A whole-slide foundation model for digital pathology from real-world data.

Digital pathology poses unique computational challenges, as a standard gigapixel slide may comprise tens of thousands of image tiles1-3. Prior models have often resorted to subsampling a small portion of tiles for each slide, thus missing the important slide-level context4. Here we present Prov-GigaPath, a whole-slide pathology foundation model pretrained on 1.3 billion 256 × 256 pathology image tiles in 171,189 whole slides from Providence, a large US health network comprising 28 cancer centres. The slides originated from more than 30,000 patients covering 31 major tissue types. To pretrain Prov-GigaPath, we propose GigaPath, a novel vision transformer architecture for pretraining gigapixel pathology slides. To scale GigaPath for slide-level learning with tens of thousands of image tiles, GigaPath adapts the newly developed LongNet5 method to digital pathology. To evaluate Prov-GigaPath, we construct a digital pathology benchmark comprising 9 cancer subtyping tasks and 17 pathomics tasks, using both Providence and TCGA data6. With large-scale pretraining and ultra-large-context modelling, Prov-GigaPath attains state-of-the-art performance on 25 out of 26 tasks, with significant improvement over the second-best method on 18 tasks. We further demonstrate the potential of Prov-GigaPath on vision-language pretraining for pathology7,8 by incorporating the pathology reports. In sum, Prov-GigaPath is an open-weight foundation model that achieves state-of-the-art performance on various digital pathology tasks, demonstrating the importance of real-world data and whole-slide modelling.

Nuclear matrix protein 22 in bladder cancer.

Bladder cancer (BC) is ranked as the ninth most common malignancy worldwide, with approximately 570,000 new cases reported annually and over 200,000 deaths. Cystoscopy remains the gold standard for the diagnosis of BC, however, its invasiveness, cost, and discomfort have driven the demand for the development of non-invasive, cost-effective alternatives. Nuclear matrix protein 22 (NMP22) is a promising non-invasive diagnostic tool, having received FDA approval. Traditional methods for detecting NMP22 require a laboratory environment equipped with specialized equipment and trained personnel, thus, the development of NMP22 detection devices holds substantial potential for application. In this review, we evaluate the NMP22 sensors developed over the past decade, including electrochemical, colorimetric, and fluorescence biosensors. These sensors have enhanced detection sensitivity and overcome the limitations of existing diagnostic methods. However, many emerging devices exhibit deficiencies that limit their potential clinical use, therefore, we propose how sensor design can be optimized to enhance the likelihood of clinical translation and discuss the future applications of NMP22 as a legacy biomarker, providing insights for the design of new sensors.

MELATONIN ATTENUATES RENAL ISCHEMIA-REPERFUSION INJURY BY REGULATING MITOCHONDRIAL DYNAMICS AND AUTOPHAGY THROUGH AMPK/DRP1.

ABSTRACT: Ischemia-reperfusion injury (IRI) often stems from an imbalance between mitochondrial dynamics and autophagy. Melatonin mitigates IRI by regulating mitochondrial dynamics. However, the precise molecular mechanism underlying the role of melatonin in reducing IRI through modulating mitochondrial dynamics remains elusive. The objective of this study was to investigate whether pretreatment with melatonin before IRI confers protective effects by modulating mitochondrial dynamics and mitophagy. Melatonin pretreatment was administered to HK-2 cells and live rats before subjecting them to hypoxia-reoxygenation or IRI, respectively. Cells and rat kidney models were evaluated for markers of oxidative stress, autophagy, mitochondrial dynamics, and the expression of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and phospho-AMPKα (P-AMPK). After renal IRI, increased mitochondrial fission and autophagy were observed, accompanied by exacerbated cellular oxidative stress injury and aggravated mitochondrial dysfunction. Nevertheless, melatonin pretreatment inhibited mitochondrial fission, promoted mitochondrial fusion, and attenuated autophagy levels. This intervention was correlated with a notable reduction in oxidative stress injury and remarkable restoration of mitochondrial functionality. Ischemia-reperfusion injury led to a decline in P-AMPK levels, whereas melatonin pretreatment increased the level of P-AMPK levels. Silencing AMPK with small interfering RNA exacerbated mitochondrial damage, and in this context, melatonin pretreatment did not alleviate mitochondrial fission or autophagy levels but resulted in sustained oxidative stress damage. Collectively, these findings indicate that melatonin pretreatment shields the kidneys from IRI by mitigating excessive mitochondrial fission, moderating autophagy levels, and preserving appropriate mitochondrial fission, all in an AMPK-dependent manner.

