Peptide receptor radionuclide therapy (PRRT) with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors (NETs). Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue (denoted as ¹⁷⁷Lu-EB-TATE) is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs. This study aimed to enhance the in vivo stability, pharmacokinetics, and pharmacodynamics of ¹⁷⁷Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain, resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical, ¹⁷⁷Lu-LNC1010, for PRRT. In preclinical studies, ¹⁷⁷Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts. Thereafter, we presented the first-in-human dose escalation study of ¹⁷⁷Lu-LNC1010 in patients with advanced/metastatic NETs. ¹⁷⁷Lu-LNC1010 was well-tolerated by all patients, with minor adverse effects, and exhibited significant uptake and prolonged retention in tumor lesions, with higher tumor radiation doses than those of ¹⁷⁷Lu-EB-TATE. Preliminary PRRT efficacy results showed an 83% disease control rate and a 42% overall response rate after two ¹⁷⁷Lu-LNC1010 treatment cycles. These encouraging findings warrant further investigations through multicenter, prospective, and randomized controlled trials.

Ever since interferon-β was introduced into China more than 20 years ago and used in the disease-modifying therapies (DMT) of multiple sclerosis (MS) patients, the Chinese translations of DMT used in China are quite puzzling, even clinicians are also difficult to understand the meaning of DMT. The authors searched and traced the origins of current DMT translations, which may be mainly due to the fact that the word "modifying" in Chinese contains two meanings: correction and alleviation, obviously currently used names prefer to correct, while the exact meaning of DMT should be to alleviate disease. Considering that inaccurate translation is widely used in domestic academic conferences and academic journals, it is easy to cause misunderstanding and ambiguity. The authors believe that the meaning of DMT should be correctly and deeply understood in the specific context, and the original meaning of alleviating disease should be returned, which is also in line with the two endpoints of immunomodulatory therapy for MS and optic neuromyelitis spectrum disease, the primary endpoint being to reduce the annual recurrence rate of the diseases, the secondary one being to slow the progression of disease disability.

Objective To establish an ultra-high liquid chromatography(UPLC)characteristic spectrum of Rheum tanguticum Maxim.ex Balf.water decoction and conduct chemical pattern recognition analysis,and to identify the medicinal materials of different origins and different processed products.Methods:UPLC was adopted to establish the characteristic spectra of 15 batches of Rheum tanguticum Maxim.ex Balf.Cluster analysis combined with principal component analysis was used to analyze their quality.Rhei Radix et Rhizoma from different origins and different processed products of Rheum tanguticum Maxim.ex Balf.were identified.Results:The characteristic spectrum of Rheum tanguticum Maxim.ex Balf.water decoction was established,18 common peaks were identi-fied,and 15 batches of Rheum tanguticum Maxim.ex Balf.were divided into 2 categories according to their origins by cluster analysis.The similarity between 15 batches of samples from different origins and the control spectrum was greater than 0.900.According to OPLS-DA analysis,a total of 6 markers(rhein-8-O-β-D-glu-cosid,resveratrol-4'-O-β-D-(6''-O-D-gallyl)glucopyranside,isolindleyin,rhein,epicatechin-3-O-D-gallate,and catechin)affecting the quality of Rheum tanguticum Maxim.ex Balf.water decoction samples were found.Rhei Radix et Rhizoma from different origins and different processed products of Rheum tanguticum Maxim.ex Balf.can be effectively distinguished.Conclusion:The established characteristic spectrum method is easy to operate and has good repeatability.It can be used for the quality control of Rheum tanguticum Maxim.ex Balf.water decoction,and can provide reference for the formulation of quality standard of formula granules of Rhei Radix et Rhizoma.

