A Diagnostic Challenge: Toxoplasmosis Masquerading as Tonsillar Neoplasm.

This case report elucidates an uncommon manifestation of toxoplasmosis characterized by an ulcerative oropharyngeal lesion and cervical lymphadenopathy, which intriguingly simulated a tonsillar neoplasm. The patient, a 28-year-old immunocompetent woman, reported symptoms such as a persistent sore throat, unilateral neck pain, and otalgia. Despite the initial clinical impressions, a diagnostic left subtotal tonsillectomy revealed no malignancy but marked acute and chronic inflammation. A comprehensive investigation subsequently indicated a recent primary infection with Toxoplasma gondii, as evidenced by the presence of high IgM antibodies and low IgG avidity. This unique case underlines the significance of incorporating toxoplasmosis into the differential diagnosis of oropharyngeal lesions, thereby necessitating a meticulous approach to laboratory testing. Laryngoscope, 134:1741-1743, 2024.

Tumor collagens predict genetic features and patient outcomes.

The extracellular matrix (ECM) is a critical determinant of tumor fate that reflects the output from myriad cell types in the tumor. Collagens constitute the principal components of the tumor ECM. The changing collagen composition in tumors along with their impact on patient outcomes and possible biomarkers remains largely unknown. The RNA expression of the 43 collagen genes from solid tumors in The Cancer Genome Atlas (TCGA) was clustered to classify tumors. PanCancer analysis revealed how collagens by themselves can identify the tissue of origin. Clustering by collagens in each cancer type demonstrated strong associations with survival, specific immunoenvironments, somatic gene mutations, copy number variations, and aneuploidy. We developed a machine learning classifier that predicts aneuploidy, and chromosome arm copy number alteration (CNA) status based on collagen expression alone with high accuracy in many cancer types with somatic mutations, suggesting a strong relationship between the collagen ECM context and specific molecular alterations. These findings have broad implications in defining the relationship between cancer-related genetic defects and the tumor microenvironment to improve prognosis and therapeutic targeting for patient care, opening new avenues of investigation to define tumor ecosystems.

Stem cell phenotype predicts therapeutic response in glioblastomas with MGMT promoter methylation.

A growing body of evidence supports the presence of a population of cells in glioblastoma (GBM) with a stem cell-like phenotype which shares certain biological markers with adult neural stem cells, including expression of SOX2, CD133 (PROM1), and NES (nestin). This study was designed to determine the relationship between the expression of these stem cell markers and the clinical outcome in GBM patients. We quantified the intensity of expression of the proteins CD133 and SOX2 by immunohistochemistry (IHC) in a cohort of 86 patients with IDH-wildtype GBM, and evaluated patient outcomes using Kaplan-Meier and Cox proportional hazards analysis. In our patients, MGMT promoter methylation status and age were predictors of overall survival and progression free survival. The levels of SOX2 and CD133 were not associated with outcome in univariate analysis; however, stratification of tumors based on low or high levels of CD133 or SOX2 expression revealed that MGMT methylation was a predictor of progression-free survival and overall survival only for tumors with high levels of expression of CD133 or SOX2. Tumors with low levels of expression of CD133 or SOX2 did not show any relationship between MGMT methylation and survival. This relationship between MGMT and stem cell markers was confirmed in a second patient cohort, the TCGA dataset. Our results show that stratification of GBM by the level of expression of CD133 and SOX2 improved the prognostic power of MGMT promoter methylation status, identifying a low-expressing group in which the clinical outcome is not associated with MGMT promoter methylation status, and a high-expressing group in which the outcome was strongly associated with MGMT promoter methylation status. These findings support the concept that the presence of a high stem cell phenotype in GBM, as marked by expression of SOX2 or CD133, may be associated with the clinical response to treatment.

Somatic mutations in collagens are associated with a distinct tumor environment and overall survival in gastric cancer.

