Deep learning enables the discovery of a novel cuproptosis-inducing molecule for the inhibition of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers in the world. The therapeutic outlook for HCC patients has significantly improved with the advent and development of systematic and targeted therapies such as sorafenib and lenvatinib; however, the rise of drug resistance and the high mortality rate necessitate the continuous discovery of effective targeting agents. To discover novel anti-HCC compounds, we first constructed a deep learning-based chemical representation model to screen more than 6 million compounds in the ZINC15 drug-like library. We successfully identified LGOd1 as a novel anticancer agent with a characteristic levoglucosenone (LGO) scaffold. The mechanistic studies revealed that LGOd1 treatment leads to HCC cell death by interfering with cellular copper homeostasis, which is similar to a recently reported copper-dependent cell death named cuproptosis. While the prototypical cuproptosis is brought on by copper ionophore-induced copper overload, mechanistic studies indicated that LGOd1 does not act as a copper ionophore, but most likely by interacting with the copper chaperone protein CCS, thus LGOd1 represents a potentially new class of compounds with unique cuproptosis-inducing property. In summary, our findings highlight the critical role of bioavailable copper in the regulation of cell death and represent a novel route of cuproptosis induction.

Recent trends in preparation and biomedical applications of iron oxide nanoparticles.

The iron oxide nanoparticles (IONPs), possessing both magnetic behavior and semiconductor property, have been extensively used in multifunctional biomedical fields due to their biocompatible, biodegradable and low toxicity, such as anticancer, antibacterial, cell labelling activities. Nevertheless, there are few IONPs in clinical use at present. Some IONPs approved for clinical use have been withdrawn due to insufficient understanding of its biomedical applications. Therefore, a systematic summary of IONPs' preparation and biomedical applications is crucial for the next step of entering clinical practice from experimental stage. This review summarized the existing research in the past decade on the biological interaction of IONPs with animal/cells models, and their clinical applications in human. This review aims to provide cutting-edge knowledge involved with IONPs' biological effects in vivo and in vitro, and improve their smarter design and application in biomedical research and clinic trials.

Clinicopathologic Predictors of Clinical Outcomes in Mammary Adenoid Cystic Carcinoma: A Multi-institutional Study.

Adenoid cystic carcinoma (AdCC) is an uncommon type of invasive breast carcinoma with a favorable prognosis. However, some cases are aggressive. The study aims to define the clinicopathologic predictors of outcome. Clinical, radiological, and pathologic variables were recorded for 76 AdCC cases from 11 institutions. The following histologic characteristics were evaluated by the breast pathologist in each respective institution, including Nottingham grade (NG), percentages of various growth patterns (solid, cribriform, trabecular-tubular), percentage of basaloid component, tumor borders (pushing, infiltrative), perineural invasion, lymphovascular invasion, necrosis, and distance from the closest margin. Various grading systems were evaluated, including NG, salivary gland-type grading systems, and a new proposed grading system. The new grading system incorporated the growth pattern (percent solid, percent cribriform), percent basaloid morphology, and mitotic count using the Youden index criterion. All variables were correlated with recurrence-free survival. Nineteen (25%) women developed local and/or distant recurrence. Basaloid morphology (≥25% of the tumor) was identified in 20 (26.3%) cases and a solid growth pattern (using ≥60% cutoff) in 22 (28.9%) cases. In the univariate analysis, the following variables were significantly correlated with worse recurrence-free survival: solid growth pattern, basaloid morphology, lymphovascular invasion, necrosis, perineural invasion, and pN-stage. In the multivariate analysis including basaloid morphology, pN-stage, lymphovascular invasion, and perineural invasion, basaloid morphology was statistically significant, with a hazard ratio of 3.872 (95% CI, 1.077; 13.924; P =.038). The NG and the new grading system both correlated with recurrence-free survival. However, grade 2 had a similar risk as grade 3 in the NG system and a similar risk as grade 1 in the new grading system. For solid growth patterns and basaloid morphology, using a 2-tier system with 1 cutoff was better than a 3-tier system with 2 cutoffs. Basaloid morphology and solid growth pattern have prognostic values for AdCC, with a 2-tier grading system performing better than a 3-tier system.

Aquilariperoxide A, a Sesquiterpene Dimer from Agarwood of Aquilaria sinensis with Dual Antitumor and Antimalarial Effects.

Aquilariperoxide A (1), an unprecedented sesquiterpene dimer characterized by a dioxepane ring connecting two sesquiterpene units via a C-C bond, was isolated from agarwood of Aquilaria sinensis-containing resins. The structure was elucidated by spectroscopic and computational methods. A bioassay revealed that 1 significantly inhibits cell proliferation and migration in human cancer cells. The mechanism of 1 against cancer cells was briefly discussed by analysis of RNA sequence data and epithelial-mesenchymal transition. Besides, the antimalarial activity of 1 was also evaluated.

