Human papillomavirus infection and the risk of cancer at specific sites other than anogenital tract and oropharyngeal region: an umbrella review.

BACKGROUND: Despite numerous studies having evaluated the associations between human papillomavirus (HPV) infection and risk of specific cancers other than anogenital tract and oropharyngeal, the findings are inconsistent and the quality of evidence has not been systematically quantified. We aimed to summarise the existing evidence as well as to evaluate the strength and credibility of these associations. METHODS: We conducted an umbrella review of systematic reviews and meta-analyses of observational studies. PubMed, EMBASE, and Web of Science were searched from inception to March 2024. Studies with systematic reviews and meta-analyses that examined associations between HPV or HPV-associated genotypes infection and specific cancers were eligible for this review. The quality of the methodology was evaluated using A Measurement Tool to Assess systematic Reviews (AMSTAR). The credibility of the evidence was assessed using GRADE. The protocol was preregistered with PROSPERO (CRD42023439070). FINDINGS: The umbrella review identified 31 eligible studies reporting 87 associations with meta-analytic estimates, including 1191 individual studies with 336,195 participants. Of those, 29 (93.5%) studies were rated as over moderate quality by AMSTAR. Only one association indicating HPV-18 infection associated with an increased risk of breast cancer (odds ratio [OR] = 3.48, 95% confidence interval [CI] = 2.24-5.41) was graded as convincing evidence. There were five unique outcomes identified as highly suggestive evidence, including HPV infection increased the risk of oral squamous cell carcinoma (OR = 7.03, 95% CI = 3.87-12.76), oesophageal cancer (OR = 3.32, 95% CI = 2.54-4.34), oesophageal squamous cell carcinoma (OR = 2.69, 95% CI = 2.05-3.54), lung cancer (OR = 3.60, 95% CI = 2.59-5.01), and breast cancer (OR = 6.26, 95% CI = 4.35-9.00). According to GRADE, one association was classified as high, indicating that compared with the controls in normal tissues, HPV infection was associated with an increased risk of breast cancer. INTERPRETATION: The umbrella review synthesised up-to-date observational evidence on HPV infection with the risk of breast cancer, oral squamous cell carcinoma, oesophageal cancer, oesophageal squamous cell carcinoma, and lung cancer. Further larger prospective cohort studies are needed to verify the associations, providing public health recommendations for prevention of disease. FUNDING: National Key Research and Development Program of China, Natural Science Foundation of China, Outstanding Scientific Fund of Shengjing Hospital of China Medical University, and 345 Talent Project of Shengjing Hospital of China Medical University.

Au/Doc/Quer@PDA/A10-3.2 Nanoparticles for targeted treatment of docetaxel-resistant prostate cancer.

Docetaxel (Doc), as a first-line chemotherapy drug for prostate cancer (PC), often loses its therapeutic efficacy due to acquired resistance and lack of targeting specificity. Therefore, there is a need to develop a novel drug that can overcome Doc resistance and enhance its targeting ability to inhibit PC progression. In this study, we prepared Au/Doc/Quer@PDA/A10-3.2 nanoparticles (NPs) composite drug by encapsulating Doc and quercetin (Quer) within polydopamine (PDA)-coated Au NPs and further modifying them with RNA oligonucleotide aptamer A10-3.2. A10-3.2 was used for specific targeting of prostate-specific membrane antigen (PSMA)-positive PC cells (LNCaP). Quer was employed to reverse the resistance of Doc-resistant cell line (LNCaP/R) to Doc. Physical characterization using ultraviolet-visible spectroscopy (UV-vis), transmission electron microscopy (TEM), dynamic light scattering (DLS), X-ray photoelectron spectroscopy (XPS), and Fourier-transform infrared spectroscopy (FTIR) confirmed the successful preparation of Au/Doc/Quer@PDA/A10-3.2 NPs. Fluorescence imaging and flow cytometry experiments demonstrated the targeting ability of Au/Doc/Quer@PDA/A10-3.2 NPs towards PSMA-positive LNCaP/R cells. Cell proliferation, apoptosis, invasion, and migration experiments revealed that Quer reversed the resistance of LNCaP/R cells to Doc. Immunoblotting experiments further confirmed the mechanism behind sensitization of chemotherapy by Quer. Finally, we evaluated the therapeutic efficacy of Au/Doc/Quer@PDA/A10-3.2 NPs in a mouse model of PC. In conclusion, this study synthesized and validated a novel nano-composite drug (Au/Doc/Quer@PDA/A10-3.2 NPs) for combating Doc-resistant PC, which could potentially be applied in clinical treatment of PC.

