The treatment process of a giant phyllodes tumor of the breast: a case report and review of the literature.

Giant phyllodes tumors are rare fibroepithelial tumors that are usually larger than 10 cm in diameter, have rapid tumor growth, and are easily recurrent. They are frequently accompanied by skin necrosis and infection, particularly in malignant phyllodes tumors. This case report presents a 50-year-old woman who presented to the hospital with a huge left breast mass that was ruptured and infected. The patient received anti-infective treatment and underwent mastectomy and skin grafting, which indicated a malignant phyllodes tumor. The tumor was completely excised after a local recurrence in the chest wall 6 months post-surgery. Unfortunately, one year later, the patient pass away due to multiple organ failure. Giant phyllodes tumor management presents challenges to the surgeon. This case is being presented to enhance understanding and treatment of phyllodes tumors, specifically giant malignant phyllodes tumors, with the aim of improving patients' quality of life.

Supportive Care Needs of Patients With Temporary Ostomy in Enhanced Recovery After Surgery: A Mixed-Methods Study.

BACKGROUND: Enhanced recovery after surgery (ERAS), a global surgical quality improvement initiative, reduces the length of stay in the hospital. Temporary stoma care for rectal cancer is complex, and patients require prolonged care services to adjust to the stoma. The shorter stay durations in the new model challenge the conventional care pathways and create new patient needs. PURPOSE: This study was designed to explore the supportive care needs of patients under the new surgical model to provide a reference for the design of ERAS nursing care plans. METHODS: A convergent parallel mixed-methods design was used in this study. Patients with temporary stomas for rectal cancer were recruited using a convenience sampling method in gastrointestinal surgery wards and wound & stoma clinics in two public tertiary care hospitals in China. Standardized questionnaires were administered to 140 patients to collect quantitative data, and semistructured interviews were conducted individually with 13 patients to collect qualitative data. The questionnaire data were analyzed using descriptive statistics, and the interview data were analyzed using thematic analysis. RESULTS: "Health system and information needs" and "care and support needs" were identified in both the qualitative and quantitative analyses as the most significant unmet needs of the participants. In addition, the qualitative analysis identified receiving focused stoma care instructions and easily understandable information as essential to fulfilling health system and information needs. Care and support needs included access to continued postdischarge services and attention from medical professionals. CONCLUSION/IMPLICATIONS FOR PRACTICE: The participants in this study experienced a variety of unmet supportive care needs under the ERAS protocol, with gaps particularly notable in two categories: "health system and information needs" and "care and support needs." Increased perioperative care and shorter hospital stays under the ERAS protocol reduce opportunities for patients to receive targeted instruction and shift much of the ostomy education and care workload out of the hospital, requiring greater attention from clinical nurses to ensure quality of care.

Identification of the succinate-CoA ligase protein gene family reveals that TaSUCL1-1 positively regulate cadmium resistance in wheat.

The Succinate-CoA ligase (SUCL1) gene family is involved in energy metabolism, phytohormone signaling, and plant growth, development, and tolerance to stress. This is the first study to analyze the SUCL1 gene family in wheat (Triticum aestivum). 17 TaSUCL1 genes were identified in the complete genome sequence and classified into five subfamilies based on related genes found in three other species. The 17 TaSUCL1 genes were unevenly distributed across 11 chromosomes, and the collinearity of these genes was further investigated. Through using real-time qPCR (RT-qPCR) analysis, we identified the expression patterns of the TaSUCL1 genes under various tissues and different heavy metal stress conditions. The functions of selected TaSUCL1-1 gene were investigated by RNA interference (RNAi). This study provided a comprehensive analysis of the TaSUCL1 gene family. Within the TaSUCL1 genes, the exon-intron structure and motif composition exhibited significant similarity among members of the same evolutionary branch. Homology analysis and phylogenetic comparison of the SUCL1 genes in different plants offered valuable insights for studying the evolutionary characteristics of the SUCL1 genes. The expression levels of the TaSUCL1 genes in different tissues and under various metal stress conditions reveal its important role in plant growth and development. Gene function analysis demonstrated that TaSUCL1-1 silenced wheat plants exhibited a decrease in the total cadmium (Cd) concentrations and gene expression levels compared to the wild type (WT). Additionally, TaSUCL1-1 belonging to class c physically interacts with the ß-amylase protein TaBMY1 as verified by yeast two-hybridization. This research provides a useful resource for further study of the function and molecular genetic mechanism of the SUCL1 gene family members.

