Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

A new TROP2-targeting antibody-drug conjugate shows potent antitumor efficacy in breast and lung cancers.

Trophoblast cell surface antigen 2 (Trop2) is considered to be an attractive therapeutic target in cancer treatments. We previously generated a new humanized anti-Trop2 antibody named hIMB1636, and designated it as an ideal targeting carrier for cancer therapy. Lidamycin (LDM) is a new antitumor antibiotic, containing an active enediyne chromophore (AE) and a noncovalently bound apoprotein (LDP). AE and LDP can be separated and reassembled, and the reassembled LDM possesses cytotoxicity similar to that of native LDM; this has made LDM attractive in the preparation of gene-engineering drugs. We herein firstly prepared a new fusion protein hIMB1636-LDP composed of hIMB1636 and LDP by genetic engineering. This construct showed potent binding activities to recombinant antigen with a KD value of 4.57 nM, exhibited binding to Trop2-positive cancer cells and internalization and transport to lysosomes, and demonstrated powerful tumor-targeting ability in vivo. We then obtained the antibody-drug conjugate (ADC) hIMB1636-LDP-AE by molecular reconstitution. In vitro, hIMB1636-LDP-AE inhibited the proliferation, migration, and tumorsphere formation of tumor cells with half-maximal inhibitory concentration (IC50) values at the sub-nanomolar level. Mechanistically, hIMB1636-LDP-AE induced apoptosis and cell-cycle arrest. In vivo, hIMB1636-LDP-AE also inhibited the growth of breast and lung cancers in xenograft models. Moreover, compared to sacituzumab govitecan, hIMB1636-LDP-AE showed more potent antitumor activity and significantly lower myelotoxicity in tumors with moderate Trop2 expression. This study fully revealed the potent antitumor efficacy of hIMB1636-LDP-AE, and also provided a new preparation method for LDM-based ADC, as well as a promising candidate for breast cancer and lung cancer therapeutics.

Risk factors, prognostic factors, and nomograms for distant metastasis in patients with diagnosed duodenal cancer: A population-based study.

BACKGROUND: Duodenal cancer is one of the most common subtypes of small intestinal cancer, and distant metastasis (DM) in this type of cancer still leads to poor prognosis. Although nomograms have recently been used in tumor areas, no studies have focused on the diagnostic and prognostic evaluation of DM in patients with primary duodenal cancer. AIM: To develop and evaluate nomograms for predicting the risk of DM and personalized prognosis in patients with duodenal cancer. METHODS: Data on duodenal cancer patients diagnosed between 2010 and 2019 were extracted from the Surveillance, Epidemiology, and End Results database. Univariate and multivariate logistic regression analyses were used to identify independent risk factors for DM in patients with duodenal cancer, and univariate and multivariate Cox proportional hazards regression analyses were used to determine independent prognostic factors in duodenal cancer patients with DM. Two novel nomograms were established, and the results were evaluated by receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: A total of 2603 patients with duodenal cancer were included, of whom 457 cases (17.56%) had DM at the time of diagnosis. Logistic analysis revealed independent risk factors for DM in duodenal cancer patients, including gender, grade, tumor size, T stage, and N stage (P < 0.05). Univariate and multivariate COX analyses further identified independent prognostic factors for duodenal cancer patients with DM, including age, histological type, T stage, tumor grade, tumor size, bone metastasis, chemotherapy, and surgery (P < 0.05). The accuracy of the nomograms was validated in the training set, validation set, and expanded testing set using ROC curves, calibration curves, and DCA curves. The results of Kaplan-Meier survival curves (P < 0.001) indicated that both nomograms accurately predicted the occurrence and prognosis of DM in patients with duodenal cancer. CONCLUSION: The two nomograms are expected as effective tools for predicting DM risk in duodenal cancer patients and offering personalized prognosis predictions for those with DM, potentially enhancing clinical decision-making.

Immunophenotype of lymphocytes and real-world outcome of COVID-19 infection in children with hematology and oncology.

