Incorporating edible oil during cooking tailors the microstructure and quality features of brown rice following heat moisture treatment.

While brown rice (BR) has numerous nutritional properties, the consumption potential of which is seriously restricted since the poor cooking quality and undesirable flavor. Here, edible oils (pork lard and corn oil, 1-5 wt%) were incorporated during the cooking of BR following heat moisture treatment. Incorporating corn oil rather than lard significantly ameliorated the texture properties (e.g. hardness, cohesiveness, and chewiness) and sensory properties of cooked BR. Both lard- and corn oil-incorporated cooked BR showed obvious structural changes accompanied by the formation of amylose-lipid complexes during cooking. It was confirmed that the incorporation of lard and corn oil allowed a higher degree of short-range molecular order, more V-type starch crystallites, and elevated nano-structural arrangements. Additionally, a decreased hardness (from 559.04 g to 424.18 g and 385.91 g, respectively) and enriched resistant starch (RS) were also observed, the highest RS content (15.95 % and 16.32 %, respectively) was observed when 1 wt% of lard and corn oil were incorporated.

Study by means of 1H nuclear magnetic resonance of the oxidation process in high oleic sunflower oil and palm oil during deep-frying of fish cakes.

This study aimed to compare the frying performance of palm oil (PO) and high oleic sunflower oil (HOSO) during frying aquatic products. The quality change and frying performance of HOSO and PO during frying of fish cakes were investigated. The oxidation and hydrolysis products of both oils were explored by the nuclear magnetic resonance technique. The results showed that the color deepening rate of PO was higher than that of HOSO. After 18 h of frying, the total polar compound content of PO and HOSO reached 25.67% and 27.50%, respectively. HOSO had lower degree of oxidation than PO after 24 h of continuous frying. The polyunsaturated fatty acid content in HOSO and PO significantly decreased. The oleic acid content in HOSO remained above 80% during the frying process. The major aldehydes in both oils were (E, E)-2,4-alkadienals and n-alkanals and glycerol diesters (DAGs) were abundant in PO. Furthermore, the addition of fish cakes had slight effect on the quality of the frying oil. Therefore, HOSO is an appropriate candidate for frying owing to its excellent frying stability and nutritional value.

Formation of AGEs in Penaeus vannamei fried with high oleic acid sunflower oil.

Here, we investigated the effects of frying process on the formation of advanced glycation end products (AGEs) in shrimps using Penaeus vannamei as the raw material. The results showed that the oil, malondialdehyde, fluorescent AGEs, carboxymethyl lysine (CML), methylglyoxal hydroimidazolone (MG-H1) and the outer layer carboxyethyl lysine (CEL) content was higher in the fried shrimps than that in the raw unfried shrimps. The outer layer CML, CEL and inner CEL, MG-H1 values all reached the maximum after the first batch of frying (22.43 mg/kg, 304.24 mg/kg, 83.76 mg/kg, and 169.42 mg/kg respectively). However, fluorescent AGEs and MG-H1 of the outer layer reached the maximum after the fifth and fourth batches of frying (1230.0 AU/g and 341.63 mg/kg). Malondialdehyde, fluorescent AGEs, CML, MG-H1, and CEL concentration in the fried shrimps firstly increased and then decreased to stabilization with more frying batches, with higher content in the outer layer of fried shrimps.

Changes in the Quality of High-Oleic Sunflower Oil during the Frying of Shrimp (Litopenaeus vannamei).

Shrimp fried in vegetable oil is a very popular food, so it is important to study the changes in the quality of the oil during frying. In order to more precisely study the nature of frying oil during the cooking process, this study investigated the quality changes of high-oleic sunflower oil during the frying of South American white shrimp (Litopenaeus vannamei). The oxidation and hydrolysis products of frying oils were investigated by integrating the proton nuclear magnetic resonance technique with traditional oil evaluation indexes in an integrated manner. The results showed that the color difference as measured using the ΔE* value increased gradually during the process. Moreover, the acid value, carbonyl value, and total oxidation significantly increased with prolonged frying time. The major oxidation products formed during frying were (E,E)-2-alkenals, (E,E)-2,4-alkadienals, and E,E-conjugated hydroperoxides. This indicated that longer treatment times corresponded with an increased accumulation of aldehydes and ketones, and an increased degree of oxidative deterioration of the oil. However, the proportion of oleic acid in the frying oil increased with the frying of shrimp, reaching 80.05% after 24 h. These results contribute to our understanding of the oxidative deterioration of high-oleic oils during frying, and provide an important reference for the application properties of high-oleic oils.

