Hypoxic tumor microenvironment: Destroyer of natural killer cell function.

In recent years, immunotherapy has made remarkable progress in treating certain tumors and hematological malignancies. However, the efficacy of natural killer (NK) cells, which are an important subset of innate lymphocytes used in anticancer immunotherapy, remains limited. Hypoxia, a critical characteristic of the tumor microenvironment (TME), is involved in tumor development and resistance to radiotherapy, chemotherapy, and immunotherapy. Moreover, hypoxia contributes to the impairment of NK cell function and may be a significant factor that limits their therapeutic effects. Targeted hypoxia therapy has emerged as a promising research area for enhancing the efficacy of NK cell therapy. Therefore, understanding how the hypoxic TME influences NK cell function is crucial for improving antitumor treatment outcomes.

The effects of the predictability of acclimatory temperature on the growth and thermal tolerance of juvenile Spinibarbus sinensis.

Heated effluent injection, cold hypolimnetic water inputs from dams, and extreme weather events can lead to unpredictable temperature fluctuations in natural waters, impacting fish performance and fitness. We hypothesized that fish exposed to such unpredictable fluctuations would exhibit weaker growth and enhanced thermal tolerance compared to predictable conditions. Qingbo (Spinibarbus sinensis) was selected as the experimental subject in this study. The qingbo were divided into a constant temperature group (C, 22 ± 0.5 °C), a predictable temperature fluctuation group (PF, 22 ± 4 °C, first warming, then cooling within a day) and an unpredictable temperature fluctuation group (UF, 22 ± 4 °C, the order of warming or cooling is random). After 40 days of temperature acclimation, the growth, metabolic rate, spontaneous activity, thermal tolerance, plasma cortisol concentration and liver hsp70 level of the fish were measured. Unexpectedly, neither the PF nor the UF group showed decreased growth compared to the C group. This could be attributed to the fact that temperature variation did not lead to a substantial increase in basic energy expenditure. Furthermore, feeding rates increased due to temperature fluctuations, although the difference was not significant. Both the PF and UF groups exhibited increased upper thermal tolerance, but only the UF group exhibited improved lower thermal tolerance and higher liver hsp70 levels compared to the C group. The qingbo that experienced unpredictable temperature fluctuations had the best thermal tolerance among the 3 groups, which might have occurred because they had the highest level of hsp70 expression. This may safeguard fish against the potential lethal consequences of extreme temperatures in the future. These findings suggested that qingbo exhibited excellent adaptability to both predictable and unpredictable temperature fluctuations, which may be associated with frequent temperature fluctuations in its natural habitat.

Identification and Validation of Lipid Metabolism Gene FASN-Associated miRNA in Wilms Tumor.

miRNA has been a research hotspot in recent years and its scope of action is very wide, involving the regulation of cell proliferation, differentiation, apoptosis, and other biological behaviors. This study intends to explore the role of miRNA in the lipid metabolism and development of Wilms tumor (WT) by detecting and analyzing the differences in the expression profiles of miRNAs between the tumor and adjacent normal tissue. Gene detection was performed in tumor tissues and adjacent normal tissues of three cases of WT to screen differentially expressed miRNAs (DEMs). According to our previous research, FASN, which participates in the lipid metabolism pathway, may be a target of WT. The starBase database was used to predict FASN-targeted miRNAs. The above two groups of miRNAs were intersected to obtain FASN-targeted DEMs and then GO Ontology (GO) functional enrichment analysis of FASN-targeted DEMs was performed. Finally, the FASN-targeted DEMs were compared and further verified by qRT‒PCR. Through gene sequencing and differential analysis, 287 DEMs were obtained, including 132 upregulated and 155 downregulated miRNAs. The top ten DEMs were all downregulated. Fourteen miRNAs targeted by the lipid metabolism-related gene FASN were predicted by starBase. After intersection with the DEMs, three miRNAs were finally obtained, namely, miR-107, miR-27a-3p, and miR-335-5p. GO enrichment analysis was mainly concentrated in the Parkin-FBXW7-Cul1 ubiquitin ligase complex and response to prostaglandin E. Further experimental verification showed that miR-27a-3p was significantly correlated with WT (P = 0.0018). Imbalanced expression of miRNAs may be involved in the occurrence and development of WT through lipid metabolism. The expression of miR-27a-3p is related to the malignant degree of WT, and it may become the target of diagnosis, prognosis, and treatment of WT in the later stage.