BACKGROUND: Patients with immunocompromise were suspected to encounter a high risk for severe coronavirus disease 2019 (COVID-19) infection on early period; however, data is lacking nowadays and immune response remain unclear. METHODS: In this retrospective study, internet questionnaire survey and medical records were acquired in pediatric hematology oncology patients. Clinical severity, immunological characteristics, and outcomes were analyzed from December 1, 2022 to January 31, 2023 at the 3rd year of pandemic in China. RESULTS: A total of 306 patients were included, with 21 patients (6.9%) asymptomatic, 262 (85.6%) mild severity, 17 (5.6%) moderate severity, 5 (1.6%) severe severity, and 1 (0.3%) critical severity. Seventy-eight (25.5%) patients were on intensive chemotherapy, and 32.0% children were on maintenance chemotherapy. Delays in cancer therapy occurred in 86.7% patients. Univariable analysis revealed active chemotherapy (P < 0.0001), long duration of symptom (P < 0.0001), low lymphocytes count (P = 0.095), low CD3 + and CD8 + T cell count (P = 0.013, P = 0.022), high percentage of CD4 + TCM (P = 0.016), and low percentage of transitional B cells (P = 0.045) were high risk factors for severe COVID-19 infection. Cox regression model showed that the absolute lymphocytes count (P = 0.027) and long duration of symptom (P = 0.002) were the independent factors for severity. Patients with CD8 + dominant and B cell depletion subtype wasn't related with severity, but had higher percentage of CD8 + effector memory T cells (TEM) and terminally differentiated effector memory T cells (TEMRA) (P < 0.001, P < 0.001), and a longer COVID-19 duration (P = 0.045). CONCLUSION: The severity was relatively mild in children with immunodeficiencies in the third year of COVID-19 pandemic. Low lymphocyte count and long duration of symptom were the independent risk factors with COVID-19 severity. Delays in cancer care remain a major concern and the long outcome is pending.

Targeted inhibition of autophagy in hepatic stellate cells by hydroxychloroquine: An effective therapeutic approach for the treatment of liver fibrosis.

BACKGROUND AND PURPOSE: Liver fibrosis is a wound-healing reaction which is the main cause of chronic liver diseases worldwide. The activated hepatic stellate cell (aHSC) is the main driving factor in the development of liver fibrosis. Inhibiting autophagy of aHSC can prevent the progression of liver fibrosis, but inhibiting autophagy of other liver cells has opposite effects. Hence, targeted inhibition of autophagy in aHSC is quite necessary for the treatment of liver fibrosis, which prompts us to explore the targeted delivery system of small molecule autophagy inhibitor hydroxychloroquine (HCQ) that can target aHSC and alleviate the liver fibrosis. METHODS: The delivery system of HCQ@retinol-liposome nanoparticles (HCQ@ROL-LNPs) targeting aHSC was constructed by the film dispersion and pH-gradient method. TGF-ß-induced HSC activation and thioacetamide (TAA)-induced liver fibrosis mice model were established, and the targeting ability and therapeutic effect of HCQ@ROL-LNPs in liver fibrosis were studied subsequently in vitro and in vivo. RESULTS: HCQ@ROL-LNPs have good homogeneity and stability. They inhibited the autophagy of aHSC selectively by HCQ and reduced the deposition of extracellular matrix (ECM) and the damage to other liver cells. Compared with the free HCQ and HCQ@LNPs, HCQ@ROL-LNPs had good targeting ability, showing enhanced therapeutic effect and low toxicity to other organs. CONCLUSION: Construction of HCQ@ROL-LNPs delivery system lays a theoretical and experimental foundation for the treatment of liver fibrosis and promotes the development of clinical therapeutic drugs for liver diseases.

Two heat shock cognate 70 genes involved in spermatogenesis regulate the male fertility of Zeugodacus cucurbitae, as potential targets for pest control.

The melon fly Zeugodacus cucurbitae Coquillett (Diptera: Tephritidae) is an agricultural quarantine pest threatening fruit and vegetable production. Heat shock cognate 70 (Hsc70), which is a homolog of the heat shock protein 70 (Hsp70), was first discovered in mice testes and plays an important role in spermatogenesis. In this study, we identified and cloned five Hsc70 genes from melon fly, namely ZcHsc70_1/2/3/4/5. Phylogenetic analysis showed that these proteins are closely related to Hsc70s from other Diptera insects. Spatiotemporal expression analysis showed that ZcHsc70_1 and ZcHsc70_2 are highly expressed in Z. cucurbitae testes. Fluorescence in situ hybridization further demonstrated that ZcHsc70_1 and ZcHsc70_2 are expressed in the transformation and maturation regions of testes, respectively. Moreover, RNA interference-based suppression of ZcHsc70_1 or ZcHsc70_2 resulted in a significant decrease of 74.61% and 63.28% in egg hatchability, respectively. Suppression of ZcHsc70_1 expression delayed the transformation of sperm cells to mature sperms. Meanwhile, suppression of ZcHsc70_2 expression decreased both sperm cells and mature sperms by inhibiting the meiosis of spermatocytes. Our findings show that ZcHsc70_1/2 regulates spermatogenesis and further affects the male fertility in the melon fly, showing potential as targets for pest control in sterile insect technique by genetic manipulation of males.

