The mechanism and experimental verification of Ixeris sonchifolia promoting apoptosis of hepatocellular carcinoma based on network pharmacology: Ixeris sonchifolia Induces Hepatocellular Carcinoma Apoptosis via the PI3K/AKT Pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Ixeris sonchifolia alias Kudiezi, it was named Ixeris sonchifolia (Bunge) Hance, a synonym for Crepidiastrum sonchifolium (Bunge) Pak & Kawano in the https://www.iplant.cn/. And it was first published in J. Linn. Soc., Bot. 13: 108 (1873), which was named Ixeris sonchifolia (Maxim.) Hance in the MPNS (http://mpns.kew.org). As a widely distributed medicinal and edible wild plant, it possesses unique bitter-cold characteristics and constituents with various pharmacological activities. Its main antitumor substances, same as artemisinin and paclitaxel, are classified as terpenoids and have become research foci in recent years. However, its specific biological activity and role in antitumor treatment remain largely unclear. AIM OF THE STUDY: This study aimed to elucidate the molecular targets and potential mechanisms of hepatocellular carcinoma apoptosis induced by Ixeris sonchifolia. MATERIALS AND METHODS: We used network pharmacology methods to analyze and screen the active ingredients and possible underlying mechanisms of Ixeris sonchifolia in treating liver cancer and employed integrative time- and dose-dependent toxicity, transcriptomics, and molecular biology approaches to comprehensively verify the function of Ixeris sonchifolia extract (IsE) in human hepatoblastoma cell (HepG2) apoptosis and its potential mechanism. RESULTS: A total of 169 common targets were screened by network pharmacology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that IsE inhibited HepG2 cell activity in a time- and dose-dependent manner. Western blot analysis confirmed that IsE promoted HepG2 cell apoptosis by inhibiting the PI3K/AKT signaling pathway and that the PI3K/AKT inhibitor LY294002 also substantially enhanced IsE-induced apoptosis. The PI3K/AKT signaling pathway exhibited significant differences compared to that in the control group. CONCLUSION: Combining network pharmacology with experimental verification, IsE inhibited mitochondrial function and the PI3K/AKT pathway while inducing hepatoma cell apoptosis. IsE may have promising potential for liver cancer treatment and chemoprevention.

Perioperative toripalimab and chemotherapy in locally advanced gastric or gastro-esophageal junction cancer: a randomized phase 2 trial.

Perioperative chemotherapy is the standard treatment for locally advanced gastric or gastro-esophageal junction cancer, and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. In this randomized, open-label, phase 2 study (NEOSUMMIT-01), patients with resectable gastric or gastro-esophageal junction cancer clinically staged as cT3-4aN + M0 were randomized (1:1) to receive either three preoperative and five postoperative 3-week cycles of SOX/XELOX (chemotherapy group, n = 54) or PD-1 inhibitor toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for up to 6 months (toripalimab plus chemotherapy group, n = 54). The primary endpoint was pathological complete response or near-complete response rate (tumor regression grade (TRG) 0/1). The results showed that patients in the toripalimab plus chemotherapy group achieved a higher proportion of TRG 0/1 than those in the chemotherapy group (44.4% (24 of 54, 95% confidence interval (CI): 30.9%-58.6%) versus 20.4% (11 of 54, 95% CI: 10.6%-33.5%)), and the risk difference of TRG 0/1 between toripalimab plus chemotherapy group and chemotherapy group was 22.7% (95% CI: 5.8%-39.6%; P = 0.009), meeting a prespecified endpoint. In addition, a higher pathological complete response rate (ypT0N0) was observed in the toripalimab plus chemotherapy group (22.2% (12 of 54, 95% CI: 12.0%-35.6%) versus 7.4% (4 of 54, 95% CI: 2.1%-17.9%); P = 0.030), and surgical morbidity (11.8% in the toripalimab plus chemotherapy group versus 13.5% in the chemotherapy group) and mortality (1.9% versus 0%), and treatment-related grade 3-4 adverse events (35.2% versus 29.6%) were comparable between the treatment groups. In conclusion, the addition of toripalimab to chemotherapy significantly increased the proportion of patients achieving TRG 0/1 compared to chemotherapy alone and showed a manageable safety profile. ClinicalTrials.gov registration: NCT04250948 .

