Targeting tumor cell-to-macrophage communication by blocking Vtn-C1qbp interaction inhibits tumor progression via enhancing macrophage phagocytosis.

Background: Cancer cells are capable of evading clearance by macrophages through overexpression of anti-phagocytic surface proteins known as "don't eat me" signals. Monoclonal antibodies that antagonize the "don't-eat-me" signaling in macrophages and tumor cells by targeting phagocytic checkpoints have shown therapeutic promises in several cancer types. However, studies on the responses to these drugs have revealed the existence of other unknown "don't eat me" signals. Moreover, identification of key molecules and interactions regulating macrophage phagocytosis is required for tumor therapy. Methods: CRISPR screen was used to identify genes that impede macrophage phagocytosis. To explore the function of Vtn and C1qbp in phagocytosis, knockdown and subsequent functional experiments were conducted. Flow cytometry were performed to explore the phagocytosis rate, polarization of macrophage, and immune microenvironment of mouse tumor. To explore the underlying molecular mechanisms, RNA sequencing, immunoprecipitation, mass spectrometry, and immunofluorescence were conducted. Then, in vivo experiments in mouse models were conducted to explore the probability of Vtn knockdown combined with anti-CD47 therapy in breast cancer. Single-cell sequencing data from the Gene Expression Omnibus from The Cancer Genome Atlas database were analyzed. Results: We performed a genome-wide CRISPR screen to identify genes that impede macrophage phagocytosis, followed by analysis of cell-to-cell interaction databases. We identified a ligand-receptor pair of Vitronectin (Vtn) and complement C1Q binding protein (C1qbp) in tumor cells or macrophages, respectively. We demonstrated tumor cell-secreted Vtn interacts with C1qbp localized on the cell surface of tumor-associated macrophages, inhibiting phagocytosis of tumor cells and shifting macrophages towards the M2-like subtype in the tumor microenvironment. Mechanistically, the Vtn-C1qbp axis facilitated FcγRIIIA/CD16-induced Shp1 recruitment, which reduced the phosphorylation of Syk. Furthermore, the combination of Vtn knockdown and anti-CD47 antibody effectively enhanced phagocytosis and infiltration of macrophages, resulting in a reduction of tumor growth in vivo. Conclusions: This work has revealed that the Vtn-C1qbp axis is a new anti-phagocytic signal in tumors, and targeting Vtn and its interaction with C1qbp may sensitize cancer to immunotherapy, providing a new molecular target for the treatment of triple-negative breast cancer.

A multicenter retrospective study of transurethral prostate split for benign prostate hyperplasia.

Background: Transurethral split of the prostate (TUSP) is effective in treating benign prostatic hyperplasia (BPH). However, there is still a lack of research focusing on the optimal target population for TUSP. This study aimed to compare the efficacy of TUSP in patients with different prostate volumes or ages. Methods: The study was a multicenter retrospective study. The outcomes of TUSP in BPH patients with different prostate volumes or different ages were compared. A total of 439 patients were included in the study. Patients were divided into two groups according to prostate volume, with a cut-off value of 50 mL. Similarly, the cut-off value for the age groups was 70 years. Baseline patient characteristics and perioperative outcomes were recorded. Follow-up was performed at 1, 6, and 12 months after surgery. Results: The mean age of the patients was 73.4 years, and the mean prostate volume was 51.2 mL. At 12-month follow-up after TUSP treatment, the patients' International Prostate Symptom Scores (IPSS), quality of life (QoL) scores, and postvoid residual (PVR) volumes decreased significantly, while peak urinary flow rate (Qmax) increased significantly. Intraoperative hemoglobin (Hb) reduction was significantly lower in the small volume group than in the large volume group. The incidence of postoperative urinary urgency and transient incontinence was lower in the small volume group. IPSS score, PVR, and Qmax in the small volume group showed more remarkable changes at several time points compared to the preoperative period. Postoperative pain scores were higher in the small volume group than in the large volume group. There were no differences between the two groups in terms of long-term complications. The younger group showed greater variation in PVR and Qmax at some time points but less variation in QoL than the older group. Conclusions: TUSP is overall safe and effective in treating BPH. This study showed differences in the outcomes of TUSP in treating different prostate volumes or ages of BPH patients. The optimal surgical approach for BPH patients might be selected clinically based on a combination of prostate volume or patient age.