A novel prognostic risk-scoring system based on m5C methylation regulator-mediated patterns for glioma patients.

N5-methylcytosine (m5C) methylation modification plays a crucial role in the epigenetic mechanisms underlying tumorigenesis, aggressiveness, and malignancy in diffuse glioma. Our study aimed to develop a novel prognostic risk-scoring system to assess the impact of m5C modification in glioma patients. Initially, we identified two distinct m5C clusters based on the expression level of m5C regulators in The Cancer Genome Atlas glioblastoma (TCGA-GBM) dataset. Differentially expressed genes (DEGs) between the two m5C cluster groups were determined. Utilizing these m5C regulation-related DEGs, we classified glioma patients into three gene cluster groups: A, B, and C. Subsequently, an m5C scoring system was developed through a univariate Cox regression model, quantifying the m5C modification patterns utilizing six DEGs associated with disease prognosis. The resulting scoring system allowed us to categorize patients into high- or low-risk groups based on their m5C scores. In test (TCGA-GBM) and validation (Chinese Glioma Genome Atlas [CGGA]-1018 and CGGA-301) datasets, glioma patients with a higher m5C score consistently exhibited shorter survival durations, fewer isocitrate dehydrogenase (IDH) mutations, less 1p/19q codeletion and higher World Health Organization (WHO) grades. Additionally, distinct immune cell infiltration characteristics were observed among different m5C cluster groups and risk groups. Our study developed a novel prognostic scoring system based on m5C modification patterns for glioma patients, complementing existing molecular classifications and providing valuable insights into prognosis for glioma patients.

Analysis of complete hydatidiform mole in one twin using traditional and molecular techniques.

A pregnant woman with hydatidiform mole in one twin was misdiagnosed as one of the twins with embryonic arrest. She chose to terminate the pregnancy and developed distant lung metastasis. After chemotherapy, she eventually recovered. This article systematically analyzes the diagnosis and treatment of hydatidiform mole in one twin to increase the awareness and reduce misdiagnosis of the disease.

Nickel Nanoparticles Protruding from Molybdenum Carbide Micropillars with Carbon Layer-Protected Biphasic 0D/1D Heterostructures for Efficient Water Splitting.

It remains a tremendous challenge to achieve high-efficiency bifunctional electrocatalysts for both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) for hydrogen production by water splitting. Herein, a novel hybrid of 0D nickel nanoparticles dispersed on the one-dimensional (1D) molybdenum carbide micropillars embedded in the carbon layers (Ni/Mo2C@C) was successfully prepared on nickel foam by a facile pyrolysis strategy. During the synthesis process, the nickel nanoparticles and molybdenum carbide were simultaneously generated under H2 and C2H2 mixed atmospheres and conformally encapsulated in the carbon layers. Benefiting from the distinctive 0D/1D heterostructure and the synergistic effect of the biphasic Mo2C and Ni together with the protective effect of the carbon layer, the reduced activation energy barriers and fast catalytic reaction kinetics can be achieved, resulting in a small overpotential of 96 mV for the HER and 266 mV for the OER at the current density of 10 mA cm-2 together with excellent durability in 1.0 M KOH electrolyte. In addition, using the developed Ni/Mo2C@C as both the cathode and anode, the constructed electrolyzer exhibits a small voltage of 1.55 V for the overall water splitting. The novel designed Ni/Mo2C@C may give inspiration for the development of efficient bifunctional catalysts with low-cost transition metal elements for water splitting.

MMP-2 Responsive Peptide Hydrogel-Based Nanoplatform for Multimodal Tumor Therapy.