Single-cell RNA sequencing deciphers the mechanism of sepsis-induced liver injury and the therapeutic effects of artesunate.

Liver, as an immune and detoxification organ, represents an important line of defense against bacteria and infection and a vulnerable organ that is easily injured during sepsis. Artesunate (ART) is an anti-malaria agent, that also exhibits broad pharmacological activities including anti-inflammatory, immune-regulation and liver protection. In this study, we investigated the cellular responses in liver to sepsis infection and ART hepatic-protective mechanisms against sepsis. Cecal ligation and puncture (CLP)-induced sepsis model was established in mice. The mice were administered ART (10 mg/kg, i.p.) at 4 h, and sacrificed at 12 h after the surgery. Liver samples were collected for preparing single-cell RNA transcriptome sequencing (scRNA-seq). The scRNA-seq analysis revealed that sepsis-induced a dramatic reduction of hepatic endothelial cells, especially the subtypes characterized with proliferation and differentiation. Macrophages were recruited during sepsis and released inflammatory cytokines (Tnf, Il1b, Il6), chemokines (Ccl6, Cd14), and transcription factor (Nfkb1), resulting in liver inflammatory responses. Massive apoptosis of lymphocytes and abnormal recruitment of neutrophils caused immune dysfunction. ART treatment significantly improved the survival of CLP mice within 96 h, and partially relieved or reversed the above-mentioned pathological features, mitigating the impact of sepsis on liver injury, inflammation, and dysfunction. This study provides comprehensive fundamental proof for the liver protective efficacy of ART against sepsis infection, which would potentially contribute to its clinical translation for sepsis therapy. Single cell transcriptome reveals the changes of various hepatocyte subtypes of CLP-induced liver injury and the potential pharmacological effects of artesunate on sepsis.

Advanced application of nanotechnology in active constituents of Traditional Chinese Medicines.

Traditional Chinese Medicines (TCMs) have been used for centuries for the treatment and management of various diseases. However, their effective delivery to targeted sites may be a major challenge due to their poor water solubility, low bioavailability, and potential toxicity. Nanocarriers, such as liposomes, polymeric nanoparticles, inorganic nanoparticles and organic/inorganic nanohybrids based on active constituents from TCMs have been extensively studied as a promising strategy to improve the delivery of active constituents from TCMs to achieve a higher therapeutic effect with fewer side effects compared to conventional formulations. This review summarizes the recent advances in nanocarrier-based delivery systems for various types of active constituents of TCMs, including terpenoids, polyphenols, alkaloids, flavonoids, and quinones, from different natural sources. This review covers the design and preparation of nanocarriers, their characterization, and in vitro/vivo evaluations. Additionally, this review highlights the challenges and opportunities in the field and suggests future directions for research. Nanocarrier-based delivery systems have shown great potential in improving the therapeutic efficacy of TCMs, and this review may serve as a comprehensive resource to researchers in this field.

Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma.

Sorafenib is the first-line medication for advanced hepatocellular carcinoma (HCC), but it can only extend limited survival. It is imperative to find a combination strategy to increase sorafenib efficacy. Artesunate is such a preferred candidate, because artesunate is clinically well-tolerated and more importantly both drugs can induce ferroptosis through different mechanisms. In this study we investigated the combined effect of sorafenib and artesunate in inducing ferroptosis of HCC and elucidated the involved molecular mechanisms. We showed that artesunate greatly enhanced the anticancer effects of low dose of sorafenib against Huh7, SNU-449, and SNU-182 HCC cell lines in vitro and against Huh7 cell xenograft model in Balb/c nude mice. The combination index method confirmed that the combined effect of sorafenib and artesunate was synergistic. Compared with the treatment with artesunate or sorafenib alone, combined treatment induced significantly exacerbated lipid peroxidation and ferroptosis, which was blocked by N-acetyl cysteine and ferroptosis inhibitors liproxstatin-1 and deferoxamine mesylate, but not by inhibitors of other types of cell death (z-VAD, necrostatin-1 and belnacasan). In Huh7 cells, we demonstrated that the combined treatment induced oxidative stress and lysosome-mediated ferritinophagy, two essential aspects of ferroptosis. Sorafenib at low dose mainly caused oxidative stress through mitochondrial impairments and SLC7A11-invovled glutathione depletion. Artesunate-induced lysosome activation synergized with sorafenib-mediated pro-oxidative effects by promoting sequential reactions including lysosomal cathepsin B/L activation, ferritin degradation, lipid peroxidation, and consequent ferroptosis. Taken together, artesunate could be repurposed to sensitize sorafenib in HCC treatment. The combined treatment can be easily translated into clinical applications.

