Non-Clinical Safety Evaluation of Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells in Cynomolgus Monkeys.

Purpose: In recent years, exosomes have been proved to be used to treat many diseases. However, due to the lack of uniform quality control standards for exosomes, the safety of exosomes is still a problem to be solved, especially now more and more exosomes are used in clinical trials, and its non-clinical safety evaluation is particularly important. However, there is no safety evaluation standard for exosomes at present. Therefore, this study will refer to the evaluation criteria of therapeutic biological products, adopt non-human primates to evaluate the non-clinical safety of human umbilical cord mesenchymal stem cell exosomes from the general pharmacology and immunotoxicity, aiming at establishing a safety evaluation system of exosomes and providing reference for the clinical application of exosomes in the future. Methods: 3.85 × 1012 exosomes derived from human umbilical cord mesenchymal stem cells were injected into cynomolgus monkeys intravenously. The changes of general clinical conditions, hematology, immunoglobulin, Th1/Th2 cytokines, T lymphocytes and B lymphocytes, and immune organs were observed before and within 14 days after injection. Results: The results showed that exosomes did not have obvious pathological effects on the general clinical conditions, blood, coagulation function, organ coefficient, immunoglobulin, Th1/Th2 cytokines, lymphocytes, major organs, and major immune organs (spleen, thymus, bone marrow) of cynomolgus monkeys. However, the number of granulocyte-macrophage colonies in exosomes group was significantly higher than that in control group. Conclusion: To sum up, the general pharmacological results and immunotoxicity results showed that the injection of 3.85 × 1012 exosomes may have no obvious adverse reactions to cynomolgus monkeys. This dose of exosomes is relatively safe for treatment, which provides basis research for non-clinical safety evaluation of exosomes and provides reliable research basis for future clinical application of exosomes.

Berberine alleviates ovarian tissue damage in mice with hepatolenticular degeneration by suppressing ferroptosis and endoplasmic reticulum stress.

OBJECTIVE: Hepatolenticular degeneration (HLD) is an autosomal recessive disorder that manifests as multiorgan damage due to impaired copper (Cu) metabolism. Female patients with HLD often experience reproductive impairments. This study investigated the protective effect of berberine against ovarian damage in toxic-milk (TX) mice, a murine model for HLD. METHODS: Mice were categorized into control group, HLD TX group (HLD group), penicillamine (Cu chelator)-treated TX group and berberine-treated TX group. Body weight, ovary weight and the number of ovulated eggs were recorded. Follicular morphology and cellular ultrastructure were examined. Total iron, ferrous iron (Fe2+) and trivalent iron (Fe3+) levels, as well as malondialdehyde (MDA), glutathione (GSH) and oxidized glutathione (GSSG), were measured in the ovaries. Western blot analysis was used to analyze the expression of proteins related to ferroptosis and endoplasmic reticulum (ER) stress. RESULTS: Ovarian tissue damage was evident in the HLD group, with a significant increase in ferroptosis and ER stress compared to the control group. This damage was inhibited by treatment with penicillamine, a Cu chelator. Compared with the HLD group, berberine increased the number of ovulations, and improved ovarian morphology and ultrastructure. Further, we found that berberine reduced total iron, Fe2+, MDA and GSSG levels, elevated GSH levels, decreased the expression of the ferroptosis marker protein prostaglandin-endoperoxide synthase 2 (PTGS2), and increased glutathione peroxidase 4 (GPX4) expression. Furthermore, berberine inhibited the expression of ER stress-associated proteins mediated by the protein kinase RNA-like ER kinase (PERK) pathway. CONCLUSION: Ferroptosis and ER stress are involved in Cu-induced ovarian damage in TX mice. Berberine ameliorates ovarian damage in HLD TX mice by inhibiting ferroptosis and ER stress. Please cite this article as: Liu QZ, Han H, Fang XR, Wang LY, Zhao D, Yin MZ, Zhang N, Jiang PY, Ji ZH, Wu LM. Berberine alleviates ovarian tissue damage in mice with hepatolenticular degeneration by suppressing ferroptosis and endoplasmic reticulum stress. J Integr Med. 2024; Epub ahead of print.

Identification and Characterization of Metastasis-Initiating Cells in ESCC in a Multi-Timepoint Pulmonary Metastasis Mouse Model.

