Combining iRGD with HuFOLactis enhances antitumor potency by facilitating immune cell infiltration and activation.

Multiple research studies have demonstrated the efficacy of lactic acid bacteria in boosting both innate and adaptive immune responses. We have created a Lactococcus lactis variant that produces a modified combination protein with Fms-like tyrosine kinase 3 ligand and co-stimulator O × 40 ligand, known as HuFOLactis. The genetically modified variant was purposely created to activate T cells, NK cells, and DC cells in a laboratory setting. Furthermore, we explored the possibility of using the tumor-penetrating peptide iRGD to deliver HuFOLactis-activated immune cells to hard-to-reach tumor areas. Following brief stimulation with HuFOLactis, immune cell phenotypes and functions were assessed using flow cytometry. Confocal microscopy was employed to demonstrate the infiltrative and cytotoxic capabilities of iRGD-modified HuFOLactis-activated immune cells within tumor spheroids. The efficacy of iRGD modified HuFOLactis-activated immune cells against tumors was assessed in xenograft mouse models. HuFOLactis treatment resulted in notable immune cell activation, demonstrated by elevated levels of CD25, CD69, and CD137. Additionally, these activated immune cells showed heightened cytokine production and enhanced cytotoxicity against MKN45 cell lines. Incorporation of the iRGD modification facilitated the infiltration of HuFOLactis-activated immune cells into multicellular spheroids (MCSs). Additionally, immune cells activated by HuFOLactis and modified with iRGD, in combination with anti-PD-1 treatment, effectively halted tumor growth and prolonged survival in a mouse model of gastric cancer.

TMJ-105, an extract of Carpesium cernuum, induced G2/M phase arrest and apoptosis via the JAK2/STAT3 axis and MAPKs signaling pathway in leukemia HEL cells.

Leukemia is a malignant tumor of the hematologic system. Studies have shown that cernuumolide J (TMJ-105), an extract of Carpesium cernuum, has anti-cancer effects, but the underlying mechanism is unclear. In this study, we investigated the effect of TMJ-105 on the proliferation of human leukemia HEL cells and its molecular mechanism. MTT analysis showed TMJ-105 had revealed that it shows significant IC50 in HEL cells at lower doses (1.79 ± 0.29 µmol/L) than in K562 cells (3.89 ± 0.80 µmol/L), and the suppression of HEL cell proliferation was time- and concentration-dependent. Meanwhile, TMJ-105 induced G2/M phase blockage, leading to DNA damage in HEL cells. TMJ-105 promoted HEL cells to release of reactive oxygen species (ROS) and changed mitochondrial membrane potential (MMP). Furthermore, TMJ-105 induced apoptosis by upregulating the cleaved-caspase9 and cleaved-caspase3 protein expression, while caspase pan inhibitor (Z-VAD-FMK) blocked the inhibition effect. Finally, TMJ-105 downregulated the phosphorylation of JAK2, STAT3 and Erk, and activated the phosphorylation of JNK and p38. Collectively, these results demonstrated that TMJ-105 inhibited proliferation of leukemia cells and the underlying mechanism via the JAK2/STAT3 axis and MAPKs signaling pathway. Based on these results, the present study suggested the sesquiterpene lactone TMJ-105 is a new chemotherapeutic agent for the treatment of leukemia.

An Immune-Enhancing Injectable Hydrogel Loaded with Esketamine and DDP Promotes Painless Immunochemotherapy to Inhibit Breast Cancer Growth.

