Clear cell hepatocellular carcinoma: Gd-EOB-DTPA-enhanced MR imaging features and prognosis.

PURPOSE: To investigate imaging findings on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) and prognosis of clear cell hepatocellular carcinoma (CCHCC) comparing with non-otherwise specified hepatocellular carcinoma (NOS-HCC). METHODS: The clinical, pathological and MR imaging features of 42 patients with CCHCC and 84 age-matched patients with NOS-HCC were retrospectively analyzed from January 2015 to October 2021. Univariate and multivariate logistic regression and Cox regression analyses were performed to identify independent diagnostic and prognostic factors for CCHCC. Disease-free survival (DFS) and overall survival (OS) were determined by Kaplan-Meier analysis. RESULTS: CCHCC showed fat content more frequently (P < 0.001) and relatively higher Edmondson tumor grade (P = 0.001) compared with NOS-HCC. The lesion-to-muscle ratio (LMR) and lesion-to-liver ratio (LLR) of CCHCC on pre-enhancement T1-weighted imaging (pre-T1WI) (P = 0.001, P = 0.003) and hepatobiliary phase (HBP) (P = 0.007, P = 0.048) were significantly higher than those of NOS-HCC. The area under the curve (AUC) for fat content, LLR on pre-T1WI and their combination with better diagnostic performance in predicting CCHCC were 0.678, 0.666, and 0.750, respectively. There was no statistically significant difference in clinical outcomes between CCHCC and NOS-HCC. Multivariate Cox analysis confirmed that tumor size > 2 cm and enhancing capsule were independent prognostic factors for DFS and OS among CCHCC patients. CONCLUSION: Fat content and adjusted lesion signal intensity on pre-T1WI and HBP could be used to differentiate CCHCC from NOS-HCC. CCHCC had similar prognosis with NOS-HCC.

Mitochondria-Modulating Liposomes Reverse Radio-Resistance for Colorectal Cancer.

Complete remission of colorectal cancer (CRC) is still unachievable in the majority of patients by common fractionated radiotherapy, leaving risks of tumor metastasis and recurrence. Herein, clinical CRC samples demonstrated a difference in the phosphorylation of translation initiation factor eIF2α (p-eIF2α) and the activating transcription factor 4 (ATF4), whose increased expression by initial X-ray irradiation led to the resistance to subsequent radiotherapy. The underlying mechanism is studied in radio-resistant CT26 cells, revealing that the incomplete mitochondrial outer membrane permeabilization (iMOMP) triggered by X-ray irradiation is key for the elevated expression of p-eIF2α and ATF4, and therefore radio-resistance. This finding guided to discover that metformin and 2-DG are synergistic in reversing radio resistance by inhibiting p-eIF2α and ATF4. Liposomes loaded with metformin and 2-DG (M/D-Lipo) are thus prepared for enhancing fractionated radiotherapy of CRC, which achieved satisfactory therapeutic efficacy in both local and metastatic CRC tumors by reversing radio-resistance and preventing T lymphocyte exhaustion.

An integrated approach to assess human health risk of neonicotinoid insecticides in surface water of the Yangtze River Basin, China.

Neonicotinoids are widely used insecticides that have raised considerable concerns for both environmental and human health. However, there lack of comprehensive evaluation of their accumulation in surface water ecosystems and exposure to various human groups. Additionally, there's a distinct lack of scientific evidence describing the carcinogenic and non-carcinogenic impacts of neonicotinoids from surface water. Using an integrated approach employing the Relative Potency Factor (RPF), Hazard Index (HI), and Monte Carlo Simulation (MCS), the study assessed neonicotinoid exposure and risk to four demographic groups via dermal contact and mistaken oral intake pathways in the Yangtze River Basin (YRB), China. Neonicotinoid concentrations range from 0.1 to 408.12 ng/L, indicating potential risk (10-3 to 10-1) across the studied demographic groups. The Incremental Lifetime Cancer Risk (ILCR) for dermal contact was within a moderate range of 2.00 × 10-3 to 1.67 × 10-2, while the mistaken oral intake was also within a moderate range of 3.07 × 10-3 to 7.05 × 10-3. The Hazard Index (HI) for dermal exposure ranged from 1.49 × 10-2 to 0.125, while for mistaken oral intake, it varied between 2.69 × 10-2 and 0.14. The findings highlight the importance of implementing specific interventions to address neonicotinoid exposure, especially among demographic groups that are more susceptible. This research underscores the urgent need for targeted strategies to address neonicotinoid risks to vulnerable populations within the YRB while contributing to insights for effective policies to mitigate neonicotinoid exposure in surface water ecosystems globally.