Metastasis is the biggest obstacle to esophageal squamous cell carcinoma (ESCC) treatment. Single-cell RNA sequencing analyses are applied to investigate lung metastatic ESCC cells isolated from pulmonary metastasis mouse model at multiple timepoints to characterize early metastatic microenvironment. A small population of parental KYSE30 cell line (Cluster S) resembling metastasis-initiating cells (MICs) is identified because they survive and colonize at lung metastatic sites. Differential expression profile comparisons between Cluster S and other subpopulations identified a panel of 7 metastasis-initiating signature genes (MIS), including CD44 and TACSTD2, to represent MICs in ESCC. Functional studies demonstrated MICs (CD44high) exhibited significantly enhanced cell survival (resistances to oxidative stress and apoptosis), migration, invasion, stemness, and in vivo lung metastasis capabilities, while bioinformatics analyses revealed enhanced organ development, stress responses, and neuron development, potentially remodel early metastasis microenvironment. Meanwhile, early metastasizing cells demonstrate quasi-epithelial-mesenchymal phenotype to support both invasion and anchorage. Multiplex immunohistochemistry (mIHC) staining of 4 MISs (CD44, S100A14, RHOD, and TACSTD2) in ESCC clinical samples demonstrated differential MIS expression scores (dMISs) predict lymph node metastasis, overall survival, and risk of carcinothrombosis.

Clinical domain knowledge-derived template improves post hoc AI explanations in pneumothorax classification.

OBJECTIVE: Pneumothorax is an acute thoracic disease caused by abnormal air collection between the lungs and chest wall. Recently, artificial intelligence (AI), especially deep learning (DL), has been increasingly employed for automating the diagnostic process of pneumothorax. To address the opaqueness often associated with DL models, explainable artificial intelligence (XAI) methods have been introduced to outline regions related to pneumothorax. However, these explanations sometimes diverge from actual lesion areas, highlighting the need for further improvement. METHOD: We propose a template-guided approach to incorporate the clinical knowledge of pneumothorax into model explanations generated by XAI methods, thereby enhancing the quality of the explanations. Utilizing one lesion delineation created by radiologists, our approach first generates a template that represents potential areas of pneumothorax occurrence. This template is then superimposed on model explanations to filter out extraneous explanations that fall outside the template's boundaries. To validate its efficacy, we carried out a comparative analysis of three XAI methods (Saliency Map, Grad-CAM, and Integrated Gradients) with and without our template guidance when explaining two DL models (VGG-19 and ResNet-50) in two real-world datasets (SIIM-ACR and ChestX-Det). RESULTS: The proposed approach consistently improved baseline XAI methods across twelve benchmark scenarios built on three XAI methods, two DL models, and two datasets. The average incremental percentages, calculated by the performance improvements over the baseline performance, were 97.8% in Intersection over Union (IoU) and 94.1% in Dice Similarity Coefficient (DSC) when comparing model explanations and ground-truth lesion areas. We further visualized baseline and template-guided model explanations on radiographs to showcase the performance of our approach. CONCLUSIONS: In the context of pneumothorax diagnoses, we proposed a template-guided approach for improving model explanations. Our approach not only aligns model explanations more closely with clinical insights but also exhibits extensibility to other thoracic diseases. We anticipate that our template guidance will forge a novel approach to elucidating AI models by integrating clinical domain expertise.

Decoupling the correlation between cytotoxic and exhausted T lymphocyte states enhances melanoma immunotherapy response prediction.

Cytotoxic T lymphocyte (CTL) and terminal exhausted T lymphocyte (ETL) activities crucially influence immune checkpoint inhibitor (ICI) response. Despite this, the efficacy of ETL and CTL transcriptomic signatures for response prediction remains limited. Investigating this across the TCGA and publicly available single-cell cohorts, we find a strong positive correlation between ETL and CTL expression signatures in most cancers. We hence posited that their limited predictability arises due to their mutually canceling effects on ICI response. Thus, we developed DETACH, a computational method to identify a gene set whose expression pinpoints to a subset of melanoma patients where the CTL and ETL correlation is low. DETACH enhances CTL's prediction accuracy, outperforming existing signatures. DETACH signature genes activity also demonstrates a positive correlation with lymphocyte infiltration and the prevalence of reactive T cells in the tumor microenvironment (TME), advancing our understanding of the CTL cell state within the TME.