Chemotherapy is the cornerstone of triple-negative breast cancer. The poor effectiveness and severe neuropathic pain caused by it have a significant impact on the immune system. Studies confirmed that immune cells in the tumor microenvironment (TME), have critical roles in tumor immune regulation and prognosis. In this study, it is revealed that the painless administration of Esketamine, combined with Cisplatin (DDP), can exert an anti-tumor effect, which is further boosted by the hydrogel delivery system. It is also discovered that Esketamine combined with DDP co-loaded in Poloxamer Hydrogel (PDEH) induces local immunity by increasing mature Dendritic Cells (mDCs) and activated T cells in PDEH group while the regulatory T cells (Tregs) known as CD4+CD25+FoxP3+decreased significantly. Finally, , CD8+ and CD4+ T cells in the spleen exhibited a significant increase, suggesting a lasting immune impact of PDEH. This study proposes that Esketamine can serve as a painless immune modulator, enhancing an anti-tumor effect while co-loaded in poloxamer hydrogel with DDP. Along with improving immune cells in the microenvironment, it can potentially alleviate anxiety and depression. With its outstanding bio-safety profile, it offers promising new possibilities for painless clinical therapy.

Determination of Volatile Halogenated Hydrocarbons in Drinking and Environmental Waters by Headspace Gas Chromatography.

Volatile halogenated hydrocarbons (VHHs) are annually produced and released into the environment, posing a threat to public health. In this study, a simple, rapid, sensitive and automated method based on headspace and gas chromatography (GC) with electron-capture detection was described for the determination of VHHs in different concentration levels in water samples. The proposed headspace GC method was initially optimized, and the optimum experimental conditions found were 10-mL water sample containing 20% w/v sodium chloride placed in a 20-mL vial and stirred at 60°C for 35 min, and then 14 VHHs were well separated on DB-35 MS capillary column with a split ratio of 12.5: 1. The limits of detection were in the low µg/L level, ranging between 0.01 and 0.6 µg/L. Finally optimized method was applied for determination 14 VHHs in drinking and environmental waters. The total mean concentrations of VHHs were 34.962, 26.183, 3.228 and 647.344 µg/L in tap water, purified water with 1-year-old filter element, seawater and effluents, respectively. However, no VHHs was detected in purified water with a new filter element. The main composition is different among different water matrix, which may be attributed to their different sources.

Expression of the αVß3 integrin affects prostate cancer sEV cargo and density and promotes sEV pro-tumorigenic activity in vivo through a GPI-anchored receptor, NgR2.

It is known that small extracellular vesicles (sEVs) are released from cancer cells and contribute to cancer progression via crosstalk with recipient cells. We have previously reported that sEVs expressing the αVß3 integrin, a protein upregulated in aggressive neuroendocrine prostate cancer (NEPrCa), contribute to neuroendocrine differentiation (NED) in recipient cells. Here, we examine the impact of αVß3 expression on sEV protein content, density and function. sEVs used in this study were isolated by iodixanol density gradients and characterized by nanoparticle tracking analysis, immunoblotting and single vesicle analysis. Our proteomic profile of sEVs containing αVß3 shows downregulation of typical effectors involved in apoptosis and necrosis and an upregulation of tumour cell survival factors compared to control sEVs. We also show that the expression of αVß3 in sEVs causes a distinct reposition of EV markers (Alix, CD81, CD9) to a low-density sEV subpopulation. This low-density reposition is independent of extracellular matrix (ECM) protein interactions with sEVs. This sEV subset contains αVß3 and an αVß3 downstream effector, NgR2, a novel marker for NEPrCa. We show that sEVs containing αVß3 are loaded with higher amounts of NgR2 as compared to sEVs that do not express αVß3. Mechanistically, we demonstrate that sEVs containing NgR2 do not affect the sEV marker profile, but when injected in vivo intratumorally, they promote tumour growth and induce NED. We show that sEVs expressing NgR2 increase the activation of focal adhesion kinase (FAK), a known promoter of cancer cell proliferation, in recipient cells. We also show that NgR2 mimics the effect of sEVs containing αVß3 since it displays increased growth of NgR2 transfectants in vivo, as compared to control cells. Overall, our results describe the changes that occur in cargo, density and functions of cancer cell-derived sEVs containing the αVß3 integrin and its effector, NgR2, without affecting the sEV tetraspanin profiles.

Integrating a deep neural network and Transformer architecture for the automatic segmentation and survival prediction in cervical cancer.