Recent advances in recurrent hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, accounting for 75%-85% of cases. Although treatments are given to cure early-stage HCC, up to 50%-70% of individuals may experience a relapse of the illness in the liver after 5 years. Research on the fundamental treatment modalities for recurrent HCC is moving significantly further. The precise selection of individuals for therapy strategies with established survival advantages is crucial to ensuring better outcomes. These strategies aim to minimize substantial morbidity, support good life quality, and enhance survival for patients with recurrent HCC. For individuals with recurring HCC after curative treatment, no approved therapeutic regimen is currently available. A recent study presented novel approaches, like immunotherapy and antiviral medication, to improve the prognosis of patients with recurring HCC with the apparent lack of data to guide the clinical treatment. The data supporting several neoadjuvant and adjuvant therapies for patients with recurring HCC are outlined in this review. We also discuss the potential for future clinical and translational investigations.

Determining plasma and cerebrospinal fluid concentrations of EGFR-TKI in lung cancer patients.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are commonly used to treat advanced non-small cell lung cancer (NSCLC). A rapid and reliable method for measuring plasma and cerebrospinal fluid (CSF) concentrations of EGFR-TKIs is needed for therapeutic drug monitoring. By using UHPLC‒MS/MS with multiple reaction monitoring mode, we developed a method for rapidly determining the plasma and CSF concentrations of gefitinib, erlotinib, afatinib, and osimertinib. Protein precipitation was employed to remove protein interference for plasma and CSF matrix. The LC‒MS/MS assay was validated to be satisfactory in terms of linearity, precision, and accuracy. This method was successfully applied to measure plasma (n = 44) and CSF (n = 6) concentrations of EGFR-TKIs in NSCLC patients. The chromatographic separation was achieved by a Hypersil Gold aQ column within 3 min. The median plasma concentrations were 325.76, 1981.50, 42.62, 40.27, and 340.92 ng/ml for gefitinib erlotinib, afatinib 30 mg/day, afatinib 40 mg/day, and osimertinib, respectively. The CSF penetration rates were 2.15% for the patients receiving erlotinib therapy, 0.59% for afatinib, 0.08-1.12% for osimertinib 80 mg/day, and 2.18% for those receiving osimertinib 160 mg/day. This assay helps to predict the effectiveness and toxicities of EGFR-TKIs in the pursuit of precision medicine for lung cancer patients.

Nicosulfuron stress on the glyoxalase system and endogenous hormone content in sweet maize seedlings.

To reduce the harmful effects of nicosulfuron on sweet corn, the physiological regulation mechanism of sweet corn detoxification was studied. This study analyzed the effects of nicosulfuron stress on the glyoxalase system, hormone content, and key gene expression of nicosulfuron-tolerant "HK301" and nicosulfuron-sensitive "HK320" sweet corn seedling sister lines. After spraying nicosulfuron, the methylglyoxal (MG) content in HK301 increased first and then decreased. Glyoxalase I (GlyI) and glyoxalase II (GlyII) activities, non-enzymatic glutathione (GSH), and the glutathione redox state glutathione/(glutathione + glutathione disulfide) (GSH/(GSH + GSSG)) showed a similar trend as the MG content. Abscisic acid (ABA), gibberellin (GA), and zeatin nucleoside (ZR) also increased first and then decreased, whereas the auxin (IAA) increased continuously. In HK301, all indices after spraying nicosulfuron were significantly greater than those of the control. In HK320, MG accumulation continued to increase after nicosulfuron spraying and GlyI and GlyII activities, and GSH first increased and then decreased after 1 day of stress. The indicators above were significantly greater than the control. The GSH/(GSH + GSSG) ratio showed a decreasing trend and was significantly smaller than the control. Furthermore, ABA and IAA continued to increase, and the GA and ZR first increased and then decreased. Compared with HK320, HK301 significantly upregulated the transcription levels of GlyI and GlyII genes in roots, stems, and leaves. Comprehensive analysis showed that sweet maize seedlings improved their herbicide resistance by changing the glyoxalase system and regulating endogenous hormones. The results provide a theoretical basis for further understanding the response mechanism of the glyoxalase system and the regulation characteristics of endogenous hormones in maize under nicosulfuron stress.

Innate immune cell activation causes lung fibrosis in a humanized model of long COVID.

