EGFR, HER2, and MET gene amplification and protein expression profiles in biliary tract cancer and their prognostic significance.

BACKGROUND: There are limited conventional chemotherapy options for biliary tract cancers (BTCs), a heterogenous group of lethal, rare malignancies. The receptor tyrosine kinase (RTK) is closely associated with the progression of human malignancies through the regulation of cell cycle. Overexpression or amplification of RTKs has been investigated as a potential biomarker and therapeutic target in BTC; herein, we investigate the value of such interventions. MATERIALS AND METHODS: Overexpression of RTK proteins was examined by immunohistochemistry in 193 BTC samples, of which 137 were gallbladder carcinoma, 29 were perihilar cholangiocarcinoma, and 27 were intrahepatic cholangiocarcinoma. Silver in situ hybridization of MET and HER2 was performed to assess gene amplification. RESULTS: In the entire cancer group, gallbladder, perihilar, and intrahepatic, MET amplification rates were 15.7%, 19.0%, 3.4%, and 14.8%, respectively, and of HER2 amplification rates were 22.4%, 27.2%, 17.2%, and 3.7%, respectively. MET and HER2 protein expressions were significantly correlated with their gene amplification status. RTKs were significantly associated with adverse clinicopathologic features such as advanced pT category and lymph node metastasis. Overall survival was significantly shorter in MET-amplified (P = .024) and EGFR-overexpressed cases (P = .045). Recurrence-free survival was significantly correlated with HER2-amplified (P = .038) and EGFR-overexpressed cases (P = .046) in all patient groups. Overall and recurrence-free survival were significantly shorter in patients who were double positive for HER2 and EGFR. CONCLUSION: Our data suggested that MET, HER2, and EGFR might be potential therapeutic targets and that their co-expression is a strong prognostic factor for BTCs.

Understanding Alkali Contamination in Colloidal Nanomaterials to Unlock Grain Boundary Impurity Engineering.

Metal nanogels combine a large surface area, a high structural stability, and a high catalytic activity toward a variety of chemical reactions. Their performance is underpinned by the atomic-level distribution of their constituents, yet analyzing their subnanoscale structure and composition to guide property optimization remains extremely challenging. Here, we synthesized Pd nanogels using a conventional wet chemistry route, and a near-atomic-scale analysis reveals that impurities from the reactants (Na and K) are integrated into the grain boundaries of the poly crystalline gel, typically loci of high catalytic activity. We demonstrate that the level of impurities is controlled by the reaction condition. Based on ab initio calculations, we provide a detailed mechanism to explain how surface-bound impurities become trapped at grain boundaries that form as the particles coalesce during synthesis, possibly facilitating their decohesion. If controlled, impurity integration into grain boundaries may offer opportunities for designing new nanogels.

Transitional cell metaplasia of the uterine cervix: A histopathological and immunohistochemical analysis suggesting a possible role of androgenic conversion during urothelial-like differentiation in peri/postmenopausal women.

Transitional cell metaplasia (TCM) of the uterine cervix and vagina is typically seen in patients with adrenogenital syndrome with high serum androgen levels and in those under androgen treatment as well as in some peri/postmenopausal women. Considering that TCM occurs in patients with increased serum androgen levels, a microenvironment with altered sex hormones might be involved in the urothelial-like differentiation observed in TCM. To investigate a histogenetic role of androgen in TCM development, we compared the distribution patterns and intensity of androgen receptor (AR), estrogen receptor (ER), GATA3 (a transcription factor involved in androgen regulation), Ki-67, and AKR1C3 (an enzyme involved in androgen biosynthesis) expression in normal exocervical mucosa in young women (n = 25), senile atrophy (n = 23), and TCM (n = 29). In TCM, AR, ER, AKR1C3, and GATA3, expression was stronger and significantly increased upward into the intermediate and superficial layers compared with the senile atrophic mucosa and normal mucosa in young women. The epithelial layer in TCM is thicker than that in senile atrophic mucosa, although both conditions may occur in the same age group. Proliferation in TCM was significantly lower than that in young women but slightly higher than that in senile atrophy. Considering the conversion activity of AKR1C3, thicker epithelial layers in TCM compared with those in senile atrophy might be due to increased conversion of androstenedione to testosterone via increased AKR1C3 activity, increased conversion of testosterone to 17ß-estradiol by aromatization, and AR activation.

Selective Solvent-Induced Stabilization of Polar Oxide Surfaces in an Electrochemical Environment.