Construction of a Zygosaccharomyces rouxii strain overexpressing the QOR gene for increased HDMF production.

4-Hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF) is a flavor compound widely found in natural products and is used in food as a flavor-enhancing agent. Quinone oxidoreductase (QOR) was verified as a key enzyme to synthesize HDMF in strawberry, while its impact on HDMF production by Zygosaccharomyces rouxii was still unknown. The QOR gene was cloned and overexpressed in Z. rouxii, and its impact on HDMF production by Z. rouxii was then further analyzed. At the same time, it is expected to obtain engineered strains of Z. rouxii with high HDMF production. The results showed that the engineered strains of Z. rouxii exhibit different levels of QOR gene expression and HDMF production; among them, the QOR6 strain exhibiting the highest gene expression level and HDMF production was named as ZrQOR. The HDMF production of the ZrQOR strain was significantly higher than that of wild-type Z. rouxii at 3 and 5 days of culture, with 1.41-fold and 1.08-fold increases, respectively. At 3 days of fermentation, the highest HDMF yield of ZrQOR strain was obtained (2.75 mg/L), 2 days ahead of the reported highest HDMF production by Z. rouxii. At 3, 5, and 7 days, QOR gene expression was 4.8-fold, 3.3-fold, and 5.6-fold higher in the ZrQOR strain than in the wild-type Z. rouxii, respectively. Therefore, overexpression of the QOR gene facilitates HDMF synthesis. The genetic stability of the 0-20 generation ZrQOR strain was stable, and there was no significant difference in colony shape, QOR expression, or HDMF production compared to the wild type. In this study, the genetic engineering Z. rouxii strain was used to improve HDMF production. This research has laid the groundwork for further industrial production of HDMF via microbial synthesis.

Lower micromolar activity of the antifungal imidazoles on the bacterial-type bifunctional aldehyde/alcohol dehydrogenase (AdhE) in Cryptosporidium parvum and in vitro efficacy against the zoonotic parasite.

Cryptosporidium parvum is a waterborne and foodborne zoonotic protozoan parasite, a causative agent of moderate to severe diarrheal diseases in humans and animals. However, fully effective treatments are unavailable for medical and veterinary uses. There is a need to explore new drug targets for potential development of new therapeutics. Because C. parvum relies on anaerobic metabolism to produce ATP, fermentative enzymes in this parasite are attractive targets for exploration. In this study, we investigated the ethanol-fermentation in the parasite and characterized the basic biochemical features of a bacterial-type bifunctional aldehyde/alcohol dehydrogenase, namely CpAdhE. We also screened 3892 chemical entries from three libraries and identified 14 compounds showing >50% inhibition on the enzyme activity of CpAdhE. Intriguingly, antifungal imidazoles and unsaturated fatty acids are the two major chemical groups among the top hits. We further characterized the inhibitory kinetics of selected imidazoles and unsaturated fatty acids on CpAdhE. These compounds displayed lower micromolar activities on CpAdhE (i.e., IC50 values ranging from 0.88 to 11.02 µM for imidazoles and 8.93 to 35.33 µM for unsaturated fatty acids). Finally, we evaluated the in vitro anti-cryptosporidial efficacies and cytotoxicity of three imidazoles (i.e., tioconazole, miconazole and isoconazole). The three antifungal imidazoles exhibited lower micromolar efficacies against the growth of C. parvum in vitro (EC50 values ranging from 4.85 to 10.41 µM and selectivity indices ranging from 5.19 to 10.95). The results provide a proof-of-concept data to support that imidazoles are worth being further investigated for potential development of anti-cryptosporidial therapeutics.

Study of Mechanical Properties of Sand Layer Grouting Reinforcement under Seawater Erosion.

Grouting serves as an effective method for mitigating geotechnical disasters in subsea tunnels. However, current theories and designs, primarily based on terrestrial tunnel contexts, seldom address the long-term effects of seawater ion erosion on reinforcement. An improved sand permeation grouting simulation test system was employed to examine the mechanical property evolution of sand layer grouting reinforcement under seawater erosion utilizing various grout types. The mechanical properties of grouting reinforcement, under varying curing conditions, were analyzed using a uniaxial compression test, permeability test, and scanning electron microscope (SEM) test. Test results indicate that seawater curing conditions initially enhance the strength and impermeability of grouting reinforcement; however, prolonged curing diminishes these mechanical benefits. The onset of this process occurs significantly sooner in cement-sodium silicate grout (28-56 days) compared to cement grout (56d to 90d). For the cement grouting reinforcement, the deformation modulus increases over time, albeit at a decreasing rate. The deformation modulus of cement-sodium silicate grouting reinforcement follows an increase-decrease-increase pattern, correlating with the volume ratio over time. The decline in mechanical properties of grouting reinforcement during the test's mid to late stages under seawater conditions results from the interplay between erosive ions, which inhibit mechanical growth and accelerate deterioration.