Overexpression of miR-927-5p suppresses stalky expression and negatively reduces the spermatid production in Zeugodacus cucurbitae.

BACKGROUND: The melon fly, Zeugodacus cucurbitae Coquillett, is one of the major pests attacking Cucurbitaceae crops. Identifying critical genes or proteins regulating fertility is essential for sustainable pest control and a research hotspot in insect physiology. MicroRNAs (miRNAs) are short RNAs that do not directly participate in protein translation, but instead function in post-transcriptional regulation of gene expression involved in male fertility. RESULTS: We found that miR-927-5p is highly expressed in the testes and investigated its function in spermatogenesis in Z. cucurbitae. Fluorescence in situ hybridization (FISH) showed miR-927-5p in the transformation and maturation region of the testis, and overexpression of miR-927-5p reduced the number of sperms by 53%. In continuation, we predicted 12 target genes of miR-927-5p using bioinformatics combined with transcriptome sequencing data, and found that miR-927-5p targets the new gene Stalky in insects, which was validated by quantitative real-time PCR, RNA pull-down and dual luciferase reporter assays. FISH also confirmed the co-localization of miR-927-5p and the transcript Stalky_1 in the testis. Moreover, silencing of Stalky_1 by RNA interference reduced the number of sperms by 32% and reduced sperm viability by 39% in physiologically mature male adults. Meanwhile, the silencing of Stalky_1 also resulted in low hatchability. CONCLUSION: Our work not only presents a new, so far unreported mechanism regulating spermatogenesis by miR-927-5p targeting a new unknown target, Stalky, which is providing new knowledge on the regulatory network of insect spermatogenesis, but also lays a foundation for the development of SIT against important tephritid fly pests. © 2024 Society of Chemical Industry.

Suppressing the expression of glutathione S-transferase gene GSTd10 increases the sensitivity of Zeugodacus cucurbitae against ß-cypermethrin.

Zeugodacus cucurbitae Coquillett (Diptera: Tephritidae) is an agriculturally and economically important pest worldwide that has developed resistance to ß-cypermethrin. Glutathione S-transferases (GSTs) have been reported to be involved in the detoxification of insecticides in insects. We have found that both ZcGSTd6 and ZcGSTd10 were up-regulated by ß-cypermethrin induction in our previous study, so we aimed to explore their potential relationship with ß-cypermethrin tolerance in this study. The heterologous expression of ZcGSTd6 and ZcGSTd10 in Escherichia coli showed significantly high activities against 1-chloro-2,4-dinitrobenzene (CDNB). The kinetic parameters of ZcGSTd6 and ZcGSTd10 were determined by Lineweaver-Burk. The Vmax and Km of ZcGSTd6 were 0.50 µmol/min·mg and 0.3 mM, respectively. The Vmax and Km of ZcGSTd10 were 1.82 µmol/min·mg and 0.53 mM. The 3D modelling and molecular docking results revealed that ß-cypermethrin exhibited a stronger bounding to the active site SER-9 of ZcGSTd10. The sensitivity to ß-cypermethrin was significantly increased by 18.73% and 27.21%, respectively, after the knockdown of ZcGSTd6 and ZcGSTd10 by using RNA interference. In addition, the inhibition of CDNB at 50% (IC50) and the inhibition constants (Ki) of ß-cypermethrin against ZcGSTd10 were determined as 0.41 and 0.33 mM, respectively. The Ki and IC50 of ß-cypermethrin against ZcSGTd6 were not analysed. These results suggested that ZcGSTd10 could be an essential regulator involved in the tolerance of Z. cucurbitae to ß-cypermethrin.