Single-cell low-pass whole genome sequencing accurately detects circulating tumor cells for liquid biopsy-based multi-cancer diagnosis.

Accurate detection of circulating tumor cells (CTCs) in blood and non-blood body fluids enables generation of deterministic cancer diagnosis and represent a less invasive and safer liquid biopsy approach. Although genomic alternations have been widely used in circulating tumor DNA (ctDNA) analysis, studies on cell-based genomic alternations profiling for CTC detection are rare due to major technical limitations in single-cell whole genome sequencing (WGS) including low throughput, low accuracy and high cost. We report a single-cell low-pass WGS-based protocol (scMet-Seq) for sensitive and accurate CTC detection by combining a metabolic function-associated marker Hexokinase 2 (HK2) and a Tn5 transposome-based WGS method with improved cell fixation strategy. To explore the clinical use, scMet-Seq has been investigated with blood and non-blood body fluids in diagnosing metastatic diseases, including ascites-based diagnosis of malignant ascites (MA) and blood-based diagnosis of metastatic small-cell lung cancer (SCLC). ScMet-Seq shows high diagnostic sensitivity (MA: 79% in >10 cancer types; metastatic SCLC: 90%) and ~100% of diagnostic specificity and positive predictive value, superior to clinical cytology that exhibits diagnostic sensitivity of 52% in MA diagnosis and could not generate blood-based diagnosis. ScMet-Seq represents a liquid biopsy approach for deterministic cancer diagnosis in different types of cancers and body fluids.

Regulation of Angiogenesis by Non-Coding RNAs in Cancer.

Non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, have been identified as crucial regulators of various biological processes through epigenetic regulation, transcriptional regulation, and post-transcriptional regulation. Growing evidence suggests that dysregulation and activation of non-coding RNAs are closely associated with tumor angiogenesis, a process essential for tumor growth and metastasis and a major contributor to cancer-related mortality. Therefore, understanding the molecular mechanisms underlying tumor angiogenesis is of utmost importance. Numerous studies have documented the involvement of different types of non-coding RNAs in the regulation of angiogenesis. This review provides an overview of how non-coding RNAs regulate tumor angiogenesis. Additionally, we discuss emerging strategies that exploit non-coding RNAs for anti-angiogenic therapy in cancer treatment. Ultimately, this review underscores the crucial role played by non-coding RNAs in tumor angiogenesis and highlights their potential as therapeutic targets for anti-angiogenic interventions against cancer.

Early Diagnosis and Prognosis Prediction of Pancreatic Cancer Using Engineered Hybrid Core-Shells in Laser Desorption/Ionization Mass Spectrometry.

