Prenatal High-Sucrose Diet Induced Vascular Dysfunction of Renal Interlobar Arteries in the Offspring via PPARγ-RXRg-ROS/Akt Signaling.

SCOPE: Prenatal nutrition imbalance correlates with developmental origin of cardiovascular diseases; however whether maternal high-sucrose diet (HS) during pregnancy causes vascular damage in renal interlobar arteries (RIA) from offspring still keeps unclear. METHODS AND RESULTS: Pregnant rats are fed with normal drinking water or 20% high-sucrose solution during the whole gestational period. Swollen mitochondria and distributed myofilaments are observed in vascular smooth muscle cells of RIA exposed to prenatal HS. Maternal HS increases phenylephrine (PE)-induced vasoconstriction in the RIA from adult offspring. NG-Nitro-l-arginine (L-Name) causes obvious vascular tension in response to PE in offspring from control group, not in HS. RNA-Seq of RIA is performed to reveal that the gene retinoid X receptor g (RXRg) is significantly decreased in the HS group, which could affect vascular function via interacting with PPARγ pathway. By preincubation of RIA with apocynin (NADPH inhibitor) or capivasertib (Akt inhibitor), the results indicate that ROS and Akt are the vital important factors to affect the vascular function of RIA exposure to prenatal HS. CONCLUSION: Maternal HS during the pregnancy increases PE-mediated vasoconstriction of RIA from adult offspring, which is mainly related to the enhanced Akt and ROS regulated by the weakened PPARγ-RXRg.

"Percentage" and "size" of residual viable tumor in lymph node, the performance in estimating pathologic response of lymph node in non-small cell lung cancer treated with neoadjuvant chemoimmunotherapy.

There is no universally accepted method for evaluating lymph node metastasis (LNM) in non-small cell lung cancer (NSCLC) after neoadjuvant chemoimmunotherapy. Different protocols recommend evaluating the percentage of residual viable tumor (RVT%) and metastatic tumor size (MTS). Our aim was to determine the prognostic significance of RVT% and MTS, and identify the more effective parameter for pathological evaluating LNM. Two independent cohorts were collected (derivation, n = 84; external validation, n = 42). All patients exhibited metastatic cancer or treatment response in lymph nodes post-surgery. In the derivation cohort, we assessed the mean and largest values of MTS and RVT% in LNM, estimating their optimal cutoffs for event-free survival (EFS) using maximally selected rank statistics. Validation was subsequently conducted in the external validation cohort. The quality of prognostic factors was evaluated using the Area Under Curve (AUC). A positive association was identified between RVT% and MTS, but an absolute association could not be conclusively established. In the derivation cohort, neither the largest MTS (cutoff = 6 mm, p = 0.28), largest RVT% (cutoff = 75%, p = 0.23), nor mean RVT% (cutoff = 55%, p = 0.06) were associated with EFS. However, mean MTS (cutoff = 4.5 mm) in lymph nodes was statistically associated with EFS (p = 0.018), validated by the external cohort (p = 0.017). The prognostic value of MTS exceeded that of ypN staging in both cohorts, as evidenced by higher AUC values. The mean value of MTS can effectively serve as a parameter for the pathological evaluation of lymph nodes, with a threshold of 4.5 mm, closely linked to EFS. Its prognostic value outperforms that of ypN staging.

Hybrid adipocyte-derived exosome nano platform for potent chemo-phototherapy in targeted hepatocellular carcinoma.

