VHL suppresses autophagy and tumor growth through PHD1-dependent Beclin1 hydroxylation.

The Von Hippel-Lindau (VHL) protein, which is frequently mutated in clear-cell renal cell carcinoma (ccRCC), is a master regulator of hypoxia-inducible factor (HIF) that is involved in oxidative stresses. However, whether VHL possesses HIF-independent tumor-suppressing activity remains largely unclear. Here, we demonstrate that VHL suppresses nutrient stress-induced autophagy, and its deficiency in sporadic ccRCC specimens is linked to substantially elevated levels of autophagy and correlates with poorer patient prognosis. Mechanistically, VHL directly binds to the autophagy regulator Beclin1, after its PHD1-mediated hydroxylation on Pro54. This binding inhibits the association of Beclin1-VPS34 complexes with ATG14L, thereby inhibiting autophagy initiation in response to nutrient deficiency. Expression of non-hydroxylatable Beclin1 P54A abrogates VHL-mediated autophagy inhibition and significantly reduces the tumor-suppressing effect of VHL. In addition, Beclin1 P54-OH levels are inversely correlated with autophagy levels in wild-type VHL-expressing human ccRCC specimens, and with poor patient prognosis. Furthermore, combined treatment of VHL-deficient mouse tumors with autophagy inhibitors and HIF2α inhibitors suppresses tumor growth. These findings reveal an unexpected mechanism by which VHL suppresses tumor growth, and suggest a potential treatment for ccRCC through combined inhibition of both autophagy and HIF2α.

Metabolic reprogramming driven by METTL1-mediated tRNA m7G modification promotes acquired anlotinib resistance in oral squamous cell carcinoma.

Tyrosine kinase inhibitors (TKIs) are frequently utilized in the management of malignant tumors. Studies have indicated that anlotinib has a significant inhibitory effect on oral squamous cell carcinoma (OSCC). However, the mechanisms underlying the development of resistance with long-term anlotinib treatment remain obscure. Our research found that METTL1 expression was heightened in anlotinib-resistant OSCC cells. We observed that METTL1 played a role in fostering resistance to anlotinib in both transgenic mouse models and in vitro. Mechanistically, the elevated METTL1 levels in anlotinib-resistant OSCC cells contributed to enhanced global mRNA translation and stimulated oxidative phosphorylation (OXPHOS) through m7G tRNA modification. Bioenergetic profiling demonstrated that METTL1 drived a metabolic shift from glycolysis to OXPHOS in anlotinib-resistant OSCC cells. Additionally, inhibition of OXPHOS biochemically negated METTL1's impact on anlotinib resistance. Overall, this study underscores the pivotal role of METTL1-mediated m7G tRNA modification in anlotinib resistance and lays the groundwork for novel therapeutic interventions to counteract resistance in OSCC.

Measuring the intensive care experience of intensive care unit patients: A cross-sectional study in western China.

BACKGROUND: The negative experiences of intensive care unit (ICU) patients seriously affect their quality of life and survival outcomes. Thus, it is of great significance to evaluate the monitoring experience of ICU patients for the clinical improvement of their experiences and promote interventions. OBJECTIVES: The objective of this study was to investigate patients' experiences of ICU and to understand the sources of patient experience and influencing factors. METHODS: From November 2021 to September 2022, a cross-sectional survey was conducted with 600 inpatients from four grade A-III hospitals in western China. Data were collected using the Chinese version of the Intensive Care Experience Questionnaire. RESULTS: 585 valid questionnaires were collected, the response rate was 97.5%. ICU patients in western China scored below-the-average for their intensive care experience. Family monthly income, occupation types, medical payment method, type of ICU, ICU admission plan, ICU admission times, mechanical ventilation use, fertility status, analgesia, sedation, and Acute Physiology and Chronic Health Evaluation II scores are important factors influencing ICU patients' intensive care experience. CONCLUSIONS: Medical staff need to pay attention to patient experience, improve the awareness of patient stressors and influencing factors, design nursing programs conducive to patient-positive experience, and promote interventions to further improve the long-term prognosis of patients. The results of this study can also be used as a set of nursing-sensitive indicators for evaluating nursing structure, process, and outcomes.

