Infection and inflammation stimulate expansion of a CD74+ Paneth cell subset to regulate disease progression.

Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC-reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level. Infection expands the pool of CD74+ PCs, whose number correlates with auto or allogeneic inflammatory disease progressions in mice. Similar correlation was found in human inflammatory disease tissues. Infection-stimulated cytokines increase production of reactive oxygen species (ROS) and expression of a PC-specific mucosal pentraxin (Mptx2) in activated PCs. A PC-specific ablation of MyD88 reduced CD74+ PC population, thus ameliorating pathogen-induced systemic disease. A similar phenotype was also observed in mice lacking Mptx2. Thus, infection stimulates expansion of a PC subset that influences disease progression.

Short-Process Regeneration of Highly Stable Spherical LiCoO2 Cathode Materials from Spent Lithium-Ion Batteries through Carbonate Precipitation.

High-efficacy recycling of spent lithium cobalt oxide (LiCoO2 ) batteries is one of the key tasks in realizing a global resource security strategy due to the rareness of lithium (Li) and cobalt (Co) resources. However, it is of great significance to develop the innovative recycle methods for spent LiCoO2 , simultaneously realizing the efficient recovery of valuable elements and the regeneration of high-performance LiCoO2 . Herein, a novel strategy of regenerating LiCoO2 cathode is proposed, which involves the preparation of micro-spherical aluminum (Al)-doped lithium-lacked precursor (Li2x Co1-x-y Al2/3y CO3, remarked as "PLCAC") via ammonium bicarbonate coprecipitation. The comprehensive conditions affecting particle growth kinetics, morphology and particle size the has been investigated in detail by physical characterizations and electrochemical measurements. And the optimized Al-doped LiCoO2 materials with high-density sphericity (LiCo1-z Alz O2 , remarked as "LCAO") shows a high initial specific capacity of 161 mAh g-1 at 0.1 C and excellent capacity retention of 99.5 % within 100 cycles at 1 C in the voltage range of 2.8 to 4.3 V. Our work provides valuable insights into the featured design of LiCoO2 precursors and cathode materials from spent LiCoO2 batteries, potentially guaranteeing the high-efficacy recycling and utilization of strategic resources.

Transitional basal cells at the squamous-columnar junction generate Barrett's oesophagus.

In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy, but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown. In the case of Barrett's oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells. On the basis of a number of experimental models, several alternative cell types have been proposed as the source of this metaplasia but in all cases the evidence is inconclusive: no model completely mimics Barrett's oesophagus in terms of the presence of intestinal goblet cells. Here we describe a transitional columnar epithelium with distinct basal progenitor cells (p63+KRT5+KRT7+) at the squamous-columnar junction of the upper gastrointestinal tract in a mouse model. We use multiple models and lineage tracing strategies to show that this squamous-columnar junction basal cell population serves as a source of progenitors for the transitional epithelium. On ectopic expression of CDX2, these transitional basal progenitors differentiate into intestinal-like epithelium (including goblet cells) and thereby reproduce Barrett's metaplasia. A similar transitional columnar epithelium is present at the transitional zones of other mouse tissues (including the anorectal junction) as well as in the gastro-oesophageal junction in the human gut. Acid reflux-induced oesophagitis and the multilayered epithelium (believed to be a precursor of Barrett's oesophagus) are both characterized by the expansion of the transitional basal progenitor cells. Our findings reveal a previously unidentified transitional zone in the epithelium of the upper gastrointestinal tract and provide evidence that the p63+KRT5+KRT7+ basal cells in this zone are the cells of origin for multi-layered epithelium and Barrett's oesophagus.

Hepatic sclerosing cavernous haemangioma can mimic the nodular elastosis stage of segmental atrophy.