Undescribed steroidal alkaloids from the bulbs of Fritillaria ussuriensis Maxim and their anti-inflammatory activities.

In total, 16 undescribed steroidal alkaloids (1-16), along with nine known ones (17-25), were isolated from the bulbs of Fritillaria ussuriensis Maxim. Among the undescribed compounds mentioned, compounds 1-6, 8 bearing an 16ß-hydroxy substituent, as well as compounds 13 and 14 exhibited an unusual seven-membered skeleton. Their structures were established based on extensive spectroscopic analyses, including HRESIMS and NMR (1D and 2D), and comparison with the data reported in the literature. Furthermore, all the compounds were evaluated for their anti-inflammatory effect on the NO production of LPS-stimulated RAW264.7 cells. Compounds 1, 4, 11, 15, 22 and 24 could significantly inhibit NO production with IC50 values below 10 µM.

CC4S: Encouraging Certainty and Consistency in Scribble-Supervised Semantic Segmentation.

Deep learning-based solutions have achieved impressive performance in semantic segmentation but often require large amounts of training data with fine-grained annotations. To alleviate such requisition, a variety of weakly supervised annotation strategies have been proposed, among which scribble supervision is emerging as a popular one due to its user-friendly annotation way. However, the sparsity and diversity of scribble annotations make it nontrivial to train a network to produce deterministic and consistent predictions directly. To address these issues, in this paper we propose holistic solutions involving the design of network structure, loss and training procedure, named CC4S to improve Certainty and Consistency for Scribble-Supervised Semantic Segmentation. Specifically, to reduce uncertainty, CC4S embeds a random walk module into the network structure to make neural representations uniformly distributed within similar semantic regions, which works together with a soft entropy loss function to force the network to produce deterministic predictions. To encourage consistency, CC4S adopts self-supervision training and imposes the consistency loss on the eigenspace of the probability transition matrix in the random walk module (we named neural eigenspace). Such self-supervision inherits the category-level discriminability from the neural eigenspace and meanwhile helps the network focus on producing consistent predictions for the salient parts and neglect semantically heterogeneous backgrounds. Finally, to further improve the performance, CC4S uses the network predictions as pseudo-labels and retrains the network with an extra color constraint regularizer on pseudo-labels to boost semantic consistency in color space. Rich experiments demonstrate the excellent performance of CC4S. In particular, under scribble supervision, CC4S achieves comparable performance to those from fully supervised methods. Comprehensive ablation experiments verify the effectiveness of the design choices in CC4S and its robustness under extreme supervision cases, i.e., when scribbles are shrunk proportionally or dropped randomly. The code for this work has been open-sourced at https://github.com/panzhiyi/CC4S.

Enhancing the selectivity for light olefins through catalytic cracking of n-hexane by phosphorus doping on lanthanum-modified ZSM-5.