Changes in choroidal hemodynamics of form-deprivation myopia in Guinea pigs.

PURPOSE: We studied changes in the choroid, particularly variation in blood flow, during the development of myopia. The hemodynamic mechanism in play remains unclear. We evaluated blood flow by quantitating indocyanine green (ICG) fluorescence in a guinea pig model of form-deprivation myopia. METHODS: Guinea pigs were divided into form-deprivation myopia (FDM) and normal control (NC) groups. Ocular biometric and choroidal hemodynamics parameters were quantitatively derived via ICG imaging, and included the maximal ICG fluorescence intensity (Imax), rising time (Trising), blood flow index (BFI), and mean transit time (MTT). RESULTS: Form deprivation was associated with significant interocular differences in terms of both refractive error and axial length. ICG fluorescence hemodynamic maps of fundal blood flow and vasculature density were evident. In deprived eyes, the fluorescence signals exhibited significantly longer Trising and MTT but lower Imax and BFI than fellow eyes and NC group. The interocular differences in terms of the ocular biometric and hemodynamic parameters were significantly correlated. Hemodynamic analysis of choriocapillaris lobules revealed weakened fluorescence intensity and prolonged arrival and filling times in deprived eyes. Form deprivation reduced the number of lobulated choriocapillaris structures. CONCLUSION: Form-deprivation myopia triggered changes in the hemodynamic and vascular network structures of the choroid and choriocapillaris. The ICG fluorescence imaging/analysis method provides a unique tool for further myopia research.

Identification of six novel mutations in EDA from 20 hypohidrotic ectodermal dysplasia families.

OBJECTIVE: To investigate the genetic causes of 22 patients with clinically high suspicion of X-linked hypohidrotic ectodermal dysplasia from 20 unrelated Chinese families, expand the spectrum of ectodysplasin-A mutations, and provide more evidence for variants of uncertain significance. SUBJECTS AND METHODS: Whole-exome sequencing was performed and potentially pathogenic variants were verified by Sanger sequencing. Western blotting, real-time PCR and immunofluorescence analyses were performed to investigate the preliminary functions of the candidate variants. RESULTS: Nineteen ectodysplasin-A variants were identified, six of which were not previously reported. Among these variants, we identified a patient who carried two mutations in ectodysplasin-A and exhibited more severe phenotypes. Additionally, mutant protein expression levels decreased, whereas mRNA transcription levels increased. Cellular sublocalisation of the variants located in the tumour necrosis factor homologous domain showed that the proteins accumulated in the nucleus, whereas wild-type proteins remained in the cell membrane. A rare indel variant and two classical splicing variants that lead to exon 7 skipping were detected. CONCLUSIONS: This study provides definitive diagnoses for 20 families with suspected X-linked hypohidrotic ectodermal dysplasia and additional information on clinical heterogeneity and genotype-phenotype relationships.

Association between inflammatory cytokines and oxidative stress levels in aqueous humor with axial length in human myopia.

This study investigated the content of inflammatory cytokines and oxidative stress levels in the aqueous humor (AH) of patients with high myopia (HM) and explored the relationship between these factors and the axial length (AL) of the eye, to explore the roles of mild intraocular inflammation and oxidative stress imbalance in the occurrence and development of myopia. AH samples from 40 patients (70 eyes) were collected during implantable collamer lens (ICL-V4c) surgery. The subjects were divided into three groups according to AL: group A (AL ≤ 26 mm), group B (26 < AL ≤ 28 mm), and group C (AL ≥ 28 mm). The concentrations of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-2 (MMP-2), and interleukin-1ß (IL-1ß) in the AH of the three groups were measured using the Luminex system. Oxidative stress levels were measured using reagent kits targeting total antioxidant capacity (T-AOC), catalase (CAT), and nitric oxide (NO) and malonaldehyde (MDA) content. The results showed compared with group A, IL-1ß, MMP-2, and IL-6 concentrations were significantly higher and T-AOC levels were significantly lower in group C. There were no significant differences in CAT, NO, MDA, or TNF-α levels among the groups. The concentrations of IL-6 (r = 0.379, p = 0.016), MMP-2 (r = 0.469, p = 0.002), and MDA (r = 0.354, p = 0.025) in AH were positively correlated with the AL, whereas T-AOC (r = -0.678, p = 0.000) was negatively correlated with AL. These results suggest that mild intraocular inflammation and oxidative stress imbalance may be associated with myopia. Further experiments are needed to confirm the role of mild intraocular inflammation and oxidative stress imbalance in the occurrence and development of myopia.