Zeolitic imidazole framework-8 loaded gelatin methacryloyl microneedles: A transdural and controlled-release drug delivery system attenuates neuroinflammation after spinal cord injury.

Spinal cord injury (SCI) is a matter of significant clinical concern, often treated through early surgical decompression along with methylprednisolone sodium succinate (MPSS). However, the side effects and the unsatisfactory focal concentration of MPSS have limited its further applications. To address this limitation, herein, a versatile drug delivery system of zeolitic imidazole framework-8 (ZIF-8) and gelatin methacryloyl microneedles (GelMA MNs) was developed for stable, transdural, and controlled sustained release of drugs in SCI. The microneedles were used to create tiny pores in the dura mater, allowing for the direct administration of drugs into the spinal cord. ZIF-8 provided a secondary extended release once they were separated from the microneedles. To attenuate the neuroinflammation, MPSS was selected. Such a combination of ZIF-8 and GelMA MNs was able to prolong the release period of MPSS to five days. The system showed transdural capacity, reduction of M1 polarization, and decrease in NLRP3-positive inflammasome and proinflammatory cytokines. In vivo studies indicated that this novel drug delivery strategy could constrict the inflammatory microenvironment, reduce glial scar formation, and promote neural regeneration. Thus, this versatile drug delivery system provides an up-and-coming alternative for stable, transdural, and controlled sustained release of drugs to those suffering from SCI.

[Optimization of extraction process for classic prescription Yihuang Decoction based on Box-Behnken design-response surface methodology, standard relation, and analytic hierarchy process combined with entropy weight method].

Based on the concept of quality by design(QbD), the Box-Behnken design-response surface methodology combined with standard relation(SR) and analytic hierarchy process(AHP)-entropy weight method(EWM) was applied to optimize the extraction process of the classic prescription Yihuang Decoction. The content of geniposidic acid, phellodendrine hydrochloride, and berberine hydrochloride in Yihuang Decoction, the extract yield, and fingerprint similarity were used as the critical quality attributes(CQAs) of the extraction process. The extraction time, water addition, and extraction times were used as the critical process parameters(CPPs). After determining the levels of each factor and level through single-factor experiments, response surface experiments were designed according to the Box-Behnken principle, and the experimental results were analyzed. The SR between each sample and the reference sample under various evaluation indicators of different extraction parameters was calculated. The weights of the five evaluation indicators were determined using AHP-EWM, followed by comprehensive evaluation. A function model between CPPs and CQAs characterized by comprehensive scores was established to predict the optimal extraction process parameters. In the final comprehensive weight coefficients, the yield rate accounted for 43.1%, and the content of berberine hydrochloride, phellodendrine hydrochloride, and geniposidic acid accounted for 35.1%, 6.3%, and 15.5%, respectively. After comprehensive score analysis with SR, the established second-order polynomial model was statistically significant(P<0.01, and the lack of fit was not significant). The predicted optimal extraction conditions for Yihuang Decoction were determined as follows: 8-fold volume of water, extraction time of 1.5 h, and extraction once. The mean comprehensive score of the validation experiment was 85.77, with an RSD of 0.99%, and it met the quality control stan-dards for the reference sample of Yihuang Decoction. The results indicate that the optimized extraction process for Yihuang Decoction is stable and reliable, and the water extract is close in quality attributes to the reference sample. This can serve as a foundation for the research and development of granules in the future. Box-Behnken design-response surface methodology combined with SR and AHP-EWM can provide references for the modern extraction process research of other classic prescriptions.

Bioprospecting of Actinobacterial Diversity and Antibacterial Secondary Metabolites from the Sediments of Four Saline Lakes on the Northern Tibetan Plateau.