Hierarchical Li electrochemistry using alloy-type anode for high-energy-density Li metal batteries.

Exploiting thin Li metal anode is essential for high-energy-density battery, but is severely plagued by the poor processability of Li, as well as the uncontrollable Li plating/stripping behaviors and Li/electrolyte interface. Herein, a thickness/capacity-adjustable thin alloy-type Li/LiZn@Cu anode is fabricated for high-energy-density Li metal batteries. The as-formed lithophilic LiZn alloy in Li/LiZn@Cu anode can effectively regulate Li plating/stripping and stabilize the Li/electrolyte interface to deliver the hierarchical Li electrochemistry. Upon charging, the Li/LiZn@Cu anode firstly acts as Li source for homogeneous Li extraction. At the end of charging, the de-alloy of LiZn nanostructures further supplements the Li extraction, actually playing the Li compensation role in battery cycling. While upon discharging, the LiZn alloy forms just at the beginning, thereby regulating the following Li homogeneous deposition. The reversibility of such an interesting process is undoubtedly verified from the electrochemistry and in-situ XRD characterization. This work sheds light on the facile fabrication of practical Li metal anodes and useful Li compensation materials for high-energy-density Li metal batteries.

Constraints of digestion on swimming performance and stress tolerance vary with habitat in freshwater fish species.

Limited aerobic scope (AS) during digestion might be the main constraint on the performance of bodily functions in water-breathing animals. Thus, investigating the postprandial changes in various physiological functions and determining the existence of a shared common pattern because of possible dependence on residual AS during digestion in freshwater fish species are very important in conservation physiology. All species from slow-flow habitats showed impaired swimming speed while digesting, whereas all species from fast-flow habitats showed strong swimming performance, which was unchanged while digesting. Only two species from slow-flow habitats showed impaired heat tolerance during digestion, suggesting that whether oxygen limitation is involved in the heat tolerance process is species-specific. Three species from slow- or intermediate-flow habitats showed impaired hypoxia tolerance during digestion because feeding metabolism cannot cease completely under hypoxia. Overall, there was no common pattern in postprandial changes in different physiological functions because: (1) the digestion process was suppressed under oxygen-limiting conditions, (2) the residual AS decreased during digestion, and (3) performance was related to residual AS, while digestion was context-dependent and species-specific. However, digestion generally showed a stronger effect on bodily functions in species from slow-flow habitats, whereas it showed no impairment in fishes from fast-flow habitats. Nevertheless, the postprandial change in physiological functions varies with habitat, possibly due to divergent selective pressure on such functions. More importantly, the present study suggests that a precise prediction of how freshwater fish populations will respond to global climate change needs to incorporate data from postprandial fishes.

Injectable hydrogels embedded with chitosan nanoparticles coated with hyaluronic acid for sequential release of dual drugs.

An effective treatment for some disease, such as the model disease acute retinal necrosis (ARN), requires a combination of different drugs which should be administered at a certain interval. The precise sequential and long-term drug release are the critical questions. In this work, the as-prepared chitosan nanoparticles (CS-NPs) coated with hyaluronic acid (HA) were embedded in the aldehyde ß-cyclodextrin (ACD)/aminated hyaluronic acid (NHA) hydrogels to synthesize injectable hydrogels loaded with dual drugs named DEX-CS-NPs/GCV-Gel and HA-DEX-CS-NPs/GCV-Gel. In the first 24 h and 48 h, the releases of DEX from DEX-CS-NPs/GCV-Gel were 128.5 % and 82.8 % faster than those from HA-DEX-CS-NPs/GCV-Gel, respectively. There was no DEX released from HA-DEX-CS-NPs/GCV-Gel at the first 7 h, which has never been reported before, although some hydrogel systems loaded with different drugs release different drugs simultaneously at different rate which have been well studied. This is a good start of a precise sequence release. The composite hydrogels possessed appropriate rheology, gel time, degradation performance, and ideal cytocompatibility. The injectable hydrogel loaded with dual drugs presenting a precise sequential and long-term release has great potential in the treatment of diseases requiring combinations of drugs being released sequentially at different treating stages.