Identification of proteomic markers for prediction of the response to 5-Fluorouracil based neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) prior to surgery is the standard treatment for patients with locally advanced rectal cancer (LARC), while parts of them show poor therapeutic response accompanied by therapy adverse effects. Predictive biomarkers for nCRT response could facilitate the guidance on treatment decisions but are still insufficient until now, which limits the clinical applications of nCRT in LARC patients. METHODS: In our study, 37 formalin-fixed paraffin-embedded tumor biopsies were obtained from patients with LARC before receiving 5-fluorouracil based nCRT. Proteomics analyses were conducted to identify the differentially expressed proteins (DEPs) between total responders (TR) and poor responders (PR). The DEPs were validated via ROC plotter web tool and their predictive performance was evaluated by receiver operating characteristic analysis. Functional enrichment analyses were performed to further explore the potential mechanisms underlying nCRT response. RESULTS: Among 3,998 total proteins, 91 DEPs between TR and PR were screened out. HSPA4, NIPSNAP1, and SPTB all with areas under the curve (AUC) ~ 0.8 in the internal discovery cohort were independently validated by the external mRNA datasets (AUC ~ 0.7), and their protein levels were linearly correlated with the graded responses to nCRT in the internal cohort. The combination of HSPA4 and SPTB could distinctly discriminate the TR and PR groups (AUC = 0.980, p < 0.0001). Moreover, multiple combinations of the three proteins realized increased specificity and/or sensitivity, while achieving favorable predictive value when moderate responders were introduced into the ROC analysis. Pathways including DNA damage repair, cell cycle, and epithelial mesenchymal transition were involved in nCRT response according to the enrichment analysis results. CONCLUSIONS: HSPA4, SPTB and NIPSNAP1 in tumor biopsies and/or their optional combinations might be potential predictive markers for nCRT response in patients with LARC. The DEPs and their related functions have implications for the potential mechanisms of treatment response to nCRT in patients with LARC.

Systematic study on expression and prognosis of E2Fs in human colorectal cancer.

BACKGROUND: E2Fs are important components of transcription factors and play key roles in occurrence or advancement of various cancers, but the expression and exact roles of each E2F in colorectal cancer (CRC) are rarely known. METHODS: To address this issue, we investigated the roles and prognostic values of E2Fs expressions in CRC patients by searching ONCOMINE, cBioPortal, GEPIA, Matascape and UALCAN. RESULTS: E2F1, 3-8 were upregulated at the mRNA level and E2F2 was less expressed in CRC tissues than in normal tissues. The eight E2Fs were correlated with tumor stages of CRC. Survival analysis using GEPIA revealed that high expressions of E2F3, 4 were related with short overall survival in all CRC patients. The mutation rate of E2Fs (60%) was high and genetic alteration in E2Fs was linked with longer overall survival in CRC patients. Functional analysis implied that E2Fs and their 50 nearby genes were concentrated in tumor-related pathways. CONCLUSIONS: E2Fs may be candidate biomarkers for CRC diagnosis and E2F3, 4 are potential prognosis biomarkers of CRC. Nevertheless, our findings must be validated in the future to popularize the clinical application of E2Fs in CRC.

Molecular mechanisms and therapeutic relevance of gasdermin E in human diseases.

Gasdermin E (GSDME) is one of the main members of the GSDM family and is originally involved in hereditary hearing loss. Recent studies have reported that GSDME expression is epigenetically silenced by methylation in several common tumours, thereby enhancing tumour proliferation and metastasis. GSDME is also downregulated in cancer tissues compared with normal tissues, which suggests that GSDME can be considered a tumour suppressor. Furthermore, GSDME is the effector protein of caspase-3 and granzyme B in pyroptosis, and it plays a significant role in innate immunity, tissue damage, cancer, and hearing loss, thus revealing potential novel therapeutic avenues. A great deal of evidence reveals that GSDME can be implemented as a biomarker in cancer diagnosis and monitoring, chemotherapy, immunotherapy, and chemoresistance. Based on the current knowledge of GSDME, this review is focussed on its mechanism of action and the most recent advances in its role in cancer and normal physiology.

Targeting Reactive Oxygen Species Capacity of Tumor Cells with Repurposed Drug as an Anticancer Therapy.

Accumulating evidence shows that elevated levels of reactive oxygen species (ROS) are associated with cancer initiation, growth, and response to therapies. As concentrations increase, ROS influence cancer development in a paradoxical way, either triggering tumorigenesis and supporting the proliferation of cancer cells at moderate levels of ROS or causing cancer cell death at high levels of ROS. Thus, ROS can be considered an attractive target for therapy of cancer and two apparently contradictory but virtually complementary therapeutic strategies for the regulation of ROS to treat cancer. Despite tremendous resources being invested in prevention and treatment for cancer, cancer remains a leading cause of human deaths and brings a heavy burden to humans worldwide. Chemotherapy remains the key treatment for cancer therapy, but it produces harmful side effects. Meanwhile, the process of de novo development of new anticancer drugs generally needs increasing cost, long development cycle, and high risk of failure. The use of ROS-based repurposed drugs may be one of the promising ways to overcome current cancer treatment challenges. In this review, we briefly introduce the source and regulation of ROS and then focus on the status of repurposed drugs based on ROS regulation for cancer therapy and propose the challenges and direction of ROS-mediated cancer treatment.