Naphtha, as the primary raw material in the production of light olefins, could well accommodate their increasing demand through the energy-efficient process of catalytic cracking with ZSM-5. In the current work, different amounts of lanthanum and phosphorous were loaded on ZSM-5 using the wet impregnation method to tune the acidic properties of ZSM-5 for selective catalytic cracking of n-hexane to produce light olefins. Various characterization techniques such as X-ray diffraction (XRD), Al nuclear magnetic resonance (NMR), temperature-programmed desorption of NH3 (NH3-TPD), Py-Fourier transform infra-red (Py-FTIR), inductively coupled plasma optical emission spectroscopy (ICP-OES), N2 adsorption-desorption, X-ray photoelectron spectra (XPS), and scanning electron microscopy were adopted to investigate the modified zeolites. It was found that adding La to ZSM-5 (0.25 wt% to 1 wt%) improved the catalytic life and increased the n-hexane conversion (to 99.7%), while the further addition had a negative impact, reducing the conversion rate and deviating the product selectivity towards a substantial, undesired benzene, toluene, and xylene (BTX) fraction (33%). On the other hand, a 64% selectivity for light olefins was achieved on phosphorous-doped ZSM-5 (at a loading amount of 1 wt%) while reducing the BTX fraction (2.3%) and converting 69% of the n-hexane. A dual metal-modified ZSM-5 with optimal loading amount, 1P0.25LaZ5 (phosphorus 1 wt% and La 0.25 wt%), helped boost the light olefin selectivity to 62% in the tuned Lewis acid sites at an n-hexane conversion of about 77% while decreasing the undesired BTX selectivity to 3% by reducing the number of Brønsted sites. Thus, the current study reveals that tuning the acidic sites of ZMS-5 by dual metal augmentation with P.La is an effective way of controlling the amount of undesirable BTX produced at a stable n-hexane conversion rate and substantial olefin selectivity.

Association of inflammatory trajectory with subarachnoid hemorrhage mortality.

OBJECTIVE: White blood cells (WBC) play an important role in the inflammatory response of the body. Elevated WBC counts on admission in patients with subarachnoid hemorrhage (SAH) correlate with a poor prognosis. However, the role of longitudinal WBC trajectories based on repeated WBC measurements during hospitalization remains unclear. We explored the association between different WBC trajectory patterns and in-hospital mortality. METHODS: We analyzed a cohort of consecutive patients with SAH between 2012 and 2020. Group-based trajectory modeling (GBTM) was used to group the patients according to their white blood cell patterns over the first 4 days. Stabilized inverse probability treatment weighting (sIPTW) was used to balance baseline demographic and clinical characteristics. We analyzed the association between the WBC trajectory groups and in-hospital mortality using a Cox proportional hazards model. RESULTS: In total, 506 patients with SAH were included in this retrospective cohort. The final model identified two distinct longitudinal WBC trajectories. After adjusting for confounding factors, multivariate regression analysis suggested that an elevated longitudinal WBC trajectory increased the risk of in-hospital mortality (hazard ratio [HR], 2.476; 95% confidence interval [CI] 1.081-5.227; P = 0.024) before sIPTW, and (HR, 2.472; 95%CI 1.489-4.977; P = 0.018) after sIPTW. CONCLUSION: In patients with SAH, different clinically relevant groups could be identified using WBC trajectory analysis. The WBC count trajectory-initially elevated and then decreased- may lead to an increased risk of in-hospital mortality following SAH.

The prognostic value of co-expression of stemness markers CD44 and CD133 in endometrial cancer.

Objective: The purpose of this study was to investigate the correlation between stemness markers (CD44 and CD133) and clinical pathological features, and to further explore the prognostic value of co-expression of CD44 & CD133 in endometrial cancer (EC). Methods: Clinical data of stage I-III EC patients who underwent initial surgical treatment at two large tertiary medical centers from 2015 to 2020 were retrospectively collected. Cohen's kappa coefficient was used to show the consistency of the expression between CD44 and CD133. The correlation between co-expression of CD44 & CD133 and prognosis of EC patients was explored using univariate and multivariate Cox regression analysis. Then, the prognosis models for early-stage (stage I-II) EC patients were constructed. Finally, stratified analysis was performed for EC patients in high-intermediate-risk and high-risk groups, Kaplan-Meier analysis was used to compare the survival differences between patients with and without adjuvant therapy in different co-expression states (low expression, mixed expression, high expression) of CD44 & CD133. Results: A total of 1168 EC patients were included in this study. The consistency of the expression between CD44 and CD133 was 70.5%, the kappa coefficient was 0.384. High expression of CD44 & CD133 was associated with early FIGO stage (P=0.017), superficial myometrial invasion (P=0.017), and negative lymphatic vessel space invasion (P=0.017). Cox regression analysis showed that the co-expression of CD44 & CD133 was significantly correlated with the prognosis of early-stage (stage I-II) patients (P=0.001 for recurrence and P=0.005 for death). Based on this, the nomogram models were successfully constructed to predict the prognosis of early-stage EC patients. Meanwhile, Kaplan-Meier analysis showed that patients with adjuvant therapy had a better overall prognosis than those without adjuvant therapy in high-intermediate-risk and high-risk groups. However, there was no statistically significant difference in survival between patients with and without adjuvant therapy in high expression of CD44 & CD133 group (P=0.681 for recurrence, P=0.621 for death). Conclusion: High expression of CD44 & CD133 was closely related to the adverse prognosis of early-stage EC patients. Meanwhile, patients with high expression of CD44 & CD133 may not be able to achieve significant survival benefits from adjuvant therapy.