Optimizing parameters for the preparation of low viscosity rubber asphalt incorporating waste engine oil using response surface methodology.

Due to the high viscosity, rubber asphalt displays poor construction workability, which ultimately compromises the comfort and safety of pavement. In this study, specified control variates were used to study the effect of the waste engine oil (WEO) addition sequence on the properties of rubber asphalt while ensuring the consistency of other preparation parameters. Initially, in order to evaluate their compatibility, the storage stability and aging properties of the three groups of samples were determined. The variation of asphalt viscosity was then analyzed using a low-field nuclear magnetic resonance (LF-NMR) test, by predicting the fluidity of each sample. Subsequently, the results showed that the rubber asphalt prepared by premixing WEO and crumb rubber (CR) had the best properties of low temperature, compatibility, and fluidity. On this basis, the effects of WEO content, shear rate, shear temperature, and shear time on the properties of low viscosity rubber asphalt were investigated separately through response surface methodology (RSM). Quantitative data from the basic performance experiment were used to fit the high precision regression equation, thereby correlating a more precise level of factors with experimental results. The response surface model prediction analysis showed that the optimal preparation parameters of the low viscosity rubber asphalt were 60 min shear time, 180 °C shear temperature, and 5000 r/min shear rate. Simultaneously, the addition of 3.5% of WEO showed great potential as an asphalt viscosity reducer. Ultimately, this study provides an accurate method for determining the optimum preparation parameters of asphalt.

Effect of different waste plastic modifiers on conventional asphalt performance: optimal preparation parameters determination and mechanism analysis.

The typical treatment of waste plastics has become a global environmental problem. In light of recent developments, waste plastics used as asphalt modifiers offer an efficient approach to solve this problem. This paper studied the effects of three kinds of waste plastic-modified asphalts (WPMA), with polypropylene (PP), polyethylene (PE) and ethylene-vinyl acetate copolymer (EVA) as their respective modifiers, on the conventional asphalt performance. Furthermore, an orthogonal experimental design (OED) was used to determine the preparation parameters of WPMA. Thereafter, thermogravimetric-differential scanning calorimetry (TG-DSC) and Fourier transform infrared spectroscopy (FTIR) were employed to expound the mechanism of WPMA. It was then subsequently ascertained that the optimum preparation parameters of PP-modified asphalt (PPMA) and PE-modified asphalt (PEMA) were 170 °C, 3000 rpm, and 30 min, while the optimum preparation parameters of EVA-modified asphalt (EVAMA) were 180 °C, 3000 rpm, and 30 min. In addition, WPMA displayed better high-temperature performance and are inherently more suitable for pavement in high-temperature regions. Ultimately, this study will effectively solve the disposal of waste plastic and promote the research and application of WPMA in the future.

An injectable hydrogel based on hyaluronic acid prepared by Schiff base for long-term controlled drug release.

Drug-loaded injectable hydrogels have been studied widely in biomedical technology while the stable long-term controlled drug release and cytotoxicity are challenges. In this work, an injectable hydrogel with good swelling resistance was in situ synthetized using aminated hyaluronic acid (NHA) and aldehyde ß-cyclodextrin (ACD) via Schiff base reaction. The composition, morphology and mechanical property were characterized with FTIR, 13C NMR, SEM and rheology test, respectively. Voriconazole (VCZ) and Endophthalmitis was selected as a model drug and disease, respectively. The drug release, cytotoxicity and antifungal properties were detected in vitro. The results showed a long-term (> 60 days) drug release was realized, the NHA/ACD2/VCZ presented a zero-order release in the later stage. The cytotoxicity of NHA/ACD was detected by live/dead staining assay and Cell Counting Kit-8 (CCK-8). The survival rate of adult retina pigment epithelial cell line-19 (ARPE-19) was over 100 % after 3 d, it indicated a good cytocompatibility. The antifungal experiment presented samples had antifungal property. Biocompatibility in vivo proved NHA/ACD2 had no adverse effects on ocular tissues. Consequently, the injectable hydrogel based on hyaluronic acid prepared by Schiff base reaction provides a new option for long-term controlled drug release in the course of disease treatment from a material perspective.