Whole grain rice: Updated understanding of starch digestibility and the regulation of glucose and lipid metabolism.

Nowadays, resulting from disordered glucose and lipid metabolism, metabolic diseases (e.g., hyperglycemia, type 2 diabetes, and obesity) are among the most serious health issues facing humans worldwide. Increasing evidence has confirmed that dietary intervention (with healthy foods) is effective at regulating the metabolic syndrome. Whole grain rice (WGR) rich in dietary fiber and many bioactive compounds (e.g., γ-amino butyric acid, γ-oryzanol, and polyphenols) can not only inhibit starch digestion and prevent rapid increase in the blood glucose level, but also reduce oxidative stress and damage to the liver, thereby regulating glucose and lipid metabolism. The rate of starch digestion is directly related to the blood glucose level in the organism after WGR intake. Therefore, the effects of different factors (e.g., additives, cooking, germination, and physical treatments) on WGR starch digestibility are examined in this review. In addition, the mechanisms from human and animal experiments regarding the correlation between the intake of WGR or its products and the lowered blood glucose and lipid levels and the reduced incidence of diabetes and obesity are discussed. Moreover, information on developing WGR products with the health benefits is provided.

Integrated mutational landscape analysis of uterine leiomyosarcomas.

Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus. We analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from The Cancer Genome Atlas (TCGA). Among them, a total of 55 Yale samples including two patient-derived xenografts (PDXs) and 27 TCGA samples have whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples have RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples have whole-genome sequencing (WGS) data. We found recurrent somatic mutations in TP53, MED12, and PTEN genes. Top somatic mutated genes included TP53, ATRX, PTEN, and MEN1 genes. Somatic copy number variation (CNV) analysis identified 8 copy-number gains, including 5p15.33 (TERT), 8q24.21 (C-MYC), and 17p11.2 (MYOCD, MAP2K4) amplifications and 29 copy-number losses. Fusions involving tumor suppressors or oncogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being potentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothripsis. Clinically actionable mutational signatures of homologous-recombination DNA-repair deficiency (HRD) and microsatellite instability (MSI) were identified in 25% (12 of 48) and 2% (1 of 48) of fresh frozen uLMS, respectively. Finally, we found olaparib (PARPi; P = 0.002), GS-626510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and suggest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.

Identification of novel antioxidant peptides from snakehead (Channa argus) soup generated during gastrointestinal digestion and insights into the anti-oxidation mechanisms.

Antioxidant peptides obtained from snakehead (Channa argus) soup (SHS) after simulated gastrointestinal (GI) digestion were separated, identified and characterized. Results showed that the fraction with MW < 3 kDa had the highest antioxidant capacity. Four novel antioxidant peptides were identified after RP-HPLC and UPLC-MS/MS. PGMLGGSPPGLLGGSPP and SDGSNIHFPN had the highest DPPH radical scavenging activity (IC50 = 1.39 mM) and Fe2+ chelating ability (IC50 = 4.60 mM), respectively. Structures in silico for IVLPDEGK, PGMLGGSPPGLLGGSPP and SDGSNIHFPN suggest at least one ß-turn and/or α-helix, which are associated with antioxidant activity. Moreover, our results showed that these three peptides docked with a recombinant Kelch-like ECH-associated protein 1 (Keap1) with a binding score greater than TX6, a good ligand of Keap1. The cell viability assay also showed significant cytoprotective effects against H2O2-induced cellular oxidative damage. This information implies that antioxidant mechanisms of novel SHS peptides occurred via activation of cellular anti-oxidation Keap1-Nrf2 signaling pathway.

Evaluation of antioxidant properties of the different tissues of vine tea (Ampelopsis grossedentata) in stripped canola oil and sunflower oil.

