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Endometrial cancer (EC) has four molecular subtypes with strong prognostic value and therapeutic implications. The most common subtype (NSMP; No Specific Molecular Profile) is assigned after exclusion of the defining features of the other three molecular subtypes and includes patients with heterogeneous clinical outcomes. In this study, we employ artificial intelligence (AI)-powered histopathology image analysis to differentiate between p53abn and NSMP EC subtypes and consequently identify a sub-group of NSMP EC patients that has markedly inferior progression-free and disease-specific survival (termed 'p53abn-like NSMP'), in a discovery cohort of 368 patients and two independent validation cohorts of 290 and 614 from other centers. Shallow whole genome sequencing reveals a higher burden of copy number abnormalities in the 'p53abn-like NSMP' group compared to NSMP, suggesting that this group is biologically distinct compared to other NSMP ECs. Our work demonstrates the power of AI to detect prognostically different and otherwise unrecognizable subsets of EC where conventional and standard molecular or pathologic criteria fall short, refining image-based tumor classification. This study's findings are applicable exclusively to females. Endometrial cancer (EC) has four molecular subtypes; of these, the No Specific Molecular Profile (NSMP) subtype encompasses patients with heterogeneous outcomes. Here, the authors use artificial intelligence and histopathology images to differentiate p53abn and NSMP subtypes in EC, and identify one distinct subgroup within NSMP with unfavourable outcome. [ABSTRACT FROM AUTHOR]

Differential equations (DEs) are a powerful tool for modeling real-world contexts. Most research in this area has examined students' understanding and reasoning with pre-packaged DEs, with little attention being given to setting up sophisticated DEs to model complicated real-world situations. This study contributes through a collective case study on how individual students constructed DEs for various real-world systems, including a mechanical, a hydraulic, and an electrical system. We examined the students' readouts (how they "read" a context), their inferential nets (inferences across knowledge resources), and their strategies (what guided their work), according to coordination class theory. Our study contributes the foundation of a knowledge base in students' DE modeling that further research and teaching work can build on. [ABSTRACT FROM AUTHOR]

In clinical oncology, many diagnostic tasks rely on the identification of cells in histopathology images. While supervised machine learning techniques necessitate the need for labels, providing manual cell annotations is time-consuming. In this paper, we propose a self-supervised framework (enVironment-aware cOntrastive cell represenTation learning: VOLTA) for cell representation learning in histopathology images using a technique that accounts for the cell's mutual relationship with its environment. We subject our model to extensive experiments on data collected from multiple institutions comprising over 800,000 cells and six cancer types. To showcase the potential of our proposed framework, we apply VOLTA to ovarian and endometrial cancers and demonstrate that our cell representations can be utilized to identify the known histotypes of ovarian cancer and provide insights that link histopathology and molecular subtypes of endometrial cancer. Unlike supervised models, we provide a framework that can empower discoveries without any annotation data, even in situations where sample sizes are limited. While machine learning platforms can improve the assessment of Hematoxylin & Eosin (H&E) stained-tumour tissue images, current models typically require manual cell-type annotations in training. Here, the authors develop VOLTA, a self-supervised machine learning framework to improve cell representation learning in H&E images based on the cells environment [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) are highly effective in specific cancers where canonical markers of antitumor immunity are used for patient selection. Improved predictors of T cell-inflammation are needed to identify ICI-responsive tumor subsets in additional cancer types. We investigated associations of a 4-chemokine expression signature (c-Score: CCL4, CCL5, CXCL9, CXCL10) with metrics of antitumor immunity across tumor types. Across cancer entities from The Cancer Genome Atlas, subgroups of tumors displayed high expression of the c-Score (c-Scorehi) with increased expression of immune checkpoint (IC) genes and transcriptional hallmarks of the cancer-immunity cycle. There was an incomplete association of the c-Score with high tumor mutation burden (TMB), with only 15% of c-Scorehi tumors displaying ≥10 mutations per megabase. In a heterogeneous pan-cancer cohort of 82 patients, with advanced and previously treated solid cancers, c-Scorehi tumors had a longer median time to progression (103 versus 72 days, P = 0.012) and overall survival (382 versus 196 days, P = 0.038) following ICI therapy initiation, compared to patients with low c-Score expression. We also found c-Score stratification to outperform TMB assignment for overall survival prediction (HR = 0.42 [0.22–0.79], P = 0.008 versus HR = 0.60 [0.29-1.27], P = 0.18, respectively). Assessment of the c-Score using the TIDE and PredictIO databases, which include ICI treatment outcomes from 10 tumor types, provided further support for the c-Score as a predictive ICI therapeutic biomarker. In summary, the c-Score identifies patients with hallmarks of T cell-inflammation and potential response to ICI treatment across cancer types, which is missed by TMB assignment. [ABSTRACT FROM AUTHOR]