AIMS: Segmental atrophy (SA) of the liver is a recently described pseudotumour that can show a broad spectrum of histological changes. The previously described histological differential diagnosis of SA has included cystic disease of the liver, amyloid, cancer-associated elastosis, and epithelioid haemangioendothelioma. We have observed that sclerosing cavernous haemangiomas (SCHs) can mimic the nodular elastosis stage of SA; the aim of this study was to explore this differential diagnosis. METHODS AND RESULTS: We identified 20 SCHs and 12 SAs, excluding haemangiomas with treatment effect. Several clinical and morphologic characteristics were examined, and elastin and CD34 staining was performed on cases with available tissue. SA was always asymptomatic, whereas SCH caused symptoms in 56% of patients (P = 0.026); SCH also tended to be larger (mean size: SCH, 47 mm; SA, 16 mm; P = 0.027). Thick-walled blood vessels were more common in SA than in SCH (92% versus 45%, P = 0.011), as was ductular reaction (50% versus 5%, P = 0.0057). The two lesions had similar rates of border irregularity, residual entrapped hepatocytes, matrix oedema, and at least mild elastic fibrosis as seen on special staining, although staining was typically dense and diffuse in SA. CD34 immunostaining demonstrated at least scattered vessels in all cases of SA and SCH. CONCLUSIONS: SCH can mimic SA, although it is generally larger and more often symptomatic. Elastin staining provides a useful adjunct to standard haematoxylin and eosin histological examination in resolving this differential diagnosis.

High expression of Claudin-2 in esophageal carcinoma and precancerous lesions is significantly associated with the bile salt receptors VDR and TGR5.

BACKGROUND: Claudins are a family of integral membrane proteins and are components of tight junctions (TJs). Many TJ proteins are known to tighten the cell structure and maintain a barrier. Claudin-2 forms gated paracellular channels and allows sodium ions and other small positively charged ions to cross between adjacent cells. Recently, we found that vitamin D receptor (VDR) enhanced Claudin-2 expression in colon and that bile salt receptors VDR and Takeda G-protein coupled receptor5 (TGR5) were highly expressed in esophageal adenocarcinoma (EAC) and precancerous lesions. Here, we examined the expression of Claudin-2 in EAC and precancerous lesions and its association with VDR and TGR5 expression. METHODS: Claudin-2 expression was examined by immunohistochemistry on tissue microarrays, containing EAC, high grade dysplasia (HGD), low grade dysplasia (LGD), Barrett's esophagus (BE), columnar cell metaplasia (CM), squamous cell carcinoma (SCC), and squamous epithelium (SE) cases. Intensity (0 to 3) and percentage were scored for each case. High expression was defined as 2-3 intensity in ≥ 10% of cells. RESULTS: Claudin-2 was highly expressed in 77% EAC (86/111), 38% HGD (5/13), 61% LGD (17/28), 46% BE (18/39), 45% CM (29/65), 88% SCC (23/26), and 14% SE (11/76). It was significantly more highly-expressed in EAC, SCC and glandular lesions than in SE and more in EAC than in BE and CM. A significant association was found between Claudin-2 expression and VDR and TGR5 expression. No significant association was found between expression of Claudin-2 and age, gender, grade, stage, or patients' survival time in EAC and SCC. CONCLUSIONS: We conclude that Claudin-2 expression is significantly associated with bile acid receptors VDR and TGR5 expression. Our studies identify a novel role of a tight junction protein in the development and progression of esophageal mucosal metaplasia, dysplasia and carcinoma.

MicroRNA-494 is a master epigenetic regulator of multiple invasion-suppressor microRNAs by targeting ten eleven translocation 1 in invasive human hepatocellular carcinoma tumors.