BACKGROUND: Gastric cancer is a heterogeneous disease with poorly understood genetic and microenvironmental factors. Mutations in collagen genes are associated with genetic diseases that compromise tissue integrity, but their role in tumor progression has not been extensively reported. Aberrant collagen expression has been long associated with malignant tumor growth, invasion, chemoresistance, and patient outcomes. We hypothesized that somatic mutations in collagens could functionally alter the tumor extracellular matrix. METHODS: We used publicly available datasets including The Tumor Cancer Genome Atlas (TCGA) to interrogate somatic mutations in collagens in stomach adenocarcinomas. To demonstrate that collagens were significantly mutated above background mutation rates, we used a moderated Kolmogorov-Smirnov test along with combination analysis with a bootstrap approach to define the background accounting for mutation rates. Association between mutations and clinicopathological features was evaluated by Fisher or chi-squared tests. Association with overall survival was assessed by Kaplan-Meier and the Cox-Proportional Hazards Model. Gene Set Enrichment Analysis was used to interrogate pathways. Immunohistochemistry and in situ hybridization tested expression of COL7A1 in stomach tumors. RESULTS: In stomach adenocarcinomas, we identified individual collagen genes and sets of collagen genes harboring somatic mutations at a high frequency compared to background in both microsatellite stable, and microsatellite instable tumors in TCGA. Many of the missense mutations resemble the same types of loss of function mutations in collagenopathies that disrupt tissue formation and destabilize cells providing guidance to interpret the somatic mutations. We identified combinations of somatic mutations in collagens associated with overall survival, with a distinctive tumor microenvironment marked by lower matrisome expression and immune cell signatures. Truncation mutations were strongly associated with improved outcomes suggesting that loss of expression of secreted collagens impact tumor progression and treatment response. Germline collagenopathy variants guided interpretation of impactful somatic mutations on tumors. CONCLUSIONS: These observations highlight that many collagens, expressed in non-physiologically relevant conditions in tumors, harbor impactful somatic mutations in tumors, suggesting new approaches for classification and therapy development in stomach cancer. In sum, these findings demonstrate how classification of tumors by collagen mutations identified strong links between specific genotypes and the tumor environment.

Senescent Tissue-Resident Mesenchymal Stromal Cells Are an Internal Source of Inflammation in Human Osteoarthritic Cartilage.

Human osteoarthritic cartilage contains not only chondrocytes (OACs), but also mesenchymal stromal cells (OA-MSCs), whose abundance increases during osteoarthritis (OA). However, it is not clear how OA-MSC contributes to OA pathogenesis. Here, we show that aging OA-MSC plays an important role in cell senescence, fibrosis, and inflammation in cartilage. Protein array analysis indicates that OA-MSC expresses pro-inflammatory senescence associated secretory phenotype (SASP) including IL-1ß, IL-6, IL-8, and CXCL1, 5, and 6, which play key roles in OA pathogenesis. OAC is a main recipient of the inflammatory signals by expressing receptors of cytokines. RNAseq analysis indicates that the transition from normal cartilage stromal cells (NCSCs) to OA-MSC during aging results in activation of SASP gene expression. This cell transition process can be recapitulated by a serial passage of primary OAC in cell culture comprising (1) OAC dedifferentiation into NCSC-like cells, and (2) its subsequent senescence into pro-inflammatory OA-MSC. While OAC dedifferentiation is mediated by transcriptional repression of chondrogenic gene expression, OA-MSC senescence is mediated by transcriptional activation of SASP gene expression. We postulate that, through replication-driven OAC dedifferentiation and mesenchymal stromal cell (MSC) senescence, OA-MSC becomes an internal source of sterile inflammation in human cartilage joint.

Towards Rapid Fabrication of Superhydrophobic Surfaces by Multi-Beam Nanostructuring with 40,401 Beams.

Superhydrophobic surfaces attract a lot of attention due to many potential applications including anti-icing, anti-corrosion, self-cleaning or drag-reduction surfaces. Despite a list of attractive applications of superhydrophobic surfaces and demonstrated capability of lasers to produce them, the speed of laser micro and nanostructuring is still low with respect to many industry standards. Up-to-now, most promising multi-beam solutions can improve processing speed a hundred to a thousand times. However, productive and efficient utilization of a new generation of kW-class ultrashort pulsed lasers for precise nanostructuring requires a much higher number of beams. In this work, we introduce a unique combination of high-energy pulsed ultrashort laser system delivering up to 20 mJ at 1030 nm in 1.7 ps and novel Diffractive Laser-Induced Texturing element (DLITe) capable of producing 201 × 201 sub-beams of 5 µm in diameter on a square area of 1 mm2. Simultaneous nanostructuring with 40,401 sub-beams resulted in a matrix of microcraters covered by nanogratings and ripples with periodicity below 470 nm and 720 nm, respectively. The processed area demonstrated hydrophobic to superhydrophobic properties with a maximum contact angle of 153°.