Controllable Synthesis of 2D Materials by Electrochemical Exfoliation for Energy Storage and Conversion Application.

2D materials have captured much recent research interest in a broad range of areas, including electronics, biology, sensors, energy storage, and others. In particular, preparing 2D nanosheets with high quality and high yield is crucial for the important applications in energy storage and conversion. Compared with other prevailing synthetic strategies, the electrochemical exfoliation of layered starting materials is regarded as one of the most promising and convenient methods for the large-scale production of uniform 2D nanosheets. Here, recent developments in electrochemical delamination are reviewed, including protocols, categories, principles, and operating conditions. State-of-the-art methods for obtaining 2D materials with small numbers of layers-including graphene, black phosphorene, transition metal dichalcogenides and MXene-are also summarized and discussed in detail. The applications of electrochemically exfoliated 2D materials in energy storage and conversion are systematically reviewed. Drawing upon current progress, perspectives on emerging trends, existing challenges, and future research directions of electrochemical delamination are also offered.

Contact-Piezoelectric Bi-Catalysis of an Electrospun ZnO@PVDF Composite Membrane for Dye Decomposition.

The treatment of organic pollutants in wastewater is becoming a great challenge for social development. Herein, a novel contact-piezoelectric bi-catalysis of a ZnO@ PVDF composite membrane was prepared by electrospinning technology. The obtained ZnO@PVDF composite membranes is superior to the pure PVDF membrane in decomposing methyl orange (MO) under ultrasonication at room temperature, which is mainly attributed to the synergy effect of the contact-electro-catalysis of dielectric PVDF, as well as the piezoelectric catalysis of tetrapodal ZnO and the ß-phase of PVDF. The heterostructure of the piezoelectric-ZnO@dielectric-PVDF composite is beneficial in reducing the electron/hole pair recombination. As compared to the pure PVDF membrane, the catalytic degradation efficiency of the ZnO@PVDF composite membrane was improved by 444.23% under ultrasonication. Moreover, the reusability and stability of the composite membrane are comparable to those of the traditional powdered catalyst. This work offers a promising strategy for improving the pollutant degradation by combining contact-electro-catalysis with piezoelectric catalysis.

Abnormal expression of HADH, an enzyme of fatty acid oxidation, affects tumor development and prognosis (Review).

Tumor occurrence and progression are closely associated with abnormal energy metabolism and energy metabolism associated with glucose, proteins and lipids. The reprogramming of energy metabolism is one of the hallmarks of cancer. As a form of energy metabolism, fatty acid metabolism includes fatty acid uptake, de novo synthesis and ß­oxidation. In recent years, the role of abnormal fatty acid ß­oxidation in tumors has gradually been recognized. Mitochondrial trifunctional protein (MTP) serves an important role in fatty acid ß­oxidation and HADH (two subtypes: α subunit, HADHA and ß subunit, HADHB) are important subunits of MTP. HADH participates in the steps of 2, 3 and 4 fatty acid ß­oxidation. However, there is no review summarizing the specific role of HADH in tumors. Therefore, the present study focused on HADH as the main indicator to explore the changes in fatty acid ß­oxidation in several types of tumors. The present review summarized the changes in HADH in 11 organs (cerebrum, oral cavity, esophagus, liver, pancreas, stomach, colorectum, lymph, lung, breast, kidney), the effect of up­ and downregulation and the relationship of HADH with prognosis. In summary, HADH can be either a suppressor or a promoter depending on where the tumor is located, which is closely associated with prognostic assessment. HADHA and HADHB have similar prognostic roles in known and comparable tumors.

Management of descending necrotizing mediastinitis with severe thoracic empyema using minimally invasive video-assisted thoracoscopic surgery: a case report.