Pembrolizumab in patients from China with microsatellite instability-high/mismatch repair deficient tumors: KEYNOTE-158.

Aim: To evaluate pembrolizumab in patients of Chinese descent with microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) tumors enrolled in KEYNOTE-158 (Cohort L). Methods: Patients with MSI-H/dMMR advanced tumors received pembrolizumab 200 mg IV Q3W. Primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: 24 patients were enrolled (20 were evaluable for efficacy). With median follow-up of 12.4 months, the ORR was 70%. DOR, PFS and OS were all not reached. A total of 19 (79%) patients had a treatment-related adverse event (AE; grade ≥3 in 4 [17%]), and 8 (33%) had an immune-mediated AE (grade ≥3 in (4 [17%]). Conclusion: Pembrolizumab provided meaningful and durable responses with manageable safety. These results are consistent with those reported for the global trial.

Optimizing Typha biochar with phosphoric acid modification and ferric chloride impregnation for hexavalent chromium remediation in water and soil.

Considering the persistent and covert nature of heavy metal soil contamination, the sustainable development of ecological environments and food safety is at significant risk. Our study focuses on remediating soils contaminated with chromium (Cr); we introduce an advanced remediation material, iron oxide phosphoric acid-loaded activated biochar (HFBC), synthesized through pyrolysis. This HFBC displays greater microporosity, fewer impurities, and enhanced efficiency for the remediation process. Our research utilized a comprehensive set of analytical techniques, including Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectroscopy (FTIR), and X-ray Photoelectron Spectroscopy (XPS), alongside adsorption studies to elucidate the Cr removal mechanism. The effectiveness of HFBC in remediation was influenced by several factors: the pH level, dosage of HFBC, the initial concentration of Cr, and the ambient temperature. Our results indicated an optimal chromium (VI) adsorption capacity of 55.5 mg/g by HFBC at a pH of 6.0 and a temperature of 25 °C, with the process adhering to the pseudo-second-order kinetic model and the Langmuir adsorption isotherm, thus suggesting spontaneity in the uptake method. Moreover, this mechanism encompasses both adsorption and reduction reactions. Using HFBC in pot experiments with cabbage indicated not only an increase in soil pH and cation exchange capacity (CEC), but also a surge in bacterial community abundance. Significant reductions in bioavailable chromium were also recorded. Interestingly, HFBC addition bolstered the growth of cabbage, while concurrently diminishing chromium accumulation within the plant, particularly notable as the HFBC application rate increased. In summation, the HFBC produced in our study has demonstrated convincing efficacy in removing chromium from aqueous solutions and soil. Moreover, the positive agronomic implications of its use, such as enhanced plant growth and reduced heavy metal uptake by plants, indicate its high potential for operational value in the domain of environmental remediation of heavy metals.

Orbital septum attachment site on the levator aponeurosis sling for mild congenital blepharoptosis.

PURPOSE: This study aimed to investigate the value of the orbital septum attachment site on the levator aponeurosis (OSASLA) sling in correcting mild congenital blepharoptosis. METHODS: A total of 60 patients (92 eyes) with mild congenital blepharoptosis (levator function ≥ 8 mm) were treated in our hospital from January to October 2021, and relevant data of these patients were collected. All patients underwent OSASLA sling for ptosis correction. The distances from the superior tarsal border to the OSASLA were measured. The primary outcome was the number of postoperative changes in the marginal reflex distance 1 (MRD1). Pearson's correlation coefficient between the distance from the superior tarsal border to the OSASLA and the height of the upper eyelid elevated was analyzed. RESULTS: Fifty-eight patients (89 eyes) successfully underwent OSASLA sling surgery. The preoperative MRD1 was 1.4-3.6 mm (mean 2.1 ± 0.5 mm), and the postoperative MRD1 was 3.4-5.0 mm (mean 3.7 ± 0.6 mm). The distance from the superior tarsal border to the OSASLA sling was significantly and positively correlated with the height of the upper eyelid elevation (r = 0.7328, P < 0.0001). The eyelid margin positions of the patients did not regress substantially during 6-18 months of follow-up. CONCLUSIONS: Compared with the shortening of levator palpebrae superioris (LPS) and pleating of LPS, the OSASLA sling is a less invasive, more effective, and easy-operating surgery for mild congenital blepharoptosis.