Effects of High Fat Versus Normal Diet on Extracellular Vesicle-Induced Angiogenesis in a Swine Model of Chronic Myocardial Ischemia.

Background Mesenchymal stem cell-derived extracellular vesicles (EVs) promote angiogenesis in the ischemic myocardium. This study examines the difference in vascular density, myocardial perfusion, molecular signaling, and gene expression between normal diet (ND) and high fat diet (HFD) groups at baseline and following intramyocardial injection of EVs. Methods and Results Intact male Yorkshire swine fed either an ND (n=17) or HFD (n=14) underwent placement of an ameroid constrictor on the left circumflex coronary artery. Subsequently, animals received either intramyocardial injection of vehicle-saline as controls; (ND-controls n=7, HFD-controls, n=6) or EVs; (ND-EVs n=10, HFD-EVs n=8) into the ischemic territory. Five weeks later, myocardial function, perfusion, vascular density, cell signaling, and gene expression were examined. EVs improved indices of myocardial contractile function, myocardial perfusion, and arteriogenesis in both dietary cohorts. Interestingly, quantification of alpha smooth muscle actin demonstrated higher basal arteriolar density in HFD swine compared with their ND counterparts; whereas EVs were associated with increased CD31-labeled endothelial cell density only in the ND tissue, which approached significance. Levels of total endothelial nitric oxide synthase, FOXO1 (forkhead box protein O1) , transforming growth factor-ß, phosphorylated VEGFR2 (vascular endothelial growth factor receptor 2), and phosphorylated MAPK ERK1/ERK2 (mitogen-activated protein kinase) were higher in ischemic myocardial lysates from ND-controls compared with HFD-controls. Conversely, HFD-control tissue showed increased expression of phosphorylated endothelial nitric oxide synthase, phosphorylated FOXO1, VEGFR2, and MAPK ERK1/ERK2 with respect to ND-controls. Preliminary gene expression studies indicate differential modulation of transcriptional activity by EVs between the 2 dietary cohorts. Conclusions HFD produces a profound metabolic disorder that dysregulates the molecular mechanisms of collateral vessel formation in the ischemic myocardium, which may hinder the therapeutic angiogenic effects of EVs.

Insights from the Menstrual Cycle in Pulmonary Arterial Hypertension.

Rationale: Sex hormones play a role in pulmonary arterial hypertension (PAH), but the menstrual cycle has never been studied.Objectives: We conducted a prospective observational study of eight women with stable PAH and 20 healthy controls over one cycle.Methods: Participants completed four study visits 1 week apart starting on the first day of menstruation. Relationships between sex hormones, hormone metabolites, and extracellular vesicle microRNA (miRNA) expression and clinical markers were compared with generalized linear mixed modeling.Results: Women with PAH had higher but less variable estradiol (E2) levels (P < 0.001) that tracked with 6-minute walk distance (P < 0.001), N-terminal prohormone of brain natriuretic peptide (P = 0.03) levels, and tricuspid annular plane systolic excursion (P < 0.01); the direction of these associations depended on menstrual phase. Dehydroepiandrosterone sulfate (DHEA-S) levels were lower in women with PAH (all visits, P < 0.001). In PAH, each 100-µg/dl increase in DHEA-S was associated with a 127-m increase in 6-minute walk distance (P < 0.001) and was moderated by the cardioprotective E2 metabolite 2-methoxyestrone (P < 0.001). As DHEA-S increased, N-terminal prohormone of brain natriuretic peptide levels decreased (P = 0.001). Expression of extracellular vesicle miRNAs-21, -29c, and -376a was higher in PAH, moderated by E2 and DHEA-S levels, and tracked with hormone-associated changes in clinical measures.Conclusions: Women with PAH have fluctuations in cardiopulmonary function during menstruation driven by E2 and DHEA-S. These hormones in turn influence transcription of extracellular vesicle miRNAs implicated in the pathobiology of pulmonary vascular disease and cancer.