Orchestrating apoptosis and ferroptosis through enhanced sonodynamic therapy using amorphous UIO-66-CoOx.

The development of efficient and multifunctional sonosensitizers is crucial for enhancing the efficacy of sonodynamic therapy (SDT). Herein, we have successfully constructed a CoOx-loaded amorphous metal-organic framework (MOF) UIO-66 (A-UIO-66-CoOx) sonosensitizer with excellent catalase (CAT)- and glutathione-oxidase (GSH-OXD)-like activities. The A-UIO-66-CoOx exhibits a 2.6-fold increase in singlet oxygen (1O2) generation under ultrasound (US) exposure compared to crystalline UIO-66 sonosensitizer, which is attributed to its superior charge transfer efficiency and consistent oxygen (O2) supply. Additionally, the A-UIO-66-CoOx composite reduces the expression of glutathione peroxidase (GPX4) by depleting glutathione (GSH) through Co3+ and Co2+ valence changes. The high levels of highly cytotoxic 1O2 and deactivation of GPX4 can lead to lethal lipid peroxidation, resulting in concurrent apoptosis and ferroptosis. Both in vitro and vivo tumor models comprehensively confirmed the enhanced SDT antitumor effect using A-UIO-66-CoOx sonosensitizer. Overall, this study emphasizes the possibility of utilizing amorphization engineering to improve the effectiveness of MOFs-based sonosensitizers for combined cancer therapies.

Evaluation of the neoadjuvant chemotherapy response in osteosarcoma using the MRI DWI-based machine learning radiomics nomogram.

Objective: To evaluate the value of a nomogram combined MRI Diffusion Weighted Imaging (DWI) and clinical features to predict the treatment response of Neoadjuvant Chemotherapy (NAC) in patients with osteosarcoma. Methods: A retrospective analysis was conducted on 209 osteosarcoma patients admitted into two bone cancer treatment centers (133 males, 76females; mean age 16.31 ± 11.42 years) from January 2016 to January 2022. Patients were classified as pathological good responders (pGRs) if postoperative histopathological examination revealed ≥90% tumor necrosis, and non-pGRs if <90%. Their clinical features were subjected to univariate and multivariate analysis, and features with statistically significance were utilized to construct a clinical signature using machine learning algorithms. Apparent diffusion coefficient (ADC) values pre-NAC (ADC 0) and post two chemotherapy cycles (ADC 1) were recorded. Regions of interest (ROIs) were delineated from pre-treatment DWI images (b=1000 s/mm²) for radiomic features extraction. Variance thresholding, SelectKBest, and LASSO regression were used to select features with strong relevance, and three machine learning models (Logistic Regression, RandomForest and XGBoost) were used to construct radiomics signatures for predicting treatment response. Finally, the clinical and radiomics signatures were integrated to establish a comprehensive nomogram model. Predictive performance was assessed using ROC curve analysis, with model clinical utility appraised through AUC and decision curve analysis (DCA). Results: Of the 209patients, 51 (24.4%) were pGRs, while 158 (75.6%) were non-pGRs. No significant ADC1 difference was observed between groups (P>0.05), but pGRs had a higher ADC 0 (P<0.01). ROC analysis indicated an AUC of 0.681 (95% CI: 0.482-0.862) for ADC 0 at the threshold of ≥1.37×10-3 mm²/s, achieving 74.7% sensitivity and 75.7% specificity. The clinical and radiomics models reached AUCs of 0.669 (95% CI: 0.401-0.826) and 0.768 (95% CI: 0.681-0.922) respectively in the test set. The combined nomogram displayed superior discrimination with an AUC of 0.848 (95% CI: 0.668-0.951) and 75.8% accuracy. The DCA suggested the clinical utility of the nomogram. Conclusion: The nomogram based on combined radiomics and clinical features outperformed standalone clinical or radiomics model, offering enhanced accuracy in evaluating NAC response in osteosarcoma. It held significant promise for clinical applications.