Introduction: Responsive drug delivery systems hold great promise for tumor treatment as they focus on therapeutic agents directly, thus minimizing systemic toxicities and drug leakage. In this study, we covalently bound a matrix metalloproteinases-2 (MMP-2) enzyme-sensitive peptide to a tissue-penetrating peptide to rationally design a MMP-2 responsive multifunctional peptide hydrogel platform (aP/IR@FMKB) for cancer photothermal-chemo-immunotherapy. The constructed aP/IR@FMKB with bufalin (BF) loaded in trimethyl chitosan nanoparticles (TB NPs), photothermal agent IR820, and immune checkpoint inhibitor aPD-L1 by self-assembly could be dissociated in the presence of MMP-2 enzyme, triggering content release. Methods: TB NPs, IR820, and aPD-L1 were encapsulated by intermolecular self-assembly and enzyme-sensitive nanogels (aP/IR@FMKB) were constructed. The in vitro cytotoxicity of the blank gels and their ability to induce immunogenic cell death (ICD) in aP/IR@FMKB were evaluated using 4T1 cells. The promotion of deep tumor penetration and enzyme responsiveness was analyzed using a 3D cell model. The retention and antitumor activity at the tumor sites were examined using the primary tumor model. To assess the antitumor effect of aP/IR@FMKB induced by the immune response and its mechanism of action, recurrent tumor and distal tumor models were constructed. Results: This hydrogel system demonstrated exceptional photothermal performance and displayed prolonged local retention. Furthermore, the induction of ICD through IR820 and TB NPs sensitized the PD-L1 blockade, resulting in a remarkable 3.5-fold and 5.2-fold increase in the frequency of intratumor-infiltrating CD8+ T-cells in the primary tumor and distal tumor, respectively. Additionally, this system demonstrated remarkable efficacy in suppressing primary, distal, and recurrent tumors, underscoring its potential as a highly potent therapeutic strategy. Conclusion: This innovative design of the responsive hydrogel can effectively modulate the tumor immune microenvironment while also demonstrating sensitivity to the PD-1/PD-L1 blockade. This significant finding highlights the promising potential of this hydrogel in the field of multimodal tumor therapy.

UCA1 Inhibits NKG2D-mediated Cytotoxicity of NK Cells to Breast Cancer.

BACKGROUND: Natural killer cells play important roles in tumor immune surveillance, and cancer cells must resist this surveillance in order to progress and metastasise. INTRODUCTION: The study aimed to explore the mechanism of how breast cancer cells become resistant to the cytotoxicity of NK cells. METHODS: We established NK-resistant breast cancer cells by exposing MDA-MB-231 cells and MCF-7 cells to NK92 cells. Profiles of lncRNA were compared between the NK-resistant and parental cell lines. Primary NK cells were isolated by MACS, and the NK attacking effect was tested by non-radioactive cytotoxicity. The change in lncRNAs was analyzed by Gene-chip. The interaction between lncRNA and miRNA was displayed by Luciferase assay. The regulation of the gene was verified by QRT-PCR and WB. The clinical indicators were detected by ISH, IH, and ELISA, respectively. RESULTS: UCA1 was found to be significantly up-regulated in both NK-resistant cell lines, and we confirmed such up-regulation on its own to be sufficient to render parental cell lines resistant to NK92 cells. We found that UCA1 up-regulated ULBP2 via the transcription factor CREB1, while it up-regulated ADAM17 by "sponging" the miR-26b-5p. ADAM17 facilitated the shedding of soluble ULBP2 from the surface of breast cancer cells, rendering them resistant to killing by NK cells. UCA1, ADAM17, and ULBP2 were found to be expressed at higher levels in bone metastases of breast cancer than in primary tumors. CONCLUSION: Our data strongly suggest that UCA1 up-regulates ULBP2 expression and shedding, rendering breast cancer cells resistant to killing by NK cells.

Knowledge, attitudes, practices and associated factors regarding high output stoma of ileostomy among colorectal surgical nurses: a multicentre cross-sectional study.

PURPOSE: High output stoma(HOS) is one of the most common complications after ileostomy, leading to fluid and electrolyte disturbances and renal dysfunction, and increasing the risk of readmission. Routine health education for HOS should be provided, and nurses, as the primary educators, should have adequate knowledge and skills in this area. However, there is a paucity of research on the knowledge and practice of HOS management. This study used the Knowledge, Attitude and Behavioural Practice Model to assess the management of HOS by colorectal surgery nurses and to explore the factors that influence it. METHOD: Using a multi-centre, cross-sectional study design, 398 colorectal surgery nurses from 6 hospitals in 6 cities in 6 provinces were surveyed using a structured electronic questionnaire to assess general information and knowledge, attitudes and management practices and training needs related to HOS of ileostomy. RESULTS: Colorectal surgery nurses' knowledge and practice of HOS was low. The presence or absence of training is an important factor influencing nurses' knowledge, attitudes and practice, with most nurses having no training and stoma specialist nurses scoring relatively high on knowledge and practice. CONCLUSIONS: Nurses play a very important role in the management of HOS, but this study shows that the current level of knowledge and practice of HOS among colorectal surgery nurses is concerning, and whether or not they have received training is the most critical influencing factor; therefore, training related to HOS is urgently needed.