Atomic-scale regulation of anionic and cationic migration in alkali metal batteries.

The regulation of anions and cations at the atomic scale is of great significance in membrane-based separation technologies. Ionic transport regulation techniques could also play a crucial role in developing high-performance alkali metal batteries such as alkali metal-sulfur and alkali metal-selenium batteries, which suffer from the non-uniform transport of alkali metal ions (e.g., Li+ or Na+) and detrimental shuttling effect of polysulfide/polyselenide anions. These drawbacks could cause unfavourable growth of alkali metal depositions at the metal electrode and irreversible consumption of cathode active materials, leading to capacity decay and short cycling life. Herein, we propose the use of a polypropylene separator coated with negatively charged Ti0.87O2 nanosheets with Ti atomic vacancies to tackle these issues. In particular, we demonstrate that the electrostatic interactions between the negatively charged Ti0.87O2 nanosheets and polysulfide/polyselenide anions reduce the shuttling effect. Moreover, the Ti0.87O2-coated separator regulates the migration of alkali ions ensuring a homogeneous ion flux and the Ti vacancies, acting as sub-nanometric pores, promote fast alkali-ion diffusion.

Constructing Atomic Heterometallic Sites in Ultrathin Nickel-Incorporated Cobalt Phosphide Nanosheets via a Boron-Assisted Strategy for Highly Efficient Water Splitting.

Identification of active sites for highly efficient catalysts at the atomic scale for water splitting is still a great challenge. Herein, we fabricate ultrathin nickel-incorporated cobalt phosphide porous nanosheets (Ni-CoP) featuring an atomic heterometallic site (NiCo16-xP6) via a boron-assisted method. The presence of boron induces a release-and-oxidation mechanism, resulting in the gradual exfoliation of hydroxide nanosheets. After a subsequent phosphorization process, the resultant Ni-CoP nanosheets are implanted with unsaturated atomic heterometallic NiCo16-xP6 sites (with Co vacancies) for alkaline hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). The optimized Ni-CoP exhibits a low overpotential of 88 and 290 mV at 10 mA cm-2 for alkaline HER and OER, respectively. This can be attributed to reduced free energy barriers, owing to the direct influence of center Ni atoms to the adjacent Co/P atoms in NiCo16-xP6 sites. These provide fundamental insights on the correlation between atomic structures and catalytic activity.

Mechanism and regulation of pyroptosis-mediated in cancer cell death.

Pyroptosis, a form of programmed cell death, has garnered increasing attention as it relates to innate immunity and diseases. The discovery of caspase-1/3/4/5/8/11 function in sensing various challenges expands the spectrum of pyroptosis mediators and also reveals that pyroptosis is not cell type specific. Recent studies have identified that pyroptosis has become a new topic in cancer research because it may affect all stages of carcinogenesis. In this mini-review, we provided a primer on pyroptosis, discussed the induction of pyroptosis in cancer and its implications in cancer management. Moreover, its two important executioners, the gasdermin D (GSDMD) and gasdermin E (GSDME), the functions and mechanisms of them involved in the regulation of cancer therapy were focused on. Small molecules-mediated pyroptosis were found to effectively inhibit various tumor cells. In brief, the findings of pyroptosis-dependent cancer progression, new drugs and therapeutic targets may lead to a promising, novel therapeutic approach for cancer patients.

Analysis of Risk Factors and Clinical Indicators in Bloodstream Infections Among Patients with Hematological Malignancy.

PURPOSE: The incidence of bloodstream infection (BSI) is more common in patients with hematological malignancy. It is important to distinguish infectious episodes from noninfectious episodes. The present study was aimed to describe the epidemiology, clinical indexes, and antibiotic use for in-hospital bloodstream infections of hematological malignancy patients. PATIENTS AND METHODS: Single-center retrospective research was performed on hematological malignancy patients admitted to our hospital from July 2015 to March 2018. Laboratory and clinical information from 322 febrile patients were acquired. These episodes were divided by blood culture results into two groups: 1) blood culture positive-group, 2) blood culture negative-group. RESULTS: In the 322 febrile cases, 81 (25.2%) patients were blood culture positive, and among them, Gram-negative (G-) bacteria (51.9%) were more isolated than Gram-positive (G+) bacteria (32.1%) and fungi (7.4%). Gram-negative bacteria were more likely to have drug resistance than G+ bacteria. Independent risk factors revealed that patients with complications, high levels of procalcitonin (PCT), glucose, interleukin-6 (IL-6), and d-dimer (D-D), and low concentration of albumin were correlated with the occurrence of BSI. PCT, IL-6 and D-D performed well in differentiating the positive group from the negative group. Moreover, IL-6 and D-D showed excellent performance in differentiating G- and G+ groups, with the areas under the curve all above 0.8. CONCLUSION: We analyzed the risk factors for BSI in patients with hematological malignancy, the distribution of bacteria, antibiotic resistance, and the changes in clinical parameters. This single-center retrospective study may provide clinicians insight into the diagnosis and treatment of BSI.