The Tibetan Plateau, known as the "Roof of the World" and "The Third Pole", harbors numerous saline lakes primarily distributed in the Northern Tibetan Plateau. However, the challenging conditions of high altitude, low oxygen level, and harsh climate have limited investigations into the actinobacteria from these saline lakes. This study focuses on investigating the biodiversity and bioactive secondary metabolites of cultivable actinobacteria isolated from the sediments of four saline lakes on the Northern Tibetan Plateau. A total of 255 actinobacterial strains affiliated with 21 genera in 12 families of 7 orders were recovered by using the pure culture technique and 16S rRNA gene phylogenetic analysis. To facilitate a high-throughput bioactivity evaluation, 192 isolates underwent OSMAC cultivation in a miniaturized 24-well microbioreactor system (MATRIX cultivation). The antibacterial activity of crude extracts was then evaluated in a 96-well plate antibacterial assay. Forty-six strains demonstrated antagonistic effects against at least one tested pathogen, and their underlying antibacterial mechanisms were further investigated through a dual-fluorescent reporter assay (pDualrep2). Two Streptomyces strains (378 and 549) that produce compounds triggering DNA damage were prioritized for subsequent chemical investigations. Metabolomics profiling involving HPLC-UV/vis, UPLC-QTOF-MS/MS, and molecular networking identified three types of bioactive metabolites belonging to the aromatic polyketide family, i.e., cosmomycin, kidamycin, and hedamycin. In-depth analysis of the metabolomic data unveiled some potentially novel anthracycline compounds. A genome mining study based on the whole-genome sequences of strains 378 and 549 identified gene clusters potentially responsible for cosmomycin and kidamycin biosynthesis. This work highlights the effectiveness of combining metabolomic and genomic approaches to rapidly identify bioactive chemicals within microbial extracts. The saline lakes on the Northern Tibetan Plateau present prospective sources for discovering novel actinobacteria and biologically active compounds.

Spine Surgery with Electronic Conductivity Device: A Prospectively Multicenter Randomized Clinical Trial and Literature Review.

OBJECTIVE: Improving accuracy and safety of pedicle screw placement is of great clinical importance. Electronic conductivity device (ECD) can be a promising technique with features of affordability, portability, and real-time detection capabilities. This study aimed to validate the safety and effectiveness of a modified ECD. METHODS: The ECD underwent a modification where six lamps of various colors, and it was utilized in a prospectively multicenter randomized controlled clinical trial involving 96 patients across three hospitals from June 2018 to December 2018. The trial incorporated a self-control randomization with an equal distribution of left or right side of vertebral pedicle among two groups: the free-hand group and the ECD group. A total of 496 pedicle screws were inserted, with 248 inserted in each group. The primary outcomes focused on the accuracy of pedicle screw placement and the frequency of intraoperative X-rays. Meanwhile, the secondary indicator measured the time required for pedicle screw placement. Results were presented as means ± SD. Paired samples t-test and χ2 -test were used for comparison. Furthermore, an updated review was conducted, which included studies published from 2006 onwards. RESULTS: Baseline patient characteristics were recorded. The primary accuracy outcome revealed a 96.77% accuracy rate in the ECD group, compared to a 95.16% accuracy rate in the free-hand group, with no significant differences noted. In contrast, ECD demonstrated a significant reduction in radiation exposure frequency when compared to the free-hand group (1.11 ± 0.32 vs. 1.30 ± 0.53; p < 0.001), resulting in a 14.6% reduction. Moreover, ECD displayed a decrease of 30.38% in insertion time (70.88 ± 30.51 vs. 101.82 ± 54.00 s; p < 0.001). According to the results of the 21 studies, ECD has been utilized in various areas of the spine such as the atlas, thoracic and lumbar spine, as well as sacral 2-alar-iliac. The accuracy of ECD ranged from 85% to 100%. CONCLUSION: The prospectively randomized trial and the review indicate that the use of ECD presents a secure and precise approach to the placement of pedicle screws, with the added benefit of reducing both procedure time and radiation exposure.

Development and Validation of a Nomogram to Predict the Risk of Tinnitus Severity in Patients With Unilateral Subjective Tinnitus.