The leaves of Ampelopsis grossedentata have a long history of use as a health tea and herbal medicine. Data on the distribution of active metabolites in, and antioxidant capacities of, different vine tea tissues remain incomplete. The aim of this work was to investigate the content of metabolites from A. grossedentata different tissues and evaluate the antioxidant capacities of the extraction of the species in vitro and in oil systems: canola oil and sunflower oil. To evaluate the degree of lipid oxidation, the peroxide value (POV) and thiobarbituric acid-reactive substance value (TBARS) were determined, and proton nuclear magnetic resonance (1 H-NMR) was performed. The results revealed a high total flavonoid content in each of the four extractions (>580 mg/g dried weigh). Leaf extractions exhibited higher antioxidant ability, followed by fruit extract and butylated hydroxytoluene (BHT). The POVs of oils bearing extracts of A. grossedentata and BHT maintained less than 21.08 meq/kg oil against to control with 1,406.33 ± 52.63 meq/kg oil on day 32 in canola oil, and 27.87 meq/kg oil comparing to 1,892.96 ± 48.63 meq/kg oil in control on day 24 in sunflower oil. Concurring results were also obtained in TBARS and 1 H-NMR analysis. Our results indicated that these different tissues of A. grossedentata could be a potential antioxidant resource, and this work may contribute to the comprehensive utilization of this species. PRACTICAL APPLICATION: Leaf extracts of Ampelopsis grossedentata showed effective antioxidant properties, followed by the fruit extract, which showed similar activity to that of the synthetic antioxidant of BHT. Moreover, the investigation of different tissues within the plant may contribute to the comprehensive utilization of this species.

Identification and characterization of novel antioxidant peptides from crucian carp (Carassius auratus) cooking juice released in simulated gastrointestinal digestion by UPLC-MS/MS and in silico analysis.

The objective of this work was to separate, identify and assess antioxidant peptides from the simulated gastrointestinal (GI) digestion of crucian carp (Carassius auratus) cooking juice (CCCJ), which has been previously found with this activity. The CCCJ after simulated GI digestion treatment was separated gradually by ultrafiltration and RP-HPLC. Five novel antioxidant peptides with 10-13 amino acid residues were identified by UPLC-MS/MS. Their in silico assessments showed amphiphilic nature, good sensory quality and different target sites in the human body. Meanwhile, their three-dimensional structure predictions exhibited at least one ß-turn, ß-sheet and/or α-helix with partial hydrophobic and/or net-charged residues exposed to the external medium, which was good evidence for high antioxidant activity. Ultimately, four novel peptides with high antioxidant activity were found, among which IREADIDGDGQVN (1401 Da), PEILPDGDHD (1107 Da) and ASDEQDSVRL (1119 Da) exerted the highest DPPH radical scavenging activity with IC50 of 1.78, 1.18 and 1.45 mM, respectively, while APLEEPSSPH (1063 Da) showed the highest Fe2+ chelating ability with IC50 of 0.09 mM. This work could help understand the mechanism of CCCJ on human health promotion and improve the economic value of the crucian carp processing industry.

Whole-exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy.

The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cervical cancer cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most of which harboring Human-Papillomavirus-type-16/18. We found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, and GNAS) and a widespread APOBEC cytidine deaminase mutagenesis pattern (TCW motif) in both adenocarcinoma (ACC) and squamous cell carcinomas (SCCs). Somatic copy number variants (CNVs) identified 12 copy number gains and 40 losses, occurring more often than expected by chance, with the most frequent events in pathways similar to those found from analysis of single nucleotide variants (SNVs), including the ERBB2/PI3K/AKT/mTOR, apoptosis, chromatin remodeling, and cell cycle. To validate specific SNVs as targets, we took advantage of primary cervical tumor cell lines and xenografts to preclinically evaluate the activity of pan-HER (afatinib and neratinib) and PIK3CA (copanlisib) inhibitors, alone and in combination, against tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway (71%). Tumors harboring ERBB2 (5.8%) domain mutations were significantly more sensitive to single agents afatinib or neratinib when compared to wild-type tumors in preclinical in vitro and in vivo models (P = 0.001). In contrast, pan-HER and PIK3CA inhibitors demonstrated limited in vitro activity and were only transiently effective in controlling in vivo growth of PIK3CA-mutated cervical cancer xenografts. Importantly, combinations of copanlisib and neratinib were highly synergistic, inducing long-lasting regression of tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway. These findings define the genetic landscape of cervical cancer, suggesting that a large subset of cervical tumors might benefit from existing ERBB2/PIK3CA/AKT/mTOR-targeted drugs.

Detailed modeling of positive selection improves detection of cancer driver genes.