Pulmonary peripheral glandular papilloma and mixed squamous cell and glandular papilloma frequently harbour the BRAF V600E mutation.

AIMS: Pulmonary peripheral glandular papilloma (GP) and mixed squamous cell and glandular papilloma (MP) have very similar histological features to pulmonary ciliated muconodular papillary tumour (CMPT)/bronchiolar adenoma (BA). The underlying genetic relationships between GP/MP and CMPT/BA have rarely been characterised. We aimed to reveal the relationship between them. METHODS AND RESULTS: We performed a clinicopathological review and next-generation sequencing (NGS) study of two GPs and five MPs. Histologically, GPs/MPs showed similar cellular and architectural features to CMPTs/BAs, such as bilayered epithelium, bronchiole-associated lesions and skipping (discontinuous) growth pattern. One MP showed partial and inconspicuous endobronchiolar growth and more glandular structures, which was very similar to the appearance of CMPT/BA. BRAF V600E mutation was detected in four papillomas (57.1%, one GP and three MPs). CONCLUSIONS: Overlapping morphological features and comparable mutation profiles support that peripheral GPs/MPs and CMPTs/BAs are on the same disease spectrum. We propose expanding the concept of CMPT/BA and including GP and MP in the CMPT/BA family.

Skeletal meroterpenoids from Ganoderma petchii mushrooms that potentially stimulate umbilical cord mesenchymal stem cells.

(±)-Petchilactones A-C (1-3), three pairs of enantiomeric meroterpenoids respectively with a 6/6/5/5 or a 5/5/5/7/6 ring system were isolated from Ganoderma petchii. Their structures including absolute configurations were assigned by using spectroscopic, computational, and X-ray diffraction methods. Compounds 1 and 2 represent a new skeletal meroterpenoid. Biological evaluation found that (-)-1 and (-)-3 could induce umbilical cord mesenchymal stem cells into keratinocyte-like cells.

Diffuse Tenosynovial Giant Cell Tumor Around the Temporomandibular Joint: An Entity With Special Radiologic and Pathologic Features.

PURPOSE: Diffuse tenosynovial giant cell tumor (TGCT) of the temporomandibular joint (TMJ) is rare. The aim of the present study was to summarize the clinical, radiologic, and pathologic features of this tumor. MATERIALS AND METHODS: Nine cases of TGCT in the TMJ region were examined. All available radiologic and pathologic documents were carefully reviewed. These cases were grouped into 3 types according to the radiologic features: bone-centered type, intraosseous type, and soft tissue type. Cases reported in the literature were reviewed to better summarize the clinical characteristics. RESULTS: TGCTs in the TMJ region showed some special radiologic and pathologic features. Radiologically, the lesion could be centered in the craniofacial bone or centered in the surrounding soft tissue. Four cases were categorized as the bone-centered type, 1 was categorized as the intraosseous type, and 4 were categorized as the soft tissue type. Pathologically, epithelioid mononuclear cells with abundant eosinophilic cytoplasm and eccentric nuclei were observed in all cases. Chondroid metaplasia was noted in 8 cases. Some areas were similar to giant cell reparative granuloma and chondroblastoma. All patients who underwent complete tumor resection showed no evidence of recurrence at follow-up. Of the 93 reported cases, only 5 developed postoperative recurrence and distant metastasis. CONCLUSION: TGCTs of the TMJ region share similar radiologic and pathologic features as other tumors, which indicates the TGCT might be a special entity within a spectrum of diseases.

Asn391Thr Mutation of ß-Myosin Heavy Chain in a Hypertrophic Cardiomyopathy Family.

The present study was performed to identify the genetic abnormalities in a family with familial hypertrophic cardiomyopathy.Peripheral blood samples were collected from 22 members of a Chinese family with hypertrophic cardiomyopathy and 307 healthy controls. A total of 26 candidate pathogenic genes were analyzed in the proband using targeted capture sequencing. Identified mutations were analyzed using Sanger sequencing in all family members and healthy controls.A missense mutation (c.1172A>C, p. Asn391Thr) in exon 12 of MYH7 was identified in eight family members, among which six of them were hypertrophic cardiomyopathy carriers. Three carriers presented with cardiac dysfunction. Four members of this pedigree died suddenly, three of whom were diagnosed with hypertrophic cardiomyopathy.From the results of this study, we concluded that the Asn391Thr mutation of MYH7 is a malignant mutation for HCM and that mutation carriers should get effective treatment to prevent sudden death.