Mechanistic Understanding of Efficient Polyethylene Hydrocracking over Two-Dimensional Platinum-Anchored Tungsten Trioxide.

Chemical upcycling of polyethylene (PE) can convert plastic waste into valuable resources. However, engineering a catalyst that allows PE decomposition at low temperatures with high activity remains a significant challenge. Herein, we anchored 0.2 wt.% platinum (Pt) on defective two-dimensional tungsten trioxide (2D WO3 ) nanosheets and achieved hydrocracking of high-density polyethylene (HDPE) waste at 200-250 °C with a liquid fuel (C5-18 ) formation rate up to 1456 gproducts ⋅ gmetal species -1 ⋅ h-1 . The reaction pathway over the bifunctional 2D Pt/WO3 is elucidated by quasi-operando transmission infrared spectroscopy, where (I) well-dispersed Pt immobilized on 2D WO3 nanosheets trigger the dissociation of hydrogen; (II) adsorption of PE and activation of C-C cleavage on WO3 are through the formation of C=O/C=C intermediates; (III) intermediates are converted to alkane products by the dissociated H. Our study directly illustrates the synergistic role of bifunctional Pt/WO3 catalyst in the hydrocracking of HDPE, paving the way for the development of high-performance catalysts with optimized chemical and morphological properties.

Diffuse Uerine Leiomyomatosis Complicated with Cerebral Thrombosis After Oral Contraceptive Treatment: A Case Report of a Athletic Patients

We would like to emphasize the differentiations of diagnosis and treatment between general uterine leiomyomas and diffuse uterine leiomyomatosis (DUL), which is a kind of extremely rare disease. Levonorgestrel-releasing intrauterine system (LNG-IUS) is an attainable option provided to treat DUL with cerebral thrombosis, as a feasible novel method. Case report: A 21-year-old female patient with DUL was due to cerebral venous thrombosis caused by oral contraceptives. The patient was persistently vaginal bleeding after decreasing intracranial pressure and anticoagulant therapy for 3 days. Subsequently, a hysteroscopic submucosal myomectomy was performed to restore the normal shape of the uterine cavity, and the placement of Mirena was given after surgery, which aimly played a good role in hemostasis, prevention of severe menorrhagia and reconstruction of endometrial function. Conclusion: This case report shows that, levonorgestrel-releasing intrauterine system (LNG-IUS) is efficient and secure to treat DUL after hysteroscopic surgery, and simultaneously does not increase the risk of venous thromboembolism (VTE). (AU)

Preparation of therapy-grade extracellular vesicles from adipose tissue to promote diabetic wound healing.

Background: Treatment of diabetic wounds is a major challenge in clinical practice. Extracellular vesicles (EVs) from adipose-derived stem cells have shown effectiveness in diabetic wound models. However, obtaining ADSC-EVs requires culturing vast numbers of cells, which is hampered by the need for expensive equipment and reagents, extended time cost, and complicated procedures before commercialization. Therefore, methods to extract EVs from discarded tissue need to be developed, for immediate application during surgery. For this reason, mechanical, collagenase-digestive, and constant in-vitro-collective methods were designed and compared for preparing therapy-grade EVs directly from adipose tissue. Methods: Characteristics and quantities of EVs were detected by transmission electron microscopy, nanoparticle tracking analysis, and Western blotting firstly. To investigate the biological effects of EVs on diabetic wound healing, angiogenesis, proliferation, migration, and inflammation-regulation assays were then evaluated in vitro, along with a diabetic wound healing mouse model in vivo. To further explore the potential therapeutic mechanism of EVs, miRNA expression profile of EVs were also identified and analyzed. Results: The adipose tissue derived EVs (AT-EVs) were showed to qualify ISEV identification by nanoparticle tracking analysis and Western blotting and the AT-EVs yield from three methods was equal. EVs also showed promoting effects on biological processes related to diabetic wound healing, which depend on fibroblasts, keratinocytes, endothelial cells, and macrophages both in vitro and in vivo. We also observed enrichment of overlapping or unique miRNAs originate from different types of AT-EVs associated with diabetic wound healing for further investigation. Conclusion: After comparative analyses, a mechanical method was proposed for preparing immediate clinical applicable EVs from adipose tissue that would result in reduced preparation time and lower cost, which could have promising application potential in treating diabetic wounds.