Background: Automated tumor segmentation and survival prediction are critical to clinical diagnosis and treatment. This study aimed to develop deep-learning models for automatic tumor segmentation and survival prediction in magnetic resonance imaging (MRI) of cervical cancer (CC) by combining deep neural networks and Transformer architecture. Methods: This study included 406 patients with CC, each with comprehensive clinical information and MRI scans. We randomly divided patients into training, validation, and independent test cohorts in a 6:2:2 ratio. During the model training, we employed two architecture types: one being a hybrid model combining convolutional neural network (CNN) and ransformer (CoTr) and one of pure CNNs. For survival prediction, the hybrid model combined tumor image features extracted by segmentation models with clinical information. The performance of the segmentation models was evaluated using the Dice similarity coefficient (DSC) and 95% Hausdorff distance (HD95). The performance of the survival models was assessed using the concordance index. Results: The CoTr model performed well in both contrast-enhanced T1-weighted (ceT1W) and T2-weighted (T2W) imaging segmentation tasks, with average DSCs of 0.827 and 0.820, respectively, which outperformed other the CNN models such as U-Net (DSC: 0.807 and 0.808), attention U-Net (DSC: 0.814 and 0.811), and V-Net (DSC: 0.805 and 0.807). For survival prediction, the proposed deep-learning model significantly outperformed traditional methods, yielding a concordance index of 0.732. Moreover, it effectively divided patients into low-risk and high-risk groups for disease progression (P<0.001). Conclusions: Combining Transformer architecture with a CNN can improve MRI tumor segmentation, and this deep-learning model excelled in the survival prediction of patients with CC as compared to traditional methods.

Evaluation of the anti-aging potential of acetyl tripeptide-30 citrulline in cosmetics.

Acetyl tripeptide-30 citrulline, a commercialized bio-active peptide, is widely used in anti-wrinkle formulations. Volunteer-based tests have demonstrated that topical application of products containing acetyl tripeptide-30 citrulline significantly reduces the visibility of stretch marks. However, there is still a lack of research dedicated to systematically and holistically evaluating its cosmetic properties and elucidating its mechanisms of action. In this study, we assessed the cosmetic potential of acetyl tripeptide-30 citrulline using human immortalized keratinocytes (HaCaT) and mouse embryonic fibroblasts (3T3). Our findings reveal that acetyl tripeptide-30 citrulline exhibits anti-inflammatory and antioxidant activities in skin cells, particularly effective against the inflammatory markers cyclooxygenase-2 (COX2), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6), and the extent of inhibition of reactive oxygen species (ROS) production ranged from 95 % to 340 %. Moreover, acetyl tripeptide-30 citrulline specifically up-regulates Collagen IV and down-regulates matrix metalloproteinase-9 (MMP9), enhances the expression of skin barrier proteins transglutaminase 1 (TGM1) and filaggrin (FLG), thereby demonstrating its reparative capabilities. Additionally, acetyl tripeptide-30 citrulline increases the expression of the water channel protein aquaporin 3 (AQP3), thus improving skin hydration function. These results substantiate the previously proclaimed cosmetic attributes of acetyl tripeptide-30 citrulline and support its efficacy as an anti-aging agent in dermatological applications.

Research progress on m6A demethylase FTO and its role in gynecological tumors.

Recent advances in genomic research have increasingly focused on the fat mass- and obesity-associated (FTO) gene due to its notable correlation with obesity. Initially explored for its contribution to increased body weight, FTO was later discovered to function as an m6A demethylase. This pivotal role enhances our understanding of its broader implications across various pathologies. Epigenetic modifications, such as m6A, have been implicated in gynecological cancers, including ovarian, endometrial, and cervical malignancies. However, the precise mechanisms by which FTO influences the development of gynecological cancers remain largely unknown. This analysis underscores the growing relevance of investigations into the FTO gene in elucidating the mechanisms underlying gynecological cancers and exploring potential therapeutic avenues.

An investigator-initiated clinical study in patients with refractory or recurrent solid tumors: 'R-ISV-FOLactis' trial.