UNLABELLED: Vascular invasion provides a direct route for tumor metastasis. The degree to which microRNA (miRNA) expression plays a role in tumor vascular invasion is unclear. Here, we report that miR-494 is up-regulated in human hepatocellular carcinoma (HCC) tumors with vascular invasion and can promote HCC cell invasiveness by gene inactivation of multiple invasion-suppressor miRNAs. Our results show that ten eleven translocation (TET) methylcytosine dioxygenase, predominantly TET1 in HCC cells, is a direct target of miR-494. The reduced 5'-hydroxymethylcytosine levels observed in the proximal cytosine-phosphate-guanine (CpG) regions of multiple invasion-suppressor miRNA genes are strongly associated with their transcriptional repression upon miR-494 overexpression, whereas enforced DNA demethylation can abolish the repression. Furthermore, TET1 knockdown shows a similar effect as miR-494 overexpression. Conversely, miR-494 inhibition or enforced TET1 expression is able to restore invasion-suppressor miRNAs and inhibit miR-494-mediated HCC cell invasion. CONCLUSIONS: miR-494 can trigger gene silencing of multiple invasion-suppressor miRNAs by inhibiting genomic DNA demethylation by direct targeting of TET1, thereby leading to tumor vascular invasion.

High expression of carbonic anhydrase IX is significantly associated with glandular lesions in gastroesophageal junction and with tumorigenesis markers BMI1, MCM4 and MCM7.

BACKGROUND: Carbonic anhydrase IX (CA9) is a transmembrane glycoprotein related to hypoxia. Increased CA9 expression has been associated with decreased survival and cancer progression and has been targeted as a potential therapy for several cancers, including esophageal cancer. The reported percentages of expression of CA9 in esophageal adenocarcinoma vary, and CA9 expression in precancerous esophageal lesions has not been well studied. METHODS: In this study, we investigated CA9 expression in esophageal cancers and in precancerous lesions and explored the association of CA9 expression with prognostic factors and with stem cell and tumorigenesis-related markers including BMI1, cyclin E, ki67, MCM4 and MCM7 expression. Previously constructed tissue microarrays consisting of samples of 7 tissue types (columnar cell metaplasia, Barrett esophagus, low- and high-grade dysplasia, esophageal adenocarcinoma, squamous epithelium, and squamous cell carcinoma) were used for the immunostaining of CA9, BMI1, cyclin E, Ki67, MCM4 and MCM7. RESULTS AND DISCUSSION: CA9 high expression occurred more frequently in glandular mucosa with or without dysplasia than in squamous epithelium or squamous cell carcinoma. Survival duration of esophageal adenocarcinoma did not significantly differ between patients with high CA9 expression and those with low expression. High CA9 expression is significantly associated with BMI1, cyclin E, Ki67, MCM4 and MCM7 expression. CONCLUSIONS: High CA9 expression may be related to the acidic environment caused by gastroesophageal reflux disease in the gastroesophageal junction and associated with tumorigenesis through BMI1, MCM4 and MCM7.

Comparison of cancer-associated genetic abnormalities in columnar-lined esophagus tissues with and without goblet cells.

OBJECTIVE: To determine and compare the frequency of cancer-associated genetic abnormalities in esophageal metaplasia biopsies with and without goblet cells. BACKGROUND: Barrett's esophagus is associated with increased risk of esophageal adenocarcinoma (EAC), but the appropriate histologic definition of Barrett's esophagus is debated. Intestinal metaplasia (IM) is defined by the presence of goblet cells whereas nongoblet cell metaplasia (NGM) lacks goblet cells. Both have been implicated in EAC risk but this is controversial. Although IM is known to harbor genetic changes associated with EAC, little is known about NGM. We hypothesized that if NGM and IM infer similar EAC risk, then they would harbor similar genetic aberrations in genes associated with EAC. METHODS: Ninety frozen NGM, IM, and normal tissues from 45 subjects were studied. DNA copy number abnormalities were identified using microarrays and fluorescence in situ hybridization. Targeted sequencing of all exons from 20 EAC-associated genes was performed on metaplasia biopsies using Ion AmpliSeq DNA sequencing. RESULTS: Frequent copy number abnormalities targeting cancer-associated genes were found in IM whereas no such changes were observed in NGM. In 1 subject, fluorescence in situ hybridization confirmed loss of CDKN2A and amplification of chromosome 8 in IM but not in a nearby NGM biopsy. Targeted sequencing revealed 11 nonsynonymous mutations in 16 IM samples and 2 mutations in 19 NGM samples. CONCLUSIONS: This study reports the largest and most comprehensive comparison of DNA aberrations in IM and NGM genomes. Our results show that IM has a much higher frequency of cancer-associated mutations than NGM.