FOXO3 regulates a common genomic program in aging and glioblastoma stem cells.

Background: Glioblastoma (GBM) is an aggressive, age-associated malignant glioma that contains populations of cancer stem cells. These glioma stem cells (GSCs) evade therapeutic interventions and repopulate tumors due to their existence in a slowly cycling quiescent state. Although aging is well known to increase cancer initiation, the extent to which the mechanisms supporting GSC tumorigenicity are related to physiological aging remains unknown. Aims: Here, we investigate the transcriptional mechanisms by which Forkhead Box O3 (FOXO3), a transcriptional regulator that promotes healthy aging, affects GSC function and the extent to which FOXO3 transcriptional networks are dysregulated in aging and GBM. Methods and results: We performed transcriptome analysis of clinical GBM tumors and observed that high FOXO3 activity is associated with gene expression signatures of stem cell quiescence, reduced oxidative metabolism, and improved patient outcomes. Consistent with these findings, we show that elevated FOXO3 activity significantly reduces the proliferation of GBM-derived GSCs. Using RNA-seq, we find that functional ablation of FOXO3 in GSCs rewires the transcriptional circuitry associated with metabolism, epigenetic stability, quiescence, and differentiation. Since FOXO3 has been implicated in healthy aging, we then investigated the extent to which it regulates common transcriptional programs in aging neural stem cells (NSCs) and GSCs. We uncover a shared transcriptional program and, most strikingly, find that FOXO3-regulated pathways are associated with altered mitochondrial functions in both aging and GBM. Conclusions: This work identifies a FOXO-associated transcriptional program that correlates between GSCs and aging NSCs and is enriched for metabolic and stemness pathways connected with GBM and aging.

[FOCUSING AND UPDATING INDICATIONS FOR VENTILATING TUBES INSERTION IN PEDIATRIC COCHLEAR IMPLANT CANDIDATES WHO SUFFER FROM OTITIS MEDIA].

BACKGROUND: After cochlear implantation (CI) there is concern regarding the potential risks of spread of middle ear infection along the electrode array into the cochlea and central nervous system and regarding late sequela of otitis media (OM): eardrum perforation, atelectasis and cholesteatoma. The age for implantation in children overlaps the peak age incidence of acute OM (AOM) and secretory OM (SOM) and delay of implantation reduces the potential benefit from the intervention. Therefore, control of OM by inserting ventilating tubes (VT) is widely performed in pediatric CI candidates who also suffer from otitis media. OBJECTIVES: To refine indications for VT insertion in candidates for cochlear implantation who also suffer from OM. METHODS: Of 200 children referred for CI and implanted one after another, 126 were classified as OM-prone, 98 due to AOM and 28 due to SOM. The rate of development of late sequela of middle ear disease was compared between the two subgroups of OM-proneness. RESULTS: A total of 15 children (7.5%) developed late sequela of middle ear disease; all belonged to the SOM group; 3.5% developed eardrum perforation; 3.5% atelectasis and 0.5% cholesteatoma. CONCLUSIONS: Pre-CI VT insertion in children with SOM who underwent CI did not prevent development of late sequela of middle ear disease; VT insertion with the object of preventing late sequela of middle ear disease in CI candidates who suffer from SOM only is not required; in otitis-prone children a long term oto-microscopic follow-up is needed in order to identify late sequela of middle ear disease.

Mesenchymal Stem Cell Extracellular Vesicles Reverse Sugen/Hypoxia Pulmonary Hypertension in Rats.