COVID-19 remains a global pandemic of an unprecedented magnitude with millions of people now developing "COVID lung fibrosis." Single-cell transcriptomics of lungs of patients with long COVID revealed a unique immune signature demonstrating the upregulation of key proinflammatory and innate immune effector genes CD47, IL-6, and JUN. We modeled the transition to lung fibrosis after COVID and profiled the immune response with single-cell mass cytometry in JUN mice. These studies revealed that COVID mediated chronic immune activation reminiscent to long COVID in humans. It was characterized by increased CD47, IL-6, and phospho-JUN (pJUN) expression which correlated with disease severity and pathogenic fibroblast populations. When we subsequently treated a humanized COVID lung fibrosis model by combined blockade of inflammation and fibrosis, we not only ameliorated fibrosis but also restored innate immune equilibrium indicating possible implications for clinical management of COVID lung fibrosis in patients.

Time to Local Recurrence as a Predictor of Survival in Adult Head and Neck Soft Tissue Sarcoma.

OBJECTIVES: We sought to evaluate the impact of the time interval from surgical resection to local recurrence (TTLR) on clinical outcomes in head and neck soft tissue sarcoma (HNSTS). METHODS: A total of 401 patients who underwent R0 resection for primary HNSTS were included in this study. Patients with local recurrence as the first event after their initial resection were divided into early local recurrence (ELR) or late local recurrence (LLR) groups according to TTLR. Multiple survival analyses were performed to identify the independent prognostic predictors of overall survival (OS) and survival after local recurrence (SAR). RESULTS: Two hundred and nine of the 401 patients (52.1%) developed local recurrence during a median follow-up period of 134.6 months. Patients in the ELR group had a shorter median OS time (35.0 vs. 120.6, p < 0.001) and lower 5-year OS rate (47.7% vs. 80.9%, p < 0.001) than those in the LLR group. Moreover, the ELR group exhibited worse SAR (p = 0.001) than the LLR group, and multivariate analyses demonstrated TTLR as an independent prognostic factor for SAR (p = 0.048) and OS (p = 0.004). Additionally, re-resection significantly prolonged SAR than other salvage interventions or no treatment (p < 0.001). CONCLUSION: In patients with HNSTS, ELR after R0 resection presents adverse effects on OS and SAR than those with LLR, and TTLR could serve as a promising predictor for survival. Salvage therapies, especially the re-resection could improve SAR and should be recommended when there are surgical indications after recurrence. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2174-2182, 2023.

A comprehensive review of BET-targeting PROTACs for cancer therapy.

Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) has emerged as an effective strategy for drug discovery, given their unique advantages over target protein inhibition. The bromodomain and extra-terminal (BET) family proteins play a key role in regulating oncogene expression and are considered attractive therapeutic targets for cancer therapy. Considering the therapeutic potential of BET proteins in cancer and the marked attractiveness of PROTACs, BET-targeting PROTACs have been extensively pursued. Recently, BET-targeting PROTACs based on new E3 ligases and novel strategies, such as light-activated, macrocyclic, folate-caged, aptamer-PROTAC conjugation, antibody-coupling, and autophagy-targeting strategies, have emerged. In the present review, we provide a comprehensive summary of advances in BET-targeting PROTACs.

Trastuzumab resistance in HER2-positive breast cancer: Mechanisms, emerging biomarkers and targeting agents.

Trastuzumab is a standard molecular targeted therapy for human epidermal growth factor receptor 2(HER2) -positive breast cancer, which can significantly improve the survival of patients with this molecular subtype of breast cancer. However, the clinical problem of onset or secondary resistance to trastuzumab has limited its efficacy. Therefore, it is very important to explore the mechanism of trastuzumab resistance and formulate countermeasures. Our study described the underlying molecular mechanism of trastuzumab resistance including ERBB2 mutations and nuclear localization, transcriptional and post-translational alterations of ERBB2, over-activation of bypass signaling pathways activation and so on. Then summarize the potential emerging predicting biomarkers and therapeutic strategies for trastuzumab resistance, in order to provide research direction for reversing trastuzumab resistance.

Ozone preconditioning protects rabbit heart against global ischemia-reperfusion injury in vitro by up-regulating HIF-1α.

