Expand available targets for CAR-T therapy to overcome tumor drug resistance based on the "Evolutionary Traps".

Based on the concept of "Evolutionary Traps", targeting survival essential genes obtained during tumor drug resistance can effectively eliminate resistant cells. While, it still faces limitations. In this study, lapatinib-resistant cells were used to test the concept of "Evolutionary Traps" and no suitable target stand out because of the identified genes without accessible drug. However, a membrane protein PDPN, which is low or non-expressed in normal tissues, is identified as highly expressed in lapatinib-resistant tumor cells. PDPN CAR-T cells were developed and showed high cytotoxicity against lapatinib-resistant tumor cells in vitro and in vivo, suggesting that CAR-T may be a feasible route for overcoming drug resistance of tumor based on "Evolutionary Trap". To test whether this concept is cell line or drug dependent, we analyzed 21 drug-resistant tumor cell expression profiles reveal that JAG1, GPC3, and L1CAM, which are suitable targets for CAR-T treatment, are significantly upregulated in various drug-resistant tumor cells. Our findings shed light on the feasibility of utilizing CAR-T therapy to treat drug-resistant tumors and broaden the concept of the "Evolutionary Trap".

Metabolic reprogramming and interventions in angiogenesis.

BACKGROUND: Endothelial cell (EC) metabolism plays a crucial role in the process of angiogenesis. Intrinsic metabolic events such as glycolysis, fatty acid oxidation, and glutamine metabolism, support secure vascular migration and proliferation, energy and biomass production, as well as redox homeostasis maintenance during vessel formation. Nevertheless, perturbation of EC metabolism instigates vascular dysregulation-associated diseases, especially cancer. AIM OF REVIEW: In this review, we aim to discuss the metabolic regulation of angiogenesis by EC metabolites and metabolic enzymes, as well as prospect the possible therapeutic opportunities and strategies targeting EC metabolism. KEY SCIENTIFIC CONCEPTS OF REVIEW: In this work, we discuss various aspects of EC metabolism considering normal and diseased vasculature. Of relevance, we highlight that the implications of EC metabolism-targeted intervention (chiefly by metabolic enzymes or metabolites) could be harnessed in orchestrating a spectrum of pathological angiogenesis-associated diseases.

In vivo manufacture and manipulation of CAR-T cells for better druggability.

The current CAR-T cell therapy products have been hampered in their druggability due to the personalized preparation required, unclear pharmacokinetic characteristics, and unpredictable adverse reactions. Enabling standardized manufacturing and having clear efficacy and pharmacokinetic characteristics are prerequisites for ensuring the effective practicality of CAR-T cell therapy drugs. This review provides a broad overview of the different approaches for controlling behaviors of CAR-T cells in vivo. The utilization of genetically modified vectors enables in vivo production of CAR-T cells, thereby abbreviating or skipping the lengthy in vitro expansion process. By equipping CAR-T cells with intricately designed control elements, using molecule switches or small-molecule inhibitors, the control of CAR-T cell activity can be achieved. Moreover, the on-off control of CAR-T cell activity would yield potential gains in phenotypic remodeling. These methods provide beneficial references for the future development of safe, controllable, convenient, and suitable for standardized production of CAR-T cell therapy products.

Armed with IL-2 based fusion protein improves CAR-T cell fitness and efficacy against solid tumors.

Chimeric antigen receptor T (CAR-T) cell therapy is regarded as a potent immunotherapy and has made significant success in hematologic malignancies by eliciting antigen-specific immune responses. However, response rates of CAR-T cell therapy against solid tumors with immunosuppressive microenvironments remain limited. Co-engineering strategies are advancing methods to overcome immunosuppressive barriers and enhance antitumor responses. Here, we engineered an IL-2 mutein co-engineered CAR-T for the improvement of CAR-T cells against solid tumors and the efficient inhibition of solid tumors. We equipped the CAR-T cells with co-expressing both tumor antigen-targeted CAR and a mutated human interleukin-2 (IL-2m), conferring enhanced CAR-T cells fitness in vitro, reshaped immune-excluded TME, enhanced CAR-T infiltration in solid tumors, and improved tumor control without significant systemic toxicity. Overall, this subject demonstrates the universal CAR-T cells armed strategy for the development and optimization of CAR-T cells against solid tumors.