Purpose: To develop and validate a nomogram for predicting the risk of tinnitus severity in patients with unilateral subjective tinnitus. Methods: The objective of this study was to establish and validate a nomogram specifically designed for patients with unilateral subjective tinnitus. We collected data on unilateral subjective tinnitus from the Air Force Medical Center, including 146 participants between January 2021 and June 2022. Risk factors for unilateral subjective tinnitus severity were evaluated by least absolute shrinkage and selection operator (LASSO) and binary logistic regression analysis. Internal verification was used to evaluate the performance of the nomogram. The discriminative ability was measured by the consistency index (C-indices) and the area under the curve (AUC) of the receiver operating characteristic (ROC) curves. Results: All included patients were randomized according to a 7:3 ratio into the training cohort (104 patients) and the validation cohort (42 patients). The LASSO regression model identified sex, tinnitus loudness, and hearing loss as candidate variables. Binary logistic regression analysis showed that gender (OR: 0.76; 95% CI: 0.6-0.95; P = 0.021) and tinnitus loudness (OR: 1.37; 95% CI: 1.09-1.72; P = 0.009) were significant predictors of unilateral subjective tinnitus severity, while age, tinnitus matching frequency, and tinnitus duration were not. The significant predictors were included in the nomogram. Hearing loss was included in the nomogram based on prior clinical experience and previous studies. The training and validation cohorts C-indexes were 0.707 (95% CI: 0.607-0.806) and 0.706 (95% CI: 0.548-0.863), respectively. The training and validation cohort's AUC of the ROC curves were 0.692 and 0.705, respectively. Conclusion: We have developed and validated a nomogram based on gender, hearing loss, and tinnitus loudness, which can effectively predict the risk of tinnitus severity in patients with unilateral subjective tinnitus. The nomogram provides personalized prediction results for patients with unilateral subjective tinnitus, which is beneficial for clinical decision-making and treatment plan development.

Elucidating the development, characterization, and antitumor potential of a novel humanized antibody against Trop2.

Trophoblast cell surface antigen 2 (Trop2) has emerged as a potential target for effective cancer therapy. In this study, we report a novel anti-Trop2 antibody IMB1636, developed using hybridoma technology. It exhibited high affinity and specificity (KD = 0.483 nM) in binding both antigens and cancer cells, as well as human tumor tissues. hIMB1636 could induce endocytosis, and enabled targeted delivery to the tumor site with an in vivo retention time of 264 h. The humanized antibody hIMB1636, acquired using CDR grafting, exhibited the potential to directly inhibit cancer cell proliferation and migration, and to induce ADCC effects. Moreover, hIMB1636 significantly inhibited the growth of MDA-MB-468 xenograft tumors in vivo. Mechanistically, hIMB1636 induced cell cycle arrest and apoptosis by regulating cyclin-related proteins and the caspase cascade. In comparison to commercialized sacituzumab, hIMB1636 recognized a conformational epitope instead of a linear one, bound to antigen and cancer cells with similar binding affinity, induced significantly more potent ADCC effects against cancer cells, and displayed superior antitumor activities both in vitro and in vivo. The data presented in this study highlights the potential of hIMB1636 as a carrier for the formulation of antibody-based conjugates, or as a promising candidate for anticancer therapy.

Effect of bladder filling status on positioning errors in post-hysterectomy cervical cancer radiotherapy.

Objective: To investigate the effect of different bladder filling states on positioning errors in radiotherapy for cervical cancer and obtain the reference range of bladder filling consistency during radiotherapy.Methods: Patients who underwent postoperative radiotherapy for cervical cancer in Nantong Tumor Hospital from October 2018 to December 2019 were selected. According to the bladder filling deviation, they were divided into group A1 (deviation < 20%) and group B1 (deviation ≥ 20%). The bladder filling variations of the two groups were compared with different positioning errors. Group A2 has a positioning error of <0.4 cm, and group B2 has a positioning error of ≥0.4 cm. The reference range of bladder filling consistency during radiotherapy is obtained by analyzing the composition ratio of different positioning errors of bladder filling deviation.Results: This study included 195 patients with cervical cancer. The error of longitudinal and vertical position in group B1 was significantly higher than that in group A1 (0.50 ± 0.34 vs. 0.26 ± 0.22 cm, p < 0.001, and 0.22 ± 0.17 vs. 0.16 ± 0.12 cm, p < 0.001). Compared with group B2, the absolute deviation of bladder filling in group A2 (54.1% ± 54.4% vs. 25.6% ± 22.7%, p < 0.001) was slight. The chi-square test showed significant differences in the proportion of the positioning state of different bladder filling forms (χ2 = 31.006, p < 0.001). In addition, there was a significant difference in the proportion of stability errors in patients with poor stability in different directions (χ2 = 118.551, p < 0.001).Conclusion: In patients with cervical cancer fixed in the supine position, a bladder capacity deviation <20% is easier to achieve excellent positioning with, and it can better control the positioning error of radiotherapy and ensure the positioning accuracy of dose distribution to the target area. It can also achieve good tumor treatment effects. This range can be used as a reference for bladder filling consistency in patients with cervical cancer undergoing radiotherapy.