The high prevalence and severity of hepatocellular carcinoma (HCC) present a significant menace to human health. Despite the significant advancements in nanotechnology-driven antineoplastic agents, there remains a conspicuous gap in the development of targeted chemotherapeutic agents specifically designed for HCC. Consequently, there is an urgent need to explore potent drug delivery systems for effective HCC treatment. Here we have exploited the interplay between HCC and adipocyte to engineer a hybrid adipocyte-derived exosome platform, serving as a versatile vehicle to specifically target HCC and exsert potent antitumor effect. A lipid-like prodrug of docetaxel (DSTG) with a reactive oxygen species (ROS)-cleavable linker, and a lipid-conjugated photosensitizer (PPLA), spontaneously co-assemble into nanoparticles, functioning as the lipid cores of the hybrid exosomes (HEMPs and NEMPs). These nanoparticles are further encapsuled within adipocyte-derived exosome membranes, enhancing their affinity towards HCC cancer cells. As such, cancer cell uptakes of hybrid exosomes are increased up to 5.73-fold compared to lipid core nanoparticles. Our in vitro and in vivo experiments have demonstrated that HEMPs not only enhance the bioactivity of the prodrug and extend its circulation in the bloodstream but also effectively inhibit tumor growth by selectively targeting hepatocellular carcinoma tumor cells. Self-facilitated synergistic drug release subsequently promoting antitumor efficacy, inducing significant inhibition of tumor growth with minimal side effects. Our findings herald a promising direction for the development of targeted HCC therapeutics.

Embrittlement Mechanisms of HR3C Pipe Steel at Room Temperature in Ultra-Supercritical Unit.

HR3C steel is an austenitic high-temperature-resistant steel. Because of its good strength and high-temperature performance, it has been widely used in ultra-supercritical power plant boilers. With the increasingly frequent start-up and shutdown of thermal power units, leakages of HR3C steel pipes have occasionally occurred due to the embrittlement of HR3C pipe steel after a long service duration. In this study, the embrittlement mechanisms of HR3C pipe steel are investigated systematically. The mechanical properties of the pipe steel after running for 70,000 h in an ultra-supercritical unit were determined. As a comparison, the pipe steel supplied in the same batch was aged at 700 degrees Celsius for 500 h. The mechanical properties and the micro-precipitation of the aged counterparts were also determined for comparison. The results show that the embrittlement of HR3C pipe steel in service for 70,000 h is obvious. The average impact absorption is only 5.5 J, which is a decrease of 96.7%. It is found that embrittlement of HR3C steel also occurs after 500 h of aging at 700 °C, and the average value of impact absorption energy decreases by 70.4%. The comparison experiment between the in-service pipe steel and the aged pipe steel shows that in the rapid decline stage of the impact toughness of HR3C steel, the M23C6 carbide in the microstructure has a continuous chain distribution in the grain boundary. There were no other precipitated phases observed. The rapid precipitation and aggregation of M23C6 carbides leads to the initial embrittlement of HR3C steel at room temperature. The CRFe-type σ phase was found in the transmission electron microscope (TEM) image of the steel pipe after 70 thousand hours of use. The precipitation of the σ phase further induces the embrittlement of HR3C pipe steel after a long service duration.

Comparison of different criteria for estimating major pathological response in resectable non-small cell lung cancer treated with neoadjuvant chemoimmunotherapy.

BACKGROUND: Major pathological response (MPR) is proposed as a surrogate endpoint for survival in non-small cell lung cancer (NSCLC) after neoadjuvant chemoimmunotherapy. However, the criteria for estimating MPR differ between the recommendations of the International Association for the Study of Lung Cancer (IASLC) and the immune-related pathologic response criterion (irPRC). IASLC's criteria focus solely on evaluating the primary tumor, while irPRC's criteria encompass both the primary tumor and lymph node metastasis. Our objective is to compare the prognostic value of different criteria for estimating MPR. METHODS: We conducted a retrospective study on a cohort of 235 patients with NSCLC after neoadjuvant chemoimmunotherapy. The survival endpoint was event-free survival (EFS). The MPR status of each patient was evaluated using both IASLC's criteria and irPRC's criteria. The prognostic value was compared using the Area Under Curve (AUC). RESULTS: The MPR rates were 63.4 % (149/235) and 57.4 % (135/235) according to IASLC's and irPRC's criteria, respectively. Inconsistent cases, characterized by MPR status according to IASLC's criteria but non-MPR status according to irPRC's criteria, constituted 6.0 % (14/235) of the overall cohort and 15.2 % (14/92) of patients with pretreatment N positive disease. Interestingly, all inconsistent patients showed no recurrence during the study period. Although both MPR statuses according to IASLC (p = 0.00039) and irPRC (p = 0.0094) were associated with improved EFS, IASLC's criteria (AUC = 0.65) were superior to irPRC's criteria (AUC = 0.62) with a higher AUC value. CONCLUSION: IASLC's criteria for estimating MPR were superior to irPRC's criteria in predicting EFS for NSCLC after neoadjuvant chemoimmunotherapy.