Myocardial ischemia-reperfusion injury (MIRI) is a major factor that leads to cardiac dysfunction in cardiovascular surgery during extracorporeal circulation. Recent studies have found that ozone (O3) has protective effect on MIRI caused by the anterior descending branch of the ligated left coronary artery. However, whether O3 preconditioning has the same protective effect on global MIRI and the mechanism underlying this clinical treatment remains elusive. Here, we hypothesized that O3 preconditioning (O3P) could protect rabbit heart against global MIRI in vitro by up-regulating HIF-1α. Rabbits were treated intraperitoneally with O2/O3 mixture with different concentrations and then injected with YC-1 (inhibitor of HIF-1α) before the establishment of the global MIRI model using the Langendorff isolated heart perfusion apparatus. We investigated the effects of O3 preconditioning on cardiac systolic function, myocardial infarction, inflammatory response, mitochondrial function, myocardial pathological changes and arrhythmias. We found that the heart with O3 preconditioning significantly increased HR, LVDP and IL-10 expression, and decreased IL-6 expression, CK-MB, cTnT and cTnI concentration, myocardial infarction area, myocardial pathological injury and the occurrence of ventricular tachycardia and ventricular fibrillation. Meanwhile, the level of HIF-1α was significantly increased. However, after treatment of specific inhibitor of HIF-1α, the protective effect of O3 preconditioning was reversed completely. Our data indicates that O3 preconditioning has protective effect on MIRI and this protective effect is positively associated with dosage of O3. Energy metabolism disorder is the initial stage of MIRI and up-regulation of HIF-1α plays an important role in reducing mitochondrial dysfunction.

Recent strategies targeting Embryonic Ectoderm Development (EED) for cancer therapy: Allosteric inhibitors, PPI inhibitors, and PROTACs.

The polycomb repressive complex 2 (PRC2), which comprised of the core subunits: Enhancer of Zeste Homolog 2 (EZH2), Suppressor of Zeste 12 (SUZ12), and Embryonic Ectoderm Development (EED), is an essential epigenetic gene silencer responsible for depositing repressive histone H3 lysine 27 trimethylation (H3K27me3) marks on chromatin. The aberrant activity of PRC2 is closely involved in tumorigenesis and progression, making its inhibition a viable strategy for epigenetic cancer therapy. Although the clinical development of small PRC2 inhibitors has made impressive progress, with one EZH2 inhibitor approved for cancer therapy and several other candidates in clinical trials, current EZH2 inhibitors are limited to treating certain hematological malignancies and have acquired drug resistance. EED is essential for PRC2 stabilization and allosterically stimulating PRC2 activity because it functions as a scaffold protein and an H3K27me3-recognizing protein. Thus, due to its novel mechanism of action, targeting EED provides a promising new strategy for inhibiting PRC2 function and exhibits the potential to overcome the issues encountered by EZH2 inhibitors. This review provides a comprehensive overview of available cancer therapy strategies that target EED, including allosteric inhibitors, protein-protein interaction (PPI) inhibitors, and proteolysis-targeting chimeras (PROTACs).

SNARE Proteins Mediate α-Synuclein Secretion via Multiple Vesicular Pathways.

The cell-to-cell transmission of pathological α-synuclein (α-syn) has been proposed to be a critical event in the development of synucleinopathies. Recent studies have begun to reveal the underlying molecular mechanism of α-syn propagation. As one of the central steps, α-syn secretion is reported to be Ca2+-dependent and mediated by unconventional exocytosis. However, the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) requirement and vesicle identity of α-syn secretion remain elusive. Here we found that α-syn secretion is SNARE-dependent by systematically knocking down Q-SNAREs and R-SNAREs in exocytosis pathways. α-Syn secretion was mainly mediated by syntaxin 4 (STX4) and synaptosomal-associated protein 23 (SNAP23), but did not require STX1 and SNAP25, in differentiated SH-SY5Y cells. On the other hand, vesicle-associated membrane protein 3 (VAMP3), VAMP7, and VAMP8 were all involved in α-syn secretion, most likely in overlapping pathways. Application of super-resolution microscopy revealed localization of both endogenous and overexpressed α-syn in endosomes, lysosomes, and autophagosomes in rat primary cortical neurons. α-Syn co-localized with microtubule-associated protein 1 light chain 3 (LC3) most extensively, suggesting its tight association with the autophagy pathway. Consistently, α-syn secretion was regulated by the autophagy-lysosome pathway. Collectively, our data suggest that α-syn secretion is SNARE-dependent and is mediated by multiple vesicular pathways including exocytosis of recycling endosomes, multivesicular bodies, autophagosomes, and lysosomes.