There is emerging evidence about the predictive role of homologous recombination deficiency (HRD), but this is less defined in gastrointestinal (GI) and thoracic malignancies. We reviewed whole genome (WGS) and transcriptomic (RNA-Seq) data from advanced GI and thoracic cancers in the Personalized OncoGenomics trial (NCT02155621) to evaluate HRD scores and single base substitution (SBS)3, which is associated with BRCA1/2 mutations and potentially predictive of defective HRD. HRD scores were calculated by sum of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions scores. Regression analyses examined the association between HRD and time to progression on platinum (TTPp). We included 223 patients with GI (n = 154) or thoracic (n = 69) malignancies. TTPp was associated with SBS3 (p < 0.01) but not HRD score in patients with GI malignancies, whereas neither was associated with TTPp in thoracic malignancies. Tumors with gBRCA1/2 mutations and a somatic second alteration exhibited high SBS3 and HRD scores, but these signatures were also present in several tumors with germline but no somatic second alterations, suggesting silencing of the wild-type allele or BRCA1/2 haploinsufficiency. Biallelic inactivation of an HR gene, including loss of XRCC2 and BARD1, was identified in BRCA1/2 wild-type HRD tumors and these patients had prolonged response to platinum. Thoracic cases with high HRD score were associated with high RECQL5 expression (p ≤ 0.025), indicating another potential mechanism of HRD. SBS3 was more strongly associated with TTPp in patients with GI malignancies and may be complementary to using HRD and BRCA status in identifying patients who benefit from platinum therapy. [ABSTRACT FROM AUTHOR]

Specific classes of DNA damage repair (DDR) defect can drive sensitivity to emerging therapies for metastatic prostate cancer. However, biomarker approaches based on DDR gene sequencing do not accurately predict DDR deficiency or treatment benefit. Somatic alteration signatures may identify DDR deficiency but historically require whole-genome sequencing of tumour tissue. We assembled whole-exome sequencing data for 155 high ctDNA fraction plasma cell-free DNA and matched leukocyte DNA samples from patients with metastatic prostate or bladder cancer. Labels for DDR gene alterations were established using deep targeted sequencing. Per sample mutation and copy number features were used to train XGBoost ensemble models. Naive somatic features and trinucleotide signatures were associated with specific DDR gene alterations but insufficient to resolve each class. Conversely, XGBoost-derived models showed strong performance including an area under the curve of 0.99, 0.99 and 1.00 for identifying BRCA2, CDK12, and mismatch repair deficiency in metastatic prostate cancer. Our machine learning approach re-classified several samples exhibiting genomic features inconsistent with original labels, identified a metastatic bladder cancer sample with a homozygous BRCA2 copy loss, and outperformed an existing exome-based classifier for BRCA2 deficiency. We present DARC Sign (DnA Repair Classification SIGNatures); a public machine learning tool leveraging clinically-practical liquid biopsy specimens for simultaneously identifying multiple types of metastatic prostate cancer DDR deficiencies. We posit that it will be useful for understanding differential responses to DDR-directed therapies in ongoing clinical trials and may ultimately enable prospective identification of prostate cancers with phenotypic evidence of DDR deficiency. [ABSTRACT FROM AUTHOR]