Background: Descending necrotizing mediastinitis (DNM) is a rare but serious complication of odontogenic or pharyngeal infection spreading into the mediastinum. Very few childhood cases of DNM have been described. Case Description: We report a case of DNM complicated with severe thoracic empyema in a previously healthy 6-year-old girl who was successfully treated using minimally invasive video-assisted thoracoscopic surgery (VATS). The patient presented with odynophagia and dental pain, followed by rapid clinical deterioration including high fever, tachypnea, and left chest pain. As chest computed tomography (CT) revealed features of DNM, she was transferred from the local hospital to our hospital for intensive care. Empirical treatment was started with meropenem and linezolid. However, her tachypnea and dyspnea progressed rapidly. An ultrasound-guided left-sided thoracentesis drained 80 mL of brown sticky pus and the pus culture yielded Streptococcus constellatus. A contrast-enhanced CT scan demonstrated large mediastinal abscess and severe thoracic empyema. We performed debridement and drainage of the mediastinum and pleura using VATS. She recovered and was discharged on hospital day 18. Conclusions: Early diagnosis by cervicothoracic CT and multidisciplinary approaches including intensive care, broad-spectrum antibiotics, and aggressive surgical intervention are crucial to reducing morbidity and mortality. VATS is a minimally invasive and appropriate treatment strategy for children with DNM, especially complicated with thoracic empyema.

Anaplastic lymphoma kinase-special immunity and immunotherapy.

Alterations in the anaplastic lymphoma kinase (ALK) gene play a key role in the development of various human tumors, and targeted therapy has transformed the treatment paradigm for these oncogene-driven tumors. However, primary or acquired resistance remains a challenge. ALK gene variants (such as gene rearrangements and mutations) also play a key role in the tumor immune microenvironment. Immunotherapy targeting the ALK gene has potential clinical applications. Here, we review the results of recent studies on the immunological relevance of ALK-altered tumors, which provides important insights into the development of tumor immunotherapies targeting this large class of tumors.

Diverse and precision therapies open new horizons for patients with advanced pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a common cause of cancer-related death, and most patients are with advanced disease when diagnosed. At present, despite a variety of treatments have been developed for PDAC, few effective treatment options are available; on the other hand, PDAC shows significant resistance to chemoradiotherapy, targeted therapy, and immunotherapy due to its heterogeneous genetic profile, molecular signaling pathways, and complex tumor immune microenvironment. Nevertheless, over the past decades, there have been many new advances in the key theory and understanding of the intrinsic mechanisms and complexity of molecular biology and molecular immunology in pancreatic cancer, based on which more and more diverse new means and reasonable combination strategies for PDAC treatment have been developed and preliminary breakthroughs have been made. With the continuous exploration, from surgical local treatment to comprehensive medical management, the research-diagnosis-management system of pancreatic cancer is improving. This review focused on the variety of treatments for advanced PDAC, including traditional chemotherapy, targeted therapy, immunotherapy, microenvironment matrix regulation as well as the treatment targeting epigenetics, metabolism and cancer stem cells. We pointed out the current research bottlenecks and future exploration directions.

Inflammatory myofibroblastic tumor from the greater omentum in children: A rare case report.

Inflammatory myofibroblastic tumor (IMT) prevalence is less than one in a million. Anaplastic lymphoma kinase (ALK)-positive IMT in the greater omentum and with a diameter greater than 8 cm is extremely rare. Here, we present a case and provide a brief literature review. A 4-year-old female was referred to our hospital with a 1-month history of intermittent fever. Computed tomography revealed a 6.4 × 5.5 × 6.5-cm lesion between the spleen and stomach. During the operation, we confirmed that the mass originated in the greater omentum and completely resected the mass, achieving a negative margin. The maximum cross-sectional area of the tumor after surgery was 8.3 × 7.5 cm. The immunohistochemistry result of this IMT was ALK (+), S100 (-), Ki-67+ (20%), Desmin (+), CD21 (-), CD35 (+), Vim (+), and SMA (+). The final pathology was IMT. No local recurrence or metastasis has been observed in the 8 months of follow-up.

Opening Wedge High Tibial Osteotomy with Combined Use of Patient-Specific 3D-Printed Plates and Taylor Spatial Frame for the Treatment of Knee Osteoarthritis.