Aim: In situ vaccination, a kind of therapeutic cancer vaccine, can be realized by radiotherapy and intratumoral immune injection. This study combines intratumoral injection, radiotherapy and PD-1 blockade for synergistic antitumor effect. Materials & methods: Patients with advanced solid tumors who are unresponsive or intolerant to standard treatment will be treated with hypofractionated radiotherapy, intratumoral injection of FOLactis, PD-1 blockade. The primary end point is to observe the efficacy and safety, with the secondary end point to evaluate abscopal effects and the correlation between the immunological rationale and efficacy. Discussion: The combined regimen will be utilized to trigger antitumor immunity and is expected to be feasible and effective and provide a novel option for the comprehensive treatment of cancer.Clinical Trial Registration: ChiCTR2200060660 (ChiCTR.gov.cn).

[Box: see text].

Stabilization of TGF-ß Receptor 1 by a Receptor-Associated Adaptor Dictates Feedback Activation of the TGF-ß Signaling Pathway to Maintain Liver Cancer Stemness and Drug Resistance.

Dysregulation of the transforming growth factor-ß (TGF-ß) signaling pathway regulates cancer stem cells (CSCs) and drug sensitivity, whereas it remains largely unknown how feedback regulatory mechanisms are hijacked to fuel drug-resistant CSCs. Through a genome-wide CRISPR activation screen utilizing stem-like drug-resistant properties as a readout, the TGF-ß receptor-associated binding protein 1 (TGFBRAP1) is identified as a TGF-ß-inducible positive feedback regulator that governs sensitivity to tyrosine kinase inhibitors (TKIs) and promotes liver cancer stemness. By interacting with and stabilizing the TGF-ß receptor type 1 (TGFBR1), TGFBRAP1 plays an important role in potentiating TGF-ß signaling. Mechanistically, TGFBRAP1 competes with E3 ubiquitin ligases Smurf1/2 for binding to TGFΒR1, leading to impaired receptor poly-ubiquitination and proteasomal degradation. Moreover, hyperactive TGF-ß signaling in turn up-regulates TGFBRAP1 expression in drug-resistant CSC-like cells, thereby constituting a previously uncharacterized feedback mechanism to amplify TGF-ß signaling. As such, TGFBRAP1 expression is correlated with TGFΒR1 levels and TGF-ß signaling activity in hepatocellular carcinoma (HCC) tissues, as well as overall survival and disease recurrence in multiple HCC cohorts. Therapeutically, blocking TGFBRAP1-mediated stabilization of TGFBR1 by selective inhibitors alleviates Regorafenib resistance via reducing CSCs. Collectively, targeting feedback machinery of TGF-ß signaling pathway may be an actionable approach to mitigate drug resistance and liver cancer stemness.

Clinical Features and Histopathological Analysis of Oral Lichen Planus: An Analysis of 105 Chinese Patients.

PURPOSE: To study the clinical and pathological characteristics of oral lichen planus (OLP) in a large sample. MATERIALS AND METHODS: A comprehensive analysis was conducted on 105 patients with oral lichen planus (OLP), considering various factors including sex, age, disease site, lesion type, lesion area, morphological characteristics, self-reported symptoms, and history of systemic diseases. Histopathological examination was performed for each patient, and the pathology results were analysed according to sex and age group. RESULTS: 70.5% of the OLP patients were female, and OLP was most likely to occur in the cheek, followed by the tongue, lips, gums and palate. The patients with moderate pain according to the VAS score accounted for 60%. Thirty-nine percent of the OLP patients had a systemic disease, and the most common clinical type of OLP was nonerosive. Most of the pathological results showed liquefaction degeneration of basal cells and infiltration of lamina propria lymphocytes. There was no statistically significant difference in pathological manifestations between male and female patients, and there were statistically significant differences in pathological manifestations among different ages patients. CONCLUSION: This study analysed the sociodemographic data and clinical manifestations of 105 OLP patients to guide follow-up treatment planning and disease monitoring. Moreover, pathological manifestations should be analysed to avoid delayed treatment and to monitor for carcinogenesis. Furthermore, the correlation of pathological manifestations among OLP patients with different sexes and ages is conducive to further research on the specific differential manifestations and possible underlying mechanisms involved.