Platelet-rich plasma combined with ozone prevents cartilage destruction and improves weight-bearing asymmetry in a surgery-induced osteoarthritis rabbit model.

BACKGROUND: Osteoarthritis (OA) is the most common degenerative disease in older adults and its treatment remains unsatisfactory. This study aimed to evaluate the effectiveness and explore the therapeutic mechanisms of the combination of platelet-rich plasma (PRP) and ozone (O3) for knee OA. METHODS: Thirty male rabbits were randomly divided into five groups (Control group, OA group, PRP group, O3 group, and PRP + O3 group). Rabbit model of OA were induced by improved Hulth surgery. Gross articular observation, histopathological examination and cartilage scoring system were used to assess the articular cartilage destruction. The bone morphogenetic protein-2 (BMP-2) mRNA expression in joint fluid was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The expression of type II collagen, matrix metalloproteinase-1 (MMP-1) of cartilage was detected via Immunohistochemistry. Pain behavior was observed by percent ipsilateral weight-bearing (PIW) asymmetry. RESULTS: The content of platelet in PRP was increased by 6.2-times that in whole blood. Among induced OA groups (the OA, PRP, O3 and PRP + O3 group), PRP + O3 significantly inhibited the surgically induced increase in gross articular alterations, histopathological damage of cartilage and Mankin score when compared to the OA, PRP and O3 groups (P<0.05). Observed pain behavior by weight-bearing asymmetry, in the PRP + O3 group was reversed at 3 and 6 weeks after the administration of PRP + O3 (PIW asymmetry: -10.66%±1.172%). In addition, surgery-induced BMP-2 mRNA expression was significantly downregulated after the treatment of PRP, O3 and PRP + O3 (P<0.01). PRP + O3 group significantly increased the expression of type II collagen but decreased MMP-1 of cartilage in comparison to OA, PRP and O3 groups (P<0.05) by immunohistochemical analysis. CONCLUSIONS: PRP combined with O3 may prevent cartilage destruction and improve weight-bearing asymmetry by restoring homeostasis between anabolism and catabolism of extracellular matrix in progressive OA. Furthermore, a combination of PRP and O3 might achieve even better results than the two agents alone.

Identification of traumatic acid as a potential plasma biomarker for sarcopenia using a metabolomics-based approach.

BACKGROUND: The pathogenesis of sarcopenia is complex and has not been well explored. Identifying biomarkers is a promising strategy for exploring the mechanism of sarcopenia. This study aimed to identify potential biomarkers of sarcopenia through a metabolomic analysis of plasma metabolites in elderly subjects (≥65 years of age) vs. younger adults (<65 years of age). METHODS: Of the 168 candidates in the Comprehensive Geriatric Assessment and Frailty Study of Elderly Outpatients, 24 elderly subjects (≥65 years of age) with sarcopenia were age and sex matched with 24 elderly subjects without sarcopenia. In addition, 24 younger adults were recruited for comparison. Muscle strength, gait speed, and metabolic and inflammatory parameters, including plasma tumour necrosis factor-α, C-reactive protein, irisin, and growth differentiation factor 15 (GDF-15) levels were assessed. Metabolomic analysis was carried out using the plasma metabolites. RESULTS: Seventy-two participants were enrolled, including 10 (41.6%) men and 14 (58.3%) women in both groups of elderly subjects. The median ages of elderly subjects with and without sarcopenia were 82 (range: 67-88) and 81.5 (range: 67-87) years, respectively. Among the 242 plasma metabolic peaks analysed among these three groups, traumatic acid was considered as a sarcopenia-related metabolite. The plasma traumatic acid signal intensity level was significantly higher in elderly subjects with sarcopenia than in elderly subjects without sarcopenia [591.5 (inter-quartile range, IQR: 491.5-664.5) vs. 430.0 (IQR: 261.0-599.5), P = 0.0063]. The plasma concentrations of traumatic acid were 15.8 (IQR: 11.5-21.7), 21.1 (IQR: 16.0-25.8), and 24.3 (IQR: 18.0-29.5) ppb in younger adults [age range: 23-37 years, 12 (50%) men], elderly subjects without sarcopenia, and elderly subjects with sarcopenia, respectively, thereby depicting an increasing tendency (P for trend = 0.034). This pattern was similar to that of GDF-15, a recognized sarcopenia-related factor. Plasma traumatic acid concentrations were also positively correlated with the presence of hypertension (r = 0.25, P = 0.034), glucose AC (r = 0.34, P = 0.0035), creatinine (r = 0.40, P = 0.0006), and GDF-15 levels (r = 0.25, P = 0.0376), but negatively correlated with the Modification of Diet in Renal Disease-simplify-glomerular filtration rate (r = -0.50, P < 0.0001). Similarly, plasma GDF-15 concentrations were associated with these factors. CONCLUSIONS: Traumatic acid might represent a potential plasma biomarker of sarcopenia. However, further studies are needed to validate the results and investigate the underlying mechanisms.