Mesenchymal stem cell extracellular vesicles attenuate pulmonary hypertension, but their ability to reverse established disease in larger animal models and the duration and mechanism(s) of their effect are unknown. We sought to determine the efficacy and mechanism of mesenchymal stem cells' extracellular vesicles in attenuating pulmonary hypertension in rats with Sugen/hypoxia-induced pulmonary hypertension. Male rats were treated with mesenchymal stem cell extracellular vesicles or an equal volume of saline vehicle by tail vein injection before or after subcutaneous injection of Sugen 5416 and exposure to 3 weeks of hypoxia. Pulmonary hypertension was assessed by right ventricular systolic pressure, right ventricular weight to left ventricle + septum weight, and muscularization of peripheral pulmonary vessels. Immunohistochemistry was used to measure macrophage activation state and recruitment to lung. Mesenchymal stem cell extracellular vesicles injected before or after induction of pulmonary hypertension normalized right ventricular pressure and reduced right ventricular hypertrophy and muscularization of peripheral pulmonary vessels. The effect was consistent over a range of doses and dosing intervals and was associated with lower numbers of lung macrophages, a higher ratio of alternatively to classically activated macrophages (M2/M1 = 2.00 ± 0.14 vs. 1.09 ± 0.11; P < 0.01), and increased numbers of peripheral blood vessels (11.8 ± 0.66 vs. 6.9 ± 0.57 vessels per field; P < 0.001). Mesenchymal stem cell extracellular vesicles are effective at preventing and reversing pulmonary hypertension in Sugen/hypoxia pulmonary hypertension and may offer a new approach for the treatment of pulmonary arterial hypertension.

Stromal ColXα1 expression correlates with tumor-infiltrating lymphocytes and predicts adjuvant therapy outcome in ER-positive/HER2-positive breast cancer.

BACKGROUND: The breast cancer microenvironment contributes to tumor progression and response to chemotherapy. Previously, we reported that increased stromal Type X collagen α1 (ColXα1) and low TILs correlated with poor pathologic response to neoadjuvant therapy in estrogen receptor and HER2-positive (ER+/HER2+) breast cancer. Here, we investigate the relationship of ColXα1 and long-term outcome of ER+/HER2+ breast cancer patients in an adjuvant setting. METHODS: A total of 164 cases with at least 5-year follow-up were included. Immunohistochemistry for ColXα1 was performed on whole tumor sections. Associations between ColXα1expression, clinical pathological features, and outcomes were analyzed. RESULTS: ColXα1 expression was directly proportional to the amount of tumor associated stroma (p = 0.024) and inversely proportional to TILs. Increased ColXα1 was significantly associated with shorter disease free survival and overall survival by univariate analysis. In multivariate analysis, OS was lower in ColXα1 expressing (HR = 2.1; 95% CI = 1.2-3.9) tumors of older patients (> = 58 years) (HR = 5.3; 95% CI = 1.7-17) with higher stage (HR = 2.6; 95% CI = 1.3-5.2). Similarly, DFS was lower in ColXα1 expressing (HR = 1.8; 95% CI = 1.6-5.7) tumors of older patients (HR = 3.2; 95% CI = 1.3-7.8) with higher stage (HR = 2.7; 95% CI = 1.6-5.7) and low TILs. In low PR+ tumors, higher ColXα1 expression was associated with poorer prognosis. CONCLUSION: ColXα1 expression is associated with poor disease free survival and overall survival in ER+/HER2+ breast cancer. This study provides further support for the prognostic utility of ColXα1 as a breast cancer associated stromal factor that predicts response to chemotherapy.

Factory optima: a web-based system for composition and analysis of manufacturing service networks based on a reusable model repository.

This paper reports on the development of Factory Optima, a web-based system that allows manufacturing process engineers to compose, optimise and perform trade-off analysis of manufacturing and contract service networks based on a reusable repository of performance models. Performance models formally describe process feasibility constraints and metrics of interest, such as cost, throughput and CO 2 emissions, as a function of fixed and control parameters, such as equipment and contract properties and settings. The repository contains performance models representing (1) unit manufacturing processes, (2) base contract services and (3) a composite steady-state service network. The proposed framework allows process engineers to hierarchically compose model instances of service networks, which can represent production cells, lines, factory facilities and supply chains, and perform deterministic optimisation based on mathematical programming and Pareto-optimal trade-off analysis. Factory Optima is demonstrated using a case study of a service network for a heat sink product which involves contract vendors and manufacturing activities, including cutting, shearing, Computer Numerical Control (CNC) machining with milling and drilling operations, quality inspection, finishing, and assembly.

ColXα1 is a stromal component that colocalizes with elastin in the breast tumor extracellular matrix.