Related cellular signaling and consequent pathophysiological outcomes of ubiquitin specific protease 24.

Ubiquitin-specific protease 24 (USP24) is an essential member of the deubiquitinating protease family found in eukaryotes. It engages in interactions with multiple proteins, including p53, MCL-1, E2F4, and FTH1, among others. Through these interactions, USP24 plays a critical role in regulating vital cellular processes such as cell cycle control, DNA damage response, cellular iron autophagy, and apoptosis. Increased levels of USP24 have been observed in various cancer types, including bladder cancer, lung cancer, myeloma, hepatocellular carcinoma, and gastric cancer. However, in certain tumors like kidney cancer, USP24 is significantly downregulated, and the specific mechanism behind this remains unclear. Currently, there are no officially approved USP24 inhibitors available for clinical use. Some existing inhibitors targeting USP24 have shown promising effects in treating malignancies; however, their precise mode of action and information regarding binding sites are not well understood. Moreover, further optimization is required to enhance the selectivity and efficacy of these inhibitors. This review aims to provide a comprehensive overview of recent advancements in understanding the cellular functions of USP24, its association with various diseases, and the development of small-molecule inhibitors that target this protein. In conclusion, USP24 represents a promising therapeutic target for various diseases, and ongoing research will contribute to validating its role and facilitating the development of effective treatments.

Clonality Analysis for the Relationship between the Pulmonary Combined Neuroendocrine Carcinoma and "the So-Called Reported Histologic Transformation".

Histologic transformation (HT) is common following targeted therapy in adenocarcinoma. However, whether the transformed tumor is a new component or a combined neuroendocrine carcinoma (C-NEC) remains controversial. We aimed to explore the relationship between pulmonary C-NEC and HT. Macro-dissection was performed on different components of surgically resected C-NEC samples. Molecular alterations and clonal evolution were analyzed using whole exome sequencing (WES). The gene statuses for TP53 and RB1 were determined using immunohistochemistry (IHC) and WES to analyze the relationship between C-NEC and reported HT. Sixteen combined small-cell lung cancer patients and five combined large-cell neuroendocrine carcinoma patients were enrolled. The frequency of p53 and Rb inactivation, assessed using IHC in NEC and non-NEC components, was 76.2/76.2% and 66.7/61.9%, respectively. The expression consistency between the components was 81.0 and 85.7% for p53 and Rb, respectively. The frequencies of TP53, RB1, and EGFR mutations, assessed using WES in NEC and non-NEC components, were 81.0/81.0%, 28.6/28.6%, and 42.9/42.9%, respectively. The concordance rates for TP53, RB1, and EGFR were 90.5, 71.4, and 90.5%, respectively. The consistency rate between IHC and WES was 81.0 and 61.9% for TP53 and RB1, respectively. The different components had a common clonal origin for the 21 C-NECs in the clonal analysis, consistent with previous studies on HT. Our study shows that IHC is more sensitive for Rb detection and C-NEC, and the reported HT may be due to differences in evaluations between pathologist and clinicians. Assessing the p53/Rb and EGFR status for such cases would help in recognizing potential transformation cases or uncovering potential combined components.

A pan-cancer analysis of Dyskeratosis congenita 1 (DKC1) as a prognostic biomarker.