The proteomic evidence on protein oxidation in pea protein concentrate-based low-moisture extrudates and its inhibition by antioxidants derived from plant extracts.

This study aimed to assess the antioxidant activity of golden chlorella (GoC) and grape pomace (GrP) extracts both in vitro and in pea protein-based extrudates. We hypothesized that GoC/GrP would limit oxidation of proteins in the extrudates compared with commercial antioxidants. The results showed that GoC extract was effective in metal chelation and GrP extract possessed excellent radical scavenging activity and reducing power. Protein oxidation inevitably occurred after low-moisture extrusion in terms of elevated level of protein carbonyls and the gradual loss of thiols. LC-MS/MS revealed that the monoxidation and 4-hydroxynonenal adduction were the major oxidative modifications, and legumin was the most susceptible globulin for oxidation. The GoC/GrP extracts effectively retarded the oxidation progress in extrudates by lower intensity of oxidized peptides, whereas protein electrophoretic profiles remained unaffected. This study highlighted the great potential of GoC/GrP as natural antioxidants in plant-based foods.

Nomogram model for predicting early recurrence for resectable pancreatic cancer: A multicenter study.

Pancreatic cancer is a highly aggressive malignancy that is characterized by early metastasis, high recurrence, and therapy resistance. Early recurrence after surgery is one of the important reasons affecting the prognosis of pancreatic cancer. This study aimed to establish an accurate preoperative nomogram model for predicting early recurrence (ER) for resectable pancreatic adenocarcinoma. We retrospectively analyzed patients who underwent pancreatectomy for pancreatic ductal adenocarcinoma between January 2011 and December 2020. The training set consisted of 604 patients, while the validation set included 222 patients. Survival was estimated using Kaplan-Meier curves. The factors influencing early recurrence of resectable pancreatic cancer after surgery were investigated, then the predictive model for early recurrence was established, and subsequently the predictive model was validated based on the data of the validation group. The preoperative risk factors for ER included a Charlson age-comorbidity index ≥ 4 (odds ratio [OR]: 0.628), tumor size > 3.0 cm on computed tomography (OR: 0.628), presence of clinical symptoms (OR: 0.515), carbohydrate antigen 19-9 > 181.3 U/mL (OR 0.396), and carcinoembryonic antigen > 6.01 (OR: 0.440). The area under the curve (AUC) of the predictive model in the training group was 0.711 (95% confidence interval: 0.669-0.752), while it reached 0.730 (95% CI: 0.663-0.797) in the validation group. The predictive model may enable the prediction of the risk of postoperative ER in patients with resectable pancreatic ductal adenocarcinoma, thereby optimizing preoperative decision-making for effective treatment.

Targeting ESE3/EHF With Nifurtimox Inhibits CXCR2+ Neutrophil Infiltration and Overcomes Pancreatic Cancer Resistance to Chemotherapy and Immunotherapy.