Objective:To explore the suitable prostate cancer screening mode under the medical community for primary hospitals.Methods:From April 2021 to April 2022, a total of 16007 male population ≥50 years from 9 branches of the medical community of the second hospital of Yinzhou participated in this study. They were divided into four groups according to age with group 1 of 50-59 years old, group 2 of 60-69 years old, group 3 of 70-79 years old, and group 4 of 80 years old and above. Serum tPSA was added to the routine physical examination, and the screening positive patients were referred to the referral hospital for further diagnosis and treatment under the mode of medical community. We proposed multi-parametric MRI (mpMRI) for those with serum PSA ≥4 ng/ml and suspicious lesions should be scored according to PI-RADS V2. The ultrasound-guided transperineal targeted prostate biopsy was performed for those with PI-RADS ≥3 and those with PI-RADS < 3 but tPSA ≥10 ng/ml. The tPSA follow-up examinations were performed every 6 months for tPSA < 10 ng/ml and PI-RADS < 3 points and once a year for tPSA < 4 ng/ml.Results:Among the 16 007 male population ≥50 years, 2 007(12.54%) were found serum PSA ≥4 ng/ml, and 634(31.59%)were referred to the referral hospital through the medical community system. Combining tPSA and mpMRI, 271 patients underwent ultrasound-guided transperineal targeted prostate biopsy. Among them, 162 were finally diagnosed with PCa, with a biopsy positive rate of 59.78%. The detection rate of PCa in all the subjects was 1.01%. According to the pathological grade, 5(3.08%) were in ISUP group 1, 95(58.64%) in ISUP group 2-3, and 62(38.27%) in ISUP group 4-5. There were 102(62.96%), 39(24.07%) and 21(12.96%) with localized, locally advanced or metastatic PCa, respectively. The levels of tPSA in the four groups were (1.13±1.44)ng/ml, (1.77±3.45)ng/ml, (3.27±17.58)ng/ml, and (4.26±11.48)ng/ml, respectively, with statistically significant differences ( P<0.01). The positive number of biopsy in each group was 1 case(0.06%), 56 cases(0.79%), 81 cases(1.36%) and 24 cases(1.82%) respectively, with statistically significant differences ( P<0.01). The number of ISUP 4-5 grades in each group was 0, 17(30.35%), 29(35.80%), and 16(66.67%) respectively, with statistically significant differences ( P<0.01). Conclusions:Based on the medical community system, according to the tPSA screening results of the primary hospitals, it is feasible and effective to refer suspicious patients to the referral hospitals for mpMRI examination, and screen prostate cancer by ultrasound-guided transperineal prostate fusion biopsy.

How to improve the performance of circulating tumor DNA (ctDNA) signal acquisition and the accuracy to authenticate ultra low-frequency mutation are major challenges of minimal residual disease (MRD) detection in solid tumors. In this study, we developed a new MRD bioinformatics algorithm, namely multi-variant joint confidence analysis (MinerVa), and tested this algorithm both in contrived ctDNA standards and plasma DNA samples of patients with early non-small cell lung cancer (NSCLC). Our results showed that the specificity of multi-variant tracking of MinerVa algorithm ranged from 99.62% to 99.70%, and when tracking 30 variants, variant signals could be detected as low as 6.3 × 10 ^-5 variant abundance. Furthermore, in a cohort of 27 NSCLC patients, the specificity of ctDNA-MRD for recurrence monitoring was 100%, and the sensitivity was 78.6%. These findings indicate that the MinerVa algorithm can efficiently capture ctDNA signals in blood samples and exhibit high accuracy in MRD detection.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Neoplasm, Residual/pathology* ; Biomarkers, Tumor/genetics* ; Computational Biology

Objective To investigate the potential of ginkgolide B(GB)in mitigating vascular endothelial injury by antagonizing endoplasmic reticulum stress(ERS)and elucidate its underlying molecular mechanism.Methods An injury model of human bone marrow-derived endothelial progenitor cells(EPCs)induced by tunica-mycin(TM)was established.Cell proliferation was assessed using MTS assay,while cell viability was determined through Calcein-AM/EthD-I double staining.Transwell assay was employed to evaluate cell migration ability.DCFH-DA staining was utilized to measure intracellular ROS levels,and NADPH activity was quantified via ELISA.JC-1 and DiOC6 staining were performed for qualitative and quantitative assessment of mitochondrial membrane potential respectively.Qrt-pcr analysis was conducted to determine mRNA expression levels,whereas western blot analysis enabled detection of protein expression levels in the cells.Results GB dose-dependently attenuated tunicamycin-induced ERS-mediated endothelial injury in hEPCs,as evidenced by decreased cell viability,impaired cell migration,and angiogenesis inhibition(P<0.01).Furthermore,GB treatment significantly reduced ROS production and NADPH levels within the cells(P<0.01),while also inhibiting ERS-mediated decline in mitochondrial membrane potential concentration-dependently(P<0.01).Additionally,GB inhibited the expression of ERS-related proteins such as GRP78,ATF4,CHOP etc.,regulated apoptosis-related protein Bcl-xl,Bax cleaved caspase-4 cytochrome c;thereby effectively counteracting endoplasmic reticulum stress-induced cellular damage.Conclusions GB exerts a protective effect on vascular endothelium by antagonizing endoplasmic reticulum stress;this mechanism may be attributed to its ability to reduce intracellular reactive oxygen species levels.It also suppresses the expression of ERS-related proteins(CHOP78 and ATF4),and modulates apoptosis-associated proteins(Bcl-xl,Bax,cleaved caspase-4,and cytochrome c).