Identifying driver genes from somatic mutations is a central problem in cancer biology. Existing methods, however, either lack explicit statistical models, or use models based on simplistic assumptions. Here, we present driverMAPS (Model-based Analysis of Positive Selection), a model-based approach to driver gene identification. This method explicitly models positive selection at the single-base level, as well as highly heterogeneous background mutational processes. In particular, the selection model captures elevated mutation rates in functionally important sites using multiple external annotations, and spatial clustering of mutations. Simulations under realistic evolutionary models demonstrate the increased power of driverMAPS over current approaches. Applying driverMAPS to TCGA data of 20 tumor types, we identified 159 new potential driver genes, including the mRNA methyltransferase METTL3-METTL14. We experimentally validated METTL3 as a tumor suppressor gene in bladder cancer, providing support to the important role mRNA modification plays in tumorigenesis.

Structural Features, Antitumor and Antioxidant Activities of Rice Bran Polysaccharides Using Different Extraction Methods.

In this study, rice bran polysaccharides (RBP) were extracted using the hydrothermal method (RBP-H), microwave-assisted extraction (RBP-M) and enzyme-assisted extraction (RBP-E). The prepared RBP samples exhibited the typical spectral patterns of polysaccharides, but differed in chemical composition, molecular features, antitumor and antioxidant activities. The molecular weights (Mw) of RBP-H, RBP-M, and RBP-E were 1.03 × 105 , 2.62 × 105 , and 0.46 × 105 g/mol, respectively. In vitro, all RBP samples significantly inhibited mouse sarcoma S180 cells viability in a dose-dependent manner. In vivo, RBP-M or RBP-E could not only inhibit the growth of the tumor, but also enhance the spleen index. In addition, RBP-E could induce an enhancement of superoxide dismutase (SOD) and glutathione peroxidase activities and a scavenging effect on malondialdehyde. This study demonstrated that the effective antitumor activity of RBP may be owed to its enhancement of antioxidant activity function. The present work suggested that RBP, especially RBP-E could be a safe and effective antitumor, bioactive agent or functional food. PRACTICAL APPLICATION: Polysaccharides is extracted from rice bran (RBP) using hydrothermal, microwave-assisted and enzyme-assisted extraction methods. The results suggested that the antitumor activity of RBP was associated with enhancement of immunization and antioxidant. RBP could be explored as a natural antitumor and antioxidant agent applied in medicines and functional foods.

Rutin attenuates isoflurane-induced neuroapoptosis via modulating JNK and p38 MAPK pathways in the hippocampi of neonatal rats.

An increasing number of infants and children undergo surgery and are exposed to anesthesia as a part of medical care each year. Isoflurane is a commonly used anesthetic in the pediatric population. However, previous studies have reported widespread isoflurane-induced neuroapoptosis and cognitive impairments in neonatal animal models, raising concerns over the administration of isoflurane in the pediatric population. The current study investigated the effects of rutin, a flavonoid, on isoflurane-induced neuroapoptosis in a neonatal rodent model. Groups of neonatal rat pups were administered rutin at doses of 10, 20 or 40 mg/kg body weight from postnatal day 1 (P1) to P15. On P7, pups were exposed to 0.75% isoflurane for 6 h. Rat pups in the control groups did not receive rutin, and did not receive anesthesia in one group. Neuroapoptosis following isoflurane exposure was determined by TUNEL assay. The expression levels of cleaved caspase-3, apoptotic pathway proteins [Bcl2-associated agonist of cell death (Bad), phospho-Bad, Bax, B-cell lymphoma 2 (Bcl-2) and Bcl-xL and mitogen-activated protein kinases (MAPK)] signalling pathway proteins [c-Jun N-terminal kinase (JNK), phospho-JNK, extracellular-signal-regulated kinase 1/2 (ERK1/2), phosphoERK1/2, p38, phospho-p38 and phospho-c-Jun], were determined by western blot analysis. The Morris water maze test was used to assess the learning and memory of pups on P30 and P31. The present study found that rutin at the tested doses of 10, 20 and 40 mg significantly reduced (P<0.05) the isoflurane-induced elevation in apoptotic cell count. The expression levels of caspase-3, Bad, Bax and MAPK proteins, which were increased following isoflurane treatment, were rescued by rutin treatment. Furthermore, rutin prevented the increase in Bcl-xL, Bcl-2 and phospho-Bad expression following isoflurane treatment, and enhanced the memory of the rats. Rutin provided neuroprotection against isoflurane-induced neuronal apoptosis and improved the learning and memory of rats by effectively regulating the expression levels of proteins in the MAPK pathway.

Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition.