CRISPR screens in mechanism and target discovery for AML.

CRISPR-based screens have discovered novel functional genes involving in diverse tumor biology and elucidated the mechanisms of the cancer pathological states. Recently, with its randomness and unbiasedness, CRISPR screens have been used to discover effector genes with previously unknown roles for AML. Those novel targets are related to AML survival resembled cellular pathways mediating epigenetics, synthetic lethality, transcriptional regulation, mitochondrial and energy metabolism. Other genes that are crucial for pharmaceutical targeting and drug resistance have also been identified. With the rapid development of novel strategies, such as barcodes and multiplexed mosaic CRISPR perturbation, more potential therapeutic targets and mechanism in AML will be discovered. In this review, we present an overview of recent progresses in the development of CRISPR-based screens for the mechanism and target identification in AML and discuss the challenges and possible solutions in this rapidly growing field.

The oncogenic role and regulatory mechanism of ACAA2 in human ovarian cancer.

Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial ß oxidation, which plays an important role in fatty acid metabolism. The expression of ACAA2 is closely related to the occurrence and malignant progression of tumors. However, the function of ACAA2 in ovarian cancer is unclear. The expression level and prognostic value of ACAA2 were analyzed by databases. Gain and loss of function were carried out to explore the function of ACAA2 in ovarian cancer. RNA-seq and bioinformatics methods were applied to illustrate the regulatory mechanism of ACAA2. ACAA2 overexpression promoted the growth, proliferation, migration, and invasion of ovarian cancer, and ACAA2 knockdown inhibited the malignant progression of ovarian cancer as well as the ability of subcutaneous tumor formation in nude mice. At the same time, we found that OGT can induce glycosylation modification of ACAA2 and regulate the karyoplasmic distribution of ACAA2. OGT plays a vital role in ovarian cancer as a function of oncogenes. In addition, through RNA-seq sequencing, we found that ACAA2 regulates the expression of DIXDC1. ACAA2 regulated the malignant progression of ovarian cancer through the WNT/ß-Catenin signaling pathway probably. ACAA2 is an oncogene in ovarian cancer and has the potential to be a target for ovarian cancer therapy.

DeepDOF-SE: affordable deep-learning microscopy platform for slide-free histology.

Histopathology plays a critical role in the diagnosis and surgical management of cancer. However, access to histopathology services, especially frozen section pathology during surgery, is limited in resource-constrained settings because preparing slides from resected tissue is time-consuming, labor-intensive, and requires expensive infrastructure. Here, we report a deep-learning-enabled microscope, named DeepDOF-SE, to rapidly scan intact tissue at cellular resolution without the need for physical sectioning. Three key features jointly make DeepDOF-SE practical. First, tissue specimens are stained directly with inexpensive vital fluorescent dyes and optically sectioned with ultra-violet excitation that localizes fluorescent emission to a thin surface layer. Second, a deep-learning algorithm extends the depth-of-field, allowing rapid acquisition of in-focus images from large areas of tissue even when the tissue surface is highly irregular. Finally, a semi-supervised generative adversarial network virtually stains DeepDOF-SE fluorescence images with hematoxylin-and-eosin appearance, facilitating image interpretation by pathologists without significant additional training. We developed the DeepDOF-SE platform using a data-driven approach and validated its performance by imaging surgical resections of suspected oral tumors. Our results show that DeepDOF-SE provides histological information of diagnostic importance, offering a rapid and affordable slide-free histology platform for intraoperative tumor margin assessment and in low-resource settings.

The value of endoscopic duodenal papilloplasty with titanium clip in improving post-operative complications of choledocholithiasis.