The tumor microenvironment regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. Increased expression of type X collagen α-1 (ColXα1) in tumor-associated stroma correlates with poor pathologic response to neoadjuvant chemotherapy in estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Evaluation of ColXα1 expression patterns suggests a potential connection with elastin fibers. To investigate the possible interaction between ColXα1 and elastin, we evaluated the expression of ColXα1 in relation to elastin fibers in normal breast tissue, ductal carcinoma in situ, and invasive breast carcinomas at cellular and subcellular levels. Our findings demonstrate that ColXα1 colocalizes with elastin in invasive breast cancer-associated stroma by immunohistochemistry, immunofluorescence, and electron microscopy. In 212 invasive breast carcinomas, this complex was aberrantly and selectively expressed in tumor extracellular matrix in 79% of ER+/HER2-, 80% of ER+/HER2+, 76% of ER-/HER2+, and 58% of triple negative breast cancers. In contrast, ColXα1 was generally absent, while elastin was present perivascularly in normal breast tissue. ColXα1 and elastin were coexpressed in 58% of ductal carcinoma in situ (DCIS) in periductal areas. In mass-forming DCIS with desmoplastic stroma, the complex was intensely expressed in periductal areas as well as within the tumor-associated stroma in all cases. Our data suggest that the breast carcinoma neoplastic process may involve aberrant expression of ColXα1 and elastin in the tumor microenvironment emerging early at the DCIS stage. Enrichment of these complexes in tumor-associated stroma may represent a stromal signature indicative of intrinsic differences between breast cancers. These findings shed light on investigation into the role of aberrant collagen complex expression in tumorigenesis and tumor progression which may be leveraged in therapeutic and theranostic applications.

Generating flat-top beams with extended depth of focus.

Two approaches for generating flat-top beams (uniform intensity profile) with extended depth of focus are presented. One involves two diffractive optical elements (DOEs) and the other only a single DOE. The results indicate that the depth of focus of such beams strongly depends on the phase distribution at the output of the DOEs. By having uniform phase distribution, it is possible to generate flat-top beams with extended depth of focus.

Stromal Clusterin Expression Predicts Therapeutic Response to Neoadjuvant Chemotherapy in Triple Negative Breast Cancer.

BACKGROUND: Expression of clusterin correlates with tumor progression and therapeutic response in several human malignancies, including breast cancer. However, its predictive value in the neoadjuvant setting in breast cancer remains unexplored. The objective of this explorative study was to determine whether clusterin expression in breast cancer correlated with clinical pathologic characteristics and whether its expression was predictive of response to neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: We determined the clusterin expression pattern in 72 triple negative breast cancers (TNBC) treated with NAC before surgery. Clusterin expression was evaluated by immunohistochemistry and was correlated with pathologic characteristics and response to NAC using residual cancer burden score. RESULTS: Immunohistochemistry analysis revealed a differential pattern of expression between tumor and stroma. Clusterin expression in the tumor associated stroma as opposed to expression by the neoplastic epithelium was significantly associated with neoadjuvant-treated TNBC. Low stromal clusterin, low stromal content, and high tumor-infiltrating lymphocytes were associated with a significantly greater likelihood of achieving a good pathologic response as reflected by lower residual cancer burden scores (P = .002, P = .003, and P = .001, respectively). Tumor and/or stromal clusterin expression were not associated with patient age, tumor histologic grade, stage, and lymph node status. CONCULSION: This study suggests a potential role for the assessment of stromal clusterin as a predictive biomarker for response of TNBC to neoadjuvant therapy. Further validation of this biomarker in a large study is needed.

Modeling and Optimization of Manufacturing Process Performance using Modelica Graphical Representation and Process Analytics Formalism.

This paper concerns the development of a design methodology and its demonstration through a prototype system for performance modeling and optimization of manufacturing processes. The design methodology uses a Modelica simulation tool serving as the graphical user interface for manufacturing domain users such as process engineers to formulate their problems. The Process Analytics Formalism, developed at the National Institute of Standards and Technology, serves as a bridge between the Modelica classes and a commercial optimization solver. The prototype system includes (1) manufacturing model components' libraries created by using Modelica and the Process Analytics Formalism, and (2) a translator of the Modelica classes to Process Analytics Formalism, which are then compiled to mathematical programming models and solved using an optimization solver. This paper provides an experiment toward the goal of enabling manufacturing users to intuitively formulate process performance models, solve problems using optimization-based methods, and automatically get actionable recommendations.

Analysis and Optimization based on Reusable Knowledge Base of Process Performance Models.

