Hydrogen is one of the possible alloying elements in the Earth's core, but its siderophile (iron-loving) nature is debated. Here we experimentally examined the partitioning of hydrogen between molten ...iron and silicate melt at 30-60 gigapascals and 3100-4600 kelvin. We find that hydrogen has a metal/silicate partition coefficient D
≥ 29 and is therefore strongly siderophile at conditions of core formation. Unless water was delivered only in the final stage of accretion, core formation scenarios suggest that 0.3-0.6 wt% H was incorporated into the core, leaving a relatively small residual H
O concentration in silicates. This amount of H explains 30-60% of the density deficit and sound velocity excess of the outer core relative to pure iron. Our results also suggest that hydrogen may be an important constituent in the metallic cores of any terrestrial planet or moon having a mass in excess of ~10% of the Earth.
Hepatitis C virus (HCV) infection is one of the primary causes of liver cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation (LT). The rate of HCV infection is high in patients on ...hemodialysis and in patients infected with human immunodeficiency virus (HIV). In liver transplant patients with HCV infection, recurrent HCV infection of the transplanted liver is universal and results in rapid liver fibrosis progression. In patients with HCV/HIV coinfection as well, liver fibrosis advances rapidly. Thus, there is an urgent need for prompt HCV infection treatment in these special populations (i.e. HIV/HCV coinfection, HCV infection after LT, and dialysis patients). Interferon (IFN)‐based therapy for HCV infection could not achieve a high rate of sustained viral response and could cause severe adverse events in the aforementioned special populations. Direct‐acting antivirals (DAAs) have recently been developed, and clinical trials have shown that IFN‐free DAA‐based therapies are associated with a significantly better safety and therapeutic profile than IFN‐based therapies. However, the majority of the initial DAA trials excluded special populations; thus, the efficacy and safety of IFN‐free DAA‐based therapy in special populations remained to be clearly established. Although recent clinical trials and clinical studies have shown the high efficacy and safety of this therapy even in special populations, several unresolved problems, including emergence of resistance‐associated variants after failure to respond to DAAs and HCC occurrence after DAA therapy, still exist. Hence, in this review, we discuss the recent advances in anti‐HCV therapy for special populations and the remaining problems regarding this therapy.
Hepatocellular carcinoma (HCC) can be lethal due to its aggressive course and lack of effective systemic therapies for advanced disease. Sorafenib is the only systemic therapy that has demonstrated ...an overall survival benefit in patients with advanced HCC, and new agents for treatment of advanced HCC are needed. The multiple pathways involved in HCC oncogenesis, proliferation and survival provide many opportunities for the development of molecularly targeted therapies. Molecular targets of interest have expanded from angiogenesis to cancer cell‐directed oncogenic signaling pathways for treatment of advanced HCC. Agents targeting vascular endothelial growth factor receptor, epidermal growth factor receptor, fibroblast growth factor receptor, platelet‐derived growth factor receptor, c‐mesenchymal‐epithelial transition factor‐1 and mammalian target of rapamycin signaling have been actively explored. This article focuses on the evaluation of molecular agents targeting pathogenic HCC and provides a review of recently completed phase III drug studies (e.g. involving sorafenib, sunitinib, brivanib, linifanib, erlotinib, everolimus, ramucirumab or orantinib) and ongoing drug studies (e.g. involving lenvatinib, regorafenib, tivantinib or cabozantinib) of molecularly targeted agents in advanced HCC, including a brief description of the biologic rationale behind these agents.
•Fast and accurate tumor segmentation approaches for colorectal cancer wholeslide images based on the novel concept of persistent homology.•Two variants of the proposed framework: one that targets ...speed without compromising accuracy and the other that targets higher accuracy.•Detailed experimentation, comparative evaluation on two independent and relatively challenging colorectal cancer data sets.
Tumor segmentation in whole-slide images of histology slides is an important step towards computer-assisted diagnosis. In this work, we propose a tumor segmentation framework based on the novel concept of persistent homology profiles (PHPs). For a given image patch, the homology profiles are derived by efficient computation of persistent homology, which is an algebraic tool from homology theory. We propose an efficient way of computing topological persistence of an image, alternative to simplicial homology. The PHPs are devised to distinguish tumor regions from their normal counterparts by modeling the atypical characteristics of tumor nuclei. We propose two variants of our method for tumor segmentation: one that targets speed without compromising accuracy and the other that targets higher accuracy. The fast version is based on a selection of exemplar image patches from a convolution neural network (CNN) and patch classification by quantifying the divergence between the PHPs of exemplars and the input image patch. Detailed comparative evaluation shows that the proposed algorithm is significantly faster than competing algorithms while achieving comparable results. The accurate version combines the PHPs and high-level CNN features and employs a multi-stage ensemble strategy for image patch labeling. Experimental results demonstrate that the combination of PHPs and CNN features outperform competing algorithms. This study is performed on two independently collected colorectal datasets containing adenoma, adenocarcinoma, signet, and healthy cases. Collectively, the accurate tumor segmentation produces the highest average patch-level F1-score, as compared with competing algorithms, on malignant and healthy cases from both the datasets. Overall the proposed framework highlights the utility of persistent homology for histopathology image analysis.