Understanding the Relationship Between Vascular Smooth Muscle Cell Function and the Efficacy of Acupuncture in Treating Cerebral Ischemic Stroke: A Preclinical Meta-Analysis and Systematic Review.

Background: Cerebral blood flow and vascular structures serve as the fundamental components of brain metabolism and circulation. Acupuncture, an alternative and complementary medical approach, has demonstrated efficacy in treating cerebral ischemic stroke (CIS). Nevertheless, the mechanisms underlying the impact of acupuncture on vascular smooth muscle cell (VSMC) function remain uncertain. The objective of this systematic review and meta-analysis is to assess the alterations in VSMC function following acupuncture stimulation in CIS models. Methods: The databases PubMed, Web of Science, SCOPUS, and EMBASE were queried until November 2022 using a predetermined search strategy. The FORMAT BY SYRCLE guidelines were adhered to, and the risk of bias of the included studies was evaluated using the Risk of Bias tool developed by the Systematic Review Centre for Laboratory Animal Experimentation. The random-effects model was employed to estimate the standardized mean difference (SMD). Results: Eighteen articles are included in this review. Acupuncture showed significant positive effects on the region cerebral blood flow (SMD=8.15 [95% CI, 4.52 to 11.78]) and neurological deficiency (SMD=-3.75 [95% CI, -5.54 to -1.97]). Descriptive analysis showed a probable mechanism of acupuncture stimulation in CIS rats related to VSMC function. Limitations and publication bias were presented in the studies. Conclusion: In this systematic review and meta-analysis, our findings indicate that acupuncture stimulation has the potential to improve regional cerebral blood flow and alleviate neurological deficits, possibly by regulating VSMC function. However, it is important to exercise caution when interpreting these results due to the limitations of animal experimental design and methodological quality.

Metabolism-inflammasome crosstalk shapes innate and adaptive immunity.

Inflammasomes are a central component of innate immunity and play a vital role in regulating innate immune response. Activation of inflammasomes is also indispensable for adaptive immunity, modulating the development and response of adaptive immunity. Recently, increasing studies have shown that metabolic alterations and adaptations strongly influence and regulate the differentiation and function of the immune system. In this review, we will take a holistic view of how inflammasomes bridge innate and adaptive (especially T cell) immunity and how inflammasomes crosstalk with metabolic signals during the immune responses. And, special attention will be paid to the metabolic control of inflammasome-mediated interactions between innate and adaptive immunity in disease. Understanding the metabolic regulatory functions of inflammasomes would provide new insights into future research directions in this area and may help to identify potential targets for inflammasome-associated diseases and broaden therapeutic avenues.

A novel perineal exposure method in laparoscopic abdominal perineal resection of rectal cancer: a case series study.

BACKGROUND: Abdominal perineal resection (APR) of rectal cancer, also known as Mile's procedure, is a classic procedure for the treatment of rectal cancer. Through the improvement of surgical skills and neoadjuvant therapy, the sphincter-preserving rate in rectal cancer patients has improved, even in patients with ultralow rectal cancer who underwent APR in the past. However, APR cannot be completely replaced by low anterior resection (LAR) in reality. APR still has its indications, when the tumor affects the external sphincter, etc. Good perineal exposure in APR is difficult and can seriously affect surgical safety and the long-term prognosis. METHODS: We reviewed the records of 16 consecutive patients with rectal cancer who underwent APR at Anqing Municipal Hospital from January 2022 to April 2023, including 11 males and 5 females, with an average age of 64.8 ± 10.3 years. The perineal operation was completed with the Lone-Star® retractor-assisted (LSRA) exposure method. After incising the skin and subcutaneous tissue, a Lone-Star® retractor was placed, and the incision was retracted in surrounding directions with 8 small retractors, which facilitated the freeing of deep tissues. We dynamically adjusted the retractor according to the plane to fully expose the surgical field. RESULTS: All 16 patients underwent laparoscopic-assisted APR successfully. Thirteen procedures were performed independently by a single person, and the others were completed by two persons due to intraoperative arterial hemostasis. All specimens were free of perforation and had a negative circumferential resection margin (CRM). Postoperative complications occurred in 4 patients, including urinary retention in 1 patient, pulmonary infection in 1 patient, intestinal adhesion in 1 patient and peristomal dermatitis in 1 patient, and were graded as ClavienDindo grade 3 or lower and cured. No distant metastasis or local recurrence was found for any of the patients in the postoperative follow-up. CONCLUSIONS: The application of the LSRA exposure method might be helpful for perineal exposure during APR for rectal cancer, which could improve intraoperative safety and surgical efficiency, achieve one-person operation, and increase the comfort of operators.