A lactate-responsive gene signature predicts the prognosis and immunotherapeutic response of patients with triple-negative breast cancer.

Background: Increased glycolytic activity and lactate production are characteristic features of triple-negative breast cancer (TNBC). The aim of this study was to determine whether a subset of lactate-responsive genes (LRGs) could be used to classify TNBC subtypes and predict patient outcomes. Methods: Lactate levels were initially measured in different breast cancer (BC) cell types. Subsequently, MDA-MB-231 cells treated with 2-Deoxy-d-glucose or l-lactate were subjected to RNA sequencing (RNA-seq). The gene set variation analysis algorithm was utilized to calculate the lactate-responsive score, conduct a differential analysis, and establish an association with the extent of immune infiltration. Consensus clustering was then employed to classify TNBC patients. Tumor immune dysfunction and exclusion, cibersort, single-sample gene set enrichment analysis, and EPIC, were used to compare the tumor-infiltrating immune cells between TNBC subtypes and predict the response to immunotherapy. Furthermore, a prognostic model was developed by combining 98 machine learning algorithms, to assess the predictive significance of the LRG signature. The predictive value of immune infiltration and the immunotherapy response was also assessed. Finally, the association between lactate and various anticancer drugs was examined based on expression profile similarity principles. Results: We found that the lactate levels of TNBC cells were significantly higher than those of other BC cell lines. Through RNA-seq, we identified 14 differentially expressed LRGs in TNBC cells under varying lactate levels. Notably, this LRG signature was associated with interleukin-17 signaling pathway dysregulation, suggesting a link between lactate metabolism and immune impairment. Furthermore, the LRG signature was used to categorize TNBC into two distinct subtypes, whereby Subtype A was characterized by immunosuppression, whereas Subtype B was characterized by immune activation. Conclusion: We identified an LRG signature in TNBC, which could be used to predict the prognosis of patients with TNBC and gauge their response to immunotherapy. Our findings may help guide the precision treatment of patients with TNBC.

Contrast-enhanced CT and PET-CT characteristics of primary tracheal lymphoepithelioma-like carcinoma: case series.

Background: Primary tracheal lymphoepithelioma-like carcinoma (LELC) is extremely rare, with only a few cases reported so far, and few studies have focused on the radiological features. This study aimed to investigate contrast-enhanced computed tomography (CECT) and positron emission tomography-computed tomography (PET-CT) presentations of primary tracheal LELC to improve diagnosis. Methods: A retrospective analysis was conducted on the clinical and imaging data of 13 patients with confirmed primary tracheal LELC between December 2013 and August 2022. We analyzed the radiological profiles of lesions on the CECT and PET-CT images. Results: In 92.3% (12/13) of the cases, primary tracheal LELC lesions predominantly occurred in the thoracic segment. They manifested as singular, wide-based, eccentric, irregular nodules, or exhibited mass-like thickening of the tracheal wall with invasive growth both internally and externally along the wall. The thickest dimension of the lesion ranged from 9 to 28 mm, affecting a length of 30.8±13.5 mm. Luminal stenosis was evident in all patients, with the narrowest point reaching a stenosis rate of 85%. Lesion margins were clear in 69.2% (9/13), indistinct in 23.1% (3/13), and unclear in 7.7% (1/13) of all cases. Among the patients, 92.3% (12/13) exhibited a relatively uniform density on CT plain scans, with a CT value of 44.5±7.8 Hounsfield units (HU). Enhancement scans revealed moderate to marked enhancement in 75% (9/12) of cases. In 2 cases undergoing PET-CT examination, lesion standardized uptake values (SUVs) were 4.4 and 5.1, whereas enlarged lymph node SUVs were 7.7 and 6.3, respectively. Mediastinal lymph node enlargement was observed in 8 patients (61.5%, 8/13), with a maximum short axis of 11.1±5.5 mm. After treatment, 9 out of 12 patients (75%) showed no evidence of distant metastasis upon CT re-examination. Conclusions: Early detection of primary tracheal LELC allows for curative resection and may lead to a favorable prognosis. It presents with characteristic CT findings, and the utilization of PET-CT improves diagnosis and staging.