Gastric cancer (GC), one of the most common human cancers, is a heterogeneous disease with different phenotypes, prognoses, and responses to treatment. Understanding the pathogenesis of GC at the ...molecular level is important for prognosis prediction and determining treatments. Microsatellite instability (MSI), silencing of
MLH1
,
MGMT
, and
CDKN2A
genes by DNA hypermethylation,
KRAS
mutation,
APC
mutation, and
ERBB2
amplification are frequently found in intestinal type GC. Inactivation of
CDH1
and
RARB
by DNA hypermethylation, and amplification of
FGFR
and
MET
, are frequently detected in diffuse type GC. In addition,
BST2
and
PCDHB9
genes are overexpressed in intestinal type GC. Both genes are associated with GC progression. GC can be divided into gastric/intestinal mucin phenotypes according to mucin expression. MSI, alterations of
TP73
,
CDH1
mutation, and DNA methylation of
MLH
are detected frequently in the gastric mucin phenotype.
TP53
mutation, deletion of
APC
, and DNA methylation of
MGMT
are detected frequently in the intestinal mucin phenotype.
FKTN
is overexpressed in the intestinal mucin phenotype, and
IQGAP3
is overexpressed in the gastric mucin phenotype. These genes are involved in GC progression. To characterize cancer stem cells, a useful method is spheroid colony formation.
KIFC1
and
KIF11
genes show more than twofold higher expression in spheroid-forming cells than that in parental cells. Both
KIF
genes are overexpressed in GC, and knockdown of these genes inhibits spheroid formation. Alterations of these molecules may be useful to understand gastric carcinogenesis. Specific inhibitors of these molecules may also be promising anticancer drugs.
Gastric cancer (GC), one of the most common human cancers, can be classified into gastric or intestinal phenotype according to mucin expression. TP53 mutation, allelic deletion of the APC gene and ...nuclear staining of β‐catenin are frequently detected in the intestinal phenotype of GC, whereas CDH1 gene mutation, microsatellite instability and DNA hypermethylation of MLH1 are common events in the gastric phenotype of GC. Our Serial Analysis of Gene Expression (SAGE) and Escherichia coli ampicillin secretion trap (CAST) analyses revealed that CDH17, REG4, OLFM4, HOXA10, DSC2, TSPAN8 and TM9SF3 are upregulated in GC and that CLDN18 is downregulated in GC. Expression of CDH17, REG4, HOXA10 and DSC2 and downregulation of CLDN18 are observed in the intestinal phenotype of GC. In contrast, OLFM4 is expressed in the gastric phenotype of GC. Expression of TSPAN8, TM9SF3 and HER2 are not associated with either gastric or intestinal phenotypes. Ectopic CDX2 expression plays a key function in the GC intestinal phenotype. MUC2, CDH17, REG4, DSC2 and ABCB1 are direct targets of CDX2. Importantly, these genes encode transmembrane/secretory proteins, indicating that the microenvironment as well as cancer cells are also different between gastric and intestinal phenotypes of GC.
Gastric cancer can be classified into gastric or intestinal phenotype according to mucin expression. Accumulating evidence has indicated that gastric/intestinal phenotypes of gastric cancer have distinct clinical characteristics and exhibit specific genetic and epigenetic changes. Here we focus on the clinical and molecular characteristics of the gastric and intestinal phenotypes of gastric cancer.
To overcome the poor prognosis of cholangiocarcinoma (CCA), highly targeted therapies, such as antibody-drug conjugates (ADCs), photodynamic therapy (PDT) with/without systemic chemotherapy, and ...experimental photoimmunotherapy (PIT), have been developed. Three preclinical trials have investigated the use of ADCs targeting specific antigens, namely HER2, MUC1, and glypican-1 (GPC1), for CCA. Trastuzumab emtansine demonstrated higher antiproliferative activity in CCA cells expressing higher levels of HER2. Similarly, "staphylococcal enterotoxin A-MUC1 antibody" and "anti-GPC1 antibody-monomethyl auristatin F" conjugates showed anticancer activity. PDT is effective in areas where appropriate photosensitizers and light coexist. Its mechanism involves photosensitizer excitation and subsequent reactive oxygen species production in cancer cells upon irradiation. Hematoporphyrin derivatives, temoporfin, phthalocyanine-4, talaporfin, and chlorine e6 derivatives have mainly been used clinically and preclinically in bile duct cancer. Currently, new forms of photosensitizers with nanotechnology and novel irradiation catheters are being developed. PIT is the most novel anti-cancer therapy developed in 2011 that selectively kills targeted cancer cells using a unique photosensitizer called "IR700" conjugated with an antibody specific for cancer cells. PIT is currently in the early stages of development for identifying appropriate CCA cell targets and irradiation devices. Future human and artificial intelligence collaboration has potential for overcoming challenges related to identifying universal CCA cell targets. This could pave the way for highly targeted therapies for CCA, such as ADC, PDT, and PIT.