The impact of an electrochemical environment on the thermodynamic stability of polar oxide surfaces is investigated for the example of ZnO(0001) surfaces immersed in water using density functional theory calculations. We show that solvation effects are highly selective: They have little effect on surfaces showing a metallic character, but largely stabilize semiconducting structures, particularly those that have a high electrostatic penalty in vacuum. The high selectivity is shown to have direct consequences for the surface phase diagram and explains, e.g., why certain surface structures could be observed only in an electrochemical environment.

Prognostic value of Dickkopf-1 and ß-catenin expression in advanced gastric cancer.

BACKGROUND: Dickkopf-1 (DKK1) is a Wnt/ß-catenin pathway antagonist related to gastric cancer (GC) carcinogenesis. However, the prognostic role of combined DKK1 and ß-catenin expression in advanced GC (AGC) is not clear. METHODS: In total, 158 patients with AGC who underwent gastric resection were enrolled in this study. DKK1 and ß-catenin expression was evaluated in whole tumor sections by immunohistochemistry. RESULTS: DKK1 expression was high in 73 (46.2%) patients, while ß-catenin expression was positive in 51 (32.3%) patients. The expression of DKK1 was positively correlated with that of ß-catenin (P < 0.001). The combined expression of DKK1 and ß-catenin was significantly associated with high N stage (N2 and N3) (P = 0.042). In addition, patients with high DKK expression demonstrated poorer overall (OS) (P < 0.001) and disease-free survival (DFS) (P = 0.001). However, there were no differences between high DKK1 expression with ß-catenin positivity and high DKK1 expression with ß-catenin negativity (OS, P = 0.379: DFS, P = 0.255). Multivariate analysis revealed that high DKK1 alone or high DKK1 with ß-catenin positivity were independent prognostic factors for both OS (high DKK1: hazard ratio [HR], 2.130; 95% confidence interval [CI]; 1.370-3.312, P = 0.001; high DKK1 with ß-catenin positivity: HR, 2.140; 95% CI, 1.343-3.409: P = 0.001) and DFS (high DKK1: HR, 2.092; 95% CI, 1.180-3.708; P = 0.012; high DKK1 with ß-catenin positivity: HR, 2.357; 95% CI, 1.291-4.306; P = 0.005). CONCLUSION: Our results indicate that high DKK1 expression regardless of ß-catenin positivity is a crucial prognostic factor for predicting tumor recurrence and survival in patients with resected AGC.

Uncovering the Thermo-Kinetic Origins of Phase Ordering in Mixed-Valence Antimony Tetroxide by First-Principles Modeling.

Phase ordering in the mixed-valence oxide Sb2O4 has been examined by density functional theory (DFT) calculations. We find that the ground-state total energies of the two phases (α and ß) are almost degenerate and are highly sensitive to the choice of the approximation to the exchange correlation (xc) functional used in our calculations. Interestingly, with the inclusion of the zero-point energy corrections, the α phase is predicted to be the ground state polymorph for most xc functionals used. We also illustrate the pronounced stereochemical activity of Sb in these polymorphs of Sb2O4, setting an exception to the Keve and Skapski rule. Here, we find that the actual bonding in the α phase is more asymmetric, while the anomalous stability of the ß phase could be rationalized from kinetic considerations. We find a non-negligible activation barrier for this α-ß phase transition, and the presence of a saddle point (ß phase) supports the separation of Sb(III) over a continuous phase transition, as observed in experiments.

Why does bromine square palladium off? An ab initio study of brominated palladium and its nanomorphology.

A first-principles description and prediction of brominated nanocrystals of Pd is presented. In particular, we conducted an extensive study of the adsorption behaviour of Br on various Pd surfaces (including both low and high Miller-index surfaces) as a function of its surface coverage. By coupling our calculated surface energies with ab initio (electrochemical) thermodynamics and the Gibbs-Wulff shape model, we find that the relative stability of the Pd surfaces is strongly modified by Br, allowing high Miller-index surfaces of Pd (namely the (210) surface) to become competitively favourable at moderate concentrations of Br. We also show that Pd nanoparticles assume a cube-like crystal shape at high concentrations of Br, exposing mainly the (100) facets with a Br surface coverage of 0.5 ML. This not only confirms and explains recent solution synthesis results, but also provides a quantitative atomic picture of the exposed surface facets, which is crucial in understanding the local surface chemistry of shape-controlled nanoparticles for better nanocatalyst design.

Data-Driven Materials Informatics for Novel Piezoelectric Janus-Type Nanomaterials Discovery.