OBJECTIVE: To investigate the value of endoscopic duodenal papillary sphincterotomy combined with balloon dilatation in the treatment of duodenal papilloplasty with titanium clip after choledocholithiasis in post-operative complications. MATERIALS AND METHODS: One hundred and twenty-five patients (69 males and 56 females) with a median age of 65 (32-81) years were included. The treatment plan was randomly divided into Group A (n = 59) and Group B (n = 66) according to the random number table. Patients in Group A were treated with endoscopic sphincterotomy (EST) combined with endoscopic papillary large balloon dilation (EPLBD), followed by a titanium clip for duodenal papilloplasty and then indwelling nasobiliary drainage, whereas those in Group B were treated with EST combined EPLBD to remove stones and then indwelling nasobiliary drainage. RESULTS: In patients with choledocholithiasis or with anatomical changes that make stone extraction difficult, this prospective study attempted to perform duodenal papilloplasty with titanium clips after EST and EPLBD lithotripsy to compare and observe post-operative papillary healing, biliary reflux, and complication rates. CONCLUSIONS: The use of endoscopic duodenal papilloplasty with a titanium clip can improve biliary reflux after lithotripsy and reduce the incidence of post-operative cholangitis complications.

OBJETIVO: Investigar el valor de la esfinterotomía papilar duodenal endoscópica combinada con dilatación con balón en el tratamiento de la papiloplastia duodenal con clip de titanio después de coledocolitiasis en complicaciones postoperatorias. MATERIALES Y MÉTODOS: Se incluyeron un total de 125 pacientes (69 hombres y 56 mujeres) con una mediana de edad de 65 (32-81) años. Los pacientes del Grupo A se trataron con esfinterotomía endoscópica (EST) combinada con dilatación papilar endoscópica con balón grande (EPLBD), seguida de clip de titanio para papiloplastia duodenal y luego drenaje nasobiliar permanente, mientras que los del Grupo B se trataron con EPLBD combinado con EST para eliminar cálculos y luego drenaje nasobiliar permanente. RESULTADOS: En pacientes con coledocolitiasis o con cambios anatómicos que dificultan la extracción de cálculos, este estudio prospectivo intentó realizar papiloplastia duodenal con clips de titanio después de litotricia EST y EPLBD para comparar y observar la cicatrización papilar postoperatoria, el reflujo biliar y las tasas de complicaciones. CONCLUSIÓN: El uso de papiloplastia duodenal endoscópica con clips de titanio puede mejorar el reflujo biliar después de la litotricia y reducir la incidencia de complicaciones de colangitis postoperatorias.

Orcinol gentiobioside inhibits RANKL-induced osteoclastogenesis by promoting apoptosis and suppressing autophagy via the JNK1 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Osteoporosis (OP) is a metabolic disorder characterized by disrupted osteoclastic bone resorption and osteoblastic bone formation. Curculigo orchioides Gaertn has a long history of application in traditional Chinese and Indian medicine for treating OP. Orcinol gentiobioside (OGB) is a principal active constituent derived from Curculigo orchioides Gaertn and has been shown to have anti-OP activity. However, the therapeutic efficacy and mechanism of OGB in modulating osteoclastic bone resorption remain undefined. AIM OF THE STUDY: To evaluate the effect of OGB on the formation, differentiation and function of osteoclasts derived from bone marrow macrophages (BMMs), and further elucidate the underlying action mechanism of OGB in OP. MATERIALS AND METHODS: Osteoclasts derived from BMMs were utilized to evaluate the effect of OGB on osteoclast formation, differentiation and bone resorption. Tartrate-resistant acid phosphatase (TRAP) staining and activity assays were conducted to denote the activity of osteoclasts. Osteoclast-related genes and proteins were determined by RT-PCR and Western blotting assays. The formation of the F-actin ring was observed by confocal laser microscopy, and bone resorption pits were observed by inverted microscopy. The target of OGB in osteoclasts was predicted by using molecular docking and further verified by Cellular Thermal Shift Assay (CETSA) and reversal effects of the target activator. The apoptosis of osteoclasts was analyzed by flow cytometry, and autophagic flux in osteoclasts was determined by confocal laser microscopy. RESULTS: OGB inhibited osteoclast formation and differentiation, osteoclast-related genes and proteins expression, F-actin ring formation, and bone resorption activity. Molecular docking and CETSA analysis demonstrated that OGB exhibited good affinity for c-Jun N-terminal Kinase 1 (JNK1). In addition, OGB induced apoptosis and inhibited autophagy in osteoclasts, and the JNK agonist anisomycin reversed the increase in apoptosis and inhibition of autophagy induced by OGB in osteoclasts. CONCLUSION: OGB inhibited osteoclastogenesis by promoting apoptosis and diminishing autophagy via JNK1 signaling.