BACKGROUND: Dyskeratosis congenita 1 (DKC1), a critical component of telomerase complex, is highly expressed in a variety of human cancers. However, the association of DKC1 with cancer occurrence and development stages is not clear, making a pan-cancer analysis crucial. METHODS: We conducted a study using various bioinformatic databases such as TIMER, GEPIA, UALCAN, and KM plotter Analysis to examine the different expressions of DKC1 in multiple tissues and its correlation with pathological stages. Through KEGG analysis, GO enrichment analysis and Venn analysis, we were able to reveal DKC1-associated genes and signaling pathways. In addition, we performed several tests including the CCK, wound healing assay, cell cycle arrest assay, transwell assay and Sa-ß-gal staining on DKC1-deleted MDA-231 cells. RESULTS: Our study demonstrates that DKC1 has relatively low expression specificity in different tissues. Furthermore, we found that in ACC, KICH, KIRP and LIHC, the expression level of DKC1 is positively correlated with pathological stages. Conversely, in NHSC, KIRP, LGG, LIHC, MESO and SARC, we observed a negative influence of DKC1 expression level on the overall survival rate. We also found a significant positive correlation between DKC1 expression and Tumor Mutational Burden in 14 tumors. Additionally, we observed a significantly negative impact of DKC1 DNA methylation on gene expression at the promoter region in BRCA. We also identified numerous phosphorylation sites concentrated at the C-terminus of the DKC1 protein. Our GO analysis revealed a correlation between DKC1 and ribosomal biosynthesis pathways, and the common element UTP14A was identified. We also observed decreased rates of cell proliferation, migration and invasion abilities in DKC1-knockout MDA-MB-231 cell lines. Furthermore, DKC1-knockout induced cell cycle arrest and caused cell senescence. CONCLUSIONS: Our findings suggest that the precise expression of DKC1 is closely associated with the occurrence and developmental stages of cancer in multiple tissues. Depletion of DKC1 can inhibit the abilities of cancer cells to proliferate, migrate, and invade by arresting the cell cycle and inducing cell senescence. Therefore, DKC1 may be a valuable prognostic biomarker for the diagnosis and treatment of cancer in various tissues.

Exploring the molecular features and genetic prognostic factors of pulmonary high-grade neuroendocrine carcinomas.

Molecular research on large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) has progressed significantly. However, there are still fewer molecular markers related to prognostic/therapeutic strategies for these conditions compared to those for adenocarcinoma. We therefore investigated the molecular characteristics of neuroendocrine carcinomas (NECs). We enrolled patients surgically diagnosed with NECs between 2011 and 2019, with complete follow-up records. All were analyzed using whole exome sequencing and p53/Rb immunohistochemistry (IHC). A total of 92 cases, comprising 45 pure SCLC, 15 combined SCLC, 27 pure LCNEC, and 5 combined LCNEC, were included. TP53 (78.3%) and RB1 (34.8%) were the most common molecular alterations, followed by KMT2D, LRP1B, FAT3, NCOR2, SPTA1, and NOTCH1. The mutation frequency for EGFR was 10.9%. Sixteen patients with LCNEC who had TP53/RB1 co-alterations were SCLC-like, while the remaining were NSCLC-like. There was no statistically significant difference between the groups regarding overall survival (OS; p = 0.458) and progression-free survival (PFS; p = 0.157). The frequency of the loss of Rb expression by IHC in SCLC-like LCNEC was 100%. Significant pathway alterations unique to SCLC included Notch and AMPK, while HIF-1 was enriched exclusively in LCNEC. NCOR2 mutation was linked to worse OS (p = 0.029) and PFS (p = 0.015), while wild-type SPTA1 was associated with poor PFS (p = 0.018). IHC for Rb was reliable for predicting LCNEC molecular subtypes, indicating its clinical value. NCOR2 and SPTA1 alterations were identified as prognostic factors that may provide therapeutic targets for patients with NEC.

Emerging platinum(IV) prodrug nanotherapeutics: A new epoch for platinum-based cancer therapy.