During early ischemic brain injury, glutamate receptor hyperactivation mediates neuronal death via osmotic cell swelling. Here we show that ischemia and excess NMDA receptor activation cause actin to rapidly and extensively reorganize within the somatodendritic compartment. Normally, F-actin is concentrated within dendritic spines. However, <5 min after bath-applied NMDA, F-actin depolymerizes within spines and polymerizes into stable filaments within the dendrite shaft and soma. A similar actinification occurs after experimental ischemia in culture, and photothrombotic stroke in mouse. Following transient NMDA incubation, actinification spontaneously reverses. Na+, Cl−, water, and Ca2+ influx, and spine F-actin depolymerization are all necessary, but not individually sufficient, for actinification, but combined they induce activation of the F-actin polymerization factor inverted formin-2 (INF2). Silencing of INF2 renders neurons vulnerable to cell death and INF2 overexpression is protective. Ischemia-induced dendritic actin reorganization is therefore an intrinsic pro-survival response that protects neurons from death induced by cell edema. Post injury cytoskeletal modifications in neurons are not fully understood. Here the authors describe a pro-survival actin cytoskeletal reorganization in neurons triggered during a model of ischemic stroke. [ABSTRACT FROM AUTHOR]

Genomic research is driving discovery for future population benefit. Limited evidence exists on immediate patient and health system impacts of research participation. This study uses real-world data and quasi-experimental matching to examine early-stage cost and health impacts of research-based genomic sequencing. British Columbia's Personalized OncoGenomics (POG) single-arm program applies whole genome and transcriptome analysis (WGTA) to characterize genomic landscapes in advanced cancers. Our cohort includes POG patients enrolled between 2014 and 2015 and 1:1 genetic algorithm–matched usual care controls. We undertake a cost consequence analysis and estimate 1-year effects of WGTA on patient management, patient survival, and health system costs reported in 2015 Canadian dollars. WGTA costs are imputed and forecast using system of equations modeling. We use Kaplan-Meier survival analysis to explore survival differences and inverse probability of censoring weighted linear regression to estimate mean 1-year survival times and costs. Non-parametric bootstrapping simulates sampling distributions and enables scenario analysis, revealing drivers of incremental costs, survival, and net monetary benefit for assumed willingness to pay thresholds. We identified 230 POG patients and 230 matched controls for cohort inclusion. The mean period cost of research-funded WGTA was $26,211 (SD: $14,191). Sequencing costs declined rapidly, with WGTA forecasts hitting $13,741 in 2021. The incremental healthcare system effect (non-research expenditures) was $5203 (95% CI: 75, 10,424) compared to usual care. No overall survival differences were observed, but outcome heterogeneity was present. POG patients receiving WGTA-informed treatment experienced incremental survival gains of 2.49 months (95% CI: 1.32, 3.64). Future cost consequences became favorable as WGTA cost drivers declined and WGTA-informed treatment rates improved to 60%. Our study demonstrates the ability of real-world data to support evaluations of only-in-research health technologies. We identify situations where precision oncology research initiatives may produce survival benefit at a cost that is within healthcare systems' willingness to pay. This economic evidence informs the early-stage healthcare impacts of precision oncology research. [ABSTRACT FROM AUTHOR]

The treatment of dyslipidemia continues to be a dynamic and controversial topic. Even the most appropriate therapeutic range for lipid levels—including that of triglycerides and low-density lipoprotein cholesterol—remain actively debated. Furthermore, with ever-increasing options and available treatment modalities, the management of dyslipidemia has progressed in both depth and complexity. An understanding of appropriate lipid-lowering therapy remains an essential topic of review for practitioners across medical specialties. The goal of this review is to provide an overview of recent research developments and recommendations for patients with dyslipidemia as a means of better informing the clinical practice of lipid management. By utilizing a guideline-directed approach, we provide a reference point on optimal lipid-lowering therapies across the spectrum of dyslipidemia. Special attention is paid to long-term adherence to lipid-lowering therapies, and the benefits derived from instituting appropriate medications in a structured manner alongside monitoring. Novel therapies and their impact on lipid lowering are discussed in detail, as well as potential avenues for research going forward. The prevention of cardiovascular disease remains paramount, and this review provides a roadmap for instituting appropriate therapies in cardiovascular disease prevention. [ABSTRACT FROM AUTHOR]