Self-Reinforced PTLG Copolymer with Shish Kebab Structures and a Bionic Surface as Bioimplant Materials for Tissue Engineering Applications.

Green and biodegradable materials with great mechanical properties and biocompatibility will offer new opportunities for next-generation high-performance biological materials. Herein, the novel oriented shish kebab crystals of a novel poly(trimethylene carbonate-lactide-glycolide) (PTLG) vascular stent are first reported to be successfully fabricated through a feasible solid-state drawing process to simultaneously enhance the mechanical performance and biocompatibility. The crystal structure of this self-reinforced vascular stent was transformed from spherulites to a shish kebab crystal, which indicates the mechanical interlocking effect and prevents the lamellae from slipping with a significant improvement of mechanical strength to 333 MPa. Meanwhile, it is different from typical biomedical polymers with smooth surface structures, and the as-obtained PTLG vascular stent exhibits a bionic surface morphology with a parallel micro groove and ridge structure. These ridges and grooves were attributed to the reorganization of cytoskeleton fiber bundles following the direction of blood flow shear stress. The structure and parameters of these morphologies were highly similar to the inner surface of blood vessels of the human, which facilitates cell adhesion growth to improve its proliferation, differentiation, and activity on the surface of PTLG.

Immunologic Crosstalk of Endoplasmic Reticulum Stress Signaling in Bladder Cancer.

Bladder cancer (BC) is a common malignant tumor of the urinary system. While current approaches involving adjuvant chemotherapy, radiotherapy, and immunotherapy have shown significant progress in BC treatment, challenges, such as recurrence and drug resistance, persist, especially in the case of muscle-invasive bladder cancer (MIBC). This is mainly due to the lack of pre-existing immune response cells in the tumor immune microenvironment. Micro-environmental changes (such as hypoxia and under-nutrition) can cause the aggregation of unfolded and misfolded proteins in the lumen, which induces endoplasmic reticulum (ER) stress. ER stress and its downstream signaling pathways are closely related to immunogenicity and tumor drug resistance. ER stress plays a pivotal role in a spectrum of processes within immune cells and the progression of BC cells, encompassing cell proliferation, autophagy, apoptosis, and resistance to therapies. Recent studies have increasingly recognized the potential of natural compounds to exhibit anti-BC properties through ER stress induction. Still, the efficacy of these natural compounds remains less than that of immune checkpoint inhibitors (ICIs). Currently, the ER stress-mediated immunogenic cell death (ICD) pathway is more encouraging, which can enhance ICI responses by mediating immune stemness. This article provides an overview of the recent developments in understanding how ER stress influences tumor immunity and its implications for BC. Targeting this pathway may soon emerge as a compelling therapeutic strategy for BC.

Choice of formal and informal care among community-dwelling older people with or without dementia under a long-term care insurance pilot program in China.

OBJECTIVE: This study examines the use of publicly funded formal and informal care among community-dwelling long-term care insurance (LTCI) beneficiaries in China and how dementia differentiates the choice of care. METHODS: Using administrative data from a LTCI pilot scheme in Guangzhou (n = 2043), we conducted a multinomial logistic regression to examine the association between dementia and the choice of family members (informal unpaid care), domestic helpers (informal paid care) and care workers (formal care), controlling for demographics, living environment and intensity of paid care hours. RESULTS: Most LTCI beneficiaries chose a family member (65%), followed by a domestic helper (21%) and a care worker (14%). After controlling for covariates, LTCI beneficiaries with dementia were more likely than their counterparts without dementia to choose care provided by a care worker (RRR: 1.73) or a living-in helper (RRR: 1.43) than a family member. CONCLUSIONS: A preference for informal care was observed among LTCI beneficiaries in China. Those with dementia were more likely than those without dementia to use care provided by non-family caregivers. The pilot scheme findings provide further insight into care recipients' preferences for service utilisation and how dementia impacts these preferences, which should be considered in future policy and service provision.

Rapid identification of full-length genome and tracing variations of monkeypox virus in clinical specimens based on mNGS and amplicon sequencing.