Owing to the unique DNA damaging cytotoxicity, platinum (Pt)-based chemotherapy has long been the first-line choice for clinical oncology. Unfortunately, Pt drugs are restricted by the severe dose-dependent toxicity and drug resistance. Correspondingly, Pt(IV) prodrugs are developed with the aim to improve the antitumor performance of Pt drugs. However, as "free" molecules, Pt(IV) prodrugs are still subject to unsatisfactory in vivo destiny and antitumor efficacy. Recently, Pt(IV) prodrug nanotherapeutics, inheriting both the merits of Pt(IV) prodrugs and nanotherapeutics, have emerged and demonstrated the promise to address the underexploited dilemma of Pt-based cancer therapy. Herein, we summarize the latest fronts of emerging Pt(IV) prodrug nanotherapeutics. First, the basic outlines of Pt(IV) prodrug nanotherapeutics are overviewed. Afterwards, how versatile Pt(IV) prodrug nanotherapeutics overcome the multiple biological barriers of antitumor drug delivery is introduced in detail. Moreover, advanced combination therapies based on multimodal Pt(IV) prodrug nanotherapeutics are discussed with special emphasis on the synergistic mechanisms. Finally, prospects and challenges of Pt(IV) prodrug nanotherapeutics for future clinical translation are spotlighted.

Progress in traditional Chinese medicine against chronic gastritis: From chronic non-atrophic gastritis to gastric precancerous lesions.

Chronic gastritis (CG) is a persistent inflammation of the gastric mucosa that can cause uncomfortable symptoms in patients. Traditional Chinese medicine (TCM) has been widely used to treat CG due to its precise efficacy, minimal side effects, and holistic approach. Clinical studies have confirmed the effectiveness of TCM in treating CG, although the mechanisms underlying this treatment have not yet been fully elucidated. In this review, we summarized the clinical research and mechanisms of TCM used to treat CG. Studies have shown that TCM mechanisms for CG treatment include H. pylori eradication, anti-inflammatory effects, immune modulation, regulation of gastric mucosal cell proliferation, apoptosis, and autophagy levels.

Effects of lauromacrogol injection under contrast-enhanced ultrasound guidance on cesarean scar pregnancy: a prospective cohort study.

Background: Compared with the current commonly used pretreatment approaches, the therapeutic effect of contrast-enhanced ultrasound-guided sclerotherapy with lauromacrogol injection (CEUSL) on cesarean scar pregnancy (CSP) is not clear. This study aimed to investigate the clinical efficacy and safety of CEUSL compared with gelatin sponge uterine artery embolization (UAE) and UAE combined with methotrexate (UAEM) in the pretreatment of CSP to prevent massive bleeding during subsequent curettage. Methods: Sixty-four patients were divided into the CEUSL (n=20), UAE (n=22), and UAEM (n=22) groups. All patients with CSP underwent curettage and hysteroscopy after CEUSL, UAE, or UAEM pretreatment. The efficacy and safety indicators after pretreatment were analyzed. Results: Time for pretreatment [95% confidence interval (CI): 31.92-39.28] and hospitalization cost (95% CI: 7,852.32-9,063.23) were significantly decreased in the CEUSL group compared with that in the UAE (95% CI: 53.55-59.99% and 95% CI: 12,901.42-15,166.63, respectively) and the UAEM group (95% CI: 52.90-58.83 and 95% CI: 11,324.66-13,302.69, respectively; P<0.001). The beta human chorionic gonadotropin (ß-hCG) percentage decrease 24 hours later and the hospital stay were significantly decreased in the CEUSL group (95% CI: 0.65-0.70 and 95% CI: 3.32-4.58 days, respectively) compared with those in the UAE (95% CI: 0.67-0.74 and 95% CI: 4.06-5.84, respectively) or UAEM (95% CI: 0.62-0.68 and 95% CI: 4.12-5.88, respectively) groups (P<0.05). After pretreatment, there were significantly fewer patients (P<0.05) with fever (95% CI: -0.52 to -0.093), pelvic pain (95% CI: -0.427 to -0.018), increased white blood cell count (95% CI: -0.359 to 0.040), and hypersensitive C-reactive protein (hs-CRP) elevation (95% CI: -0.572 to -0.118) in the CEUSL group than in the UAE or UAEM groups. At follow-up, all patients resumed normal menstruation, with no residual gestational sac on ultrasound imaging or sequel. Conclusions: The pretreatment procedures were all technically successful, with good outcomes in different pretreatment procedures. Compared with UAE with or without methotrexate, CEUSL may be as effective and safe for pretreatment of CSP, with fewer adverse effects and shorter pretreatment time and hospital stay.