Dry suction versus wet suction technique of endoscopic ultrasound-guided fine-needle biopsy for diagnosis of solid pancreatic lesions: study protocol of a multicenter randomized controlled non-inferiority trial.

BACKGROUND: Studies have shown that the wet suction technique in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) generates better histological diagnostic accuracy and specimen quality than the dry suction technique. However, conclusions of wet suction on the diagnostic accuracy of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) are still controversial. Besides, the optimal number of passes for EUS-FNB has not been determined. We aimed to design a large multicenter randomized trial to compare the diagnostic accuracy of dry suction versus wet suction technique in solid pancreatic lesions (SPLs) using 22G Franseen needles and determine the optimal number of passes required for EUS-FNB. METHODS: This is a multi-center open-label, randomized controlled non-inferiority trial with two parallel groups. Two hundred patients with SPLs will undergo EUS-FNB using 22G Franseen needles in 4 tertiary hospitals in China and will be randomly assigned to the dry suction group and wet suction group in a ratio of 1:1. The primary endpoint is diagnostic accuracy. Secondary endpoints include the optimal number of needle passes, sensitivity, specificity, specimen quality, cytological diagnoses, time of the procedure, and incidence of complications. DISCUSSION: This study has been designed to determine (i) whether EUS-FNB using 22G Franseen needle with dry suction is non-inferior to wet suction in terms of diagnostic accuracy and (ii) the optimal number of passes during EUS-FNB of SPLs using 22G Franseen needle. TRIAL REGISTRATION: ClinicalTrials.gov NCT05549856. Registered on September 22, 2022.

Correlation between membrane proteins and sizes of extracellular vesicles and particles: A potential signature for cancer diagnosis.

Extracellular vesicles and particles (EVPs) are recognized as ideal liquid biopsy tools for cancer detection, and membrane proteins are commonly used EVP biomarkers. However, bulk analysis of EVP membrane protein biomarkers typically fails to meet the clinical requirement for diagnostic accuracy. We investigated the correlation between the membrane protein expression level, the binding kinetics to aptamers and the sizes of EVPs with interferometric plasmonic microscopy (iPM), and demonstrated the implementation of the correlative signature to determine cancer types. Using EVPs collected from both cell model and clinical plasma samples with liver, lung, breast, or prostate cancer, we found that the selective set of membrane protein expression levels of five protein markers and their binding kinetics were highly heterogeneous across various sizes of EVPs, resulting in the low overall accuracy (<50%) in cancer classification with bulk analysis of all populations. By grouping the EVPs into three subpopulations according to their sizes, the overall accuracy could be increased to about 70%. We further grouped the EVPs into subpopulations with a 10 nm interval in sizes and analysed the correlation between the membrane proteins and sizes with a machine learning algorithm. The results show that the overall accuracy to discriminate cancer types could be improved to 85%. Therefore, this work highlights the significance of size-dependent subtyping of EVPs and suggests that the correlation between the selective set of membrane proteins and sizes of EVP can serve as a signature for clinical cancer diagnosis.

A pilot study of multi-antigen stimulated cell therapy-I plus camrelizumab and apatinib in patients with advanced bone and soft-tissue sarcomas.