A triggered DNA nanomachine with enzyme-free for the rapid detection of telomerase activity in a one-step method.

BACKGROUND: Telomerase is considered a biomarker for the early diagnosis and clinical treatment of cancer. The rapid and sensitive detection of telomerase activity is crucial to biological research, clinical diagnosis, and drug development. However, the main obstacles facing the current telomerase activity assay are the cumbersome and time-consuming procedure, the easy degradation of the telomerase RNA template and the need for additional proteases. Therefore, it is necessary to construct a new method for the detection of telomerase activity with easy steps, efficient reaction and strong anti-interference ability. RESULTS: Herein, an efficient, enzyme-free, economical, sensitive, fluorometric detection method for telomerase activity in one-step, named triggered-DNA (T-DNA) nanomachine, was created based on target-triggered DNAzyme-cleavage activity and catalytic molecular beacon (CMB). Telomerase served as a switch and extended few numbers of (TTAGGG)n repeat sequences to initiate the signal amplification in the T-DNA nanomachine, resulting in a strong fluorescent signal. The reaction was a one-step method with a shortened time of 1 h and a constant temperature of 37 °C, without the addition of any protease. It also sensitively distinguished telomerase activity in various cell lines. The T-DNA nanomachine offered a detection limit of 12 HeLa cells µL-1, 9 SK-Hep-1 cells µL-1 and 3 HuH-7 cells µL-1 with a linear correlation detection range of 0.39 × 102-6.25 × 102 HeLa cells µL-1 for telomerase activity. SIGNIFICANCE: In conclusion, our study demonstrated that the triggered-DNA nanomachine fulfills the requirements for rapid detection of telomerase activity in one-step under isothermal and enzyme-free conditions with excellent specificity, and its simple and stable structure makes it ideal for complex systems. These findings indicated the application prospect of DNA nanomachines in clinical diagnostics and provided new insights into the field of DNA nanomachine-based bioanalysis.

Methylseleninic acid inhibits human glioma growth in vitro and in vivo by triggering ROS-dependent oxidative damage and apoptosis.

Selenium-containing agents showed novel anticancer activity by triggering pro-oxidative mechanism. Studies confirmed that methylseleninic acid (MeSe) displayed broad-spectrum anti-tumor activity against kinds of human cancers. However, the anticancer effects and mechanism of MeSe against human glioma growth have not been explored yet. Herein, the present study showed that MeSeA dose-dependently inhibited U251 and U87 human glioma cells growth in vitro. Flow cytometry analysis indicated that MeSe induced significant U251 cells apoptosis with a dose-dependent manner, followed by the activation of caspase-7, caspase-9 and caspase-3. Immunofluorescence staining revealed that MeSe time-dependently caused reactive oxide species (ROS) accumulation and subsequently resulted in oxidative damage, as convinced by the increased phosphorylation level of Ser428-ATR, Ser1981-ATM, Ser15-p53 and Ser139-histone. ROS inhibition by glutathione (GSH) effectively attenuated MeSe-induced ROS generation, oxidative damage, caspase-3 activation and cytotoxicity, indicating that ROS was an upstream factor involved in MeSe-mediated anticancer mechanism in glioma. Importantly, MeSe administration in nude mice significantly inhibited glioma growth in vivo by inducing apoptosis through triggering oxidative damage. Taken together, our findings validated the possibility that MeSe as a selenium-containing can act as potential tumor chemotherapy agent for therapy of human glioma.