Selectively compromised inner retina function following hypoxic-ischemic encephalopathy in mice: A noninvasive measure of severity of the injury.

The intricate system of connections between the eye and the brain implies that there are common pathways for the eye and brain that get activated following injury. Hypoxia-ischemia (HI) related encephalopathy is a consequence of brain injury caused by oxygen and blood flow deprivation that may result in visual disturbances and neurodevelopmental disorders in surviving neonates. We have previously shown that the tyrosine receptor kinase B (TrkB) agonist/modulator improves neuronal survival and long-term neuroprotection in a sexually differential way. In this study, we tested the hypotheses that; 1) TrkB agonist therapy improves the visual function in a sexually differential way; 2) Visual function detected by electroretinogram (ERG) correlates with severity of brain injury detected by magnetic resonance (MRI) imaging following neonatal HI in mice. To test our hypotheses, we used C57/BL6 mice at postnatal day (P) 9 and subjected them to either Vannucci's rodent model of neonatal HI or sham surgery. ERG was performed at P 30, 60, and 90. MRI was performed following the completion of the ERG. ERG in these mice showed that the a-wave is normal, but the b-wave amplitude is severely abnormal, reducing the b/a wave amplitude ratio. Inner retina function was found to be perturbed as we detected severely attenuated oscillatory potential after HI. No sex differences were detected in the injury and severity pattern to the retina as well as in response to 7,8-DHF therapy. Strong correlations were detected between the percent change in b/a ratio and percent hemispheric/hippocampal tissue loss obtained by MRI, suggesting that ERG is a valuable noninvasive tool that can predict the long-term severity of brain injury.

Sonographic Features of Primary Breast Lymphoma: An Analysis of 10 Cases.

BACKGROUND: Primary breast lymphoma (PBL) is a rare malignant breast tumor. The literature concerning PBL ultrasound is based primarily on case reports, with only a few cases reported to date. PURPOSE: This study aimed to elucidate the sonographic characteristics of PBL and explore the value of ultrasonography in the preoperative diagnosis of PBL using the Breast Imaging Reporting and Data System (BI-RADS). METHODS: A retrospective review of files involving a diagnosis of PBL (2013-2020) was conducted in the Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, and the First Affiliated Hospital of Wenzhou Medical University, Wenzhou. The clinical characteristics and sonographic features of 12 lesions in 10 patients were analyzed and discussed in light of the literature. RESULTS: All patients, aged 50.40 ± 14.31 years (range 30-66 years), had clinically palpable lumps. Most cases were on the right breast and were unilateral. Only one patient had mucosa-associated lymphoma. The histological type of the other patients was diffuse large B-cell lymphoma (DLBCL). Ultrasonography revealed nodular and diffuse PBL lesions without internal calcification. The nodular PBL was hypoechoic or mixed hypo- to hyperechoic, with a differential lobulated shape and horizontal growth. Although color Doppler flow imaging (CDFI) showed no significant features, the ultrasound findings were categorized as BI-RADS 4 in 10 of the 12 lesions and BI-RADS 5 in two lesions. All patients were suspected of having malignancies (BI-RADS 4 or 5). CONCLUSION: PBL was mostly found in middle-aged and elderly women, and the right breast was more prone to the development of malignancies. PBL lesions were classified as either nodular or diffuse based on the boundaries of the tumors in the ultrasound images. Typical PBL was characterized by hypoechoic or heterogeneous lesions with circumscribed or microlobulated margins and horizontal growth. The sonographic features of the PBL lesions and the BI-RADS categorizations of the lesions analyzed suggested malignancy.