Cyclin E involved in early stage carcinogenesis of esophageal adenocarcinoma by SNP DNA microarray and immunohistochemical studies.

BACKGROUND: Cyclin E is a cell cycle regulator which is critical for driving G1/S transition. Abnormal levels of cyclin E have been found in many cancers. However, the level changes of cyclin E in esophageal adenocarcinoma and its precancerous lesion have not been well studied. Here, we focus on the gene amplification and expression of cyclin E in these lesions, and aim to ascertain the relationship with clinicopathological characteristics. METHODS: Genomic DNA was analyzed from 116 esophageal adenocarcinoma and 26 precancerous lesion patients using Affymetrix SNP 6.0 arrays. The protein overexpression of cyclin E was also detected using immunohistochemistry from tissue microarrays containing esophageal adenocarcinoma and precancerous lesions. Patient survival and other clinical data were collected and analyzed. The intensity and percentage of the cyclin E expressing cells in tissue microarrays were scored by two pathologists. Fisher exact tests and Kaplan-Meier methods were used to analyze data. RESULTS: By genomic analysis, cyclin E was amplified in 19.0% of the EAC samples. By immunohistochemistry, high expression of cyclin E was observed in 2.3% of squamous mucosa tissues, 3.7% in columnar cell metaplasia, 5.8% in Barrett's esophagus, 19.0% in low grade dysplasia, 35.7% in high grade dysplasia, and 16.7% in esophageal adenocarcinoma. The differences in cyclin E high expression between neoplastic groups and non-dysplasia groups are statistically significant (p < 0.05). The prognosis for patients with high cyclin E expression appeared slightly better than for those with low cyclin E expression although this was not statistically significant (p = 0.13). CONCLUSIONS: The expression of cyclin E significantly increases from non-dysplasia esophageal lesion to low and high grade dysplasia, suggesting that cyclin E plays an important role in the early stage of carcinogenesis. Importantly, cyclin E is also amplified and highly expressed in a subset of esophageal adenocarcinoma patients, but this increase is not associated with worse prognosis.

Bile exposure inhibits expression of squamous differentiation genes in human esophageal epithelial cells.

OBJECTIVE: This study aimed to identify pathways and cellular processes that are modulated by exposure of normal esophageal cells to bile and acid. BACKGROUND: Barrett's esophagus most likely develops as a response of esophageal stem cells to the abnormal reflux environment. Although insights into the underlying molecular mechanisms are slowly emerging, much of the metaplastic process remains unknown. METHODS: We performed a global analysis of gene expression in normal squamous esophageal cells in response to bile or acid exposure. Differentially expressed genes were classified into major biological functions using pathway analysis and interaction network software. Array data were verified by quantitative PCR and western blot both in vitro and in human esophageal biopsies. RESULTS: Bile modulated expression of 202 genes, and acid modulated expression of 103 genes. Genes involved in squamous differentiation formed the largest functional group (n = 45) all of which were downregulated by bile exposure. This included genes such as involucrin (IVL), keratinocyte differentiation-associated protein (KRTDAP), grainyhead-like 1 (GRHL1), and desmoglein1 (DSG1) the downregulation of which was confirmed by quantitative PCR and western blot. Bile also caused expression changes in genes involved in cell adhesion, DNA repair, oxidative stress, cell cycle, Wnt signaling, and lipid metabolism. Analysis of human esophageal biopsies demonstrated greatly reduced expression of IVL, KRTDAP, DSG1, and GRHL1 in metaplastic compared to squamous epithelia. CONCLUSIONS: We report for the first time that bile inhibits the squamous differentiation program of esophageal epithelial cells. This, coordinated with induction of genes driving intestinal differentiation, may be required for the development of Barrett's esophagus.

Clinicopathologic characteristics of high expression of Bmi-1 in esophageal adenocarcinoma and squamous cell carcinoma.