Identification of four snoRNAs (SNORD16, SNORA73B, SCARNA4, and SNORD49B) as novel non-invasive biomarkers for diagnosis of breast cancer.

BACKGROUND: Emerging data point to the critical role of snoRNA in the emergence of different types of cancer, but scarcely in breast cancer (BC). This study aimed to clarify the differential expressions and potential diagnostic value of SNORD16, SNORA73B, SCARNA4, and SNORD49B in BC. METHODS: We screened differential snoRNAs in BC tissues and adjacent tissues through SNORic datasets, and then we further verified them in the plasma of BC patients and healthy volunteers by quantitative polymerase chain reaction (qPCR). RESULTS: These four snoRNAs: SNORD16, SNORA73B, SCARNA4, and SNORD49B were considerably more abundant in cancerous tissues than in neighboring tissues in the TCGA database. Their plasma levels were also higher in BC and early-stage BC patients when compared to healthy controls. Furthermore, the ROC curve demonstrated that BC (AUC = 0.7521) and early-stage BC (AUC = 0.7305) might be successfully distinguished from healthy people by SNORD16, SNORA73B, SCARNA4, and SNORD49B. CONCLUSION: Plasma snoRNAs: SNORD16, SNORA73B, SCARNA4, and SNORD49B were upregulated in BC and early-stage BC and can be used as potential diagnostic markers for BC and early-stage BC.

Effects of occupational exposure to dust, gas, vapor and fumes on chronic bronchitis and lung function.

Background: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality worldwide, and therefore the identification of the modifiable risk factors [such as exposure to vapors, gases, dust and fumes (VGDF)] for accelerate disease progression has important significance. Methods: We conducted COPD surveillance in six cities of southern China between 2014 and 2019. We recorded the diagnosis of chronic bronchitis, respiratory symptoms, occupational exposure to VGDF and other covariates by using a structured questionnaire. Logistic regression and multivariate linear regression model were adopted for analysis. We performed sensitivity analyses based on two methods of propensity score (PS) methods to evaluate the robustness of our results. Results: A total of 7,418 participants were included. Cough [odds ratios (ORs): 1.60, 95% confidence interval (CI): 1.22 to 2.08] and phlegm (OR: 1.49, 95% CI: 1.19 to 1.85) correlated significantly with exposure to dust. There was an increased risk of cough (OR: 1.53, 95% CI: 1.11 to 2.07) for occupational exposure to gas/vapor/fume. Dual exposure to dust and gas/vapor/fume was associated with a significantly increased risk of chronic bronchitis (OR: 1.74, 95% CI: 1.20 to 2.52), cough (OR: 1.43, 95% CI: 1.15 to 1.79) and phlegm (OR: 1.49, 95% CI: 1.24 to 1.79). In 5,249 participants with complete data of spirometry, gas/vapor/fume was associated with a decreased ratio of forced expiratory volume in one second and forced vital capacity (FEV1/FVC) (ß: -1.05, 95% CI: -1.85 to -0.26) and maximal mid-expiratory flow (MMEF) (ß: -0.15, 95% CI: -0.23 to -0.07). Dual exposure to dust and gas/vapor/fume was significantly associated with decreased FEV1/FVC (ß: -0.74, 95% CI: -1.28 to -0.20) and MMEF (ß: -0.06, 95% CI: -0.12 to -0.01). Results of sensitivity analysis were not materially changed. Conclusions: VGDF exposure is associated with chronic bronchitis, respiratory symptoms and decreased lung function, suggesting that VGDF contributes to the pathogenesis and progression of COPD.

Neutrophil extracellular traps induced by chemotherapy inhibit tumor growth in murine models of colorectal cancer.