Therapeutic experience of a pancreatic mixed serous neuroendocrine neoplasm invading peripancreatic vessels: A case report.

RATIONALE: Pancreatic mixed serous neuroendocrine neoplasm (PMSNN) is an extremely rare disease. Only a few cases on the surgical treatment of PMSNN have been reported in the literature, and it is unclear whether there is invasion of important peripancreatic vessels. PATIENT CONCERNS: We report the case of a 39-year-old female patient with PMSNN accompanied by invasion of important peripancreatic vessels. She underwent surgery and achieved satisfactory recovery. DIAGNOSIS: Abdominal enhanced CT images showed an enhanced mass with a nonenhanced cyst involving the head and body of the pancreas, which invaded important peripancreatic vessels. The lesion had been misdiagnosed and mistreated as a metastatic carcinoma before admission. INTERVENTIONS: CT 3-dimensional (3D) visualization reconstruction images showed intact peripancreatic vessels. Radical pancreatoduodenectomy was successfully performed and confirmed that the main blood vessels around the pancreas were only compressed or even wrapped by the mass, but not penetrated. OUTCOMES: The patient recovered well and was discharged on the 19th day after surgery. Pathological examination reported the diagnosis of PMSNN with the collision type combination and the well-differentiated grade 2 pancreatic neuroendocrine tumor. She was followed up for 18 months without any abnormalities. LESSONS: This case demonstrates that surgical treatment of PMSNN with invasion of peripancreatic vessels can be successful. Preoperative abdominal CT 3D visualization reconstruction is helpful in determining the degree of invasion of important peripancreatic vessels, and plays a key role in formulating an accurate surgical plan and improving patient outcome.

TLR2 agonist promotes myeloid-derived suppressor cell polarization via Runx1 in hepatocellular carcinoma.

Myeloid-derived suppressor cells (MDSCs) play a critical role in maintaining the tumor immune microenvironment; thus, the promotion of MDSC polarization will improve immunotherapies for cancers. However, the mechanisms involved in controlling MDSC polarization in hepatocellular carcinoma remain largely unclear. In this study, we found that injection of Pam3CSK4 attenuated the process of tumor growth, along with reduction of MDSC and recovery of T cell function. Moreover, Pam3CSK4 promoted MDSC polarization by targeting Runx1. Runx1 inhibitor reversed the therapeutic effect of Pam3CSK4 by increasing tumor size and weight and decreasing the survival rate of tumor mice. In addition, targeting Runx1 reduced the expression of CD11c, F4/80, CD80/CD86 and MHC-II in MDSC after Pam3CSK4 stimulation in vivo and in vitro. MDSC also exhibited consistent changes with increasing reactive oxygen species (ROS) production after Pam3CSK4 and Ro5-3335 treatment. RNA sequence data revealed that tfrc, steap3, and gclm were up-regulated in the Pam3CSK4/Ro5-3335 group compared with Pam3CSK4 treatment alone, suggesting that the regulatory effect of TLR2 and Runx1 on MDSC might act through the ferroptosis pathway. Overall, our study has identified a critical role for TLR2 and Runx1 in regulating the differentiation and function of MDSCs and has provided a new mechanism of controlling MDSC polarization during HCC immunotherapy.

Tumor-on-a-chip model for advancement of anti-cancer nano drug delivery system.

Despite explosive growth in the development of nano-drug delivery systems (NDDS) targeting tumors in the last few decades, clinical translation rates are low owing to the lack of efficient models for evaluating and predicting responses. Microfluidics-based tumor-on-a-chip (TOC) systems provide a promising approach to address these challenges. The integrated engineered platforms can recapitulate complex in vivo tumor features at a microscale level, such as the tumor microenvironment, three-dimensional tissue structure, and dynamic culture conditions, thus improving the correlation between results derived from preclinical and clinical trials in evaluating anticancer nanomedicines. The specific focus of this review is to describe recent advances in TOCs for the evaluation of nanomedicine, categorized into six sections based on the drug delivery process: circulation behavior after infusion, endothelial and matrix barriers, tumor uptake, therapeutic efficacy, safety, and resistance. We also discuss current issues and future directions for an end-use perspective of TOCs.