BACKGROUND: High expression of Bmi-1, a key regulatory component of the polycomb repressive complex-1, has been associated with many solid and hematologic malignancies including esophageal squamous cell carcinoma. However, little is known about the role of Bmi-1 in esophageal adenocarcinoma. The aim of this study is to investigate the amplification and high expression of Bmi-1 and the associated clinicopathologic characteristics in esophageal adenocarcinoma and squamous cell carcinoma. METHODS: The protein expression level of Bmi-1 was detected by immunohistochemistry (IHC) from tissue microarrays (TMA) constructed at the University of Rochester from using tissues accrued between 1997 and 2005. Types of tissues included adenocarcinoma, squamous cell carcinoma and precancerous lesions. Patients' survival data, demographics, histologic diagnoses and tumor staging data were collected. The intensity (0-3) and percentage of Bmi-1 expression on TMA slides were scored by two pathologists. Genomic DNA from 116 esophageal adenocarcinoma was analyzed for copy number aberrations using Affymetrix SNP 6.0 arrays. Fisher exact tests and Kaplan-Meier methods were used to analyze data. RESULTS: By IHC, Bmi-1 was focally expressed in the basal layers of almost all esophageal squamous mucosa, which was similar to previous reports in other organs related to stem cells. High Bmi-1 expression significantly increased from squamous epithelium (7%), columnar cell metaplasia (22%), Barrett's esophagus (22%), to low- (45%) and high-grade dysplasia (43%) and adenocarcinoma (37%). The expression level of Bmi-1 was significantly associated with esophageal adenocarcinoma differentiation. In esophageal adenocarcinoma, Bmi-1 amplification was detected by DNA microarray in a low percentage (3%). However, high Bmi-1 expression did not show an association with overall survival in both esophageal adenocarcinoma and squamous cell carcinoma. CONCLUSIONS: This study demonstrates that high expression Bmi-1 is associated with esophageal adenocarcinoma and precancerous lesions, which implies that Bmi-1 plays an important role in early carcinogenesis in esophageal adenocarcinoma.

NR4A3 fluorescence in situ hybridization analysis in cytologic and surgical specimens of acinic cell carcinoma.

Acinic cell carcinoma (AciCC) may pose a diagnostic challenge, particularly on small biopsies and fine needle aspiration (FNA) because of its variable histology including potential high-grade transformation and its mimickers. Immunoreactivity with circumferential membranous staining for DOG1 can support the diagnosis of AciCC but is not entirely specific. A novel rearrangement t(4;9)(q13;q31) leading to up-regulation of nuclear receptor subfamily 4 group A member 3 (NR4A3) has been described in AciCC, is potentially detectable by fluorescence in situ hybridization (FISH) and may be useful in the evaluation for AciCC. Using NR4A3 Dual Color Break Apart Probe (ZytoVision, Germany) FISH was performed on AciCCs from 3 large academic institutions. NR4A3 rearrangement was defined as positive signal patterns in 15% of tissue interphase nuclei. Fifty-two AciCCs including 47 resections and 5 FNAs (including 5 paired FNA/resections) were analyzed. Five non-AciCC salivary gland tumors and 2 sialadenitis cases were used as controls. Eight AciCCs (15%; 8/52) failed FISH testing. FISH was positive in 23 AciCCs (sensitivity 59%, 23/39) with 100% concordance between 5 matched resection/FNAs (3 were positive for FISH and 2 were negative). FISH was negative in all non-AciCCs (specificity: 100%, 0/7). NR4A3 FISH has a sensitivity of 59% and specificity of 100% in detecting AciCC, which suggests that NR4A3 rearrangement-driven up-regulation is a recurrent, specific oncogenic event in AciCC, consistent with prior results. Hundred percent concordance between matched FNA/resection samples validates its potential utility on cytology samples.

BRAFV600E mutation test on fine-needle aspiration specimens of thyroid nodules: Clinical correlations for 4600 patients.