BACKGROUND: Cell-based  immunotherapy shows the therapeutic potential in sarcomas, in addition to angiogenesis-targeted tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI). Multi-antigen stimulated cell therapy-I (MASCT-I) technology is a sequential immune cell therapy for cancer, which composes of multiple antigen-loaded dendritic cell (DC) vaccines followed by the adoptive transfer of anti-tumor effector T-cells. METHODS: In this phase 1 study, we assessed MASCT-I plus camrelizumab (an ICI against PD-1) and apatinib (a highly selective TKI targeting VEGFR2) in patients with unresectable recurrent or metastatic bone and soft-tissue sarcoma after at least one line of prior systemic therapy. One MASCT-I course consisted of 3 DC subcutaneous injections, followed by 3 active T cell infusions administered 18-27 days after each DC injection. In schedule-I group, 3 DC injections were administered with a 28-day interval in all courses; in schedule-II group, 3 DC injections were administered with a 7-day interval in the first course and with a 28-day interval thereafter. All patients received intravenous camrelizumab 200 mg every 3 weeks and oral apatinib 250 mg daily. RESULTS: From October 30, 2019, to August 12, 2021, 19 patients were enrolled and randomly assigned to schedule-I group (n = 9) and schedule-II group (n = 10). Of the 19 patients, 11 (57.9%) experienced grade 3 or 4 treatment-related adverse events. No treatment-related deaths occurred. Patients in schedule-II group showed similar objective response rate (ORR) with those in schedule-I group (30.0% versus 33.3%) but had higher disease control rate (DCR; 90.0% versus 44.4%) and longer median progression-free survival (PFS; 7.7 versus 4.0 months). For the 13 patients with soft-tissue sarcomas, the ORR was 30.8%, DCR was 76.9%, and median PFS was 12.9 months; for the 6 patients with osteosarcomas, the ORR was 33.3%, the DCR was 50.0%, and median PFS was 5.7 months. CONCLUSIONS: Overall, MASCT-I plus camrelizumab and apatinib was safe and showed encouraging efficacy in advanced bone and soft-tissue sarcoma, and schedule-II administration method was recommended. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04074564.

Erratum: Author correction to "Coordinated regulation of BACH1 and mitochondrial metabolism through tumor targeted self-assembled nanoparticles for effective triple negative breast cancer combination therapy" [Acta Pharmaceutica Sinica B 12 (2022) 3934-3951].

[This corrects the article DOI: 10.1016/j.apsb.2022.06.009.].

System analysis of Huang-Lian-Jie-Du-Tang and their key active ingredients for overcoming CML resistance by suppression of leukemia stem cells.

BACKGROUND: BCR-ABL1-based resistance to imatinib, mainly resulting from BCR-ABL1 mutations, is largely solved after second- and third-generation tyrosine kinase inhibitors (TKIs) are discovered. Nonetheless, imatinib resistance without BCR-ABL1 mutations, including intrinsic resistance induced by stem cells within chronic myeloid leukemia (CML), remains the major clinical challenge for many patients. PURPOSE: To study the key active ingredients and corresponding target proteins in Huang-Lian-Jie-Du-Tang (HLJDT) against BCR-ABL1-independent CML resistance to therapeutics, and then explore its mechanism of against CML drug resistance. METHODS: Cytotoxicity of HLJDT and its active ingredients in BCR-ABL1-independent imatinib resistance cells was analyzed through MTT assay. The cloning ability was measured through soft agar assay. Monitoring therapeutic effect on Xenografted mice CML model by in vivo imaging technology and mice survival time. Predicting the potential target protein binding sites by the technology of photocrosslinking sensor chip, molecular space simulation docking, and use Surface Plasmon Resonance (SPR) technology . Flow cytometry to detect the ratio of stem progenitor cells (CD34+). Constructing bone marrow transplantation mice CML leukemia model, detect the effects on leukemia stem cells LSK (Lin-\ Sca-1+ \C-kit+) self-renewal. RESULTS: Treatment with HLJDT, berberine and baicalein inhibited cell viability and colony formation of BCR-ABL1-independent imatinib-resistant cells in vitro while prolonging survival in mouse with CML xenografts and transplatation CML-like mouse models in vivo. JAK2 and MCL1were identified as targets of berberine and baicalein. JAK2 and MCL1 are involved in multi-leukemia stem cell-related pathways. Moreover, the ratio of CD34+ cells in resistant CML cells is higher than in treatment-sensitive CML cells. Treatment with BBR or baicalein partially suppressed CML leukemic stem cells (LSCs) self-renewal in vitro and in vivo. CONCLUSION: From the above, we concluded that HLJDT and its key active ingredients (BBR and baicalein) allowed to overcome imatinib resistance with BCR-ABL1 independent by eradication of LSCs by targeting the JAK2 and MCL1 protein levels. Our results lay the foundation for applying HLJDT in patients with TKI-resistant CML.

PPFIA1-targeting miR-181a mimic and saRNA overcome imatinib resistance in BCR-ABL1-independent chronic myeloid leukemia by suppressing leukemia stem cell regeneration.