BACKGROUND: High tibial osteotomy (HTO) is used to treat medial degeneration of the osteoarthritis (OA) knee. However, shortcomings still exist in the current procedure, like unprecise creation, inability to correct knee rotation, and internal fixed failure. Here, we reported a novel procedure: patient-specific 3D-printed plates for opening wedge high tibial osteotomy (OWHTO) combined with Taylor spatial frame (TSF). The detailed technique was described, and the clinical outcomes were evaluated. METHODS: We prospectively evaluate outcomes of patient-specific 3D-printed plates for OWHTO with use of TSF in 25 patients with knee OA and varus alignment. Postoperative efficacy was evaluated using the HSS knee score, pain visual simulation score (VAS), and knee joint motion (ROM), and lower limb alignment was evaluated by measuring femorotibial angle (FTA) and hip-knee-ankle (HKA). Results and Conclusion. All patients did not experience complications such as wound infection, nerve damage, or bone amputation. 25 patients were followed up for 6-18 months. The bony union at bone amputation was achieved in 3 months after surgery, and the pain symptoms were significantly alleviated or disappeared. The VAS score was significantly reduced in 6 months after surgery compared with preoperative; the HSSS score was significantly added in 6 months after surgery compared with preoperative. The ROM of knee joint increased significantly 6 months after operation compared with that before operation, and the difference was statically significant (P < 0.05). The FTA and HKA after operation were significantly superior to that before operation, and the difference was statically significant (P < 0.01). CONCLUSIONS: Our study showed that patient-specific 3D-printed plates for HTO with the use of TSF have the advantages of small trauma, few complications, simple operation, and fast recovery in treating knee OA and varus alignment.

Correlation of Peripheral Blood Parameters and Immune-Related Adverse Events with the Efficacy of Immune Checkpoint Inhibitors.

OBJECTIVE: We aimed to retrospectively analyze the predictors of immune checkpoint inhibitors (ICIs)-efficacy in patients with advanced pancancer who were treated with various ICIs in the real world and focused on the correlation between ICIs-efficacy and immune-related adverse events (irAEs). METHODS: We retrospectively analyzed data from 103 patients with advanced pancancer treated receiving various ICIs in the First Hospital of Jilin University from January 1, 2016 to August 1, 2020. Survival probabilities of progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier curves and log-rank tests and the multivariate Cox proportional hazards model. Receiver-operating characteristic curve was used to determine a cutoff value for parameters and area under the curve. Correlations between the two variables were analyzed by logistic regression. RESULTS: All patients were analyzed for survival predictors of OS, while 87 of 103 patients experienced evaluable disease progression of immunotherapy and were included in the analysis of predictors of PFS. First, we found that lower platelet (cutoff = 201.5 × 109/L) and lactate dehydrogenase (LDH) (cutoff = 227 U/L) were independently associated with significantly improved PFS, while lower platelet-lymphocyte ratio (cutoff = 206.5), absolute monocyte count (cutoff = 0.62 × 109/L), and LDH (cutoff = 194.5 U/L) were significantly and independently associated with better OS. In the analysis of the immune cell subgroup, a lower absolute countof CD8+CD28-suppressor T cells was an independent factor associated with better PFS (6.60 vs.4.13 months (mo), hazard ratios (HR) = 3.17, p = 0.0038), and OS (29.4 vs. 9.57 mo, HR = 3.05, p = 0.03). Second, the results of the analysis for irAEs showed that patients with any grade irAEs had higher objective response rate (30% vs. 10%, HR = 4.34, p = 0.009), disease control rate (69.7% vs. 50%, HR = 2.3, p = 0.028), PFS (8.37 vs. 3.77 mo, HR = 2.02, p = 0.0038), and OS (24.77 vs.13.83 mo, HR = 1.84, p = 0.024). Moreover, the groups with irAEs of grade ≥2 and with "multi-site" irAEs had significantly better PFS and OS (p < 0.05) compared with the other groups. We also proved that endocrine irAEs (usually thyroid dysfunction) were significantly associated with better mPFS (p = 0.01), and hepatic irAEs were significantly associated with better mOS (p = 0.023). CONCLUSIONS: This retrospective study explored the availability and effectiveness of some cost-effective and readily available blood biochemical parameters in routine clinical practice to predict the ICIs-efficacy and demonstrated the predictive role of different categories of irAEs on efficacy.