Systematic analysis of IGF2BP family members in non-small-cell lung cancer.

BACKGROUND: The insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 (IGF2BP1, IGF2BP2, and IGF2BP3) are known to be involved in tumorigenesis, metastasis, prognosis, and cancer immunity in various human cancers, including non-small cell lung cancer (NSCLC). However, the literature on NSCLC largely omits the specific context of lung squamous cell carcinoma (LUSC), an oversight we aim to address. METHODS: Our study evaluated the differential expression of IGF2BP family members in tumors and normal tissues. Meta-analyses were conducted to assess the prognostic value of IGF2BPs in lung adenocarcinoma (LUAD) and LUSC. Additionally, correlations between IGF2BPs and tumor immune cell infiltration, mutation characteristics, chemotherapy sensitivity, and tumor mutation burden (TMB) were investigated. GSEA was utilized to delineate biological processes and pathways associated with IGF2BPs. RESULTS: IGF2BP2 and IGF2BP3 expression were found to be upregulated in LUSC patients. IGF2BP2 mRNA levels were correlated with cancer immunity in both LUSC and LUAD patients. A higher frequency of gene mutations was observed in different IGF2BP1/2/3 expression groups in LUAD compared to LUSC. Meta-analyses revealed a significant negative correlation between overall survival (OS) and IGF2BP2/3 expression in LUAD patients but not in LUSC patients. GSEA indicated a positive association between VEGF and IGF2BP family genes in LUAD, while matrix metallopeptidase activity was inversely correlated with IGF2BP family genes in LUSC. Several chemotherapy drugs showed significantly lower IC50 values in high IGF2BP expression groups in both LUAD and LUSC. CONCLUSION: Our findings indicated that IGF2BPs play different roles in LUAD and LUSC. This divergence highlights the need for tailored therapeutic strategies and prognostic tools, cognizant of the unique molecular profiles of LUAD and LUSC.

Nab-paclitaxel, cisplatin, and capecitabine versus cisplatin and gemcitabine as first line chemotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma: randomised phase 3 clinical trial.

OBJECTIVE: To compare the effectiveness and safety of nab-paclitaxel, cisplatin, and capecitabine (nab-TPC) with gemcitabine and cisplatin as an alternative first line treatment option for recurrent or metastatic nasopharyngeal carcinoma. DESIGN: Phase 3, open label, multicentre, randomised trial. SETTING: Four hospitals located in China between September 2019 and August 2022. PARTICIPANTS: Adults (≥18 years) with recurrent or metastatic nasopharyngeal carcinoma. INTERVENTIONS: Patients were randomised in a 1:1 ratio to treatment with either nab-paclitaxel (200 g/m2 on day 1), cisplatin (60 mg/m2 on day 1), and capecitabine (1000 mg/m2 twice on days 1-14) or gemcitabine (1 g/m2 on days 1 and 8) and cisplatin (80 mg/m2 on day 1). MAIN OUTCOME MEASURES: Progression-free survival was evaluated by the independent review committee as the primary endpoint in the intention-to-treat population. RESULTS: The median follow-up was 15.8 months in the prespecified interim analysis (31 October 2022). As assessed by the independent review committee, the median progression-free survival was 11.3 (95% confidence interval 9.7 to 12.9) months in the nab-TPC cohort compared with 7.7 (6.5 to 9.0) months in the gemcitabine and cisplatin cohort. The hazard ratio was 0.43 (95% confidence interval 0.25 to 0.73; P=0.002). The objective response rate in the nab-TPC cohort was 83% (34/41) versus 63% (25/40) in the gemcitabine and cisplatin cohort (P=0.05), and the duration of response was 10.8 months in the nab-TPC cohort compared with 6.9 months in the gemcitabine and cisplatin cohort (P=0.009). Treatment related grade 3 or 4 adverse events, including leukopenia (4/41 (10%) v 13/40 (33%); P=0.02), neutropenia (6/41 (15%) v 16/40 (40%); P=0.01), and anaemia (1/41 (2%) v 8/40 (20%); P=0.01), were higher in the gemcitabine and cisplatin cohort than in the nab-TPC cohort. No deaths related to treatment occurred in either treatment group. Survival and long term toxicity are still being evaluated with longer follow-up. CONCLUSION: The nab-TPC regimen showed a superior antitumoural efficacy and favourable safety profile compared with gemcitabine and cisplatin for recurrent or metastatic nasopharyngeal carcinoma. Nab-TPC should be considered the standard first line treatment for recurrent or metastatic nasopharyngeal carcinoma. Longer follow-up is needed to confirm the benefits for overall survival. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900027112.