Neutrophil extracellular traps (NETs), a web-like structure of cytosolic and granule proteins assembled on decondensed chromatin, kill pathogens and cause tissue damage in diseases. Whether NETs can kill cancer cells is unexplored. Here, we report that a combination of glutaminase inhibitor CB-839 and 5-FU inhibited the growth of PIK3CA-mutant colorectal cancers (CRCs) in xenograft, syngeneic, and genetically engineered mouse models in part through NETs. Disruption of NETs by either DNase I treatment or depletion of neutrophils in CRCs attenuated the efficacy of the drug combination. Moreover, NETs were present in tumor biopsies from patients treated with the drug combination in a phase II clinical trial. Increased NET levels in tumors were associated with longer progression-free survival. Mechanistically, the drug combination induced the expression of IL-8 preferentially in PIK3CA-mutant CRCs to attract neutrophils into the tumors. Further, the drug combination increased the levels of ROS in neutrophils, thereby inducing NETs. Cathepsin G (CTSG), a serine protease localized in NETs, entered CRC cells through the RAGE cell surface protein. The internalized CTSG cleaved 14-3-3 proteins, released BAX, and triggered apoptosis in CRC cells. Thus, our studies illuminate a previously unrecognized mechanism by which chemotherapy-induced NETs kill cancer cells.

TEP SNORD12B, SNORA63, and SNORD14E as novel biomarkers for hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC).

PURPOSE: The alterations of RNA profile in tumor-educated platelets (TEPs) have been described as a novel biosource for cancer diagnostics. This study aimed to explore the potential snoRNAs in TEP as biomarkers for diagnostics of hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC). METHODS: Platelets were isolated using low-speed centrifugation and subjected to a quantitative polymerase chain reaction (qPCR) for snoRNAs detection. RESULTS: Down-regulated SNORD12B and SNORD14E as well as up-regulated SNORA63 were identified in TEP from HBV-related HCC, which could act as diagnostic biomarkers for HBV-related HCC as well as the early disease. Besides, TEP SNORD12B, SNORD14E, and SNORA63 facilitate the diagnostic performance of AFP and achieve favorable diagnostics efficiency for HBV-related HCC when combined with platelet parameters. CONCLUSIONS: Aberrant expression of SNORD12B, SNORA63, and SNORD14E in TEPs could serve as the novel and non-invasive biomarkers for HBV-related HCC diagnosis.

Allogeneic CAR-T cells with of HLA-A/B and TRAC disruption exhibit promising antitumor capacity against B cell malignancies.

BACKGROUND: Although chimeric antigen receptor T (CAR-T) cells have been proven to be an effective way of treating B cell malignancies, a lot of patients could not benefit from it because of failure in CAR-T cell manufacturing, disease progression, and unaffordable price. The study aimed to explore universal CAR-T cell products to extend the clinical accessibility. METHODS: The antitumor activity of CRISPR/Cas9-edited allogeneic anti-CD19 CAR-T (CAR-T19) cells was assessed in vitro, in animal models, and in patients with relapsed/refractory (R/R) acute B cell lymphoblastic leukemia (B-ALL) or diffuse large B cell lymphoma. RESULTS: B2M-/TRAC- universal CAR-T19 (U-CAR-T19) cells exhibited powerful anti-leukemia abilities both in vitro and in animal models, as did primary CD19+ leukemia cells from leukemia patients. However, expansion, antitumor efficacy, or graft-versus-host-disease (GvHD) was not observed in six patients with R/R B cell malignancies after U-CAR-T19 cell infusion. Accordingly, significant activation of natural killer (NK) cells by U-CAR-T19 cells was proven both clinically and in vitro. HLA-A-/B-/TRAC- novel CAR-T19 (nU-CAR-T19) cells were constructed with similar tumoricidal capacity but resistance to NK cells in vitro. Surprisingly, robust expansion of nU-CAR-T19 cells, along with rapid eradication of CD19+ abnormal B cells, was observed in the peripheral blood and bone marrow of another three patients with R/R B-ALL. The patients achieved complete remission with no detectable minimal residual disease 14 days after the infusion of nU-CAR-T19 cells. Two of the three patients had grade 2 cytokine release syndrome, which were managed using an IL-6 receptor blocker. Most importantly, GvHD was not observed in any patient, suggesting the safety of TRAC-disrupted CAR-T cells generated using the CRISPR/Cas9 method for clinical application. CONCLUSIONS: The nU-CAR-T19 cells showed a strong response in R/R B-ALL. nU-CAR-T19 cells have the potential to be a promising new approach for treating R/R B cell malignancies.