Organochlorine pesticides accumulation and breast cancer: A hospital-based case-control study.

The aim of this study is to detect the accumulation status of organochlorine pesticides in breast cancer patients and to explore the relationship between organochlorine pesticides contamination and breast cancer development. We conducted a hospital-based case-control study in 56 patients with breast cancer and 46 patients with benign breast disease. We detected the accumulation level of several organochlorine pesticides products (ß-hexachlorocyclohexane, γ-hexachlorocyclohexane, polychlorinated biphenyls-28, polychlorinated biphenyls-52, pentachlorothioanisole, and pp'-dichlorodiphenyldichloroethane) in breast adipose tissues of all 102 patients using gas chromatography. Thereafter, we examined the expression status of estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 (HER2), and Ki-67 in 56 breast cancer cases by immunohistochemistry. In addition, we analyzed the risk of breast cancer in those patients with organochlorine pesticides contamination using a logistic regression model. Our data showed that breast cancer patients suffered high accumulation levels of pp'-dichlorodiphenyldichloroethane and polychlorinated biphenyls-52. However, the concentrations of pp'-dichlorodiphenyldichloroethane and polychlorinated biphenyls-52 were not related to clinicopathologic parameters of breast cancer. Further logistic regression analysis showed polychlorinated biphenyls-52 and pp'-dichlorodiphenyldichloroethane were risk factors for breast cancer. Our results provide new evidence on etiology of breast cancer.

Familial hypertrophic cardiomyopathy caused by a de novo Gly716Arg mutation of the ß-myosin heavy chain.

The present study was performed to identify the genotype of a hypertrophic cardiomyopathy family and investigate the clinicopathogenic characteristics and prognostic features of relevant genetic abnormalities. Target sequence capture sequencing was performed to screen for pathogenic alleles in a 32-year-old female patient (proband). Sanger sequencing was carried out to verify the results. Sanger sequencing was also performed on other family members to identify allele carriers. A survival analysis was carried out using published literature and our findings. We found that the proband and her son harboured a Gly716Arg sequence variant of the ß-myosin heavy chain. Neither the proband's father nor the mother were carriers of this sequence variant; thus, the mutation was classified as "de novo". Further survival analysis revealed that female patients appear to have a longer life expectancy compared with males. Our study may provide an effective approach for the genetic diagnosis of hypertrophic cardiomyopathy.

Decreased HCRP1 promotes breast cancer metastasis by enhancing EGFR phosphorylation.

Previous study showed that hepatocellular carcinoma related protein 1 (HCRP1) is decreased in breast cancer. HCRP1 expression is inversely related to epithelial growth factor receptor (EGFR) in breast cancer tissues, and patients with breast cancer expressing lower HCRP1 tended to suffer a shorter life expectancy. However, the detailed biological functions of HCRP1 in breast cancer as well as the interaction between HCRP1 and EGFR remain unexplored. In this study, we examined HCRP1 expression in breast cancer tissues and cell lines by western blot. Thereafter, we performed transwell migration and matrigel invasion assays after siRNA interference and lentiviral vector of HCRP1 infection. To further investigate the interaction between HCRP1 downregulation and EGFR signaling pathway, we evaluated the phosphorylation status of EGFR, Erk1/2 and Akt by western blot following HCRP1-siRNA transfection. Moreover, we investigated the in vivo functions of HCRP1 using a breast cancer xenograft model. We found that HCRP1 depletion significantly promoted breast cancer migration and invasion while HCRP1 overexpression produced an opposite effect. In addition, HCRP1 depletion decreased EGFR degradation and enhanced phosphorylation of EGFR. Interestingly, HCRP1 depletion also led to insensitivity to EGFR inhibitors treatment. The in vivo experiment confirmed the metastasis inhibition function of HCRP1. The present data indicate that HCRP1 inhibits breast cancer metastasis through downregulating EGFR phosphorylation.

Primary Cardiac Osteosarcoma.

BACKGROUND: Primary cardiac osteosarcoma is extremely rare. There is no cohort study on such tumours to date. The aim of this study is to investigate the clinical characteristics and outcome patterns of such tumours. METHODS: A thorough literature review was performed, and all relevant clinical items were collected. A total of 53 cases of primary cardiac osteosarcoma were enrolled in this study, including 25 males and 28 females. RESULTS: The age at diagnosis ranged from 14 to 77 years with a mean age of 43.6 years. The clinical manifestations, imaging features, and laboratory tests of the primary cardiac osteosarcomas were similar to other types of primary cardiac tumours. Sex, tumour size and adjunctive chemo-radiotherapy were found to affect the overall survival pattern. CONCLUSIONS: The present study may provide an effective consultation for the diagnosis and treatment of this tumour.