A swift expanding trend of extracellular vesicles in spinal cord injury research: a bibliometric analysis.

Extracellular vesicles (EVs) in the field of spinal cord injury (SCI) have garnered significant attention for their potential applications in diagnosis and therapy. However, no bibliometric assessment has been conducted to evaluate the scientific progress in this area. A search of articles in Web of Science (WoS) from January 1, 1991, to May 1, 2023, yielded 359 papers that were analyzed using various online analysis tools. These articles have been cited 10,842 times with 30.2 times per paper. The number of publications experienced explosive growth starting in 2015. China and the United States led this research initiative. Keywords were divided into 3 clusters, including "Pathophysiology of SCI", "Bioactive components of EVs", and "Therapeutic effects of EVs in SCI". By integrating the average appearing year (AAY) of keywords in VoSviewer with the time zone map of the Citation Explosion in CiteSpace, the focal point of research has undergone a transformative shift. The emphasis has moved away from pathophysiological factors such as "axon", "vesicle", and "glial cell" to more mechanistic and applied domains such as "activation", "pathways", "hydrogels" and "therapy". In conclusions, institutions are expected to allocate more resources towards EVs-loaded hydrogel therapy and the utilization of innovative materials for injury mitigation.

DNA intercalation makes possible superior-gain organic photoelectrochemical transistor detection.

DNA intercalation has increasingly been studied for various scenario implementations due to the diverse functions of DNA/intercalators. Nascent organic photoelectrochemical transistor (OPECT) biosensing taking place in organic electronics and photoelectrochemical bioanalysis represents a promising technological frontier in the arena. In this work, we first devise DNA intercalation-enabled OPECT for miRNA detection with a superior gain up to 17100. Intercalation of [Ru(bpy)2dppz]2+ within the miRNA-initiated hybrid chain reaction (HCR)-derived duplex DNA is realized for producing anodic photocurrent upon light stimulation, causing the corresponding target-dependent alternation in gate voltage (VG) and hence the modulated channel current (IDS) of poly (3,4-ethylenedioxythiophene) doped with poly (styrene sulfonate) (PEDOT:PSS) under specific drain voltage (VDS) for quantitative miRNA-21 analysis, which shows a wide linear relationship and a low detection limit of 5.5 × 10-15 mol L-1. This study features the DNA intercalation-enabled organic electronics with superior gain and is envisaged to attract more attention to explore DNA adducts for innovative bioelectronics and biosensing, given the diverse DNA binders with multiple functions.

Microneedle/CD-MOF-mediated transdural controlled release of methylprednisolone sodium succinate after spinal cord injury.

A new method of transdural delivering drugs to the spinal cord has been developed, involving the use of microneedles (MNs) and a ß-cyclodextrin metal-organic framework (CD-MOF). This epidural microneedle array, dubbed MNs@CD-MOF@MPSS, can be utilized to deliver methylprednisolone sodium succinate (MPSS) to the site of spinal cord injury (SCI) in a controlled manner. MNs allows to generate micropores in the dura for direct drug delivery to the spinal cord, overcoming tissue barriers and targeting damaged regions. Additionally, the CD-MOF provides a secondary extended release after separating from the MNs. In in vitro study, inward MNs increased cellular absorption of MPSS and then reduced LPS-induced M1 polarization of microglia. And animal studies have shown that this method of drug delivery results in improved BMS scores and a reduction in M1 phenotype microphage and glial scar formation. Furthermore, the downregulation of the NLRP3-positive inflammasome and related pro-inflammatory cytokines was observed. In conclusion, this new drug platform has potential for clinical application in spinal cord diseases and is a valuable composite for minimally transdural controlled drug delivery. STATEMENT OF SIGNIFICANCE: This research presents a new epidural microneedle patch made up of microneedles (MNs) and a ß-cyclodextrin metal-organic framework (CD-MOF). The epidural microneedle patch boasts high drug loading capacity, the ability to penetrate the dura, and controlled release. When loaded with methylprednisolone sodium succinate (MPSS), it effectively reduces inflammation and improves neurological function after spinal cord injury. Therefore, it is a novel and promising drug platform for the treatment of spinal cord diseases in a clinical setting.