Background
The attainment of drug resistance in gastric cancer (GC) is a problematic issue. Although many studies have shown that cancer stem cells (CSCs) play an important role in the acquisition of ...drug resistance, there is no clinically available biomarker for predicting oxaliplatin (L-OHP) resistance in relation to CSCs. Organoid technology, a novel 3D cell culture system, allows harboring of patient-derived cancer cells containing abundant CSCs using niche factors in a dish.
Methods
In this study, we established L-OHP-resistant gastric cancer organoids (GCOs) and evaluated their gene expression profile using microarray analysis. We validated the upregulated genes in the L-OHP-resistant GCOs compared to their parental GCOs to find a gene responsible for L-OHP resistance by qRT-PCR, immunohistochemistry, in vitro, and in vivo experiments.
Results
We found myoferlin (MYOF) to be a candidate gene through microarray analysis. The results from cell viability assays and qRT-PCR showed that high expression of MYOF correlated significantly with the IC50 of L-OHP in GCOs. Immunohistochemistry of MYOF in GC tissue samples revealed that high expression of MYOF was significantly associated with poor prognosis, T grade, N grade, and lymphatic invasion, and showed MYOF to be an independent prognostic indicator, especially in the GC patients treated with platinum-based chemotherapy. The knockdown of MYOF repressed L-OHP resistance, cell growth, stem cell features, migration, invasion, and in vivo tumor growth.
Conclusions
Our results suggest that MYOF is highly involved in L-OHP resistance and tumor progression in GC. MYOF could be a promising biomarker and therapeutic target for L-OHP-resistant GC cases.
Background
Ultrasonography (US) is widely used for the diagnosis of liver tumors. However, the accuracy of the diagnosis largely depends on the visual perception of humans. Hence, we aimed to ...construct artificial intelligence (AI) models for the diagnosis of liver tumors in US.
Methods
We constructed three AI models based on still B-mode images: model-1 using 24,675 images, model-2 using 57,145 images, and model-3 using 70,950 images. A convolutional neural network was used to train the US images. The four-class liver tumor discrimination by AI, namely, cysts, hemangiomas, hepatocellular carcinoma, and metastatic tumors, was examined. The accuracy of the AI diagnosis was evaluated using tenfold cross-validation. The diagnostic performances of the AI models and human experts were also compared using an independent test cohort of video images.
Results
The diagnostic accuracies of model-1, model-2, and model-3 in the four tumor types are 86.8%, 91.0%, and 91.1%, whereas those for malignant tumor are 91.3%, 94.3%, and 94.3%, respectively. In the independent comparison of the AIs and physicians, the percentages of correct diagnoses (accuracies) by the AIs are 80.0%, 81.8%, and 89.1% in model-1, model-2, and model-3, respectively. Meanwhile, the median percentages of correct diagnoses are 67.3% (range 63.6%–69.1%) and 47.3% (45.5%–47.3%) by human experts and non-experts, respectively.
Conclusion
The performance of the AI models surpassed that of human experts in the four-class discrimination and benign and malignant discrimination of liver tumors. Thus, the AI models can help prevent human errors in US diagnosis.
Endoscopic biliary decompression is a minimally invasive procedure for cholestasis since the first endoscopic retrograde cholangiopancreatography‐guided biliary stenting performed by Soehendra and ...Reynders‐Frederix. Among the endoscopic biliary decompression, endoscopic transpapillary biliary stenting (EBS), is a mainstream choice and presently has two methods of placement: stenting above the sphincter of Oddi (SO) (suprapapillary) and stenting across the SO (transpapillary). Stent patency is the most important concern for patients, endoscopists and physicians because it can affect both the life prognosis and treatment schedule of patients. Biliary stent occlusion can occur because of several factors. Among them, direct food impaction, biofilm formation, and sludge formation play important roles and are presumed to be theoretically overcome by EBS above the SO. Thus, EBS above the SO is expected to result in a longer patency than EBS across the SO. In the literature, there have been six comparative studies on EBS for distal biliary obstruction in which the stent was placed above or across the SO, including two randomized controlled trials (RCTs) with negative results of stenting above the SO. With respect to EBS for hilar biliary obstruction, there have been no RCTs, whereas four retrospective comparative studies with negative results and four retrospective comparative studies showing positive results of stenting above the SO have been reported. In this review, we focused on EBS above and across the SO, and summarized the positive and negative results of the two types of stenting to promote effective clinical practice and to provide a basis for future studies.
PDF