Carrot intake and incidence of urothelial cancer: a systematic review and meta-analysis.

Previous studies regarding the relationship between carrot intake and risk of urothelial cancer have reported conflicting results. Hence we performed a meta-analysis of eligible studies to summarize evidence on this association. A comprehensive search up to January 2017 was performed in PubMed, Web of Science, Scopus, EMBASE, Cochrane register, and Chinese National Knowledge Infrastructure (CNKI) databases. The combined odds ratio (OR) with 95% confidence interval (CI) for the highest versus the lowest intake of carrot was calculated. A total of six epidemiological studies consisting of four case-control and two cohort studies were included. Overall analysis indicated a significantly reduced risk of urothelial cancer for high intake of carrot (OR = 0.63, 95% CI 0.44-0.90). Obvious significant heterogeneity was observed among included studies (P < 0.001 for heterogeneity; I2 = 79.6%). There was no significant publication bias by Begg's test (P = 0.348) or Egger's test (P = 0.130). In conclusion, this meta-analysis indicates that high intake of carrot is associated with a low incidence of urothelial cancer. Considering the limited included studies and huge heterogeneity, further large well-designed prospective cohort studies are warranted to confirm the findings from our meta-analysis.

Radiomic analysis reveals DCE-MRI features for prediction of molecular subtypes of breast cancer.

The purpose of this study was to investigate the role of features derived from breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and to incorporated clinical information to predict the molecular subtypes of breast cancer. In particular, 60 breast cancers with the following four molecular subtypes were analyzed: luminal A, luminal B, human epidermal growth factor receptor-2 (HER2)-over-expressing and basal-like. The breast region was segmented and the suspicious tumor was depicted on sequentially scanned MR images from each case. In total, 90 features were obtained, including 88 imaging features related to morphology and texture as well as dynamic features from tumor and background parenchymal enhancement (BPE) and 2 clinical information-based parameters, namely, age and menopausal status. An evolutionary algorithm was used to select an optimal subset of features for classification. Using these features, we trained a multi-class logistic regression classifier that calculated the area under the receiver operating characteristic curve (AUC). The results of a prediction model using 24 selected features showed high overall classification performance, with an AUC value of 0.869. The predictive model discriminated among the luminal A, luminal B, HER2 and basal-like subtypes, with AUC values of 0.867, 0.786, 0.888 and 0.923, respectively. An additional independent dataset with 36 patients was utilized to validate the results. A similar classification analysis of the validation dataset showed an AUC of 0.872 using 15 image features, 10 of which were identical to those from the first cohort. We identified clinical information and 3D imaging features from DCE-MRI as candidate biomarkers for discriminating among four molecular subtypes of breast cancer.

Highly unsaturated binuclear butadiene iron carbonyls: quintet spin states, perpendicular structures, agostic hydrogen atoms, and iron-iron multiple bonds.

The highly unsaturated binuclear butadiene iron carbonyls (C(4)H(6))(2)Fe(2)(CO)(n) (n = 2, 1) have been examined using density functional theory. For (C(4)H(6))(2)Fe(2)(CO)(n) (n = 2, 1), both coaxial and perpendicular structures are found. The global minima of (C(4)H(6))(2)Fe(2)(CO)(n) (n = 2, 1) are the perpendicular structures 2Q-1 and 1Q-1, respectively, with 17- and 15-electron configurations for the iron atoms leading to quintet spin states. The Fe=Fe distance of 2.361 Å (M06-L) in the (C(4)H(6))(2)Fe(2)(CO)(2) structure 2Q-1 suggests a formal double bond. The Fe≡Fe bond distance in the (C(4)H(6))(2)Fe(2)(CO) structure 1Q-1 is even shorter at 2.273 Å (M06-L), suggesting a triple bond. Higher energy (C(4)H(6))(2)Fe(2)(CO)(n) (n = 2, 1) structures include structures in which a bridging butadiene ligand is bonded to one of the iron atoms as a tetrahapto ligand and to the other iron atom through two agostic hydrogen atoms from the end CH(2) groups. Singlet (C(4)H(6))(2)Fe(2)(CO) structures with formal Fe-Fe quadruple bonds of lengths ∼2.05 Å were also found but at very high energies (∼47 kcal/mol) relative to the global minimum.