Low-dose doxorubicin loaded extracellular vesicles combined Fas/FasL pathway-mediated chemo-sensitization and immunotherapy against tumor.

The clinical application of doxorubicin (DOX) is mainly restricted by its serious side effects, poor drug delivery efficiency, and limited immunogenic death (ICD) effect. To improve DOX-based chemotherapy and ameliorate its adverse effects, we utilized 3LL cell-derived extracellular vesicles to encapsulate DOX and sodium nitroprusside (SNP) to obtain DOX/SNP@CM, which could effectively target the tumor site by harnessing the inherent homologous targeting property of tumor cell membranes. DOX performed its role on chemotherapy, and SNP successfully respond to the intracellular GSH to continuously generate nitric oxide (NO). The in situ-produced NO upregulated the Fas expression on the tumor cell surface, thereby sensitizing the Fas/FasL pathway-mediated tumor cell apoptosis of DOX. Furthermore, NO also boosted the intratumoral infiltration of cytotoxic T cells by promoted ICD effect towards tumor cells. Importantly, the anti-tumor immunity tightly cooperated with Fas/FasL mediated tumor cell apoptosis by NO-mediated manipulation on Fas/FasL interaction, collectively making DOX/SNP@CM exert significant tumor growth inhibition with low-dose DOX. Remarkably, DOX and SNP both are widely used clinical medicines, ensuring DOX/SNP@CM a potential opportunity for future practical applications.

HSP70-mediated mitochondrial dynamics and autophagy represent a novel vulnerability in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC), the most prevalent type of pancreatic cancer, is one of the deadliest forms of cancer with limited therapy options. Overexpression of the heat shock protein 70 (HSP70) is a hallmark of cancer that is strongly associated with aggressive disease and worse clinical outcomes. However, the underlying mechanisms by which HSP70 allows tumor cells to thrive under conditions of continuous stress have not been fully described. Here, we report that PDAC has the highest expression of HSP70 relative to normal tissue across all cancers analyzed. Furthermore, HSP70 expression is associated with tumor grade and is further enhanced in metastatic PDAC. We show that genetic or therapeutic ablation of HSP70 alters mitochondrial subcellular localization, impairs mitochondrial dynamics, and promotes mitochondrial swelling to induce apoptosis. Mechanistically, we find that targeting HSP70 suppresses the PTEN-induced kinase 1 (PINK1) mediated phosphorylation of dynamin-related protein 1 (DRP1). Treatment with the HSP70 inhibitor AP-4-139B was efficacious as a single agent in primary and metastatic mouse models of PDAC. In addition, we demonstrate that HSP70 inhibition promotes the AMP-activated protein kinase (AMPK) mediated phosphorylation of Beclin-1, a key regulator of autophagic flux. Accordingly, we find that the autophagy inhibitor hydroxychloroquine (HCQ) enhances the ability of AP-4-139B to mediate anti-tumor activity in vivo. Collectively, our results suggest that HSP70 is a multi-functional driver of tumorigenesis that orchestrates mitochondrial dynamics and autophagy. Moreover, these findings support the rationale for concurrent inhibition of HSP70 and autophagy as a novel therapeutic approach for HSP70-driven PDAC.