BACKGROUND & AIMS: Because pancreatic cancer responds poorly to chemotherapy and immunotherapy, it is necessary to identify novel targets and compounds to overcome resistance to treatment. METHODS: This study analyzed genomic single nucleotide polymorphism sequencing, single-cell RNA sequencing, and spatial transcriptomics. Ehf-knockout mice, KPC (LSL-KrasG12D/+, LSL-Trp53R172H/+ and Pdx1-Cre) mice, CD45.1+ BALB/C nude mice, and CD34+ humanized mice were also used as subjects. Multiplexed immunohistochemistry and flow cytometry were performed to investigate the proportion of tumor-infiltrated C-X-C motif chemokine receptor 2 (CXCR2)+ neutrophils. In addition, multiplexed cytokines assays and chromatin immunoprecipitation assays were used to examine the mechanism. RESULTS: The TP53 mutation-mediated loss of tumoral EHF increased the recruitment of CXCR2+ neutrophils, modulated their spatial distribution, and further induced chemo- and immunotherapy resistance in clinical cohorts and preclinical syngeneic mice models. Mechanistically, EHF deficiency induced C-X-C motif chemokine ligand 1 (CXCL1) transcription to enhance in vitro and in vivo CXCR2+ neutrophils migration. Moreover, CXCL1 or CXCR2 blockade completely abolished the effect, indicating that EHF regulated CXCR2+ neutrophils migration in a CXCL1-CXCR2-dependent manner. The depletion of CXCR2+ neutrophils also blocked the in vivo effects of EHF deficiency on chemotherapy and immunotherapy resistance. The single-cell RNA-sequencing results of PDAC treated with Nifurtimox highlighted the therapeutic significance of Nifurtimox by elevating the expression of tumoral EHF and decreasing the weightage of CXCL1-CXCR2 pathway within the microenvironment. Importantly, by simultaneously inhibiting the JAK1/STAT1 pathway, it could significantly suppress the recruitment and function of CXCR2+ neutrophils, further sensitizing PDAC to chemotherapy and immunotherapies. CONCLUSIONS: The study demonstrated the role of EHF in the recruitment of CXCR2+ neutrophils and the promising role of Nifurtimox in sensitizing pancreatic cancer to chemotherapy and immunotherapy.

Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability.

Tumor cells must rewire nucleotide synthesis to satisfy the demands of unbridled proliferation. Meanwhile, they exhibit augmented reactive oxygen species (ROS) production which paradoxically damages DNA and free deoxy-ribonucleoside triphosphates (dNTPs). How these metabolic processes are integrated to fuel tumorigenesis remains to be investigated. MYC family oncoproteins coordinate nucleotide synthesis and ROS generation to drive the development of numerous cancers. We herein perform a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based functional screen targeting metabolic genes and identified nudix hydrolase 1 (NUDT1) as a MYC-driven dependency. Mechanistically, MYC orchestrates the balance of two metabolic pathways that act in parallel, the NADPH oxidase 4 (NOX4)-ROS pathway and the Polo like kinase 1 (PLK1)-NUDT1 nucleotide-sanitizing pathway. We describe LC-1-40 as a potent, on-target degrader that depletes NUDT1 in vivo. Administration of LC-1-40 elicits excessive nucleotide oxidation, cytotoxicity and therapeutic responses in patient-derived xenografts. Thus, pharmacological targeting of NUDT1 represents an actionable MYC-driven metabolic liability.

High-dose oxaliplatin induces severe hypersensitivity reactions and high recurrence rates during rechallenge in patients treated with hepatic arterial infusion chemotherapy.

AIM: To analyze the risk factors for oxaliplatin (OXA)-induced severe hypersensitivity reactions and identify the recurrence rate of the reactions after an OXA rechallenge in patients treated with hepatic arterial infusion chemotherapy (HAIC). METHODS: Among the 2251 patients treated with HAIC (OXA), 84 patients with gastrointestinal cancer who displayed hypersensitivity reactions between May 2013 and May 2022 were included in this study. Among the 84 patients, 23 (27.4%) developed severe anaphylactic reactions (grade III/IV), and 61 (72.6%) developed grade I/II reactions. We explored the risk factors for severe OXA-induced hypersensitivity reactions. Twenty-seven patients with grade I/II reactions underwent retreatment (HAIC with OXA), and the recurrence rate of the hypersensitivity reactions was determined. A multivariate logistic regression model was used to analyze the risk factors for OXA-induced hypersensitivity reaction. RESULTS: In the study, multivariate analysis indicated that the dose of OXA (odds ratio [OR] 3.077, 95 % confidence interval [CI] 1.106-8.558, p = 0.031) was an independent risk factor for OXA-induced severe hypersensitivity reactions. Twenty-seven patients with non-severe hypersensitivity reactions underwent retreatment HAIC with OXA and 14 (51.9 %) experienced HSR recurrence, including 2 (7.4 %) who experienced hypersensitivity shock. CONCLUSIONS: The administration of OXA doses is a risk factor for OXA-induced severe hypersensitivity reactions in patients treated with HAIC (OXA). Rechallenging HAIC with OXA appears to be associated with a higher recurrence rate of the HSR.