[Non-Destructive Identification of Pigments Printed on the Bank Bill Issued in 1945].

Three-dimensional video microscopy, Raman spectrometer and scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) were employed to analyze the pigments of various colors on a sample of bank bill issued in 1945. The results indicated that organic pigments including C. I. Pigment Red 146 and C. I. Pigment Red 53∶1, and inorganic pigments such as cinnabar, parareaglar, χ-phase of realgar, carbon black and Prussian blue were used in printing; the brown-black handwriting letters were speculated to be formed from the fading black-blue ink. Most areas of the bank bill were in one single color with one pigment, but two areas of orange-red seals were checked to be colored with cinnabar and two different phases of realgar, and the parareaglar, and χ-phase of realgar were found to be used as printing pigments firstly. This study shows that combining with three technologies above-mentioned is viable and it has great application potential in non-destructive identification of organic and inorganic pigments on paper-based cultural heritage.

[A Non-Destructive Study of Printing Materials of an Imperial China Green Engraved Coiling Dragon Stamp].

Non-destructive measurement methods including video microscopy (VM), Raman spectrometer (RS), and scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) were employed to analyze the printing materials of a green curled-up dragon stamp sample from the late Qing Dynasty in terms of the paper and ink. The results indicated that the plate-making process of the sample belonged to handcrafted gravure while the slender and dense paper fiber with no coating, watermark, or gumming. Elements of Al and Si were inspected in fillers of paper, therefore, it could be inferred that kaolin (Al2O3·2SiO2·2H2O) was the filler of paper. Green ink was made up of blue pigment Prussian Blue (Fe4[Fe(CN)6]3·14-16H2O) and yellow pigment Lead(II) chromate(PbCrO4). According to theories of additive color and subtractive color, ink presented green color due to the effect of Prussian blue and Lead chromate mixed together. Elements of Na, Mg, S, Cl, K, Ca, V, Zn and Ba were measured from fillers of the ink and it could be inferred that MgCO3, BaSO4, CaCO3 and other substances might be contained in ink fillers. This study with three techniques mentioned above is viable and it has a broad application in non-destructive analysis of printing and paper-based artwork.

[Study of Paints and Drawing Techniques of Fine Brushwork Yunlong Ripples Painting in Qing Dynasty].

In order to study the paints and techniques of decorative patterns of dragon among clouds and water waves, the materials based on a Qing Dynasty meticulous painting were measured by three-dimensional video microscopy, Raman microscopy and energy dispersive X-ray fluorescence spectroscopy. The results showed that the green clothes was firstly colored by Paris green, the decorative patterns of dragon among clouds and water waves were then painted by hematite, the edge was delineated by brass powder at last. The dark yellow area within the decorative patterns was presented due to the interaction of green and red paints. In addition, ultramarine blue was checked in the painting. According to the first synthesized time of ultramarine blue and Paris green, we can make sure the time limit of the painting finished.

Cardiac paragangliomas.

Cardiac paraganglioma is a rare entity. We review the clinical data from 158 patients reported in 132 isolated papers, and discuss clinical presentations, imaging findings, pathology, location, therapy, and outcomes.

Evaluation of ultrasound-processed rapid cell blocks in the cytopathologic diagnosis of cavity fluids.

OBJECTIVE: The technique of conventional cell blocks is rather labor- and time-consuming. The purpose of this study was to generate a convenient and quick manual procedure using ultrasound processing which could be applied in most developing countries and to evaluate its efficacy in the cytopathologic diagnosis of cavity fluids. STUDY DESIGN: We carried out a rapid cell block procedure using egg albumen as the pre-embedded adjuvant and using ultrasound to accelerate fixation, dehydration, clearing and waxing. The diagnostic efficacy was evaluated as compared with tissue blocks and liquid-based cytology tests (LCTs). RESULTS: A total of 155 samples underwent rapid cell block detection, and 61 were diagnosed as malignancies. The method was able to produce high-quality formalin-fixed paraffin-embedded cell block sections and has similar diagnostic validity to the LCT. The immunohistochemistry and in situ hybridization staining patterns in rapid cell block sections were similar to those in their tissue block counterparts. CONCLUSIONS: The ultrasound-processed rapid cell block is a convenient and quick method for cytopathologic diagnosis. We consider it may serve as an effective adjuvant technique for most primary medical institutions.