Effective detection of bio-molecules relies on the precise design and preparation of materials, particularly in laser desorption/ionization mass spectrometry (LDI-MS). Despite significant advancements in substrate materials, the performance of single-structured substrates remains suboptimal for LDI-MS analysis of complex systems. Herein, designer Au@SiO2@ZrO2 core-shell substrates are developed for LDI-MS-based early diagnosis and prognosis of pancreatic cancer (PC). Through controlling Au core size and ZrO2 shell crystallization, signal amplification of metabolites up to 3 orders is not only achieved, but also the synergistic mechanism of the LDI process is revealed. The optimized Au@SiO2@ZrO2 enables a direct record of serum metabolic fingerprints (SMFs) by LDI-MS. Subsequently, SMFs are employed to distinguish early PC (stage I/II) from controls, with an accuracy of 92%. Moreover, a prognostic prediction scoring system is established with enhanced efficacy in predicting PC survival compared to CA19-9 (p < 0.05). This work contributes to material-based cancer diagnosis and prognosis.

Clinicopathological analysis of bronchiolar adenoma combined with lung adenocarcinoma: Report of eight cases and literature review.

AIMS: To investigate the clinicopathological characteristics and potential diagnostic pitfalls of bronchiolar adenoma (BA) combined with lung adenocarcinoma (LUAD) in the same lesion. METHODS: We analyzed eight cases of BA combined with LUAD from our hospital pathology department between July 2020 and January 2022, and summarized their clinical data, radiological features, histopathological characteristics and immunohistochemical phenotypes. RESULTS: Upon macroscopic examination, the lesions were characterized by gray-white or gray-brown solid nodules with well-defined borders, measuring 0.6-1.8cm in maximum diameter. The incidence of proximal-type BA (6/8) was higher than that of distal-type BA (2/8), and they combined with different stages of LUAD, including adenocarcinoma in situ, minimally invasive adenocarcinoma, invasive adenocarcinoma, and invasive mucinous adenocarcinoma (IMA). Immunohistochemistry showed that cytokeratin 5/6 and P40 were positive in the continuous basal cell layer in BA, but only scattered positive basal cells were seen at the junction of BA and LUAD. TTF-1 was positive in proximal-type BA ciliated cells in five cases and in LUAD cells in seven cases, and weakly positive in some basal cells. One case of IMA and mucinous cells of BA were TTF-1 negative. There was partially positive Napsin-A expression in BA luminal cells and LUAD cells of all cases except IMA. CONCLUSION: There is no obvious boundary when BA and LUAD are in the same lesion. The luminal epithelial cells in the area where the two components migrate toward each other are atypical and lack a continuous underlying basal cell layer. Microscopic diagnosis should be aided by immunohistochemistry.

Expression and clinical significance of PD-L1 and infiltrated immune cells in the gastric adenocarcinoma microenvironment.

Programmed death-ligand 1 (PD-L1) is a crucial negative costimulatory molecule expressed on both tumor and immune cells. It binds to programmed death-1, facilitating tumor escape. Tumor-infiltrating immune cells play a vital role in this process. However, the clinical relationship between PD-L1 expression and tumor-infiltrating immune cells remains uncertain. Immunohistochemistry (IHC) was utilized to assess PD-L1 expression and TIIC markers (CD3, CD4, CD8, CD19, CD31, CD68, CD11c, CD56, and α-smooth muscle actin) in gastric adenocarcinoma tissues from 268 patients. The aim was to explore the prognostic significance of PD-L1 and the infiltration of different immune cell types. The study analyzed overall survival and the correlations between PD-L1 expression, immune cell infiltration, and clinicopathological characteristics. Among the 268 patients, 52 (19.40%) exhibited high PD-L1 expression on tumor cells (TPD-L1), while 167 (62.31%) displayed high PD-L1 expression on immune cells (IPD-L1). Patients with high IPD-L1 expression showed improved survival compared to those with low IPD-L1 expression (P = .028). High TPD-L1 expression associated with various clinicopathological features, such as larger tumor size, poorer differentiation, deeper invasion depth, and higher tumor stage. Conversely, patients with high IPD-L1 expression exhibited shallower tumor invasion and lower mortality rates. Univariate analysis indicated that superficial tumor infiltration, absence of lymph node and distant metastasis, low tumor stage, high IPD-L1 expression, and elevated CD8 and CD19 expression were associated with a reduced risk of tumor progression. Multivariate analysis revealed that patients with high IPD-L1 and CD8 expression or high TPD-L1 and low CD31 expression experienced significantly better overall survival than patients with other combinations. The findings indicate that patients with high PD-L1 expression in immune cells have a substantially improved prognosis. Additionally, the combination of PD-L1 with CD8 or CD31 expression status can serve as an indicator of prognosis in patients with gastric adenocarcinoma.