Application of magnetic susceptibility and heavy metal bioaccessibility to assessments of urban sandstorm contamination and health risks: Case studies from Dunhuang and Lanzhou, Northwest China.

Direct ingestion of sandstorm particles is an important pathway in human exposure to heavy metals. This study investigated the potential health risks of heavy metals transported in sandstorms from Dunhuang to Lanzhou in northwestern China using environmental magnetic parameters and metal bioaccessibilities in simulated gastric and intestinal tracts. The mean magnetic susceptibility of sandstorms in Lanzhou was 366.86 × 10-8 m3/kg, which was more than 5-fold higher than that of sandstorms in Dunhuang, indicating that these sandstorms continuously receive heavy metals with high magnetic mineral content along their pathways. Heavy metal concentrations in sandstorms were higher than background values and those in urban topsoil. Enrichment factors and pollution load indices showed that these heavy metals were derived from both natural and anthropogenic sources, with Cu, Zn, Pb, and Cd being strongly influenced by anthropogenic sources. The bioaccessibilities of Cd, Cu, Zn, and Pb in the sandstorms of Lanzhou were very high, ranging from 22.69% (Cu) to 50.86% (Pb) for gastric phase, and 12.07% (Pb)-22.11% (Cd) for interstinal phase, with the significant reduction in χlf of the physiologically-based extraction testing (PBET) treated sandstorms. The magnetic minerals are significant correlation with the concentrations of heavy metals in sandstorm and effect the release of heavy metals during human digestion process. The overall ecological risk posed by heavy metals contained in sandstorms was relatively low; however, the risk was moderate to high at individual sites. Ingestion posed the highest carcinogenic and non-carcinogenic risks for both adults and children, with the risk for children being higher.

A prognostic classification based on the International Association for the Study of Lung Cancer histologic grading and immunoscore in KRAS-mutant invasive non-mucinous adenocarcinoma.

BACKGROUND: Tumor immune cell infiltration is important in the prognosis of patients with lung adenocarcinoma. The aim of this study was to develop a prognostic classification based on the tumor immunoscore. METHODS: Patients with KRAS-mutant invasive non-mucinous lung adenocarcinoma who underwent radical surgery were enrolled in the study. Histologic grading was assessed according to the recommendations of the International Association for the Study of Lung Cancer. Programmed death-ligand 1 (PD-L1) and CD8 expression was detected using immunohistochemistry. The number of CD8+ tumor-infiltrating lymphocytes (TILs) per high-power field was assessed. A classification based on histological grade and CD8+ TIL level was established (Grading-Immunoscore type): low-to-medium grade with high or low infiltration (type A); high-grade, high-infiltration (type B); and high-grade, low-infiltration (type C). RESULTS: A total of 112 patients participated. In the multivariable analysis, histological grading and level of CD8+ TILs were independent prognostic factors for overall survival (OS) and progression-free survival (PFS) (p < 0.001 and p = 0.007, respectively). Patients with type A tumors had the best OS and PFS, whereas those with type C tumors had the worst OS (89.6%, 65.0%, and 29.5% 5-year OS for types A, B, and C, respectively). PD-L1 positivity and high expression rate was highest in type B tumors (tumor proportion score [TPS] ≥ 1%: 29.4%, 73.1%, and 42.9%; TPS ≥50%: 7.8%, 42.3%, and 17.1%, for types A, B, and C, respectively). CONCLUSIONS: The Grading-Immunoscore classification refines the prognostic grouping of histological grading and might aid in the screening of potential candidates for immunotherapy in patients with KRAS-mutant adenocarcinoma.