Analysis of characteristics and predictive factors of immune checkpoint inhibitor-related adverse events.

OBJECTIVE: We aimed to retrospectively analyze the toxicity profiles and predictors of immune-related adverse events (irAEs) as well as the correlation between irAEs and the clinical efficacy of multi-type immune checkpoint inhibitors (ICIs) in patients with advanced pan-cancer in a real-world setting. METHODS: We retrospectively analyzed data from 105 patients with advanced pan-cancer treated with multi-type ICIs at the First Hospital of Jilin University between January 1, 2016 and August 1, 2020. We used logistic regression analyses to investigate the associations of irAEs with clinical baseline characteristics, blood count parameters, and biochemical indicators during treatment. Receiver operating characteristic curves were used to determine cutoff values for parameters and area under the curve values. KaplanMeier and Cox multivariate regression analyses were performed to estimate the relationships of baseline characteristics and irAEs with progression-free survival (PFS) and overall survival (OS). RESULTS: A lower relative lymphocyte count (cutoff = 28.5%), higher albumin level (cutoff = 39.05 g/L), and higher absolute eosinophil count (AEC) (cutoff = 0.175 × 109/L) were significantly associated with the occurrence of irAEs, among which a higher AEC (cutoff = 0.205 × 109/L) was strongly associated with skin-related irAEs [odds ratios (ORs) = 0.163, P = 0.004]. Moreover, a higher lactate dehydrogenase level (cutoff = 237.5 U/L) was an independent predictor of irAEs of grade ≥ 3 (OR = 0.083, P = 0.023). In immune cell subgroup analysis, a lower absolute count of CD8+CD28- suppressor T cells (OR = 0.806; 95% confidence interval: 0.643-1.011; P = 0.062), which are regulatory T lymphocytes, was associated with the occurrence of irAEs, although the difference was not statistically significant. Furthermore, a higher percentage of CD19+ B cells was associated with the occurrence of irAEs of grade ≥ 3 (P = 0.02) and grade ≥ 2 (P = 0.051). In addition, patients with any grade of irAE had a significantly high PFS (8.37 vs. 3.77 months, hazard ratios (HR) = 2.02, P = 0.0038) and OS (24.77 vs. 13.83 months, HR = 1.84; P = 0.024). CONCLUSIONS: This retrospective study reports clinical profile data for irAEs in unselected patients in a real-world setting and explored some parameters that may be potential predictive markers of the occurrence, type, or grade of irAEs in clinical practice. Evidence of a correlation between safety and efficacy may facilitate a complete assessment of the risk-benefit ratio for patients treated with ICIs.

The promising role of antibody drug conjugate in cancer therapy: Combining targeting ability with cytotoxicity effectively.

INTRODUCTION: Traditional cancer therapy has many disadvantages such as low selectivity and high toxicity of chemotherapy, as well as insufficient efficacy of targeted therapy. To enhance the cytotoxic effect and targeting ability, while reducing the toxicity of antitumor drugs, an antibody drug conjugate (ADC) was developed to deliver small molecular cytotoxic payloads directly to tumor cells by binding to specific antibodies via linkers. METHOD: By reviewing published literature and the current progress of ADCs, we aimed to summarize the basic characteristics, clinical progress, and challenges of ADCs to provide a reference for clinical practice and further research. RESULTS: ADC is a conjugate composed of three fundamental components, including monoclonal antibodies, cytotoxic payloads, and stable linkers. The mechanisms of ADC including the classical internalization pathway, antitumor activity of antibodies, bystander effect, and non-internalizing mechanism. With the development of new drugs and advances in technology, various ADCs have achieved clinical efficacy. To date, nine ADCs have received US Food and Drug Administration (FDA) approval in the field of hematologic tumors and solid tumors, which have become routine clinical treatments. CONCLUSION: ADC has changed traditional treatment patterns for cancer patients, which enable the same treatment for pancreatic cancer patients and promote individualized precision treatment. Further exploration of indications could focus on early-stage cancer patients and combined therapy settings. Besides, the mechanisms of drug resistance, manufacturing techniques, optimized treatment regimens, and appropriate patient selection remain the major topics.