BACKGROUND: The BRAFV600E mutation is valuable for the diagnosis, prognosis, and therapy of papillary thyroid cancer (PTC). However, studies related to this mutation have involved only a small number of patients. Therefore, we performed a large-scale analysis from a single institute to evaluate the accuracy of combined fine-needle aspiration (FNA) and BRAFV600E mutation tests for PTC diagnosis. METHODS: A total of 4600 patients with thyroid nodules who underwent both FNA cytology and BRAFV600E mutation analysis on FNA specimens were enrolled. The association between the BRAFV600E mutation and clinicopathological features was analyzed. A separate analysis was performed for the 311 patients who underwent repeated FNA for comparison of cytological evaluation and BRAFV600E mutation results. The diagnostic efficacy of the BRAFV600E mutation test and cytologic diagnoses was evaluated for 516 patients who underwent preoperative FNA tests in comparison with conclusive postoperative histopathologic results. RESULTS: The cytology results of all 4600 FNA samples were categorized according to The Bethesda System for Reporting Thyroid Cytology (TBSRTC) stages I-VI, which accounted for 11.76%, 60.02%, 6.46%, 3.61%, 6.71%, and 11.43% of the samples, respectively. The BRAFV600E mutation was detected in 762 (16.57%) FNA samples, with rates of 1.48%, 0.87%, 20.20%, 3.01%, 66.02%, and 87.81% for TBSRTC I-VI lesions, respectively. Among the 311 repeat FNA cases, 81.0% of the BRAFV600E -positive and 4.3% of the BRAFV600E -negative specimens with an initial indication of cytological non-malignancy were ultimately diagnosed as malignant by repeat FNA (p < 0.001). Among the 516 patients who underwent thyroidectomy, the sensitivity and specificity of the BRAFV600E mutation test alone for PTC diagnosis were 76.71% and 100.0%, respectively, which increased to 96.62% and 88.03%, respectively, when combining the BRAFV600E mutation test with cytology. BRAFV600E mutation was significantly associated with lymph node metastasis (p < 0.001), but not with age, gender, or tumor size. CONCLUSIONS: The BRAFV600E mutation test in FNA samples has potential to reduce false negatives in PTC diagnosis, and therefore plays an important role in the diagnosis of thyroid nodules, especially those with an indeterminate or nondiagnostic cytology, which should be considered for repeat FNA.

Renal Cell Carcinoma with Cardiac Metastases: A Case Report and Review of the Literature.

Cardiac metastases from renal cell carcinoma (RCC) are very rare. We describe the case of a woman with RCC with cardiac metastases involving the entire right atrium, penetrating through the myocardium, with extension into the tricuspid valve and right ventricle. This report highlights the unique challenge of the diagnosis and treatment of cardiac metastases in RCC.

Wingless homolog Wnt11 suppresses bacterial invasion and inflammation in intestinal epithelial cells.

Wnt11 plays an essential role in gastrointestinal epithelial proliferation, and previous investigations have focused on development and immune responses. However, the roles of how enteric bacteria regulate Wnt11 and how Wnt11 modulates the host response to pathogenic bacteria remain unexplored. This study investigated the effects of Salmonella infection on Wnt activation in intestinal epithelial cells. We found that Wnt11 mRNA and protein expression were elevated after Salmonella colonization. Wnt11 protein secretion in epithelial cells was also elevated after bacterial infection. Furthermore, we demonstrated that pathogenic Salmonella regulated Wnt11 expression and localization in vivo. We found a decrease in Salmonella invasion in cells with Wnt11 overexpression compared with cells with normal Wnt11 level. IL-8 mRNA in Wnt11-transfected cells was low; however, it was enhanced in cells with a low level of Wnt11 expression. Functionally, Wnt11 overexpression inhibited Salmonella-induced apoptosis. AvrA is a known bacterial effector protein that stabilizes ß-catenin, the downstream regulator of Wnt signaling, and inhibits bacterially induced intestinal inflammation. We observed that Wnt11 expression, secretion, and transcriptional activity were regulated by Salmonella AvrA. Overall, Wnt11 is involved in the protection of the host intestinal cells by blocking the invasion of pathogenic bacteria, suppressing inflammation, and inhibiting apoptosis. Wnt11 is a novel and important contributor to intestinal homeostasis and host defense.