Multi-omics analyses reveal spatial heterogeneity in primary and metastatic oesophageal squamous cell carcinoma.

BACKGROUND: Biopsies obtained from primary oesophageal squamous cell carcinoma (ESCC) guide diagnosis and treatment. However, spatial intra-tumoral heterogeneity (ITH) influences biopsy-derived information and patient responsiveness to therapy. Here, we aimed to elucidate the spatial ITH of ESCC and matched lymph node metastasis (LNmet ). METHODS: Primary tumour superficial (PTsup ), deep (PTdeep ) and LNmet subregions of patients with locally advanced resectable ESCC were evaluated using whole-exome sequencing (WES), whole-transcriptome sequencing and spatially resolved digital spatial profiling (DSP). To validate the findings, immunohistochemistry was conducted and a single-cell transcriptomic dataset was analysed. RESULTS: WES revealed 15.72%, 5.02% and 32.00% unique mutations in PTsup , PTdeep and LNmet , respectively. Copy number alterations and phylogenetic trees showed spatial ITH among subregions both within and among patients. Driver mutations had a mixed intra-tumoral clonal status among subregions. Transcriptome data showed distinct differentially expressed genes among subregions. LNmet exhibited elevated expression of immunomodulatory genes and enriched immune cells, particularly when compared with PTsup (all P < .05). DSP revealed orthogonal support of bulk transcriptome results, with differences in protein and immune cell abundance between subregions in a spatial context. The integrative analysis of multi-omics data revealed complex heterogeneity in mRNA/protein levels and immune cell abundance within each subregion. CONCLUSIONS: This study comprehensively characterised spatial ITH in ESCC, and the findings highlight the clinical significance of unbiased molecular classification based on multi-omics data and their potential to improve the understanding and management of ESCC. The current practices for tissue sampling are insufficient for guiding precision medicine for ESCC, and routine profiling of PTdeep and/or LNmet should be systematically performed to obtain a more comprehensive understanding of ESCC and better inform treatment decisions.

Canadine inhibits epithelial mesenchymal transformation of HPV-negative cervical cancer.

Although the majority of the population will be protected due to the advent and widespread use of the HPV vaccine, the treatment of cervical cancer for all causes, including HPV-negative cervical cancer, is still worthy of further research. The focal point of this study was Canadine's inhibition of epithelial-mesenchymal transformation (EMT) in cervical cancer. Immunoblotting, wound healing and tumor invasion experiments showed that low concentration of Canadine could inhibit the EMT process, proliferation and migration of HT-3 cells (HPV-negative cell line). Combined with GEO database, it was found that the expression levels of several genes highly expressed in cervical tumor tissues could be inhibited by Canadine, especially MAGEA3. Further experiments confirmed that the inhibition of Canadine on MAGEA3 protein increased with time. The small interference and overexpression plasmid of MAGEA3 were designed and verified. In HT-3 cells, when MAGEA3 levels were directly decreased, mesenchymal phenotypic markers were decreased and epithelial phenotypic markers were increased. The opposite result was obtained by overexpression of MAGEA3. In addition, the inhibition of EMT due to the reduction of endogenous MAGEA3 by Canadine was also offset by the overexpression of exogenous MAGEA3. The study concludes that Canadine inhibits EMT of cervical cancer by inhibiting MAGEA3.

FAM134B-induced endoplasmic reticulum (ER)-phagy exacerbates cisplatin-insulted hair cell apoptosis ：Possible relation to excessive ER stress.