In this paper, we propose an architectural design and software framework for fast development of descriptive, diagnostic, predictive, and prescriptive analytics solutions for dynamic production processes. The proposed architecture and framework will support the storage of modular, extensible, and reusable Knowledge Base (KB) of process performance models. The approach requires developing automated methods that can translate the high-level models in the reusable KB into low-level specialized models required by a variety of underlying analysis tools, including data manipulation, optimization, statistical learning, estimation, and simulation. We also propose an organization and key structure for the reusable KB, composed of atomic and composite process performance models and domain-specific dashboards. Furthermore, we illustrate the use of the proposed architecture and framework by prototyping a decision-support system for process engineers. The decision support system allows users to hierarchically compose and optimize dynamic production processes via a graphical user interface.

Fatty acid-binding protein 1 is preferentially lost in microsatellite instable colorectal carcinomas and is immune modulated via the interferon γ pathway.

Fatty acid-binding protein 1 (FABP1) is an intracellular protein responsible for the transportation of long chain fatty acids. Aside from its functions in lipid metabolism and cellular differentiation, FABP1 also plays a role in inflammation through its interaction with peroxisome proliferator-activated receptors (PPARs). Previously, we compared expression of colonic epithelium genes in a subset of microsatellite instable (MSI) colorectal carcinomas (medullary carcinomas) to normal colonic mucosa and found that FABP1 expression was markedly decreased in the tumors. Further analysis of RNA expression in the colorectal subtypes and The Cancer Genome Atlas data set found that FABP1 expression is decreased in the CMS1 subset of colorectal carcinomas, which is characterized by microsatellite instability. As MSI colorectal carcinomas are known for their robust immune response, we then aimed to link FABP1 to the immune microenvironment of MSI carcinomas. To confirm the gene expression results, we performed immunohistochemical analysis of a cohort of colorectal carcinomas. FABP1 was preferentially lost in MSI carcinomas (123/133, 93%) compared with microsatellite stable carcinomas (240/562, 43%, P<0.0001). In addition, higher numbers of tumor-infiltrating lymphocytes were present in tumors with loss of FABP1 (P<0.0001). Decreased expression of the fatty acid storage and glucose regulator, PPARγ, was associated with the loss of FABP1 (P<0.0001). Colorectal cancer cell lines treated with interferon γ exhibited decreased expression of FABP1. FABP1 expression was partially recovered with the treatment of the cell lines with rosiglitazone, a PPARγ agonist. This study demonstrated that the loss of FABP1 expression is associated with MSI carcinomas and that interferon γ stimulation plays a role in this process via its interaction with PPARγ.

Does narrow band imaging improve preoperative detection of glottic malignancy? A matched comparison study.

OBJECTIVES/HYPOTHESIS: The primary suspicion for glottic malignancy during office laryngoendoscopy is based on lesion appearance. Previous studies investigating laryngeal use of narrow band imaging (NBI) are mostly descriptive. The additive value of NBI relative to white light (WL) requires further investigation. STUDY DESIGN: Observational matched study. METHODS: NBI was compared with WL images of 45 vocal fold lesions suspected for malignancy (21 carcinoma, 22 dysplasia, two benign). All images were presented randomly and evaluated by six independent otolaryngology specialists. The observers were asked to estimate lesion size, location, and pathology. The results for the two imaging modalities were compared with each other and with the final pathology. RESULTS: The observers estimated lesion size to be larger in the NBI images by an average of 9% (2.4 mm2 ; P =.04) compared to WL. In 64.6% of cases, the observers estimated similar pathology for NBI and WL. When there was a discrepancy, the estimated pathology was "malignant" in 24.3% by NBI, compared with 11.1% by WL. Overall, 44.7% of the lesions were estimated to be malignant by NBI, compared with 33.8% by WL (P =.001). The sensitivity and specificity rates for malignancy detection by NBI were 58.6% and 61.2%, respectively, compared to 48.7% and 76.1% by WL. CONCLUSIONS: Observers tend to estimate vocal fold lesions to be larger and more frequently suspect malignancy while assessing NBI images. Compared with WL, NBI demonstrates increased sensitivity and decreased specificity for detection of malignancy. Nevertheless, the specificity and sensitivity of NBI alone are considerably low. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:894-899, 2017.