HER2 amplification, overexpression and score criteria in esophageal adenocarcinoma.

The HER2 oncogene was recently reported to be amplified and overexpressed in esophageal adenocarcinoma. However, the relationship of HER2 amplification in esophageal adenocarcinoma with prognosis has not been well defined. The scoring systems for clinically evaluating HER2 in esophageal adenocarcinoma are not established. The aims of the study were to establish a HER2 scoring system and comprehensively investigate HER2 amplification and overexpression in esophageal adenocarcinoma and its precursor lesion. Using a tissue microarray, containing 116 cases of esophageal adenocarcinoma, 34 cases of Barrett's esophagus, 18 cases of low-grade dysplasia and 15 cases of high-grade dysplasia, HER2 amplification and overexpression were analyzed by HercepTest and chromogenic in situ hybridization methods. The amplification frequency in an independent series of 116 esophageal adenocarcinoma samples was also analyzed using Affymetrix SNP 6.0 microarrays. In our studies, we have found that HER2 amplification does not associate with poor prognosis in total 232 esophageal adenocarcinoma patients by chromogenic in situ hybridization and high-density microarrays. We further confirm the similar frequency of HER2 amplification by chromogenic in situ hybridization (18%; 21 out of 116) and SNP 6.0 microarrays (16%, 19 out of 116) in esophageal adenocarcinoma. HER2 protein overexpression was observed in 12% (14 out of 116) of esophageal adenocarcinoma and 7% (1 out of 15) of high-grade dysplasia. No HER2 amplification or overexpression was identified in Barrett's esophagus or low-grade dysplasia. All HER2 protein overexpression cases showed HER2 gene amplification. Gene amplification was found to be more frequent by chromogenic in situ hybridization than protein overexpression in esophageal adenocarcinoma (18 vs 12%). A modified two-step model for esophageal adenocarcinoma HER2 testing is recommended for clinical esophageal adenocarcinoma HER2 trial.

Comparison of programmed death ligand 1 immunostaining for pancreatic ductal adenocarcinoma between paired cytological and surgical samples.

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with surgery or chemotherapy. Programmed death ligand 1 expression (PD-L1) immunotherapy has been successful for treating lung and other cancers with PD-L1 expression. However, in many unresectable PDAC cases, cytological samples are the only available tissues for PD-L1 testing. The aim of this study is to retrospectively compare the expression of PD-L1 using cytological and surgical samples. MATERIAL AND METHODS: Paired formalin-fixed cell blocks and surgical samples from the same patients with confirmed diagnoses of PDAC (n = 28) were sectioned for PD-L1 immunohistochemistry. Using tumor proportion score (TPS) and combined positive score (CPS) to evaluate paired cell blocks and surgical samples, we counted and analyzed the data. RESULTS: With TPS, the PD-L1 was expressed in 9/28 (32%) of PDAC surgical samples and in 9/28 (32%) of paired cytological samples. Overall, the PD-L1 expression had a correlation of 26/28 (93%). With CPS, the PD-L1 was expressed in 20/28 (71%) of PDAC surgical samples and in 16/28 (57%) of paired cytological samples. The PD-L1 expression had a correlation of 20/28 (71%) and a discrepancy of 8/28 (29%). The PD-L1 expression was significantly higher in moderately-differentiated PDAC than in well-differentiated with TPS. CONCLUSION: Cytological samples are useful for evaluating PD-L1 expression with TPS because the concordant rate was 93%. With CPS, cytological samples are limited due to the scant inflammatory cells with the concordant rate of 71%. Extensive sampling of the pancreatic tumor may improve the detection of immune cells expressing PD-L1 in cytological samples. With TPS, PD-L1 expression was significantly higher in moderate-differentiation of PDAC than in poor- and well-differentiation.