Production and Biological Effects of Extracellular Vesicles from Adipose-Derived Stem Cells Were Markedly Increased by Low-Intensity Ultrasound Stimulation for Promoting Diabetic Wound Healing.

Diabetic wound treatment has posed a significant challenge in clinical practice. As a kind of cell-derived nanoparticles, extracellular vesicles produced by adipose-derived stem cells (ADSC-EVs) have been reported to be potential agents for diabetic wound treatment. However, ADSC-EV yield is insufficient to meet the demands of clinical therapy. In this study, a novel method involving the use of low-intensity ultrasound stimulation on ADSCs is developed to promote EV secretion for clinical use. A proper low-intensity ultrasound stimulation parameter which significantly increases ADSC-EV quantity has been found. In addition, EVs secreted by ADSCs following low-intensity ultrasound stimulation (US-EVs) are enriched in wound healing-related miRNAs. Moreover, US-EVs promote the biological functions of fibroblasts, keratinocytes, and endothelial cells in vitro, and promote diabetic wound healing in db/db mice in vivo through re-epithelialization, collagen production, cell proliferation, keratinocyte differentiation and migration, and angiogenesis. This study proposes low-intensity ultrasound stimulation as a new method for promoting significant EV secretion by ADSCs and for improving the diabetic wound-healing potential of EVs, which will meet the clinical needs for these nanoparticles. The production of extracellular vesicles of adipose-derived stem cells is obviously promoted by a low-intensity ultrasound stimulation method, and the biological effects of promoting diabetic wound healing were markedly increased in vitro and in vivo.

Bioinformatic analysis identifies HPV-related tumor microenvironment remodeling prognostic biomarkers in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinomas (HNSCCs) are highly aggressive tumors with rapid progression and poor prognosis. Human papillomavirus (HPV) infection has been identified as one of the most important carcinogens for HNSCC. As an early event in HNSCC, infection with HPV leads to altered immune profiles in the tumor microenvironment (TME). The TME plays a key role in the progression and transformation of HNSCC. However, the TME in HNSCC is a complex and heterogeneous mix of tumor cells, fibroblasts, different types of infiltrating immune cells, and extracellular matrix. Biomarkers relevant to the TME, and the biological role of these biomarkers, remain poorly understood. To this end, we performed comprehensive analysis of the RNA sequencing (RNA-Seq) data from tumor tissue of 502 patients with HNSCC and healthy tissue of 44 control samples. In total, we identified 4,237 differentially expressed genes, including 2,062 upregulated and 2,175 downregulated genes. Further in-depth bioinformatic analysis suggested 19 HNSCC tumor tissue-specific genes. In the subsequent analysis, we focused on the biomarker candidates shown to be significantly associated with unfavorable patient survival: ITGA5, PLAU, PLAUR, SERPINE1, TGFB1, and VEGFC. We found that the expression of these genes was negatively regulated by DNA methylation. Strikingly, all of these potential biomarkers are profoundly involved in the activation of the epithelial-mesenchymal transition (EMT) pathway in HNSCCs. In addition, these targets were found to be positively correlated with the immune invasion levels of CD4+ T cells, macrophages, neutrophils, and dendritic cells, but negatively correlated with B-cell infiltration and CD8+ T-cell invasion. Notably, our data showed that the expression levels of ITGA5, PLAU, PLAUR, SERPINE1, and TGFB1 were significantly overexpressed in HPV-positive HNSCCs compared to normal controls, indicating the potential role of these biomarkers as transformation and/or malignant progression markers for HNSCCs in patients with HPV infection. Taken together, the results of our study propose ITGA5, PLAU, PLAUR, SERPINE1, and TGFB1 as potential prognostic biomarkers for HNSCCs, which might be involved in the HPV-related TME remodeling of HNSCC. Our findings provide important implications for the development and/or improvement of patient stratification and customized immunotherapies in HNSCC.