AIMS: FAM134B, the initial endoplasmic reticulum (ER)-phagy receptor identified, facilitates ER-phagy during ER stress. The malfunction of FAM134B has been demonstrated to have a crucial role in the pathological mechanisms of diverse human ailments. However, the role of FAM134B-mediated ER-phagy in ototoxicity, particularly in cisplatin-induced ototoxicity, remains unclear. The present study endeavors to investigate whether FAM134B is expressed in House Ear Institute-Organ of Corti 1 (HEI-OC1) and C57BL/6 murine cochlear hair cells (HCs), and to explore its potential function in cisplatin-mediated ototoxicity, with the aim of discovering new insights that can mitigate or forestall the irreversible adverse effect of cisplatin. METHODS: Immunofluorescence (IF) staining was used to test the expression pattern of FAM134B, levels of C/EBP-homologous protein (CHOP), autophagy, and co-localization ratio of lysosomes and ER. Western blotting was employed to measure changes in expression levels of FAM134B, LC3B, ER stress-related proteins, LAMP1 and apoptotic mediators. Cell apoptosis was examined using transferase dUTP nick end labeling (TUNEL) assay and flow cytometry. RESULTS: In the present investigation, it was observed that FAM134B exhibited a diffuse expression pattern in the cytoplasm and nuclei of control HEI-OC1 cells. Following cisplatin administration, FAM134B was found to accumulate and form distinct dots around the nuclei, concomitant with increased levels of ER-phagy, ER stress, unfolded protein response (UPR), and cell apoptosis. Additionally, knockdown of FAM134B resulted in reduced ER-phagy, mitigated ER stress and UPR, and decreased apoptotic activity in HEI-OC1 cells following cisplatin exposure. CONCLUSIONS: Collectively, the findings of this study demonstrate that FAM134B-mediated ER-phagy enhances the susceptibility of HCs to ER stress and apoptosis in response to cisplatin-induced stress. This suggests a sequential progression of ER-phagy, ER stress and apoptosis following cisplatin stimulus, and implies the potential therapeutic benefit of inhibiting of FAM134B-mediated ER-phagy in the prevention of cisplatin-related ototoxicity.

Regulation of Ion Homeostasis for Enhanced Tumor Radio-Immunotherapy.

Intra/extracellular ion content affects the growth and metastasis of tumor cells, as well as the efficacy of various antitumor therapies. Herein, a carbonic anhydrase inhibitor (CAI) is loaded onto pH-responsive calcium carbonate (CaCO3 ) nanoparticles and then modify theses nanoparticles with liposomes to obtain biocompatible CaCO3 /CAI@Lipsome (CCL) for enhance tumor radio-immunotherapy. CCL can specially decompose in tumor microenvironment, releasing calcium ion (Ca2+ ) and CAI, as well as increasing the pH value of extracellular fluid. CAI restrains the flow of hydrogen ion (H+ ) inside and outside the tumor cells, resulting in the reversal of tumor acidic microenvironment and the increase of intracellular H+ , both of which can improve the sensitivity of tumor to radiotherapy. Afterward, the increased intracellular H+ together with radiotherapy-causes reactive oxygen species promotes calcium influx, leading to cellular calcium overload. Moreover, the CCL-tailored content of H+ and Ca2+ strengthens radiotherapy-induced immunogenic cell death and dendritic cell maturation, amplifying systemic anti-tumor adaptive immunity. Meanwhile, macrophages in the CCL-treated tumors are polarized from pro-tumor M2 to anti-tumor M1 under X-ray exposure, owing to the neutralization of tumor acidic microenvironment and enhances Ca2+ content. Therefore, multi-directional regulation of the intra/extra tumor cell pH/calcium by simple nano-preparation would provide a powerful way to improve the efficacy of radio-immunotherapy.

Clinical significance of CD155 expression and correlation with cellular components of tumor microenvironment in gastric adenocarcinoma.