Carcinosarcomas (CSs) of the uterus and ovary are highly aggressive neoplasms containing both carcinomatous and sarcomatous elements. We analyzed the mutational landscape of 68 uterine and ovarian CSs by whole-exome sequencing. We also performed multiregion whole-exome sequencing comprising two carcinoma and sarcoma samples from six tumors to resolve their evolutionary histories. The results demonstrated that carcinomatous and sarcomatous elements derive from a common precursor having mutations typical of carcinomas. In addition to mutations in cancer genes previously identified in uterine and ovarian carcinomas such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4, and BCOR, we found an excess of mutations in genes encoding histone H2A and H2B, as well as significant amplification of the segment of chromosome 6p harboring the histone gene cluster containing these genes. We also found frequent deletions of the genes TP53 and MBD3 (a member with CHD4 of the nucleosome remodeling deacetylase complex) and frequent amplification of chromosome segments containing the genes PIK3CA, TERT, and MYC Stable transgenic expression of H2A and H2B in a uterine serous carcinoma cell line demonstrated that mutant, but not wild-type, histones increased expression of markers of epithelial-mesenchymal transition (EMT) as well as tumor migratory and invasive properties, suggesting a role in sarcomatous transformation. Comparison of the phylogenetic relationships of carcinomatous and sarcomatous elements of the same tumors demonstrated separate lineages leading to these two components. These findings define the genetic landscape of CSs and suggest therapeutic targets for these highly aggressive neoplasms.

Dual CCNE1/PIK3CA targeting is synergistic in CCNE1-amplified/PIK3CA-mutated uterine serous carcinomas in vitro and in vivo.

BACKGROUND: Clinical options for patients harbouring advanced/recurrent uterine serous carcinoma (USC), an aggressive variant of endometrial tumour, are very limited. Next-generation sequencing (NGS) data recently demonstrated that cyclin E1 (CCNE1) gene amplification and pik3ca driver mutations are common in USC and may therefore represent ideal therapeutic targets. METHODS: Cyclin E1 expression was evaluated by immunohistochemistry (IHC) on 95 USCs. The efficacy of the cyclin-dependent kinase 2/9 inhibitor CYC065 was assessed on multiple primary USC cell lines with or without CCNE1 amplification. Cell-cycle analyses and knockdown experiments were performed to assess CYC065 targeting specificity. Finally, the in vitro and in vivo activity of CYC065, Taselisib (a PIK3CA inhibitor) and their combinations was tested on USC xenografts derived from CCNE1-amplified/pik3ca-mutated USCs. RESULTS: We found that 89.5% of the USCs expressed CCNE1. CYC065 blocked cells in the G1 phase of the cell cycle and inhibited cell growth specifically in CCNE1-overexpressing USCs. Cyclin E1 knockdown conferred increased resistance to CYC065, whereas CYC065 treatment of xenografts derived from CCNE1-amplified USCs significantly reduced tumour growth. The combination of CYC065 and Taselisib demonstrated synergistic effect in vitro and was significantly more effective than single-agent treatment in decreasing tumour growth in xenografts of CCNE1-amplified/pik3ca-mutated USCs. CONCLUSIONS: Dual CCNE1/PIK3CA blockade may represent a novel therapeutic option for USC patients harbouring recurrent CCNE1-amplified/pi3kca-mutated tumours.

Protective Effects of Green Tea Polyphenol Against Renal Injury Through ROS-Mediated JNK-MAPK Pathway in Lead Exposed Rats.

To investigate the potential therapeutic effects of polyphenols in treating Pb induced renal dysfunction and intoxication and to explore the detailed underlying mechanisms. Wistar rats were divided into four groups: control groups (CT), Pb exposure groups (Pb), Pb plus Polyphenols groups (Pb+PP) and Polyphenols groups (PP). Animals were kept for 60 days and sacrificed for tests of urea, serum blood urea nitrogen (BUN) and creatinine. Histological evaluations were then performed. In vitro studies were performed using primary kidney mesangial cells to reveal detailed mechanisms. Cell counting kit-8 (CCK-8) was used to evaluate cell viability. Pb induced cell apoptosis was measured by flow cytometry. Reactive oxygen species (ROS) generation and scavenging were tested by DCFH-DA. Expression level of tumor necrosis factor-α (TNF-α), interleukin-1-ß (IL-1-ß) and IL-6 were assayed by ELISA. Western blot and qPCR were used to measure the expression of ERK1/2, JNK1/2 and p38. Polyphenols have obvious protective effects on Pb induced renal dysfunction and intoxication both in vivo and in vitro. Polyphenols reduced Pb concentration and accumulation in kidney. Polyphenols also protected kidney mesangial cells from Pb induced apoptosis. Polyphenols scavenged Pb induced ROS generation and suppressed ROS-mediated ERK/JNK/p38 pathway. Downstream pro-inflammatory cytokines were inhibited in consistency. Polyphenol is protective in Pb induced renal intoxication and inflammatory responses. The underlying mechanisms lie on the antioxidant activity and ROS scavenging activity of polyphenols.