WDR73 Depletion Destabilizes PIP4K2C Activity and Impairs Focal Adhesion Formation in Galloway-Mowat Syndrome.

(1) Background: Galloway-Mowat syndrome (GAMOS) is a rare genetic disease, classically characterized by a combination of various neurological symptoms and nephrotic syndrome. WDR73 is the pathogenic gene responsible for GAMOS1. However, the pathological and molecular mechanisms of GAMOS1, especially nephrotic syndrome caused by WDR73 deficiency, remain unknown. (2) Methods and Results: In this study, we first observed remarkable cellular morphological changes including impaired cell adhesion, decreased pseudopodia, and G2/M phase arrest in WDR73 knockout (KO) HEK 293 cells. The differentially expressed genes in WDR73 KO cells were enriched in the focal adhesion (FA) pathway. Additionally, PIP4K2C, a phospholipid kinase also involved in the FA pathway, was subsequently validated to interact with WDR73 via protein microarray and GST pulldown. WDR73 regulates PIP4K2C protein stability through the autophagy-lysosomal pathway. The stability of PIP4K2C was significantly disrupted by WDR73 KO, leading to a remarkable reduction in PIP2 and thus weakening the FA formation. In addition, we found that podocyte-specific conditional knockout (Wdr73 CKO) mice showed high levels of albuminuria and podocyte foot process injury in the ADR-induced model. FA formation was impaired in primary podocytes derived from Wdr73 CKO mice. (3) Conclusions: Since FA has been well known for its critical roles in maintaining podocyte structures and function, our study indicated that nephrotic syndrome in GAMOS1 is associated with disruption of FA caused by WDR73 deficiency.

Preparation of glycosyl carboxylic acids via stereoselective synthesis and oxidative cleavage of C-vinyl glycosides.

We have developed an improved cyanide-free strategy for the synthesis of glycosyl carboxylic acids, employing stereoselective C-vinyl glycosylation and oxidative cleavage of C-vinyl glycosides as key steps. Compared to our previous work, the amount of NaIO4 required for the oxidative cleavage step is reduced significantly from 18 equivalents to 4.5 equivalents. This modification not only is advantageous in terms of operation and costs but also avoids the over-oxidation problem, thus greatly expanding the substrate scope, which is evidenced by the fact that 10 out of 21 glycosyl carboxylic acids synthesized are undocumented. With differently O5-protected furanosyl acids in hand, we demonstrate that an electron-rich protecting group is beneficial for the decarboxylative arylation of furanosyl carboxylic acids. This represents a rare example of protecting groups affecting the reaction efficiency in radical C-glycosylation. As C-vinyl glycosides can be prepared stereoselectively and the oxidative step is stereoretentive, the approach provides an effective means to access 1,2-trans or 1,2-cis glycosyl acids, which would be a valuable alternative to the cyanide-based synthesis of glycosyl carboxylic acids.

Identification of four novel mutations in BTK from six Chinese families with X-linked agammaglobulinemia.

BACKGROUND: The defect of Bruton's tyrosine kinase (BTK) gene resulted in X-linked agammaglobulinemia (XLA), which is characterized by recurrent bacterial infections, immunodeficiency with low B-cell numbers and immunoglobulin. Diagnosis of XLA depends on clinical phenotype and genetic testing. METHODS: Six unrelated Chinese families with high suspicion of XLA were enrolled in this study. Potential pathogenic variants were detected and validated by Whole Exome Sequencing (WES) and Sanger Sequencing. Western blot, Quantitative PCR (qPCR) analysis and immunofluorescence analysis were used to evaluate the preliminary function of candidate BTK variants. RESULTS: A total of six variants were identified, four of which were not reported before. The novel missense mutation(c.1900 T > G) and deletion(c.897delG) were found that the mutant protein and mRNA expression levels have fallen by Western Blot and qPCR identification. We also constructed minigene expression vector to determine the deletion (c.1751-6_1755delttctagGGGTT) resulting a 35 bp skipping in exon 18. Meanwhile, the break point of gross deletion (Exon2-5) discovered based on WES was confirmed to be located at site ChX:101367539_101376531 through qPCR and Gap-PCR. CONCLUSION: This study makes definitive diagnosis for 6 families with suspected XLA and further expands the spectrum of BTK mutations, providing new information for the diagnosis of the disease.