Introduction: CD155 is recently emerging as a promising target in malignancies. However, the relationship between CD155 expression and tumor microenvironment (TME) cell infiltration in gastric adenocarcinoma (GAC) has rarely been clarified. Methods: We measured CD155 expression in specimens of gastric precancerous disease and GAC by immunohistochemistry. The association of CD155 expression with GAC progression and cells infiltration in TME was evaluated through 268 GAC tissues and public dataset analysis. Results: We showed that the expression of CD155 was positively correlated with the pathological development of gastric precancerous disease (r = 0.521, P < 0.0001). GAC patients with high CD155 expression had a poorer overall survival (P = 0.033). Moreover, CD155 expression correlated with aggressive clinicopathological features including tumor volume, tumor stage, lymph node involvement, and cell proliferation (P <0.05). Remarkably, CD155 expression positively related to the infiltration of CD68+ macrophages in TME (P = 0.011). Meanwhile, the positive correlation was observed between CD155 and CD31 (P = 0.026). In addition, patients with high CD155 expression combined with low CD3, CD4, CD8, IL-17, IFN-γ or CD19 expression as well as those with high CD155 and α-SMA expression showed significantly worse overall survival (P < 0.05). Conclusions: CD155 may play a pivotal role in the development of GAC through both immunological and non-immunological mechanisms and be expected to become a novel target of immunotherapy in GAC patients.

Mechanistic insights of NAC1 nuclear export and its role in ovarian cancer resistance to docetaxel.

In this study, we uncovered the nuclear export of nucleus accumbens-associated protein-1 (NAC1) as a novel mechanism involved in ovarian cancer resistance to taxanes, the chemotherapeutic drugs commonly used in treatment of this malignancy. We showed that NAC1, a nuclear factor of the BTB/POZ gene family, has a nuclear export signal (NES) at the N terminus (aa 17-28), and this NES critically contributes to the NAC1 nuclear-cytoplasmic shuttling when tumor cells were treated with docetaxel. Mechanistically, the nuclear-exported NAC1 bound to cullin3 (Cul3) and Cyclin B1 via its BTB and BOZ domains respectively, and the cyto-NAC1-Cul3 E3 ubiquitin ligase complex promotes the ubiquitination and degradation of Cyclin B1, thereby facilitating mitotic exit and leading to cellular resistance to docetaxel. We also showed in in vitro and in vivo experiments that TP-CH-1178, a membrane-permeable polypeptide against the NAC1 NES motif, blocked the nuclear export of NAC1, interfered with the degradation of Cyclin B1 and sensitized ovarian cancer cells to docetaxel. This study not only reveals a novel mechanism by which the NAC1 nuclear export is regulated and Cyclin B1 degradation and mitotic exit are impacted by the NAC1-Cul3 complex, but also provides the nuclear-export pathway of NAC1 as a potential target for modulating taxanes resistance in ovarian cancer and other malignancies.

Silencing of FAM111B inhibits tumor growth and promotes apoptosis by decreasing AKT activity in ovarian cancer.

Ovarian cancer is the most lethal gynecological tumor in women worldwide. FAM111B (family with sequence similarity 111 member B) is an oncoprotein associated with multiple cancers, but its biological functions in ovarian cancer remain elusive. In this study, FAM111B was overexpressed in ovarian cancer tissues and cell lines. Functional studies in vitro revealed that silencing of FAM111B inhibited ovarian cancer cell proliferation, invasion, and migration, as well as increased cell apoptosis. Furthermore, FAM111B silencing arrested the ovarian cancer cell cycle at the G1/S phase. Furthermore, western blot assays demonstrated that silencing of FAM111B resulted in downregulation of phospho-AKT (p-AKT) protein expression, as well as upregulation of p53 and caspase-1 protein expression. The xenograft animal model of ovarian cancer demonstrated that FAM111B silencing inhibited tumor growth, enhanced cell apoptosis, and inhibited Ki-67 and proliferating cell nuclear antigen (PCNA) protein expression in vivo. Conversely, the overexpression of FAM111B exhibited opposite effects on the ovarian cancer xenograft. It was previously established that inactivating AKT inhibited ovarian cancer progression. This study found that silencing of FAM111B inhibits tumor growth and promotes apoptosis by decreasing AKT activity in ovarian cancer. Caspase-1 and p53 signaling also influenced the function of FAM111B in SKOV3 cells. Collectively, our results demonstrate that silencing of FAM111B is a potential therapeutic strategy against ovarian cancer.