Busulfan Plus Fludarabine Compared With Busulfan Plus Cyclophosphamide for AML Undergoing HLA-Haploidentical Hematopoietic Cell Transplantation: A Multicenter Randomized Phase III Trial.

PURPOSE: The busulfan plus fludarabine (BuFlu) conditioning regimen has lower transplant-related mortality (TRM) than busulfan plus cyclophosphamide (BuCy) in HLA-matched transplantation. We aimed to compare outcomes of the BuFlu regimen with those of the BuCy regimen in HLA-haploidentical hematopoietic cell transplantation (haplo-HCT). METHODS: We performed an open-label, randomized phase III trial at 12 hospitals in China. Eligible patients with AML (18-65 years) were randomly assigned 1:1 to receive BuFlu (busulfan 0.8 mg/kg four times per day on days -6 to -3; fludarabine 30 mg/m2 once daily on days -7 to -3) or BuCy (same dose of busulfan; cyclophosphamide 60 mg/kg once daily on days -3 and -2). The primary end point was 1-year TRM in the intention-to-treat population and safety in the per-protocol population. This trial is registered with ClinicalTrials.gov (identifier: NCT02487069) and is complete. RESULTS: From November 20, 2015, to September 30, 2019, 386 patients were randomly assigned to receive the BuFlu (n = 194) or BuCy (n = 192) regimen. The median follow-up was 55.0 (IQR, 46.5-69.0) months after random assignment. The 1-year TRM was 7.2% (95% CI, 4.1 to 11.4) and 14.1% (95% CI, 9.6 to 19.4; hazard ratio [HR], 0.51; 95% CI, 0.27 to 0.97; P = .041), the 5-year relapse was 17.9% (95% CI, 9.6 to 28.3) and 14.2% (95% CI, 9.1 to 20.5; HR, 1.12; 95% CI, 0.65 to 1.95; P = .670), and the 5-year overall survival was 72.5% (95% CI, 62.2 to 80.4) and 68.2% (95% CI, 58.9 to 75.9; HR, 0.84; 95% CI, 0.56 to 1.26; P = .465) in two groups, respectively. Grade 3 regimen-related toxicity (RRT) was reported for 0 of 191 patients following the BuFlu regimen and 9 (4.7%) of 190 patients following the BuCy regimen (P = .002). At least one type of grade 3-5 adverse event was reported for 130 (68.1%) of the 191 patients and 147 (77.4%) of the 190 patients in two groups, respectively (P = .041). CONCLUSION: The BuFlu regimen has a lower TRM and RRT and similar relapse for patients with AML undergoing haplo-HCT compared with the BuCy regimen.

High ligation of the hernia sac in open nonmesh inguinal herniorrhaphy is an important cause of iatrogenic vas deferens injury.

Vasectomy damage is a common complication of open nonmesh hernia repair. This study was a retrospective analysis of the characteristics and possible causes of vas deferens injuries in patients exhibiting unilateral or bilateral vasal obstruction caused by open nonmesh inguinal herniorrhaphy. The site of the obstructed vas deferens was intraoperatively confirmed. Data, surgical methods, and patient outcomes were examined. The Anderson-Darling test was applied to test for Gaussian distribution of data. Fisher's exact test or Mann-Whitney U test and unpaired t-test were used for statistical analyses. The mean age at operation was 7.23 (standard deviation [s.d.]: 2.09) years and the mean obstructive interval was 17.72 (s.d.: 2.73) years. Crossed (n = 1) and inguinal ( n = 42) vasovasostomies were performed. The overall patency rate was 85.3% (29/34). Among the 43 enrolled patients (mean age: 24.95 [s.d.: 2.20] years), 73 sides of their inguinal regions were explored. The disconnected end of the vas deferens was found in the internal ring on 54 sides (74.0%), was found in the inguinal canal on 16 sides (21.9%), and was found in the pelvic cavity on 3 sides (4.1%). Location of the vas deferens injury did not significantly differ according to age at the time of hernia surgery ( ≥ 12 years or <12 years) or obstructive interval (≥15 years or <15 years). These results underscore that high ligation of the hernial sac warrants extra caution by surgeons during open nonmesh inguinal herniorrhaphy.