In the recent era of green and sustainable energy, the demand for effective and efficient energy harvesting has dramatically increased. Piezoelectric energy harvesting, which converts mechanical energy into electrical energy, is considered a viable strategy to achieve this goal. Janus-type nanomaterial, a noncentrosymmetric material with different elemental species in the upper and lower atomic layers, has gained interest due to its exotic properties compared to conventional bulk and symmetric materials. In this work, we systematically design and investigate a new class of Janus nanomaterials with enhanced intrinsic polarization via the successive ionic exchange method. Multiple layers of stability standards, including both thermodynamic and dynamic stabilities, are employed in the high-throughput screening procedure of novel Janus-type nanomaterials. The newly proposed Janus-type nanomaterials exhibit more than 10 times higher piezoelectric response compared to that of reported low-dimensional materials and even comparable to that of bulk materials.

Embryonal rhabdomyosarcoma arising from a mediastinal teratoma: an unusual case report.

We report an unusual case of 9.5-cm-sized embryonal rhabdomyosarcoma arose from a mediastinal mature teratoma in a 46-yr-old man. A man presented with chest trauma as a result of an accident at 10 September 2011. On chest X-ray, an anterior mediastinal mass was detected. To obtain further information, chest computed tomography (CT) with contrast enhancement was performed, revealing an anterior mediastinal mass. Complete surgical excision was performed and entire specimen was evaluated. Pathologic diagnosis was embryonal rhabdomyosarcoma arising in mature cystic teratoma. After surgical excision, two cycles of dactinomycin-based chemotherapy were performed. Lung metastasis was detected on follow up CT in September 2012, and wedge resection was performed. Pathological finding of the lung lesion showed same feature with that of primary rhabdomyosarcoma.

Dopant Evolution in Electrocatalysts after Hydrogen Oxidation Reaction in an Alkaline Environment.

Introduction of interstitial dopants has opened a new pathway to optimize nanoparticle catalytic activity for, e.g., hydrogen evolution/oxidation and other reactions. Here, we discuss the stability of a property-enhancing dopant, B, introduced through the controlled synthesis of an electrocatalyst Pd aerogel. We observe significant removal of B after the hydrogen oxidation reaction. Ab initio calculations show that the high stability of subsurface B in Pd is substantially reduced when H is adsorbed/absorbed on the surface, favoring its departure from the host nanostructure. The destabilization of subsurface B is more pronounced, as more H occupies surface sites and empty interstitial sites. We hence demonstrate that the H2 fuel itself favors the microstructural degradation of the electrocatalyst and an associated drop in activity.

Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma.

Mucinous adenocarcinoma is an uncommon type of endometrial adenocarcinoma for which precursor lesions have yet to be clarified. During a review of noncancerous endometrial lesions in postmenopausal women, we found that mucinous endometrial glands showed variable degrees of epithelial changes that ranged from the formation of simple tubular glands to the formation of complex glands with papillary tufts, and some of the glands with papillary tufts were architecturally similar to low-grade mucinous adenocarcinomas. Based on histological similarities, we have postulated that mucinous metaplasia could be a precursor lesion of mucinous adenocarcinoma. To explain the pathogenetic significance of endometrial mucinous metaplasia, we analyzed the immunohistochemical expression of ER, PR, MKI67, PTEN, ß-catenin, P16(INK4A), TP53, and PAX2 in 21 endometrial mucinous metaplasias, screened for KRAS (n=16) and PTEN (n=14) mutations, and compared expression patterns between samples with simple mucinous glands, those with complex glands having intraglandular papillary tufts, and endometrioid adenocarcinomas. Compared with the surrounding flat mucinous epithelium and simple mucinous metaplasia, the intraglandular papillary tufts associated with papillary mucinous metaplasia were characterized by selectively decreased expression of PAX2 (P=0.029) and PR (P<0.001), and overexpression of P16(INK4A) (P=0.014). There were no significant differences in the levels of expression of ER, PTEN, ß-catenin, TP53, and MKI67 between the two groups. In contrast with endometrioid adenocarcinomas, rates of MKI67 proliferation were very low in both groups. Mutations in KRAS were identified in 89% of cases with papillary mucinous metaplasia, in contrast to 14% in simple mucinous metaplasia (P=0.001). No PTEN mutations were observed in either of the two groups. In conclusions, immunohistochemical and molecular genetic profiling suggest that papillary mucinous metaplasia is a possible precancerous lesion in a subset of endometrial carcinomas.

Papillary mucinous metaplasia: a distinct precursor of mucinous adenocarcinoma of the endometrium.

