancies. Methods: The data of 82 patients with hematologic malignancies who received haplo-cord HSCT from January 2017 to June 2021 in the Affiliated Cancer Hospital of Zhengzhou University were retrospectively analyzed. There were 52 male and 30 female patients, aged [M(Q1, Q3)] 29 (20, 41) years. All patients received myeloablative preconditioning regimen. The day of the donor stem cell infusion was recorded as day 0 (0 d), the day before the infusion was recorded as day-1 (-1 d), and the day after the infusion was recorded as day+1 (+1 d), and so on. Eighty-two patients received transfusion of peripheral blood and/or bone marrow stem cells from unrelated cord blood and haplotype donors after the myeloablative preconditioning regimen. The graft-versus-host disease (GVHD) prophylaxis regimen was 8 mg/kg ATG combined with cyclosporine, morte-macrolide, and methotrexate. Patients were evaluated for implantation and the occurrence of transplant-related complications such as GVHD, infection, hemorrhagic cystitis, and long-term patient survival. Results: The time of neutrophil engraftment [M(Q1, Q3)] was 13 (11, 15) days and 15 (13, 21) days for platelet. The 30-day cumulative incidence of neutrophil engraftment was 98.8% (81/82) and 100-day cumulative incidence of platelet engraftment was 92.7% (76/82). The cumulative incidence of acute graft-versus-host disease (aGVHD) in degree Ⅱ-Ⅳ and Ⅲ-Ⅳ was 24.4% (20/82) and 6.1% (5/82), respectively. The cumulative incidence of chronic GVHD in+18 months was 13.5% (11/82). The follow-up time [M(Q1, Q3)] was 26 (13, 41) months, and the overall survival (OS) rate, event-free survival (EFS) rate, cumulative recurrence rate (CIR) and non-recurrence mortality (NRM) rate at 3 years after transplantation were 70.5% (95%CI: 59.7%-81.3%), 66.1% (95%CI: 56.1%-76.1%), 6.3% (95%CI: 5.7%-26.9%) and 20.8% (95%CI: 12.0%-29.6%), respectively. The cumulative incidence of cytomegalovirus and EBV reactivation was 37.8% (31/82) and 14.6% (12/82), respectively. The cumulative incidence of hemorrhagic cystitis was 32.9% (27/82). Conclusion: The efficacy of haplo-cord HSCT in the treatment of hematologic malignancies is reliable, with rapid hematopoietic reconstitution, low incidence of GVHD and virus reactivation.

[Efficacy and safety of low-dose rasburicase for refractory chronic gouty arthritis].

Objective: To explore the efficacy and safety of low-dose rasburicase for refractory chronic gouty arthritis. Methods: A cohort study. The clinical data of patients with refractory chronic gouty arthritis who were treated with rasburicase at Sun Yat-sen Memorial Hospital, Sun Yat-sen University between January 2021 and July 2022 were retrospectively analyzed. Refractory chronic gouty arthritis was defined as serum uric acid (sUA)>360 µmol/L and urate volume>10 cm3 under dual-energy computed tomography after tolerable maximal oral urate-lowering therapy for at least 3 months. The administration of low-dose rasburicase was applied intravenously with total dosage ranging from 4.5 to 7.5 mg each dose, at 4-week intervals for a maximum of three doses. Efficacy was evaluated by the changes of sUA level, tophus and urate volume. Results: A total of 22 patients were included for analysis, with 95.4% (21/22) male, the mean age was (44±15) years, and the median duration of gout was 11 (6-15) years. The mean sUA at baseline was (667±112) µmol/L. The levels of sUA significantly decreased after each dose of rasburicase (P<0.001), and the median reduction of sUA after each dose of rasburicase was 568 (471-635), 187 (66-335) and 123 (49-207) µmol/L, respectively. At week 12, nine patients (40.9%) exhibited sUA<360 µmol/L and tophus disappeared in one patient. The urate volume significantly decreased at week 12 when compared with that before the first dose of rasburicase in all the patients [40 (16-172) cm3 vs 17 (7-134) cm3, P<0.001], with a median reduction rate of 41.6% (22.9%-58.5%). The everall safety of rasburicase was good, and no serious adverse reactions occurred. Conclusions: Low-dose rasburicase is well-tolerated and effective for decreasing the urate burden in patients with refractory chronic gouty arthritis. Further prospective randomized controlled trials are needed to validate these findings.