Efficacy and safety of different chemotherapy regimens concurrent with radiotherapy in the treatment of locally advanced cervical cancer.

BACKGROUND: Evaluate the efficacy and safety of different chemotherapy regimens concurrent with radiotherapy in treating locally advanced cervical cancer (LACC). METHODS: Retrospective data was collected from LACC patients who were treated at our institution. These patients were categorized into three groups: the single-agent cisplatin (DDP) chemoradiotherapy group, the paclitaxel plus cisplatin (TP) chemoradiotherapy group, and the nanoparticle albumin-bound (nab-) paclitaxel combined with cisplatin (nPP) chemoradiotherapy group. The primary endpoints were overall survival (OS) and progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR) and incidence of adverse events (AEs). RESULTS: A total of 124 patients were enrolled (32 in the DDP group, 41 in the TP group, and 51 in the nPP group). There were differences in OS (P = 0.041, HR 0.527, 95% CI 0.314-0.884) and PFS (P = 0.003, HR 0.517, 95% CI 0.343-0.779) between the three groups. Notably, the 2-year OS rate was significantly higher in the nPP group compared to the DDP group (92.2% vs. 85.4%, P = 0.012). The 2-year PFS rates showed a marked increase in the TP group (78.0% vs. 59.4%, P = 0.048) and the nPP group (88.2% vs. 59.4%, P = 0.001) relative to the DPP group, with multiple comparisons indicating that the 2-year PFS rate was significantly superior in the nPP group versus the DDP group (88.2% vs. 59.4%, P = 0.001). Moreover, the ORR was also significantly higher in the nPP group than in the DDP group (P = 0.013); and no statistically significant differences were found in the incidence of AEs among the groups (P > 0.05). CONCLUSIONS: In LACC treatment, the two cisplatin-based doublet chemotherapy regimens are associated with better outcomes, with the nab-paclitaxel plus cisplatin regimen showing better efficacy than the paclitaxel plus cisplatin regimen. Furthermore, the AEs associated with these regimens were deemed tolerable. These findings could provide a reference for the clinical treatment of LACC. However, further prospective studies are needed to verify it.

CAR T Cell Membrane Camouflaged Nanocatalyst Augments CAR T Cell Therapy Efficacy Against Solid Tumor.

The immunosuppressive tumor microenvironment (TME) reduces the chimeric antigen receptor (CAR) T-cell therapy against solid tumors. Here, a CAR T cell membrane-camouflaged nanocatalyst (ACSP@TCM) is prepared to augment CAR T cell therapy efficacy against solid tumors. ACSP@TCM is prepared by encapsulating core/shell Au/Cu2- xSe and 3-bromopyruvate with a CAR T cell membrane. It is demonstrated that the CAR T cell membrane camouflaging has much better-targeting effect than the homologous tumors cell membrane camouflaging. ACSP@TCM has an appealing synergistic chemodynamic/photothermal therapy (CDT/PTT) effect that can induce the immunogenic cell death (ICD) of NALM 6 cells. Moreover, 3-bromopyruvate can inhibit the efflux of lactic acid by inhibiting the glycolysis process, regulating the acidity of TME, and providing a more favorable environment for the survival of CAR T cells. In addition, the photoacoustic (PA) imaging and computed tomography (CT) imaging performance can guide the ACSP@TCM-mediated tumor therapy. The results demonstrated that the ACSP@TCM significantly enhanced the CAR T cell therapy efficacy against NALM 6 solid tumor mass, and completely eliminated tumors. This work provides an effective tumor strategy for CAR T cell therapy in solid tumors.