Interpretable deep learning insights: Unveiling the role of 1 Gy volume on lymphopenia after radiotherapy in breast cancer.

BACKGROUND: Lymphopenia is known for its significance on poor survivals in breast cancer patients. Considering full dosimetric data, this study aimed to develop and validate predictive models for lymphopenia after radiotherapy (RT) in breast cancer. MATERIAL AND METHODS: Patients with breast cancer treated with adjuvant RT were eligible in this multicenter study. The study endpoint was lympopenia, defined as the reduction in absolute lymphocytes and graded lymphopenia after RT. The dose-volume histogram (DVH) data of related critical structures and clinical factors were taken into account for the development of dense neural network (DNN) predictive models. The developed DNN models were validated using external patient cohorts. RESULTS: A total of 918 consecutive patients with invasive breast cancer enrolled. The training, testing, and external validating datasets consisted of 589, 203, and 126 patients, respectively. Treatment volumes at nearly all dose levels of the DVH were significant predictors for lymphopenia following RT, including volumes at very low-dose 1 Gy (V1) of organs at risk (OARs) including lung, heart and body, especially ipsilateral-lung V1. A final DNN model, combining full DVH dosimetric parameters of OARs and three key clinical factors, achieved a predictive accuracy of 75 % or higher. CONCLUSION: This study demonstrated and externally validated the significance of full dosimetric data, particularly the volume of low dose at as low as 1 Gy of critical structures on lymphopenia after radiation in patients with breast cancer. The significance of V1 deserves special attention, as modern VMAT RT technology often has a relatively high value of this parameter. Further study is warranted for RT plan optimization.

Human amniotic epithelial stem cell is a cell therapy candidate for preventing acute graft-versus-host disease.

Graft-versus-host disease (GVHD), an immunological disorder that arises from donor T cell activation through recognition of host alloantigens, is the major limitation in the application of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Traditional immunosuppressive agents can relieve GVHD, but they induce serious side effects. It is highly required to explore alternative therapeutic strategy. Human amniotic epithelial stem cells (hAESCs) were recently considered as an ideal source for cell therapy with special immune regulatory property. In this study, we evaluated the therapeutic role of hAESCs in the treatment of GVHD, based on our previous developed cGMP-grade hAESCs product. Humanized mouse model of acute GVHD (aGVHD) was established by injection of huPBMCs via the tail vein. For prevention or treatment of aGVHD, hAESCs were injected to the mice on day -1 or on day 7 post-PBMC infusion, respectively. We showed that hAESCs infusion significantly alleviated the disease phenotype, increased the survival rate of aGVHD mice, and ameliorated pathological injuries in aGVHD target organs. We demonstrated that hAESCs directly induced CD4+ T cell polarization, in which Th1 and Th17 subsets were downregulated, and Treg subset was elevated. Correspondingly, the levels of a series of pro-inflammatory cytokines were reduced while the levels of the anti-inflammatory cytokines were upregulated in the presence of hAESCs. We found that hAESCs regulated CD4+ subset polarization in a paracrine mode, in which TGFß and PGE2 were selectively secreted to mediate Treg elevation and Th1/Th17 inhibition, respectively. In addition, transplanted hAESCs preserved the graft-versus-leukemia (GVL) effect by inhibiting leukemia cell growth. More intriguingly, hAESCs infusion in HSCT patients displayed potential anti-GVHD effect with no safety concerns and confirmed the immunoregulatory mechanisms in the preclinical study. We conclude that hAESCs infusion is a promising therapeutic strategy for post-HSCT GVHD without compromising the GVL effect. The clinical trial was registered at www.clinicaltrials.gov as #NCT03764228.