Hsa_circ_0046430 promotes the progression of colorectal cancer by targeting miR-6785-5p/SRCIN1 axis as a ceRNA.

The correlation among circular RNAs (circRNAs), microRNAs, and messenger RNAs have gained increasing attention in recent years. However, the mechanism of such discoveries in colorectal cancer (CRC) is not yet elucidated. The present study aimed to clarify whether the novel circRNAs regulate the prognosis-related genes through the competing endogenous RNAs (ceRNA). An analysis of the Weighted Gene Co-Expression Network Analysis was conducted to screen a module-trait circRNAs, and other big data mining technologies were used to predict the related microRNAs and the downstream genes. Prognosis-related gene model was built using the Cox regression analysis for the 138 messenger RNAs associated with hsa circ 0046430. The qRT-PCR was adopted to verify ceRNA network. Immunohistochemistry verified the correlation between SRCIN1 and patient prognosis. In summary, these results demonstrated that hsa_circ_0046430 is a tumor-related circRNA based on the clinical characteristics module of Weighted Gene Co-Expression Network Analysis. The prognostic risk score signature model analysis indicated that CRC risk was independently related to the risk score and SRCIN1 was independently associated with overall survival. Therefore, the hsa_circ_0046430/miR-6785-5p/SRCIN1 axis was constructed. Hsa_circ_0046430/miR-6785-5p/SRCIN1 axis relative expression level was determined by qRT-PCR. Immunohistochemical staining further validated that SCRIN1 was significantly higher in cancer than in adjacent normal tissues. Our study identified and primarily validated the hsa_circ_0046430/miR-6785-5p/SRCIN1 regulatory axis impacted on CRC prognosis, suggesting novel biomarkers and therapeutic targets for CRC patients. Further in-depth studies are essential to confirm the underlying ceRNA mechanism.

MIST: multiple instance learning network based on Swin Transformer for whole slide image classification of colorectal adenomas.

Colorectal adenoma is a recognized precancerous lesion of colorectal cancer (CRC), and at least 80% of colorectal cancers are malignantly transformed from it. Therefore, it is essential to distinguish benign from malignant adenomas in the early screening of colorectal cancer. Many deep learning computational pathology studies based on whole slide images (WSIs) have been proposed. Most approaches require manual annotation of lesion regions on WSIs, which is time-consuming and labor-intensive. This study proposes a new approach, MIST - Multiple Instance learning network based on the Swin Transformer, which can accurately classify colorectal adenoma WSIs only with slide-level labels. MIST uses the Swin Transformer as the backbone to extract features of images through self-supervised contrastive learning and uses a dual-stream multiple instance learning network to predict the class of slides. We trained and validated MIST on 666 WSIs collected from 480 colorectal adenoma patients in the Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School. These slides contained six common types of colorectal adenomas. The accuracy of external validation on 273 newly collected WSIs from Nanjing First Hospital was 0.784, which was superior to the existing methods and reached a level comparable to that of the local pathologist's accuracy of 0.806. Finally, we analyzed the interpretability of MIST and observed that the lesion areas of interest in MIST were generally consistent with those of interest to local pathologists. In conclusion, MIST is a low-burden, interpretable, and effective approach that can be used in colorectal cancer screening and may lead to a potential reduction in the mortality of CRC patients by assisting clinicians in the decision-making process. © 2022 The Pathological Society of Great Britain and Ireland.