Mucinous adenocarcinoma of the endometrium is heterogeneous, consisting of endometrioid adenocarcinoma composed of >50% mucinous cells, low-grade mucinous adenocarcinoma, microglandular adenocarcinoma, and gastric (gastrointestinal)-type adenocarcinoma. Previous studies have reported that papillary mucinous metaplasia is a possible precancerous lesion of mucinous adenocarcinoma with frequent KRAS mutations. Recently, we encountered a case of pure mucinous adenocarcinoma of the endometrium with concurrent papillary mucinous metaplasia in a 35-year-old woman. She underwent 6-month hormonal therapy for atypical endometrial hyperplasia. A follow-up biopsy led to a diagnosis of mucinous adenocarcinoma; therefore, total hysterectomy was performed. The tumor showed abundant intracytoplasmic mucin and mild-to-moderate cytologic atypia with papillary architecture. KRAS mutation analysis revealed a point mutation from GGT to GTT in codon 12. Although papillary mucinous metaplasia showed an overexpression of p16INK4, especially in the intragrandular papillary tufts, and a low MKi67 labeling index, overt mucinous adenocarcinoma with a loss of P16INK4a expression showed a high proliferating index of MKI67. The mass presented with stage ІA disease. During follow-up, the patient was stable and showed no recurrence. Considering the histologic similarity and incidence of KRAS mutations between papillary mucinous metaplasia and mucinous adenocarcinoma, papillary mucinous metaplasia may be a precancerous lesion for a subset of mucinous adenocarcinoma of the endometrium.

Imaging Findings of Metaplastic Breast Carcinoma with Chondroid Differentiation: A Case Reports.

Metaplastic carcinoma of the breast is a heterogeneous group of neoplasms with mixed epithelial and mesenchymal differentiation. Metaplastic carcinoma of the breast is a rare and aggressive malignancy, with high recurrence and metastasis. Metaplastic carcinoma with chondroid differentiation is an uncommon subtype that tends to have a relatively good prognosis than that of other subtypes. We report the imaging features of three cases of pathologically proven metaplastic carcinoma with chondroid differentiation as follows: a high-density mass with amorphous or coarse heterogeneous calcifications on mammography; a microlobulated or partially indistinct, complex cystic, and solid mass on sonography; and a relatively circumscribed or partially indistinct, irregular mass with heterogeneous T2 high-signal intensity and heterogeneous or rim enhancement with initial fast enhance ment and delayed washout on MRI.

Controlled Doping of Electrocatalysts through Engineering Impurities.

Fuel cells recombine water from H2 and O2 thereby can power, for example, cars or houses with no direct carbon emission. In anion-exchange membrane fuel cells (AEMFCs), to reach high power densities, operating at high pH is an alternative to using large volumes of noble metals catalysts at the cathode, where the oxygen-reduction reaction occurs. However, the sluggish kinetics of the hydrogen-oxidation reaction (HOR) hinders upscaling despite promising catalysts. Here, the authors observe an unexpected ingress of B into Pd nanocatalysts synthesized by wet-chemistry, gaining control over this B-doping, and report on its influence on the HOR activity in alkaline conditions. They rationalize their findings using ab initio calculations of both H- and OH-adsorption on B-doped Pd. Using this "impurity engineering" approach, they thus design Pt-free catalysts as required in electrochemical energy conversion devices, for example, next generations of AEMFCs, that satisfy the economic and environmental constraints, that is, reasonable operating costs and long-term stability, to enable the "hydrogen economy."

Strategic Significance of Low Viral Load of Human Papillomavirus in Uterine Cervical Cytology Specimens.

Infection with high-risk (HR) Human Papillomavirus (HPV) is associated with the development of precancerous lesions or invasive carcinoma of the uterine cervix. Thus, the high viral load (VL) of HR-HPV DNA currently serves as a representative quantitative marker for cervical cancer. However, the clinical significance of low HPV DNA VL remains undetermined. This study aimed to evaluate the clinical association between the low HPV DNA VL and cytology/histologic diagnosis of cervical samples. We searched the electronic medical databases for the resultant analyses of HPV genotyping among patients who underwent treatment for any cervical lesion or who had undergone gynecological examinations with any positive HPV results according to the national cancer screening service between 2015 and 2016. HPV testing with genotyping and semi-quantitative VL measurement was conducted using an AnyplexTM II H28 Detection assay (H28 assay, Seegene, Seoul, Republic of Korea). The H28 assay is a multiplex semi-quantitative real-time PCR test using the tagging of oligonucleotide cleavage and extension (TOCE) technology. The VL was semi-quantified as high (3+; positive signal before 31 PCR cycles), intermediate (2+; positive between 31 and 39 PCR cycles), or low (1+; positive after 40 PCR cycles). Out of 5940 HPV VL analyses, 356 assays (5.99%) were reported as low VL (1+) of HPV DNA. Matched cytology diagnoses were mostly negative findings (n = 347, 97.5%), except for seven cases of atypical squamous cells of undetermined significance (1.9%) and two cases of atypical glandular cells (0.6%). During the follow-up periods, abnormal cytologic diagnoses were identified, including one case of high-grade squamous intraepithelial lesion (HSIL) and two low-grade squamous intraepithelial lesions (LSILs). The matched, confirmative histologic diagnosis of HSIL cytology was compatible with chronic inflammation, wherein the two LSILs had regular check-ups. None revealed clinically concerned outcomes associated with HPV-related squamous lesions. The cytology was most likely negative for malignancy when the VL of HPV DNA was low (1+). Additional strategic monitoring and management may thus be unnecessary.