The monkeypox virus (MPXV) has triggered a current outbreak globally. Genome sequencing of MPXV and rapid tracing of genetic variants will benefit disease diagnosis and control. It is a significant challenge but necessary to optimize the strategy and application of rapid full-length genome identification and to track variations of MPXV in clinical specimens with low viral loads, as it is one of the DNA viruses with the largest genome and the most AT-biased, and has a significant number of tandem repeats. Here we evaluated the performance of metagenomic and amplicon sequencing techniques, and three sequencing platforms in MPXV genome sequencing based on multiple clinical specimens of five mpox cases in Chinese mainland. We rapidly identified the full-length genome of MPXV with the assembly of accurate tandem repeats in multiple clinical specimens. Amplicon sequencing enables cost-effective and rapid sequencing of clinical specimens to obtain high-quality MPXV genomes. Third-generation sequencing facilitates the assembly of the terminal tandem repeat regions in the monkeypox virus genome and corrects a common misassembly in published sequences. Besides, several intra-host single nucleotide variations were identified in the first imported mpox case. This study offers an evaluation of various strategies aimed at identifying the complete genome of MPXV in clinical specimens. The findings of this study will significantly enhance the surveillance of MPXV.

Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial.

Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures: The primary end point was overall survival time from randomization. Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03745170.

Phase Ib study of anti-EGFR antibody (SCT200) in combination with anti-PD-1 antibody (SCT-I10A) for patients with RAS/BRAF wild-type metastatic colorectal cancer.

OBJECTIVE: This study evaluated the safety and efficacy of an anti-epidermal growth factor receptor (EGFR) antibody (SCT200) and an anti-programmed cell death 1 (PD-1) antibody (SCT-I10A) as third-line or subsequent therapies in patients with rat sarcoma viral oncogene (RAS)/v-raf murine sarcoma viral oncogene homolog B (BRAF) wild-type (wt) metastatic colorectal cancer (mCRC). METHODS: We conducted a multicenter, open-label, phase Ib clinical trial. Patients with histologically confirmed RAS/BRAF wt mCRC with more than two lines of treatment were enrolled and treated with SCT-I10A and SCT200. The primary endpoints were the objective response rate (ORR) and safety. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: Twenty-one patients were enrolled in the study through January 28, 2023. The ORR was 28.57% and the DCR was 85.71% (18/21). The median PFS and OS were 4.14 and 12.84 months, respectively. The treatment-related adverse events (TRAEs) were tolerable. Moreover, compared with the monotherapy cohort from our previous phase I study evaluating SCT200 for RAS/BRAF wt mCRC in a third-line setting, no significant improvements in PFS and OS were observed in the combination group. CONCLUSIONS: SCT200 combined with SCT-I10A demonstrated promising efficacy in previously treated RAS/BRAF wt mCRC patients with an acceptable safety profile. Further head-to-head studies with larger sample sizes are needed to validate whether the efficacy and safety of combined anti-EGFR and anti-PD-1 therapy are superior to anti-EGFR monotherapy in the third-line setting. (Registration No. NCT04229537).

Sintilimab-induced inflammatory myopathy in a patient with esophageal cancer: a case report.

The use of immune checkpoint inhibitors (ICIs) has shown remarkable efficacy in the treatment of various malignancies, significantly reshaping cancer treatment. However, as a result of the widespread use of ICIs, several immune-related adverse events (iRAEs) have emerged, some of which can be rare and potentially fatal. In this paper, we reported the earliest case of Sintilimab used in the treatment of esophageal cancer with severe inflammatory myopathy (involving the cardiac, respiratory, and skeletal muscles)in China. This patient was an elderly female who presented to our institution with progressive limb weakness and ptosis. Prior to the onset of symptoms, the patient had undergone a radical esophagectomy for esophageal cancer, experienced several cycles of of radiotherapy and chemotherapy, as well as two doses of Sintilimab treatment. Shortly after initiating immunotherapy, the patient developed symptoms including bilateral ptosis, limb weakness, and difficulty swallowing and breathing. The levels of creatine kinase and troponin I in the patient's blood were significantly elevated, and positive results were observed for anti-skeletal and anti-cardiac muscle antibodies, indicating that the patient might be developing ICIs-related inflammatory myopathy. Fortunately, the patient responded well to treatment including corticosteroids, plasmapheresis, intravenous immunoglobulin, and other supportive therapies. Here, we discuss the incidence, mechanisms, and management strategies of fatal iRAEs. Early detection and timely intervention may be critical in reducing the incidence and mortality rates of iRAEs and improving patient outcomes.

Joint analysis of the metabolomics and transcriptomics uncovers the dysregulated network and develops the diagnostic model of high-risk neuroblastoma.