Role of artificial intelligence in digital pathology for gynecological cancers.

The diagnosis of cancer is typically based on histopathological sections or biopsies on glass slides. Artificial intelligence (AI) approaches have greatly enhanced our ability to extract quantitative information from digital histopathology images as a rapid growth in oncology data. Gynecological cancers are major diseases affecting women's health worldwide. They are characterized by high mortality and poor prognosis, underscoring the critical importance of early detection, treatment, and identification of prognostic factors. This review highlights the various clinical applications of AI in gynecological cancers using digitized histopathology slides. Particularly, deep learning models have shown promise in accurately diagnosing, classifying histopathological subtypes, and predicting treatment response and prognosis. Furthermore, the integration with transcriptomics, proteomics, and other multi-omics techniques can provide valuable insights into the molecular features of diseases. Despite the considerable potential of AI, substantial challenges remain. Further improvements in data acquisition and model optimization are required, and the exploration of broader clinical applications, such as the biomarker discovery, need to be explored.

Efficacy and Safety of HepaSphere Drug-Eluting Bead Transarterial Chemoembolization Combined with Hepatic Arterial Infusion Chemotherapy as the Second-Line Treatment in Advanced Hepatocellular Carcinoma.

Purpose: Recently, hepatic arterial infusion chemotherapy (HAIC) has also gained popularity for hepatocellular carcinoma (HCC). Several studies have compared HAIC and Transarterial chemoembolization (TACE). However, comparisons between TACE plus HAIC and HAIC are rarely reported. Here, we evaluated the performance of HepaSphere DEB-TACE combined with HAIC (Hepa-HAIC) compared to HAIC in patients with advanced HCC. Patients and Methods: In this retrospective study, we enrolled 167 patients diagnosed with advanced HCC and treated at Peking University Cancer Hospital from May 2018 to May 2022. The cohort comprised 74 patients who received HepaSphere DEB-TACE combined with HAIC-FOLFOX (Hepa-HAIC) and 93 patients who received HAIC-FOLFOX. Over 60% of patients received prior treatments. To avoid selection bias, propensity score matching was applied to the efficacy and safety analyses. The primary endpoints are progression-free survival (PFS) and overall survival (OS); the secondary endpoints include objective response rate (ORR), disease control rate (DCR), and safety. Results: Propensity-matching yielded 48 pairs, and group baselines were almost equal after matching. Median PFS and median OS were both higher in the matched Hepa-HAIC cohort (median PFS: 8.9 vs 5.8 months, p = 0.035; median OS: 22.4 vs 9.5 months, p = 0.027), which was consistent with pre-matching analysis. The ORR in the Hepa-HAIC and HAIC cohorts was 75.0% and 37.5%, respectively; the DCR was 93.8% after Hepa-HAIC and 81.3% after HAIC. There was no treatment-related death. Grade 3-4 ALT elevation was more frequent in the Hepa-HAIC group (33.3% vs 8.3%, p = 0.003), while vomiting was more frequent in the HAIC group (29.2% vs 12.5%, p = 0.084). Conclusion: The Hepa-HAIC group is superior to the HAIC group in metrics of PFS, OS, ORR, and DCR, which indicates the combination of HepaSphere DEB-TACE and HAIC may lead to improved outcomes with a comparable safety profile in advanced HCC.

Optimized rat models better mimic patients with irinotecan-induced severe diarrhea.