The human melanoma proteome atlas-Defining the molecular pathology.

The MM500 study is an initiative to map the protein levels in malignant melanoma tumor samples, focused on in-depth histopathology coupled to proteome characterization. The protein levels and localization were determined for a broad spectrum of diverse, surgically isolated melanoma tumors originating from multiple body locations. More than 15,500 proteoforms were identified by mass spectrometry, from which chromosomal and subcellular localization was annotated within both primary and metastatic melanoma. The data generated by global proteomic experiments covered 72% of the proteins identified in the recently reported high stringency blueprint of the human proteome. This study contributes to the NIH Cancer Moonshot initiative combining detailed histopathological presentation with the molecular characterization for 505 melanoma tumor samples, localized in 26 organs from 232 patients.

Symptom Clusters and Quality of Life in Cervical Cancer Patients Receiving Concurrent Chemoradiotherapy: The Mediating Role of Illness Perceptions.

OBJECTIVES: Although studies shows that symptom clusters and illness perceptions are negatively associated with quality of life (QoL), it is unclear how these variables of cervical cancer patients who receive concurrent chemoradiotherapy (CCRT) relate to each other. This study aimed to identify the symptom clusters in cervical cancer patients who receive CCRT and evaluate the mediating effect of illness perceptions on the relationship between symptom clusters and QoL. METHODS: A cross-sectional survey was conducted on 286 cervical cancer patients receiving CCRT from October 2019 to October 2020. M.D. Anderson Symptom Inventory, Brief Illness Perception Questionnaire, and Functional Assessment Cancer Therapy-Cervix were applied to investigate the symptom clusters, illness perceptions and QoL of the participants, respectively. Exploratory factor analysis was conducted to identify symptom clusters. The relationships among symptom clusters, illness perceptions, and QoL were analyzed with the structural equation modeling. RESULTS: A total of four symptom clusters were identified, including psychological status symptom cluster, therapy side-effect symptom cluster, sickness symptom cluster, and gastrointestinal symptom cluster (χ2 = 1,552.282, Df = 78, P < 0.001). Symptom clusters, illness perceptions, and QoL were significantly correlated. Symptom clusters had significant direct (ß = -0.38, P < 0.001) and indirect effects (ß = -0.21, P < 0.001) on QoL. CONCLUSION: Illness perceptions played a significant mediating role between symptom clusters and QoL in cervical cancer patients receiving CCRT. Strategies like prompting effective symptom management for the purposes of alleviating illness perceptions may contribute to improving their QoL.

YAP1 is an independent prognostic marker in pancreatic cancer and associated with extracellular matrix remodeling.