Sulforaphane activates CD8+ T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis'.

BACKGROUND: Extensive attention has been given to the role of myeloid-derived suppressor cells (MDSCs) in driving tumor progression and treatment failure. Preclinical studies have identified multiple agents that eliminate MDSCs. However, none have been authorized in the cliniccal ues due to the safety reasons. In the present study, we investigated the efficacy and mechanism of sulforaphane (SFN) to eliminate MDSCs in the tumor microenvironment (TME). METHODS: We monitored SFN effect on tumor growth and the percents or apoptosis of immune cell subsets in mice models bearing LLC or B16 cells. Flow cytometry, quantitative reverse transcription-PCR, immunohistochemistry, ELISA, immunofluorescence, imaging flow cytometry and western blot were performed to validate the role of SFN on MDSCs function in vivo and in vitro. RNA sequencing was then used to interrogate the mechanisms of how SFN regulated MDSCs function. Tumor xenograft models were established to evaluate the involvement of IL-12RB2/MMP3/FasL induced MDSCs apoptosis in vivo. We verified the effect of SFN on MDSCs and CD8+ T cells in the blood samples from a phase I clinical trial (KY-2021-0350). RESULTS: In this study, we elucidated that SFN liberated CD8+ T-cell antitumor ability by reducing MDSCs abundance, leading to repressed tumor growth. SFN treatment suppressed MDSCs accumulation in the peripheral blood and tumor sites of mice, but had no effect on the bone marrow. Mechanistically, SFN activates IL-12RB2, which stimulates the MMP3/FasL signaling cascade to trigger caspase 3 cleavage and induce apoptosis in MDSCs. Clinically, SFN treatment eliminates peripheral MDSCs and increases the percentage and activation of CD8+ T cells. CONCLUSIONS: Collectively, we uncovered the role of SFN in eliminating MDSCs to emancipate CD8+ T cells through IL-12RB2/MMP3/FasL induced apoptosis, thus providing a strategy for targeting MDSCs to control tumors and improve clinical efficacy.

Risk Factors of Acute Pain in Elderly Patients After Laparoscopic Radical Resection of Colorectal Cancer.

OBJECTIVE: To investigate the risk factors of acute pain after laparoscopic radical resection of colorectal cancer (CRC) in elderly patients. METHODS: Totally, 143 elderly patients (≥ 60 y old) who received laparoscopic radical resection of CRC in the People's Hospital of Xinjiang Uygur Autonomous Region from March 2021 to August 2022 were retrospectively analyzed. The patients were divided into 2 groups according to visual analog scale (VAS) scores 24 h after surgery: mild pain group (VAS score ≤ 3, n=108) and moderate to severe pain group (VAS score >3, n=35). The data of the patients, including sex, age, height, body mass, intraoperative blood loss, intraoperative urine volume, intraoperative opioid dosage, operation duration, preoperative Hospital Anxiety and Depression Scale (HADS) scores, preoperative Mini-Mental State Examination scores, VAS scores, postoperative nausea and vomiting scores were recorded. Multivariate logistic regression analysis was used to screen the risk factors of postoperative acute pain in elderly patients undergoing laparoscopic radical resection of CRC. RESULTS: The preoperative HADS score of the moderate to severe pain group was significantly increased compared with that of the mild pain group (10.8±2.4 vs. 6.2±1.9), as well as the operation duration (226.4±18.3 vs. 186.1±12.7), the intraoperative dosage of remifentanil (3.7±0.2 vs. 3.2±0.4), the preoperative VAS score [4(2, 7) vs. 2 (0, 4)] and postoperative VAS score [5 (4, 6) vs. 3 (2, 3)] ( P <0.05). Multivariate logistic regression analysis showed that high preoperative HADS score, long operation duration, and high preoperative VAS score ( P <0.05) were independent risk factors for acute pain after laparoscopic radical resection of CRC in elderly patients. CONCLUSION: Preoperative anxiety and depression, preoperative pain, and long operation duration are risk factors for acute pain in elderly patients after laparoscopic radical resection of CRC.