Objective To explore the joint contact force, ligament tensile force and force transmission mode of foot internal structure in Down’s syndrome child (DSC) during standing. Methods The finite element models of foot were constructed based on CT image data from one DSC and one typically developing child (TDC). The models were validated by plantar pressure measurement during static standing. To simulate foot force during standing, the ground reaction force and the triceps surae force were applied as the loading condition. Contact pressure of the tibiotalar, talonavicular and calcaneocuboid joints, tensile force of the spring and plantar calcaneocuboid ligaments, and force transmission mode in transverse tarsal joints were calculated and analyzed. Results The finite element models of foot were validated to be reliable. Compared with the TDC, the DSC showed higher contact pressure at the tibiotalar joint and lower contact pressure at the talonavicular joint. The tensile force of spring and plantar calcaneocuboid ligaments of DSC was 10 times and 58 times of TDC, respectively. The forces transmitted through both mediate and lateral columns in DSC were lower than those in TDC. Conclusions Abnormal contact pressure of the tibiotalar joint, larger tensile force of midfoot ligaments and smaller force of the transverse tarsal joint were found in DSC during standing. The abnormal alteration of stress patterns in foot internal structure of DSC should be fully considered in clinical rehabilitation, so as to provide theoretical references for screening and making intervention plans for early rehabilitation, as well as designing individualized orthopedic insoles.

Objective:To investigate the impact of a reduced portacaval shunt on hepatic myelopathy (HM) in patients with cirrhosis after a transjugular intrahepatic portosystemic shunt (TIPS).Methods:Patients who developed HM after receiving TIPS at the First Affiliated Hospital of Xi'an Jiaotong University from January 2013 to June 2018 were retrospectively analyzed. HM severity was quantified by clinical spasticity index (CSI) and Fugl-Meyer Assessment (FMA) of the lower extremity. Clinical manifestations were combined with grades Ⅰ-Ⅳ. HM patients were divided into drug treatment (group A) and flow restriction group (group B) according to different treatment methods. The changes in CSI and FMA of the lower extremity after treatment were statistically analyzed in the two groups. P<0.05 was considered a statistically significant difference. Results:A total of 421 cases of cirrhosis who underwent TIPS were enrolled. Among them, 30 developed HM, with 22 in group A and 8 in group B. The incidence of HM after TIPS surgery was about 7.13%. After treatment, CSI was gradually increased and FMA of lower extremity was gradually decreased in group A, while vice-versa in group B. CSI in the two groups were differed significantly at 6, 12, 18, and 24 months after treatment ( P<0.05), while the difference in FMA of the lower extremity was statistically significant at 12, 18, and 24 months after treatment ( P<0.05). CSI was decreased and FMA of lower extremity was increased after treatment in patients with group A HM grade I. CSI, and FMA of lower extremity changes were statistically significant ( P<0.05) when compared with patients with HM grades Ⅱ-Ⅳ. The incidence of hepatic encephalopathy was significantly lower in group B than that in group A ( P=0.034), but there was no statistically significant difference between the two groups in the incidence of gastrointestinal bleeding, ascites, infection, MELD score and mortality. Conclusion:A reduced portacaval shunt can improve HM in patients with liver cirrhosis after TIPS, and drug therapy alone is effective for patients with early HM grade I.

Objective:To report our experience in the emergent foot and ankle surgery in the epidemic of COVID-19.Methods:The data of 18 patients with acute foot and ankle injury were reviewed who had been admitted to the Department of Foot and Ankle Surgery, Wuhan Fourth Hospital from 20th January, 2020 to 26th February, 2020. They were 11 men and 7 women, aged from 18 to 70 years (average, 42.5 years). There were 5 cases of acute open injury and 13 ones of acute closed injury. COVID-19 infection was diagnosed or suspected in 5 cases but not in the other 13 cases. Emergency operation was carried out for 2 patients with open injury plus COVID-19 infection and one with complicated pilon fracture plus COVID-19 infection, one of whom received secondary operation. One patient with closed fracture of the left calcaneus plus COVID-19 infection was hospitalized from emergency department for secondary surgery, and another with closed fracture of the right lateral malleolus was referred to the isolation ward after emergency plaster fixation. Of the 10 patients with closed injury but without COVID-19 infection, 3 received conventional secondary surgery after admission and the others conservative treatment at the outpatient department. Recorded were COVID-19 infections in the patients after admission and in the medical staff. The measures taken and experience in control and prevention of COVID-19 infection after outbreak of the epidemic were reviewed.Results:Of the 11 patients who had been hospitalized for foot and ankle injury in emergency, 5 were definitely diagnosed of or suspected of COVID-19 infection and 6 free of COVID-19 infection. During hospitalization, COVID-19 infection was confirmed in the 5 cases and no COVID-19 infection occurred in the other 6 patients. No COVID-19 infection occurred in the medical staff; no cross infection was observed between the patients and the medical staff.Conclusions:Reasonable strategies are advised to balance the foot and ankle surgery and epidemic prevention. A simplified management is not advised for all the cases. The operative procedures in emergent foot and ankle surgery should be optimized in line with the epidemic control and prevention principles to facilitate functional rehabilitation for the patients.