BACKGROUND: Pancreatic cancer is a major cause of cancer-related mortality. The identification of effective biomarkers is essential in order to improve management of the disease. Yes-associated protein 1 (YAP1) is a downstream effector of the Hippo pathway, a signal transduction system implicated in tissue repair and regeneration, as well as tumorigenesis. Here we evaluate the biomarker potential of YAP1 in pancreatic cancer tissue. METHODS: YAP1 was selected as a possible biomarker for pancreatic cancer from global protein sequencing of fresh frozen pancreatic cancer tissue samples and normal pancreas controls. The prognostic utility of YAP1 was evaluated using mRNA expression data from 176 pancreatic cancer patients in The Cancer Genome Atlas (TCGA), as well as protein expression data from immunohistochemistry analysis of a local tissue microarray (TMA) cohort comprising 140 pancreatic cancer patients. Ingenuity Pathway Analysis was applied to outline the interaction network for YAP1 in connection to the pancreatic tumor microenvironment. The expression of YAP1 target gene products was evaluated after treatment of the pancreatic cancer cell line Panc-1 with three substances interrupting YAP-TEAD interaction, including Super-TDU, Verteporfin and CA3. RESULTS: Mass spectrometry based proteomics showed that YAP1 is the top upregulated protein in pancreatic cancer tissue when compared to normal controls (log2 fold change 6.4; p = 5E-06). Prognostic analysis of YAP1 demonstrated a significant correlation between mRNA expression level data and reduced overall survival (p = 0.001). In addition, TMA and immunohistochemistry analysis suggested that YAP1 protein expression is an independent predictor of poor overall survival [hazard ratio (HR) 1.870, 95% confidence interval (CI) 1.224-2.855, p = 0.004], as well as reduced disease-free survival (HR 1.950, 95% CI 1.299-2.927, p = 0.001). Bioinformatic analyses coupled with in vitro assays indicated that YAP1 is involved in the transcriptional control of target genes, associated with extracellular matrix remodeling, which could be modified by selected substances disrupting the YAP1-TEAD interaction. CONCLUSIONS: Our findings indicate that YAP1 is an important prognostic biomarker for pancreatic cancer and may play a regulatory role in the remodeling of the extracellular matrix.

Effective metric learning with co-occurrence embedding for collaborative recommendations.

In recommender systems, matrix factorization and its variants have grown up to be dominant in collaborative filtering due to their simplicity and effectiveness. In matrix factorization based methods, dot product which is actually used as a measure of distance from users to items, does not satisfy the inequality property, and thus may fail to capture the inner grained preference information and further limits the performance of recommendations. Metric learning produces distance functions that capture the essential relationships among rating data and has been successfully explored in collaborative recommendations. However, without the global statistical information of user-user pairs and item-item pairs, it makes the model easy to achieve a suboptimal metric. For this, we present a co-occurrence embedding regularized metric learning model (CRML) for collaborative recommendations. We consider the optimization problem as a multi-task learning problem which includes optimizing a primary task of metric learning and two auxiliary tasks of representation learning. In particular, we develop an effective approach for learning the embedding representations of both users and items, and then exploit the strategy of soft parameter sharing to optimize the model parameters. Empirical experiments on four datasets demonstrate that the CRML model can enhance the naive metric learning model and significantly outperforms the state-of-the-art methods in terms of accuracy of collaborative recommendations.

Alpha-1-acid glycoprotein 1 is upregulated in pancreatic ductal adenocarcinoma and confers a poor prognosis.

Pancreatic cancer is an aggressive malignancy that carries a high mortality rate. A major contributor to the poor outcome is the lack of effective molecular markers. The purpose of this study was to develop protein markers for improved prognostication and noninvasive diagnosis. A mass spectrometry (MS)-based discovery approach was applied to pancreatic cancer tissues and healthy pancreas. In the verification phase, extracellular proteins with differential expression were further quantified in targeted mode using parallel reaction monitoring (PRM). Next, a tissue microarray (TMA) cohort including 140 pancreatic cancer resection specimens was constructed, in order to validate protein expression status and investigate potential prognostic implications. The levels of protein candidates were finally assessed in a prospective series of 110 serum samples in an accredited clinical laboratory using the automated Cobas system. Protein sequencing with nanoliquid chromatography tandem MS (nano-LC-MS/MS) and targeted PRM identified alpha-1-acid glycoprotein 1 (AGP1) as an upregulated protein in pancreatic cancer tissue. Using TMA and immunohistochemistry, AGP1 expression was significantly associated with shorter overall survival (HR = 2.22; 95% CI 1.30-3.79, P = 0.004). Multivariable analysis confirmed the results (HR = 1.87; 95% CI 1.08-3.24, P = 0.026). Circulating levels of AGP1 yielded an area under the curve (AUC) of 0.837 for the discrimination of resectable pancreatic cancer from healthy controls. Combining AGP1 with CA 19-9 enhanced the diagnostic performance, with an AUC of 0.963. This study suggests that AGP1 is a novel prognostic biomarker in pancreatic cancer tissue. Serum AGP1 levels may be useful as part of a biomarker panel for early detection of pancreatic cancer but further studies are needed.