High-risk neuroblastoma (HR-NB) has a significantly lower survival rate compared to low- and intermediate-risk NB (LIR-NB) due to the lack of risk classification diagnostic models and effective therapeutic targets. The present study aims to characterize the differences between neuroblastomas with different risks through transcriptomic and metabolomic, and establish an early diagnostic model for risk classification of neuroblastoma.Plasma samples from 58 HR-NB and 38 LIR-NB patients were used for metabolomics analysis. Meanwhile, NB tissue samples from 32 HR-NB and 23 LIR-NB patients were used for transcriptomics analysis. In particular, integrative metabolomics and transcriptomic analysis was performed between HR-NB and LIR-NB. A total of 44 metabolites (P < 0.05 and fold change > 1.5) were altered, including 12 that increased and 32 that decreased in HR-NB. A total of 1,408 mRNAs (P < 0.05 and |log2(fold change)|> 1) showed significantly altered in HR-NB, of which 1,116 were upregulated and 292 were downregulated. Joint analysis of both omic data identified 4 aberrant pathways (P < 0.05 and impact ≥ 0.5) consisting of glycerolipid metabolism, retinol metabolism, arginine biosynthesis and linoleic acid metabolism. Importantly, a HR-NB risk classification diagnostic model was developed using plasma circulating-free S100A9, CDK2, and UNC5D, with an area under receiver operating characteristic curve of 0.837 where the sensitivity and specificity in the validation set were both 80.0%. This study presents a novel pioneering study demonstrating the metabolomics and transcriptomics profiles of HR-NB. The glycerolipid metabolism, retinol metabolism, arginine biosynthesis and linoleic acid metabolism were altered in HR-NB. The risk classification diagnostic model based on S100A9, CDK2, and UNC5D can be clinically used for HR-NB risk classification.

Cr(VI) removal from wastewater using nano zero-valent iron and chromium-reducing bacteria.

Significant global efforts are currently underway to alleviate the presence of toxic metals in water bodies, aiming to encourage a sustainable environment. Nevertheless, the scientific community has yet to methodically inspect the performance and mechanisms underlying the interaction between nanomaterials and microorganisms in this context. Therefore, this study seeks to address this knowledge gap by developing a novel system that integrates nano zero-valent iron (nZVI) with chromium-reducing bacteria (CrRB) to efficiently remove Cr(VI) from water sources. The combined use of RBC600 and CrRB resulted in a Cr(VI) removal rate of 77.73%, displaying a substantial improvement of 17.61% compared to the use of CrRB alone. The efficacy of Cr(VI) elimination was observed to be affected by several factors within the system, such as the pH value, the quantity of nZVI added, the degree of CrRB inoculation, and the initial concentration of Cr(VI) at the onset of the experiment. When the pH was adjusted to 5, the complete removal of 200 mg/L Cr(VI) was achieved within 36 h. Increasing the dosage of nZVI to above 2 g/L resulted in the complete elimination of Cr(VI) from the solution within 72 h. This can be attributed to the availability of more reaction sites for the reduction of Cr(VI), facilitated by the higher nZVI dose. Additionally, the increased dose of nZVI allowed for the dissolution of more reactive Fe(II) ions. The characterization analysis, high-throughput sequencing, and fluorescence quantitative PCR results have established that CrRB and its extracellular polymer effectively reduce and complex Cr(VI). This process facilitated the dissolution of the passivated layer on the surface of nZVI, thus significantly enhancing the efficiency of nZVI in responding to Cr(VI). Additionally, the presence of nZVI created a favorable living environment for CrRB, resulting in increased richness and diversity within the CrRB community. These findings provide valuable preliminary insights into the mechanism underlying Cr(VI) elimination by the synergistic interaction between nZVI and CrRB. Therefore, this study establishes a solid theoretical foundations for the application of nano-bio synergy in the remediation of Cr(VI).

Axillary Lymph Node Metastasis as the First Symptom of Colon Cancer.

ABSTRACT: Axillary lymph node metastasis in colon cancer is extremely rare. We describe the FDG PET/CT findings in a 61-year-old woman who presented with a mass in the right axilla, which revealed irregular thickening of the ascending colon wall, as well as multiple enlarged lymph nodes in the ileocecal mesentery, para-aortic region, and right axilla with higher uptake of FDG. Ascending colon carcinoma with lymph node metastasis in the right axilla was confirmed by pathological examination.