Cadmium Removal from Rice by Separating and Washing Protein Isolate.

In this study detoxification of 3 Chinese Cd-contaminated cultivars (Jinyou463, Yuchi, and Xiangzaoxian 32) of rice was explored. By separation with an alkaline method, Cd concentrations of the starch isolates were decreased from 0.2769, 0.4037, and 0.5156 mg/kg in starting milled rice to 0.1056, 0.1585, and 0.1923 mg/kg, respectively. However, the Cd concentrations reached up to 2.5905, 3.1628, and 4.8593 mg/kg in the protein isolates, respectively. Therefore, 10 common acids in food industry were investigated to remove Cd from protein isolate by washing process. The optimal washing conditions were 0.5 M citric acid, acid to rice protein isolate ratio of 6:1 v/w, shaking time of 1 h at room temperature. The rice protein isolate showed a significant decrease in Cd concentration and the removal efficiency was more than 95% after 2 washings at optimized conditions. Rice proteins were not degraded at all and had very little loss during citric acid washing process. The study presents a promising way of depurating Cd-contaminated rice, and meanwhile it reduces the risk of heavy metal causing food safety issues effectively.

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.

The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10(-4)), increased frequency of nonsynonymous SSNVs in Pan-Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10(-17)); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers AT-rich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.

Preliminary evaluation of a virtual reality dental simulation system on drilling operation.

To evaluate the fidelity of the iDental system and investigate its utility and performance on simulated drilling operations, user studies consisting of objective and subjective evaluations were performed. A voxel-based drilling simulation sub-system in the iDental system was employed for evaluation. Twenty participants were enrolled to take part in the experiments and were divided into two groups: novice and resident. A combined evaluation method including objective and subjective methods was employed. The objective evaluation included two dental drilling tasks: caries removal operation and pulp chamber opening operation. In the subjective method, participants were required to complete a questionnaire to evaluate the fidelity of the system after the operation task. Based on the structured global assessment scales in the questionnaire, the average subjective evaluation scores of the proposed metrics were greater than 4.5, demonstrating that the system operated above medium fidelity. Dentists expressed great interest and positive attitudes toward the potential of the iDental system. The objective evaluation data including time spent and the volume of removed healthy and carious tissue were obtained. Although no significant differences could be found between the two groups, the volume of removed caries and the depth of pulp chamber insertion manifested small standard deviations. Evaluation results illustrated that dentists were willing to use the virtual reality training system. Several future research topics were identified, including increasing the task difficulty, improving the system fidelity and introducing appropriate finger rest points.

Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma.

Uterine serous carcinoma (USC) is a biologically aggressive subtype of endometrial cancer. We analyzed the mutational landscape of USC by whole-exome sequencing of 57 cancers, most of which were matched to normal DNA from the same patients. The distribution of the number of protein-altering somatic mutations revealed that 52 USC tumors had fewer than 100 (median 36), whereas 5 had more than 3,000 somatic mutations. The mutations in these latter tumors showed hallmarks of defects in DNA mismatch repair. Among the remainder, we found a significantly increased burden of mutation in 14 genes. In addition to well-known cancer genes (i.e., TP53, PIK3CA, PPP2R1A, KRAS, FBXW7), there were frequent mutations in CHD4/Mi2b, a member of the NuRD-chromatin-remodeling complex, and TAF1, an element of the core TFIID transcriptional machinery. Additionally, somatic copy-number variation was found to play an important role in USC, with 13 copy-number gains and 12 copy-number losses that occurred more often than expected by chance. In addition to loss of TP53, we found frequent deletion of a small segment of chromosome 19 containing MBD3, also a member of the NuRD-chromatin-modification complex, and frequent amplification of chromosome segments containing PIK3CA, ERBB2 (an upstream activator of PIK3CA), and CCNE1 (a target of FBXW7-mediated ubiquitination). These findings identify frequent mutation of DNA damage, chromatin remodeling, cell cycle, and cell proliferation pathways in USC and suggest potential targets for treatment of this lethal variant of endometrial cancer.