Unveiling the synergistic mechanism of autochthonous fungal bioaugmentation and ammonium nitrogen biostimulation for enhanced phenanthrene degradation in oil-contaminated soils.

Autochthonous bioaugmentation and nutrient biostimulation are promising bioremediation methods for polycyclic aromatic hydrocarbons (PAHs) in contaminated agricultural soils, but little is known about their combined working mechanism. In this study, a microcosm trial was conducted to explore the combined mechanism of autochthonous fungal bioaugmentation and ammonium nitrogen biostimulation, using DNA stable-isotope-probing (DNA-SIP) and microbial network analysis. Both treatments significantly improved phenanthrene (PHE) removal, with their combined application producing the best results. The microbial community composition was notably altered by all bioremediation treatments, particularly the PHE-degrading bacterial and fungal taxa. Fungal bioaugmentation removed PAHs through extracellular enzyme secretion but reduced soil microbial diversity and ecological stability, while nitrogen biostimulation promoted PAH dissipation by stimulating indigenous soil degrading microbes, including fungi and key bacteria in the soil co-occurrence networks, ensuring the ecological diversity of soil microorganisms. The combination of both approaches proved to be the most effective strategy, maintaining a high degradation efficiency and relatively stable soil biodiversity through the secretion of lignin hydrolytic enzymes by fungi, and stimulating the reproduction of soil native degrading microbes, especially the key degraders in the co-occurrence networks. Our findings provide a fresh perspective of the synergy between fungal bioaugmentation and nitrogen biostimulation, highlighting the potential of this combined bioremediation approach for in situ PAH-contaminated soils.

Associations Between Serum TNF-α, IL-6, hs-CRP and GLMD in Obese Children and Adolescents: A Cross-Sectional Study.

Purpose: To explore the relationships between serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP) levels and glucolipid metabolism disorders (GLMD) in obese children and adolescents. Patients and Methods: In this cross-sectional study, 105 obese children and adolescents were selected for the detection of TNF-α, IL-6, hs-CRP, and glycolipid metabolism indicators. All participants were divided into elevated TNF-α group (≥8.1 pg/mL; n=49) and normal TNF-α group (<8.1 pg/mL; n=56), elevated IL-6 group (≥5.9 pg/mL; n=13) and normal IL-6 group (<5.9 pg/mL; n=92), elevated hs-CRP group (≥3.0 mg/L; n=44) and normal hs-CRP group (<3.0 mg/L; n=61), respectively. Results: Low-density lipoprotein cholesterol (LDL-C) in the elevated TNF-α group was higher than that in the normal TNF-α group (P=0.010). TNF-α was positively correlated with LDL-C (P=0.005). Fasting insulin (FINS) and homeostasis model assessment of insulin resistance (HOMA-IR) in the elevated IL-6 group were higher than those in the normal IL-6 group (all for P <0.05), while high-density lipoprotein cholesterol (HDL-C) in the elevated IL-6 group was lower than that in the normal IL-6 group (P<0.001). IL-6 was positively correlated with FINS, 2-hour postprandial insulin, HOMA-IR and triglyceride (all for P <0.01), while was negatively correlated with HDL-C (P=0.006). Moreover, hs-CRP was positively correlated with FINS and HOMA-IR (all for P <0.05). Conclusion: There may be correlations between serum TNF-α, IL-6, hs-CRP levels and GLMD in obese children and adolescents. Attention should be paid to monitoring serum inflammatory factors and preventing their elevation in obese children and adolescents, thus reducing the occurrence of GLMD.