DNA methylation markers in esophageal cancer: an emerging tool for cancer surveillance and treatment.

Esophageal carcinoma (EC) is one of the most pervasive cancers in the world, with upwards of 500,000 new diagnoses, annually. Despite its prominence, advancements in the detection and treatment of EC have been marginal over the past 30 years and the survival rate continues to stay below 20%. This is due to the uncommonly heterogeneous presentation of EC which presents unprecedented challenges in improving patient survival and quality of care. However, distinct epigenetic alterations to the DNA methylome may provide an avenue to drastically improve the detection and treatment of EC. Specifically, the creation of novel biomarker panels that consist of EC-specific methylation markers have shown promise as a potential alternative to the more invasive, contemporary diagnostic methods. Additionally, growing insight into the biological and clinical properties of EC-specific methylation patterns have opened a window of opportunity for enhanced treatment; of growing interest is the application of "DNMT inhibitors" - a class of drugs which inhibit excessive methylation and have been shown to re-sensitize chemoresistant tumors. Here we provide a comprehensive review of the current advancements in EC DNA methylation to underscore a potential approach to its detection and treatment.

Engineering a Robust Interface on Ni-Rich Cathodes via a Novel Dry Doping Process toward Advanced High-Voltage Performance.

Ni-rich layered oxides have become the main force of cathode materials for EV cells with high energy density owing to their satisfactory theoretical capacity, cost-effectiveness, and low toxicity. However, the high-voltage stability of Ni-rich cathode materials still has not fulfilled the demand of power batteries due to their intrinsic structural and electrochemical instability. The commonly used modification procedures are achieved via a wet process, which may lead to surface lithium-ion deficiency, phase change, and high costs during manufacturing. Herein, we construct a multifunctional Ti-based interfacial architecture on the surface of LiNi0.6Co0.2Mn0.2O2 (NCM) cathode materials via a novel dry interface modifying process in which no solvent is employed. The Ti-based interfacial architecture accelerates the transportation of lithium ions and consequently stabilizes the interfacial structure. This approach significantly improves the cycling stability in half cells, with a 15% increase in capacity retention over 100 cycles at 1 C under a high voltage of 4.5 V. Impressively, few internal cracks are observed in a modified sample after 500 times of charge and discharge between 2.75 and 4.35 V at 1 C rate, and the capacity retention can reach 93%.

Phosphomannose Isomerase High Expression Associated with Better Prognosis in Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States. The need for increased patient survival has not been met for PDAC. The addition of mannose to conventional chemotherapy leads to accumulation of mannose metabolite in cancer cells and increases subsequent cell death. This susceptibility to mannose depends on the levels of phosphomannose isomerase (PMI). The cancer cells with lower levels of PMI are more sensitive to mannose than cells with higher levels. In this study, we investigated the association of PMI expression with clinical and pathological features of PDAC cases. METHODS: PMI antibody immunohistochemistry (AbCam) was performed on tissue microarrays from 235 PDAC by a standard protocol on Ventana automated immunostainer. The PMI intensity was graded (0-3) and the proportion of positivity was scored. Correlation of PMI expression with staging and survival was analyzed. RESULTS: Of the 235 cases, 51.5% (n=121) cases demonstrated grade 2 intensity with 90.1% of these (n=109) showing positivity in ≥70% of tumor cells. Ninety-eight (41.7%) cases exhibited grade 3 intensity with 94.9% (n=93) of these cases showing ≥70% reactivity. Sixteen cases (6.8%) were nonreactive (intensity grade 0-1). Intensity of PMI expression was associated with significantly better prognosis as assessed by median survival in months (M): grade 0-1 intensity group: 11.2 M; grade 2 intensity group: 25.2 M; and grade 3 intensity group: 33.2 M (p=0.03). A minority (6.8%) of PDACs show non-high PMI expression with poorer prognosis. DISCUSSION: Mannose may be a particularly useful adjunct with chemotherapy to treat this aggressive subgroup. PMI expression is also a potential biomarker to predict the prognosis of PDAC.