Exploring potential targets of HPV&BC based on network pharmacology and urine proteomics.

BACKGROUND: Bladder cancer (BC) caused by Human papillomavirus (HPV) infection remains a complex public health problem in developing countries. Although the HPV vaccine effectively prevents HPV infection, it does not benefit patients with BC who already have HPV. METHODS: Firstly, the differential genes of HPV-related BC patients were screened by transcriptomics, and then the prognostic and clinical characteristics of the differential genes were analyzed to screen out the valuable protein signatures. Furthermore, the compound components and targets of Astragali Radix (AR) were analyzed by network pharmacology, and the intersection targets of drug components and HPV_BC were screened out for pathway analysis. In addition, the binding ability of the compound to the Astragali-HPV_BC target was verified by molecular docking and virtual simulation. Finally, to identify potential targets in BC patients through urine proteomics and in vitro experiments. RESULTS: Eleven HPV_BC-related protein signatures were screened out, among which high expression of EGFR, CTNNB1, MYC, GSTM1, MMP9, CXCR4, NOTCH1, JUN, CXCL12, and KRT14 had a poor prognosis, while low expression of CASP3 had a poor prognosis. In the analysis of clinical characteristics, it was found that high-risk scores, EGFR, MMP9, CXCR4, JUN, and CXCL12 tended to have higher T stage, pathological stage, and grade. Pharmacological and molecular docking analysis identified a natural component of AR (Quercetin) and it corresponding core targets (EGFR). The OB of the natural component was 46.43, and the DL was 0.28, respectively. In addition, EGFR-Quercetin has high affinity. Urine proteomics and RT-PCR showed that EGFR was expressed explicitly in BC patients. Mechanism analysis revealed that AR component targets might affect HPV_BC patients through Proteoglycans in the cancer pathway. CONCLUSION: AR can target EGFR through its active component (Quercetin), and has a therapeutic effect on HPV_BC patients.

Rethinking neutrophil extracellular traps.

Neutrophils are a major subset of leukocytes in human circulating blood. In some circumstances, neutrophils release neutrophil extracellular traps (NETs). lnitially, NETs were considered to have a strong antibacterial capacity. However, currently, NETs have been shown to have a pivotal impact on various diseases. Different stimulators induce the production of different types of NETs, and their biological functions and modes of clearance do not appear to be the same. In this review, we will discuss several important issues related to NETs in order to better understand the relationship between NETs and diseases, as well as how to utilize the characteristics of NETs for disease treatment.

Nimotuzumab Plus Gemcitabine for K-Ras Wild-Type Locally Advanced or Metastatic Pancreatic Cancer.

PURPOSE: In a phase IIb trial of nimotuzumab plus gemcitabine, substantial clinical benefits were observed in patients with locally advanced or metastatic pancreatic cancer (PC). Therefore, we conducted a phase III clinical study to verify the efficacy and safety of this combination regimen in patients with K-Ras wild-type tumors (ClinicalTrials.gov identifier: NCT02395016). PATIENTS AND METHODS: Eligible patients were randomly assigned to receive nimotuzumab (400 mg once per week) or placebo followed by gemcitabine (1,000 mg/m2 on days 1, 8, and 15, once every 4 weeks) until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) and the secondary end points were progression-free survival (PFS), response rates, and safety. RESULTS: A total of 480 patients were screened; 92 patients were enrolled and 82 patients with K-Ras wild-type tumors were eligible. In the full analysis set, the median OS was 10.9 versus 8.5 months, while the restricted mean survival time (RMST) was 18.05 versus 11.14 months for the investigational versus control arm (ratio of control v investigation = 0.62 [0.40-0.97]; P = .036). Median PFS was 4.2 versus 3.6 months in the investigational versus control arm (log-rank P = .04; hazard ratio, 0.60 [0.37-0.99]) and the restricted mean PFS time was 8.08 versus 4.76 months (RMST ratio, 0.58 [0.38-0.90]; P = .036). Both OS and PFS were longer in the nimotuzumab group than in the placebo group. The objective response rates and disease control rates were 7% versus 10% and 68% versus 63% for the investigational and control groups, respectively. The incidence of adverse events were comparable between the two groups. CONCLUSION: In patients with locally advanced or metastatic K-Ras wild-type PC, nimotuzumab plus gemcitabine significantly improved OS and PFS with a good safety profile.