Irinotecan-induced severe diarrhea (IISD) not only limits irinotecan's application but also significantly affects patients' quality of life. However, existing animal models often inadequately represent the dynamics of IISD development, progression, and resolution across multiple chemotherapy cycles, yielding non-reproducible and highly variable response with limited clinical translation. Our studies aim to establish a reproducible and validated IISD model that better mimics the pathophysiology progression observed in patients, enhancing translational potential. We investigated the impact of dosing regimens (including different dose, infusion time, and two cycles of irinotecan administration), sex, age, tumor-bearing conditions, and irinotecan formulation on the IISD incidence and severity in mice and rats. Lastly, we investigated above factors' impact on pharmacokinetics of irinotecan, intestinal injury, and carboxylesterase activities. In summary, we successfully established a standard model establishment procedure for an optimized IISD model with highly reproducible severe diarrhea incidence rate (100%) and a low mortality rate (11%) in F344 rats. Additionally, the rats tolerated at least two cycles of irinotecan chemotherapy treatment. In contrast, the mouse model exhibited suboptimal IISD incidence rates (60%) and an extremely high mortality rate (100%). Notably, dosing regimen, age and tumor-bearing conditions of animals emerged as critical factors in IISD model establishment. In conclusion, our rat IISD model proves superior in mimicking pathophysiology progression and characteristics of IISD in patients, which stands as an effective tool for mechanism and efficacy studies in future chemotherapy-induced gut toxicity research.

High-Level De Novo Production of (2S)-Eriodictyol in Yarrowia Lipolytica by Metabolic Pathway and NADPH Regeneration Engineering.

(2S)-Eriodictyol, a polyphenolic flavonoid, has found widespread applications in health supplements and food additives. However, the limited availability of plant-derived (2S)-eriodictyol cannot meet the market demand. Microbial production of (2S)-eriodictyol faces challenges, including the low catalytic efficiency of flavone 3'-hydroxylase/cytochrome P450 reductase (F3'H/CPR), insufficient precursor supplementation, and inadequate NADPH regeneration. This study systematically engineered Yarrowia lipolytica for high-level (2S)-eriodictyol production. In doing this, the expression of F3'H/CPR was balanced, and the supply of precursors was enhanced by relieving feedback inhibition of the shikimate pathway, promoting fatty acid ß-oxidation, and increasing the copy number of synthetic pathway genes. These strategies, combined with NADPH regeneration, achieved an (2S)-eriodictyol titer of 423.6 mg/L. Finally, in fed-batch fermentation, a remarkable 6.8 g/L (2S)-eriodictyol was obtained, representing the highest de novo microbial titer reported to date and paving the way for industrial production.

Emerging Role of Interleukin-38 (IL-38) in the Development of Rheumatoid Arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is an incurable autoimmune disease. The role of interleukin-38 (IL-38), an anti-inflammatory cytokine, in RA is not fully understood, and its clinical relevance in RA remains unclear. This study aims to investigate the correlation of IL-38 with disease activity and the clinical manifestation of RA. METHODS: In this cross-sectional study, patients with treatment-naïve RA (n = 63) and healthy controls (HC) (n = 60) were consecutively enrolled over a 15-month period. Patients with RA were categorized into three subgroups-low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA)-using the Disease Activity Score in 28 joints based on C-reactive protein (DAS28-CRP). Circulating levels of IL-38, tumour necrosis factor (TNF), IL-6, IL-17, IL-1ß, and 25(OH)D were assessed using enzyme-linked immunosorbent assay (ELISA). Clinical data, including duration, tender joints count (TJC), swollen joints count (SJC), patient global assessment (PGA), evaluator global assessment (EGA), bone mineral density (BMD), clinical disease activity index (CDAI), simplified disease activity index (SDAI), DAS28-CRP, joint musculoskeletal ultrasound (MSUS), and serological indicators were recorded. We determined the correlation between IL-38 and disease activity, as well as clinical manifestation in RA. RESULTS: At the macroscopic level, musculoskeletal ultrasonography of joints in different stages of disease activity in RA suggests that, as the disease progresses, arthritis in the hand becomes more severe, accompanied by synovial thickening and pronounced blood flow signals in the joint area. The expression of IL-38, TNF, IL-6, IL-17 and IL-1ß significantly increased in patients with RA compared to HC. Noteworthy differences were observed in the blood flow signal score, synovial signal score, IL-38, TNF, IL-6, IL-17 and IL-1ß among the three subgroups (LDA, MDA and HDA). As disease activity increased in patients with RA, the blood flow signal score, synovial signal score and expression of TNF, IL-6, IL-17 and IL-1ß exhibited a gradual increase, while the expression of IL-38 showed the opposite pattern. Inverse correlations were identified between IL-38 and pro-inflammatory cytokines (IL-6, IL-17), as well as key clinical parameters, including disease duration, SJC, TJC and DAS28-CRP score. CONCLUSION: IL-38, intricately linked to the pathogenesis of RA, emerges as a promising therapeutic target for the management of this debilitating disease.