vB-ApyS-JF1, the First Trueperella pyogenes Phage, Shows Potential as an Alternative Treatment Strategy for Trueperella pyogenes Infections.

Trueperella pyogenes (T. pyogenes) is an important opportunistic animal pathogen that causes huge economic losses to the animal husbandry industry. The emergence of bacterial resistance and the unsatisfactory effect of the vaccine have prompted investigators to explore alternative strategies for controlling T. pyogenes infection. Due to the ability of phages to kill multidrug-resistant bacteria, the use of phage therapy to combat multidrug-resistant bacterial infections has attracted attention. In this study, a T. pyogenes phage, vB-ApyS-JF1 (JF1), was isolated from sewage samples, and its whole genome and biological characteristics were elucidated. Moreover, the protective effect of phage JF1 on a mouse bacteremic model caused by T. pyogenes was studied. JF1 harbors a double-stranded DNA genome with a length of 90,130 bp (30.57% G + C). The genome of JF1 lacked bacterial virulence-, antibiotic resistance- and lysogenesis-related genes. Moreover, the genome sequence of JF1 exhibited low coverage (<6%) with all published phages in the NCBI database, and a phylogenetic analysis of the terminase large subunits and capsid indicated that JF1 was evolutionarily distinct from known phages. In addition, JF1 was stable over a wide range of pH values (3 to 11) and temperatures (4 to 50°C) and exhibited strong lytic activity against T. pyogenes in vitro. In murine experiments, a single intraperitoneal administration of JF1 30 min post-inoculation provided 100% protection for mice against T. pyogenes infection. Compared to the phosphate-buffered saline (PBS) treatment group, JF1 significantly (P < 0.01) reduced the bacterial load in the blood and tissues of infected mice. Meanwhile, treatment with phage JF1 relieved the pathological symptoms observed in each tissue. Furthermore, the levels of the inflammatory cytokines tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-6 (IL-6) in the blood of infected mice were significantly (P < 0.01) decreased in the phage-treated group. Taken together, these results indicate that phage JF1 demonstrated great potential as an alternative therapeutic treatment against T. pyogenes infection.

A human multi-lineage hepatic organoid model for liver fibrosis.

To investigate the pathogenesis of a congenital form of hepatic fibrosis, human hepatic organoids were engineered to express the most common causative mutation for Autosomal Recessive Polycystic Kidney Disease (ARPKD). Here we show that these hepatic organoids develop the key features of ARPKD liver pathology (abnormal bile ducts and fibrosis) in only 21 days. The ARPKD mutation increases collagen abundance and thick collagen fiber production in hepatic organoids, which mirrors ARPKD liver tissue pathology. Transcriptomic and other analyses indicate that the ARPKD mutation generates cholangiocytes with increased TGFß pathway activation, which are actively involved stimulating myofibroblasts to form collagen fibers. There is also an expansion of collagen-producing myofibroblasts with markedly increased PDGFRB protein expression and an activated STAT3 signaling pathway. Moreover, the transcriptome of ARPKD organoid myofibroblasts resemble those present in commonly occurring forms of liver fibrosis. PDGFRB pathway involvement was confirmed by the anti-fibrotic effect observed when ARPKD organoids were treated with PDGFRB inhibitors. Besides providing insight into the pathogenesis of congenital (and possibly acquired) forms of liver fibrosis, ARPKD organoids could also be used to test the anti-fibrotic efficacy of potential anti-fibrotic therapies.