Primary retroperitoneal dysgerminoma presenting as an adrenal tumor: a case report and literature review.

Primary extragonadal germ cell tumors are rare and mostly occur in young men with predominance of nonseminomatous histology. We report an undescribed case of primary retroperitoneal dysgerminoma presenting as an adrenal tumor in a 17-year-old girl. Surgery was performed on a 10 × 9.5 cm sized adrenal gland tumor and the resected tumor showed unequivocal histological features of dysgerminoma. The diagnosis was confirmed by the tumor's germ cell immunophenotype. Postoperative ultrasonography, CT and PET over a 6-month period revealed no evidence of ovarian lesion. The patient is stable, but with a suspicious residual tumor after adjuvant chemotherapy.

Going beyond the equilibrium crystal shape: re-tracing the morphological evolution in group 5 tetradymite nanocrystals.

Nanocrystals of group 5 tetradymites M2X3 (where M = Bi and Sb, X = Se and Te) are of high technological relevance in modern topological nanoelectronics. However, there is a current lack of a systematic understanding to predict the preferred nanocrystal morphology in experiments where commonly-used equilibrium thermodynamic models appear to fail. In this work, using first-principles DFT calculations with a rationally-extended ab initio atomistic thermodynamics approach coupled to implicit solvation models and Gibbs-Wulff shape constructions, we demonstrate that this absence of predictive power stems from the limitation of equilibrium thermodynamics. By re-tracing and carefully addressing with a more realistic chemical potential definition, we illustrate this shortcoming can be overcome and afford a more rational route to size-engineer and shape-design highly-functional group 5 tetradymite nanoparticles for targeted applications.

A Review and Update on Papillary Immature Metaplasia of the Uterine Cervix: A Distinct Subset of Low-Grade Squamous Intraepithelial Lesion, Proposing a Possible Cell of Origin.

CONTEXT: - Papillary immature metaplasia (PIM) is a known papillary cervical lesion associated with low-risk human papillomavirus (LR-HPV). OBJECTIVE: - To evaluate additional clinicopathologic features and the HPV genotypes of PIM and discuss the presumptive cell of origin. DESIGN: - A total of 26 PIM cases were evaluated by p16INK4a, cytokeratin (CK) 7, and CK17 immunohistochemical stainings. Human papillomavirus genotyping was performed, by using HPV DNA Chip, HPV polymerase chain reaction (PCR), and real-time PCR. RESULTS: - Histologically, PIM forms either a papillary mass (n = 21 of 26, 81%) or a slightly elevated/flat plaque (n = 5, 19%). All cases contain variable amounts of mucinous epithelia within the lesions. Koilocytosis was identified in 15 of the 26 cases (58%). Sixteen cases (61%) were associated with LR-HPV (types 6, 11, or 42), but 3 cases (12%) with high-risk (HR) HPV (16, 16/18, and 33), 2 cases (8%) with mixed LR- and HR-HPV (6/16 and 11/58), while 2 cases (8%) were negative, but p16INK4a immunostaining showed nonblock positivity in all cases. Eight (31%) had high-grade squamous intraepithelial lesion (HSIL) in the adjacent mucosa, 4 (50%) of which showed direct continuity. Identical HPV subtypes were confirmed in separately microdissected cases from PIM and adjacent HSIL. Most lesions (n = 24, 92%) expressed CK17 (reserve cell marker) in a bottom-heavy pattern and CK7 (squamocolumnar junction [SCJ] marker) in a top-heavy pattern, while most cases of low-grade squamous intraepithelial lesion (LSIL) were negative for both markers. CONCLUSIONS: - Our results suggest that PIM is a distinct subset of LSIL showing a productive HPV infection, but PIM involves the transformation zone and is proximal to SCJ, while LSIL is mostly from ectocervix or distal to the SCJ.