Calcium-sensing receptor and NF-κB pathways in TN breast cancer contribute to cancer-induced cardiomyocyte damage via activating neutrophil extracellular traps formation.

Cardiovascular disorders are commonly prevalent in cancer patients, yet the mechanistic link between them remains poorly understood. Because neutrophil extracellular traps (NETs) have implications not just in cardiovascular diseases (CVD), but also in breast cancer (BC), it was hypothesized to contribute to CVD in the context of oncogenesis. We established a mouse model using nude mice to simulate liver metastasis of triple-negative BC (TNBC) through the injection of MDA-MB-231 cells. Multiple imaging and analysis techniques were employed to assess the cardiac function and structure, including echocardiography, HE staining, Masson staining, and transmission electron microscopy (TEM). MDA-MB-231 cells underwent treatment with a CaSR inhibitor, CaSR agonist, and NF-κB channel blocker. The phosphorylation of NF-κB channel protein p65 and the expression and secretion of IL-8 were assessed using qRT-PCR, Western Blot, and ELISA, respectively. In addition, MDA-MB-231 cells were co-cultured with polymorphonuclear neutrophils (PMN) under varying conditions. The co-localization of PMN extracellular myeloperoxidase (MPO) and DNA were observed by cellular immunofluorescence staining to identify the formation of NETs. Then, the cardiomyocytes were co-cultured with the above medium that contains NETs or not, respectively; the effects of NETs on cardiomyocytes apoptosis were perceived by flow cytometry. The ultrastructural changes of myocardial cells were perceived by TEM, and ELISA detected the levels of myocardial enzyme (LDH, MDA and SOD). Overall, according to our research, CaSR has been found to have a regulatory role in IL-8 secretion in MDA-MB-231 cells, as well as in the formation of NETs by PMN cells. These findings suggest CaSR-mediated stimulation in PMN can lead to increased NETs formation and subsequently to cytotoxicity in cardiomyocytes, which potentially via activation of the NF-κB signaling cascade of BC cell.

Tumor-derived interleukin 35 mediates the dissemination of gemcitabine resistance in pancreatic adenocarcinoma.

Rapid development of drug resistance after chemotherapy is a major cause of treatment failure in individuals with pancreatic ductal adenocarcinoma (PDAC). In this study, we illustrate that tumor-derived interleukin 35 (IL-35) mediates the accelerated resistance of PDAC to gemcitabine (GEM). We observe that GEM resistance can spread from GEM-resistant PDAC cells to GEM-sensitive cells, and that IL-35 is responsible for the propagation of chemoresistance, which is supported by sequencing and experimental data. Additionally, we discover that GEM-resistant cells have significantly higher levels of IL-35 expression. Mechanistically, aberrantly expressed IL-35 triggers transcriptional activation of SOD2 expression via GP130-STAT1 signaling, scavenging reactive oxygen species (ROS) and leading to GEM resistance. Furthermore, GEM treatment stimulates IL-35 expression through activation of the NF-κB pathway, resulting in acquired chemoresistance. In the mouse model, a neutralizing antibody against IL-35 enhances the tumor suppressive effect of GEM. Collectively, our data suggests that IL-35 is critical in mediating GEM resistance in pancreatic cancer, and therefore could be a valuable therapeutic target in overcoming PDAC chemoresistance.