Associations between serum polychlorinated biphenyls, halogen flame retardants, and renal function indexes in residents of an e-waste recycling area.

E-waste handling activities release large quantities of polychlorinated biphenyls (PCBs) and halogen flame retardants (HFRs) into the surrounding area, creating a high exposure risk for local residents. However, the possibility of PCBs and HFRs exposure contributing to renal injury has not been extensively studied. To fill this knowledge gap, we conducted an epidemiological analysis of adolescents and adults recruited from an e-waste recycling area and a control area. Some PCBs and HFRs compounds were statistically significantly associated with the levels of ß2-microglobulin (ß2-MG), blood urea nitrogen (BUN), serum creatinine (SCr), and uric acid, with thyroid hormone-related genes found to partly mediate these associations. The interactions of PCBs and HFRs with metals also influenced renal function indexes. Exposure to high concentrations of PCBs and HFRs resulted in higher levels of ß2-MG and lower levels of BUN and SCr in the exposed group. As indicated by the elevated ß2-MG levels, high exposure to PCBs and HFRs may increase the risk of early renal injury for adolescents. These findings help to clarify the impacts of PCBs and HFRs on renal function and highlight the need to protect the health of residents in regions impacted by e-waste handling activities.

Specific Overexpression of YAP in Vascular Smooth Muscle Attenuated Abdominal Aortic Aneurysm Formation by Activating Elastic Fiber Assembly via LTBP4.

Abdominal aortic aneurysm (AAA) is a fatal vascular disease. Vascular smooth muscle cells (VSMCs) play a crucial role in the pathogenesis of AAA. Increasing evidence has shown that Yes-associated protein (YAP) is involved in diverse vascular diseases. However, the role of YAP in AAA remains unclear. The current study aimed to determine the role of YAP in AAA formation and the underlying mechanism. We found that YAP expression in VSMCs was markedly decreased in human and experimental AAA samples. Furthermore, VSMC-specific YAP overexpression prevented several pathogenic factor-induced AAA. Mechanistically, YAP overexpression in VSMCs promoted latent transforming growth factor-ß binding protein 4 (LTBP4) expression, an important factor in elastic fiber assembly. Finally, silencing of LTBP4 in VSMCs abolished the protective role of YAP in AAA formation in vivo. Our results suggest that YAP promotes LTBP4-mediated elastic fibril assembly in VSMCs, which mitigates elastin degradation and AAA formation.

Mesenchymal stem/stromal cells primed by inflammatory cytokines alleviate psoriasis-like inflammation via the TSG-6-neutrophil axis.

Psoriasis is currently an incurable skin disorder mainly driven by a chronic inflammatory response. We found that subcutaneous application of umbilical cord- derived mesenchymal stem/stromal cells (MSCs) primed by IFN-γ and TNF-α, referred to as MSCs-IT, exhibited remarkable therapeutic efficacy on imiquimod (IMQ)-induced psoriasis-like inflammation in mice. Neutrophil infiltration, a hallmark of psoriasis, was significantly reduced after treatment with MSCs-IT. We further demonstrated that the effects of MSCs-IT were mediated by tumor necrosis factor (TNF) stimulating gene-6 (TSG-6), which was greatly upregulated in MSCs upon IFN-γ and TNF-α stimulation. MSCs transduced with TSG-6 siRNA lost their therapeutic efficacy while recombinant TSG-6 applied alone could also reduce neutrophil infiltration and alleviate the psoriatic lesions. Furthermore, we demonstrated that TSG-6 could inhibit neutrophil recruitment by decreasing the expression of CXCL1, which may be related to the reduced level of STAT1 phosphorylation in the keratinocytes. Thus, blocking neutrophil recruitment by MSCs-IT or TSG-6 has potential for therapeutic application in human psoriasis.