Whole Volume Apparent Diffusion Coefficient (ADC) Histogram as a Quantitative Imaging Biomarker to Differentiate Breast Lesions: Correlation with the Ki-67 Proliferation Index.

OBJECTIVES: To evaluate the value of the whole volume apparent diffusion coefficient (ADC) histogram in distinguishing between benign and malignant breast lesions and differentiating different molecular subtypes of breast cancers and to assess the correlation between ADC histogram parameters and Ki-67 expression in breast cancers. METHODS: The institutional review board approved this retrospective study. Between September 2016 and February 2019, 189 patients with 84 benign lesions and 105 breast cancers underwent magnetic resonance imaging (MRI). Volumetric ADC histograms were created by placing regions of interest (ROIs) on the whole lesion. The relationships between the ADC parameters and Ki-67 were analysed using Spearman's correlation analysis. RESULTS: Of the 189 breast lesions included, there were significant differences in patient age (P < 0.001) and lesion size (P = 0.006) between the benign and malignant lesions. The results also demonstrated significant differences in all ADC histogram parameters between benign and malignant lesions (all P < 0.001). The median and mean ADC histogram parameters performed better than the other ADC histogram parameters (AUCs were 0.943 and 0.930, respectively). The receiver operating characteristic (ROC) analysis revealed that the 10th percentile ADC value and entropy could determine the human epidermal growth factor receptor 2 (HER-2) status (both P = 0.001) and estrogen receptor (ER)/progesterone receptor (PR) status (P = 0.020 and P = 0.041, respectively). Among all breast cancer lesions, 35 tumours in the low-proliferation group (Ki - 67 < 14%) and 70 tumours in the high-proliferation group (Ki - 67 ≥ 14) were analysed with ROC curves and correlation analyses. The ROC analysis revealed that entropy and skewness could determine the Ki-67 status (P = 0.007 and P < 0.001, respectively), and there were weak correlations between ADC entropy (r = 0.383) and skewness (r = 0.209) and the Ki-67 index. CONCLUSION: The volumetric ADC histogram could serve as an imaging marker to determine breast lesion characteristics and may be a supplemental method in predicting tumour proliferation in breast cancer.

17ß-estradiol induces temozolomide resistance through NRF2-mediated redox homeostasis in glioblastoma.

Glioblastoma multiforme (GBM) is the most fatal cancer among brain tumors, and the standard treatment of GBM patients is surgical tumor resection followed by radiotherapy and temozolomide (TMZ) chemotherapy. However, tumors always recur due to the developing drug resistance. It has been shown that neurosteroids, including dehydroepiandrosterone and 17ß-estradiol, are synthesized in TMZ-resistant GBM tumors. Therefore, we sought to explore the possible role of 17ß-estradiol in the development of drug resistance in GBM. Bioinformatics analysis revealed that aromatase/cytochrome P450 19A1 expression was gradually increased in the development from normal, astrocytoma to GBM. The level of 17ß-estradiol was significantly increased in TMZ-resistant cells characterized by ultra performance liquid chromatography-tandem mass spectrometry. Furthermore, 17ß-estradiol attenuated TMZ-induced cell death and reduced reactive oxygen species production by mitochondria. In addition, 17ß-estradiol attenuated oxidative stress by increasing the expression of superoxide dismutase 1/2, catalase, and nuclear factor erythroid 2-related factor (NRF) 2. We found that NRF2 expression was essential for the induction of drug resistance by 17ß-estradiol through the reduction of oxidative stress in GBM.

Research progress of dual inhibitors targeting crosstalk between histone epigenetic modulators for cancer therapy.

Abnormal epigenetics is a critical hallmark of human cancers. Anticancer drug discovery directed at histone epigenetic modulators has gained impressive advances with six drugs available for cancer therapy and numerous other candidates undergoing clinical trials. However, limited therapeutic profile, drug resistance, narrow safety margin, and dose-limiting toxicities pose intractable challenges for their clinical utility. Because histone epigenetic modulators undergo intricate crosstalk and act cooperatively to shape an aberrant epigenetic profile, co-targeting histone epigenetic modulators with a different mechanism of action has rapidly emerged as an attractive strategy to overcome the limitations faced by the single-target epigenetic inhibitors. In this review, we summarize in detail the crosstalk of histone epigenetic modulators in regulating gene transcription and the progress of dual epigenetic inhibitors targeting this crosstalk.