A large proportion of patients with chronic myeloid leukemia (CML; 20%-50%) develop resistance to imatinib in a BCR-ABL1-independent manner. Therefore, new therapeutic strategies for use in this subset of imatinib-resistant CML patients are urgently needed. In this study, we used a multi-omics approach to show that PPFIA1 was targeted by miR-181a. We demonstrate that both miR-181a and PPFIA1-siRNA reduced the cell viability and proliferative capacity of CML cells in vitro, as well as prolonged the survival of B-NDG mice harboring human BCR-ABL1-independent imatinib-resistant CML cells. Furthermore, treatment with miR-181a mimic and PPFIA1-siRNA inhibited the self-renewal of c-kit+ and CD34+ leukemic stem cells and promoted their apoptosis. Small activating (sa)RNAs targeting the promoter of miR-181a increased the expression of endogenous primitive miR-181a (pri-miR-181a). Transfection with saRNA 1-3 inhibited the proliferation of imatinib-sensitive and -resistant CML cells. However, only saRNA-3 showed a stronger and more sustained inhibitory effect than the miR-181a mimic. Collectively, these results show that miR-181a and PPFIA1-siRNA may overcome the imatinib resistance of BCR-ABL1-independent CML, partially by inhibiting the self-renewal of leukemia stem cells and promoting their apoptosis. Moreover, exogenous saRNAs represent promising therapeutic agents in the treatment of imatinib-resistant BCR-ABL1-independent CML.

Novel Combination Therapy for Triple-Negative Breast Cancer based on an Intelligent Hollow Carbon Sphere.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high mortality, and the efficacy of monotherapy for TNBC is still disappointing. Here, we developed a novel combination therapy for TNBC based on a multifunctional nanohollow carbon sphere. This intelligent material contains a superadsorbed silicon dioxide sphere, sufficient loading space, a nanoscale hole on its surface, a robust shell, and an outer bilayer, and it could load both programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) small-molecule immune checkpoints and small-molecule photosensitizers with excellent loading contents, protect these small molecules during the systemic circulation, and achieve accumulation of them in tumor sites after systemic administration followed by the application of laser irradiation, thereby realizing dual attack of photodynamic therapy and immunotherapy on tumors. Importantly, we integrated the fasting-mimicking diet condition that can further enhance the cellular uptake efficiency of nanoparticles in tumor cells and amplify the immune responses, further enhancing the therapeutic effect. Thus, a novel combination therapy "PD-1/PD-L1 immune checkpoint blockade + photodynamic therapy + fasting-mimicking diet"was developed with the aid of our materials, which eventually achieved a marked therapeutic effect in 4T1-tumor-bearing mice. The concept can also be applied to the clinical treatment of human TNBC with guiding significance in the future.

Dihydroartemisinin Potentiates VEGFR-TKIs Antitumorigenic Effect on Osteosarcoma by Regulating Loxl2/VEGFA Expression and Lipid Metabolism Pathway.

Anti-angiogenesis therapy has shown significant anti-tumor effects against a variety of cancers. But resistance to antiangiogenic drugs, intrinsic and evasive, is frequently found in patients during treatment. Here, we report that dihydroartemisinin (DHA), a derivative of the Chinese medicine artemisinin, enhances antiangiogenic drug-induced cytotoxicity in osteosarcoma (OS) cells. Proteomics analysis revealed that DHA treatment significantly affected the activity of the collagen-modifying enzyme lysyl oxidase-like 2 (LOXL2), a regulatory gene associated with poor prognosis of OS. Furthermore, we found that DHA reduced the expression of vascular endothelial growth factor (VEGFA) by downregulating LOXL2. This mechanism was confirmed by QRT-PCR, western blot, and ELISA assays. Correspondingly, vector-enforced expression of LOXL2 markedly reduced VEGFA secretion. Untargeted metabolomic analysis revealed that the lipid metabolism that confers antiangiogenic drug resistance, was also interfered with by DHA. Thus, DHA not only exerts antitumor effects in OS cells directly but also synergizes with the antiangiogenic drug by regulating vascular endothelial growth factor A (VEGFA) expression and lipid metabolism.

ExamPle: explainable deep learning framework for the prediction of plant small secreted peptides.