[Feasibility and safety of transseptal transcatheter mitral valve replacement for severe mitral regurgitation].

A prospective, single-center, single-arm, and open-design study was performed to evaluate the feasibility and safety of transseptal transcatheter mitral valve replacement in the treatment of severe mitral regurgitation. Patients with symptomatic moderate-severe or severe mitral regurgitation at high-surgical risk and anatomically appropriate for the HighLife transseptal mitral valve replacement (TSMVR) system in West China Hospital, Sichuan University from December 2021 to August 2022 were enrolled. Four patients (1 male and 3 females) with severe mitral regurgitation were included, with a median age of 68.5 (64.0-77.0) years and a median Society of Thoracic Surgeons (STS) score of 8.1% (6.4%-8.9%). Technical success was achieved in all the patients. There was no residual mitral regurgitation, paravalvular leakage, or left ventricular outflow tract obstruction. Three major cardiovascular and cerebrovascular adverse events occurred within 30 days after the procedure, including ventricular tachycardia, iatrogenic atrial septal defect closure, and heart failure readmission. The current study preliminarily demonstrates that transcatheter mitral valve replacement using the HighLife system via the transseptal approach for severe mitral regurgitation is feasible and relatively safe.

[Survey of Helicobacter pylori levofloxacin and clarithromycin resistance rates and drug resistance genes in Ningxia, 2020-2022].

Objective: To explore the rate of Helicobacter pylori (Hp) resistance to levofloxacin and clarithromycin and the common mutation patterns of resistance genes in Ningxia, and to assess the concordance between phenotypic resistance and genotypic resistance. Methods: Cross-sectional study. Patients diagnosed with Hp infection in 14 hospitals in Ningxia region from February 2020 to May 2022 were retrospectively selected. Hp strains were isolated from gastric biopsy specimens of Hp-infected patients and subjected to phenotypic drug sensitivity testing and detection of resistance genes to analyze the rate of Hp resistance to levofloxacin and clarithromycin and the common mutation patterns of resistance genes in Ningxia region; and the concordance rate and Kappa concordance test were used to assess the concordance between phenotypic resistance and genotypic resistance. Results: A total of 1 942 Hp strains were isolated and cultured, and among the infections, 1 069 cases (55.0%) were male and 873 cases (45.0%) were female, aged (50.0±12.5) years (15-86 years). The rates of Hp resistance to levofloxacin and clarithromycin in Ningxia were 42.1% (818/1 942) and 40.1% (779/1 942), respectively, and the rate of dual resistance to both was 22.8% (443/1 942). The rate of resistance to levofloxacin and clarithromycin of Hp strains from female patients was higher than in male patients (levofloxacin: 50.4%(440/873) vs 35.4%(378/1 069); clarithromycin: 44.4%(388/873) vs 36.6%(391/1 069), both P<0.001). Among the GyrA gene mutations associated with levofloxacin resistance, the differences in mutation rate of amino acid at positions 87 and 91 were statistically significant in both drug-resistant and sensitive strains(both P<0.001), except for Asn87Thr. Hp strains were statistically significant for levofloxacin (Kappa=0.834, P<0.001) and clarithromycin (Kappa=0.829, P<0.001) had good concordance in resistance at the phenotypic and genotypic levels. Conclusion: The resistance of Hp to levofloxacin and clarithromycin in Ningxia region is severe, and there is good consistency between genotypic and phenotypic resistance.