Objective To investigate the influence of immune function and its changes on the prognosis of patients with sepsis. Methods 393 patients who met the diagnostic criteria of Sepsis-3 admitted to General Hospital of Southern War Zone of PLA from April 2003 to April 2017 were enrolled. Clinical data were collected and analyzed retrospectively. According to the initial immune status, patients with more than 4 days course of disease were divided into the initial immune suppression group (219 cases) and the initial immune function normal group (174 cases). According to the changes of immune function, patients with more than 7 days course of disease were divided into persistent inhibition group (113 cases), persistent normal group (96 cases), first normal inhibition group (22 cases) and first inhibited normal group (59 cases). In addition, the patients were divided into the elderly group (≥ 65 years old) and the young group (< 65 years old). Acute physiology and chronic health evaluation Ⅱ(APACHEⅡ), sequential organ failure assessment (SOFA), procalcitonin (PCT), C-reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine (SCr) within 24 hours after diagnosis of sepsis, whether respiratory failure and circulatory failure occur, hormone, immunomodulatory drugs and high-volume hemofiltration treatment within 28 days, the absolute value of lymphocyte counts for 4 consecutive days after diagnosis and 4 consecutive days before the end point event (death or survival within 28 days or more than 28 days) were collected and compared between each group. Results Among 393 sepsis patients, 174 cases had normal initial immune function, of whom 85 cases were older than 65 years old;219 cases had depression of initial immune function, of whom 118 cases were older than 65 years old. Compared with the initial immune function normal group, the levels of PCT, CRP, ALT, AST and SCr in the initial immunosuppressive group were significantly increased [PCT (μg/L): 9.32 (2.13, 34.01) vs. 4.28 (1.02, 19.02), CRP (mg/L): 89.00 (26.00, 142.00) vs. 65.25 (19.88, 119.04), ALT (mmol/L): 39.0 (39.0, 99.0) vs. 27.0 (16.2, 73.0), AST (mmol/L): 55.0 (31.0, 148.0) vs. 39.0 (23.0, 100.8), SCr (μmol/L): 132.00 (74.75, 245.00) vs. 100.25 (61.00, 182.54)], the mean absolute value of lymphocyte counts for 4 consecutive days was significantly decreased [0.615 (0.380, 0.810) vs. 1.442 (1.217, 1.742)], SOFA and APACHEⅡ were significantly increased (SOFA: 9.25±4.19 vs. 6.87±4.66, APACHEⅡ:22.27±8.96 vs. 18.25±9.47), the incidence of circulatory failure (66.2% vs. 50.0%), the incidence of respiratory failure (87.7% vs. 69.0%) and 28-day mortality (65.3% vs. 33.9%) were significantly increased, with statistically significant differences (all P < 0.05). When combined with immunosuppression, there was no significant difference in 28-day mortality between the elderly group and the young group (26.3% vs. 15.8%, P > 0.05); when the immune function was normal, the 28-day mortality of the elderly group was significantly higher than that of the young group (48.2% vs. 20.2%, P < 0.01). The 28-day mortality of the persistent inhibition group and the first normal inhibition group were significantly higher than those of the persistent normal group and the first inhibition normal group [83.2% (94/113), 81.8% (18/22) vs. 26.0% (25/96), 40.7% (24/59), all P < 0.05]. The incidence of immunosuppression in elderly patients [33.3% (14/42) vs. 10.5% (8/76)] and the incidence of persistent immunosuppression [77.0% (67/87) vs. 54.1% (46/85)] were higher than those in young patients (all P < 0.01). Conclusions Immune function is closely related to the prognosis of sepsis patients. Elderly patients with sepsis are more likely to have immunosuppression or persistent immunosuppression than young patients, and the prognosis is worse.