MOTIVATION: Plant Small Secreted Peptides (SSPs) play an important role in plant growth, development, and plant-microbe interactions. Therefore, the identification of SSPs is essential for revealing the functional mechanisms. Over the last few decades, machine learning-based methods have been developed, accelerating the discovery of SSPs to some extent. However, existing methods highly depend on handcrafted feature engineering, which easily ignores the latent feature representations and impacts the predictive performance. RESULTS: Here, we propose ExamPle, a novel deep learning model using Siamese network and multi-view representation for the explainable prediction of the plant SSPs. Benchmarking comparison results show that our ExamPle performs significantly better than existing methods in the prediction of plant SSPs. Also, our model shows excellent feature extraction ability. Importantly, by utilizing in silicomutagenesis experiment, ExamPle can discover sequential characteristics and identify the contribution of each amino acid for the predictions. The key novel principle learned by our model is that the head region of the peptide and some specific sequential patterns are strongly associated with the SSPs' functions. Thus, ExamPle is expected to be a useful tool for predicting plant SSPs and designing effective plant SSPs. AVAILABILITY AND IMPLEMENTATION: Our codes and datasets are available at https://github.com/Johnsunnn/ExamPle.

Antitumor effect of neoantigen-reactive T cells combined with PD1 inhibitor therapy in mouse lung cancer.

PURPOSE: Neoantigens produced from mutations in tumors are important targets of T-cell-based immunotherapy and immune checkpoint blockade has been approved for treating multiple solid tumors. We investigated the potential benefit of adoptive neoantigen-reactive T (NRT) cells in combination with programmed cell death protein 1 inhibitor (anti-PD1) for treating lung cancer in a mouse model. METHODS: NRT cells were prepared by co-culturing T cells and neoantigen-RNA vaccine-induced dendritic cells. Then, adoptive NRT cells in combination with anti-PD1 were administered to tumor-bearing mice. Pre- and post-therapy cytokine secretion, antitumor efficacy, and tumor microenvironment (TME) changes were determined both in vitro and in vivo. RESULTS: We successfully generated NRT cells based on the 5 neoantigen epitopes identified in this study. NRT cells exhibited an enhanced cytotoxic phenotype in vitro and the combination therapy led to attenuated tumor growth. In addition, this combination strategy downregulated the expression of the inhibitory marker PD-1 on tumor-infiltrating T cells and promoted the trafficking of tumor-specific T cells to the tumor sites. CONCLUSION: The adoptive transfer of NRT cells in association with anti-PD1 therapy can exert an antitumor effect on lung cancer, and is a feasible, effective, and novel immunotherapy regimen for treating solid tumors.

An oncolytic herpes simplex virus type 1 strain expressing a single-chain variable region antibody fragment against PD-1 and a PI3K inhibitor synergize to elicit antitumor immunity in ovarian cancer.

Due to recurrence and resistance to chemotherapy, the current standard therapeutics are not fully effective against ovarian cancer. Therefore, we aimed to find an effective approach to improve the prognosis and therapy of ovarian cancer. NG34ScFvPD-1 is a modified oncolytic herpes simplex virus NG34 strain that expresses a single-chain antibody against programmed cell death protein 1 (PD-1) (ScFvPD-1). We assessed its efficacy and its regulatory mechanism in a mouse model of ovarian cancer. Enzyme-linked immunosorbent assay and western blot techniques were used to measure protein expression. Oncolysis caused by NG34ScFvPD-1 was examined using cytotoxicity and replication assays. The mechanism by which NG34ScFvPD-1 regulates apoptosis of ovarian cancer cells in vitro was also evaluated. We assessed the antitumor immunity and therapeutic potency of NG34ScFvPD-1 in combination with a phosphoinositide 3-kinase (PI3K) inhibitor. We found that NG34ScFvPD-1-infected ovarian cancer cells expressed and secreted ScFvPD-1, which bound mouse PD-1. The insertion of the ScFvPD-1 sequence did not inhibit the oncolytic activity of NG34ScFvPD-1, which induced apoptosis of ovarian cancer cells via the caspase-dependent pathway in vitro and activated the PI3K/AKT signaling pathway. Synergy was observed between NG34ScFvPD-1 and a PI3K inhibitor, and the combination was able to suppress tumor development, to prolong survival, and to elicit potent antitumor immunity. Thus, inhibition of PI3K enhanced the potent antitumor immunity induced by NG34ScFvPD-1 against ovarian cancer.