Aurora kinase A-mediated phosphorylation triggers structural alteration of Rab1A to enhance ER complexity during mitosis.

Morphological rearrangement of the endoplasmic reticulum (ER) is critical for metazoan mitosis. Yet, how the ER is remodeled by the mitotic signaling remains unclear. Here, we report that mitotic Aurora kinase A (AURKA) employs a small GTPase, Rab1A, to direct ER remodeling. During mitosis, AURKA phosphorylates Rab1A at Thr75. Structural analysis demonstrates that Thr75 phosphorylation renders Rab1A in a constantly active state by preventing interaction with GDP-dissociation inhibitor (GDI). Activated Rab1A is retained on the ER and induces the oligomerization of ER-shaping protein RTNs and REEPs, eventually triggering an increase of ER complexity. In various models, from Caenorhabditis elegans and Drosophila to mammals, inhibition of Rab1AThr75 phosphorylation by genetic modifications disrupts ER remodeling. Thus, our study reveals an evolutionarily conserved mechanism explaining how mitotic kinase controls ER remodeling and uncovers a critical function of Rab GTPases in metaphase.

Hydrophilic Peptide and Glycopeptide as Immobilized Sorbents for Glycosylation Analysis.

Hydrophilic interaction liquid chromatography (HILIC) is widely used for glycopeptide enrichment in shot-gun glycoproteomics to enhance the glycopeptide signal and minimize the ionization competition of peptides. In this work, we have developed a novel hydrophilic material (glycoHILIC) based on glycopeptides and peptides to provide hydrophilic properties. GlycoHILIC was synthesized by oxidizing cotton and then reacting the resulting aldehyde with the N-terminus of the glycopeptide or peptide by reductive amination. Due to the large amount of hydrophilic carbohydrates and hydrophilic amino acids contained in glycopeptides, glycoHILIC showed significantly better enrichment of glycopeptides than cotton itself. Our results demonstrate that glycoHILIC has high selectivity, a low detection limit, and good stability. Over 257 unique N-linked glycosylation sites in 1477 intact N-glycopeptides from 146 glycoproteins were identified from 1 µL of human serum using glycoHILIC. Serum analysis of pancreatic cancer patients found that 38 N-glycopeptides among 21 glycoproteins changed significantly, of which 7 N-glycopeptides increased and 31 N-glycopeptides decreased. These results demonstrate that glycoHILIC can be used for glycopeptide enrichment and analysis.

Prognostic significance of grade of malignancy based on histopathological differentiation and Ki-67 in pancreatic ductal adenocarcinoma.

OBJECTIVE: Tumor cell malignancy is indicated by histopathological differentiation and cell proliferation. Ki-67, an indicator of cellular proliferation, has been used for tumor grading and classification in breast cancer and neuroendocrine tumors. However, its prognostic significance in pancreatic ductal adenocarcinoma (PDAC) remains uncertain. METHODS: Patients who underwent radical pancreatectomy for PDAC were retrospectively enrolled, and relevant prognostic factors were examined. Grade of malignancy (GOM), a novel index based on histopathological differentiation and Ki-67, is proposed, and its clinical significance was evaluated. RESULTS: The optimal threshold for Ki-67 was determined to be 30%. Patients with a Ki-67 expression level > 30% rather than ≤ 30% had significantly shorter 5-year overall survival (OS) and recurrence-free survival (RFS). In multivariate analysis, both histopathological differentiation and Ki-67 were identified as independent prognostic factors for OS and RFS. The GOM was used to independently stratify OS and RFS into 3 tiers, regardless of TNM stage and other established prognostic factors. The tumor-node-metastasis-GOM stage was used to stratify survival into 5 distinct tiers, and surpassed the predictive performance of TNM stage for OS and RFS. CONCLUSIONS: Ki-67 is a valuable prognostic indicator for PDAC. Inclusion of the GOM in the TNM staging system may potentially enhance prognostic accuracy for PDAC.