Background: A subgroup of those with bipolar spectrum disorders experience ongoing mood fluctuations outside of full episodes. We conducted a randomised, controlled feasibility study of a Dialectical Behavioural Therapy-informed approach for bipolar mood fluctuations (Therapy for Inter-episode mood Variability in Bipolar [ThrIVe-B]). Our study aimed to examine the feasibility and acceptability of a future definitive trial evaluating the clinical and cost effectiveness of the ThrIVe-B programme. Participants were required to meet diagnostic criteria for a bipolar spectrum disorder and report frequent mood swings outside of acute episodes. They were randomised to treatment as usual (control arm) or the ThrIVe-B intervention plus treatment as usual (intervention arm). Follow-up points were at 3, 6, 9 and 15 months after baseline, with 9 months as the primary end point. To evaluate feasibility and acceptability we examined recruitment and retention rates, completion rates for study measures, adverse events and feedback from participants on their experience of study participation and therapy. Results: Of the target 48 participants, 43 were recruited (22 in the intervention arm; 21 in the control arm), with a recruitment rate of 3.9 participants per month. At 9 months 74% of participants engaged in research follow-up assessment, exceeding the pre-specified criterion of 60%. There were no serious concerns about the safety of the research procedures or the intervention. On one of the four candidate primary outcome measures, the 95% CI for the between-group mean difference score excluded the null effect and included the minimal clinically important difference, favouring the intervention arm, whilst on no measure was there evidence of deterioration in the intervention arm relative to the control arm. Attendance of the intervention (50% attending at least half of the mandatory sessions) was below the pre-specified continuation criterion of 60%, and qualitative feedback from participants indicated areas that may have hampered or facilitated engagement. Conclusions: It is broadly feasible to conduct a trial of this design within the population of people with frequent bipolar mood swings. Changes should be made to the therapy to increase uptake, such as simplifying content and considering individual rather than group delivery. Trial registration ISRCTN: ISRCTN54234300. Registered 14th July 2017, http://www.isrctn.com/ISRCTN54234300 [ABSTRACT FROM AUTHOR]

As more clinically-relevant genomic features of myeloid malignancies are revealed, it has become clear that targeted clinical genetic testing is inadequate for risk stratification. Here, we develop and validate a clinical transcriptome-based assay for stratification of acute myeloid leukemia (AML). Comparison of ribonucleic acid sequencing (RNA-Seq) to whole genome and exome sequencing reveals that a standalone RNA-Seq assay offers the greatest diagnostic return, enabling identification of expressed gene fusions, single nucleotide and short insertion/deletion variants, and whole-transcriptome expression information. Expression data from 154 AML patients are used to develop a novel AML prognostic score, which is strongly associated with patient outcomes across 620 patients from three independent cohorts, and 42 patients from a prospective cohort. When combined with molecular risk guidelines, the risk score allows for the re-stratification of 22.1 to 25.3% of AML patients from three independent cohorts into correct risk groups. Within the adverse-risk subgroup, we identify a subset of patients characterized by dysregulated integrin signaling and RUNX1 or TP53 mutation. We show that these patients may benefit from therapy with inhibitors of focal adhesion kinase, encoded by PTK2, demonstrating additional utility of transcriptome-based testing for therapy selection in myeloid malignancy. Several genomic features have been found for acute myeloid leukaemia (AML) but targeted clinical genetic testing fails to predict prognosis. Here, the authors generate an AML prognostic score from RNA-seq data of patients, which successfully stratifies AML patients and which may provide guidance for therapeutic strategies. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Type 2 diabetes prevention requires the accurate identification of those at high risk. Beyond the association of fasting serum triacylglycerols with diabetes, triacylglycerol-enriched remnant lipoproteins (TRLs) more accurately reflect pathophysiological changes that underlie progression to diabetes, such as hepatic insulin resistance, pancreatic steatosis and systemic inflammation. We hypothesised that TRL-related factors could improve risk prediction for incident diabetes. Methods: We included individuals from the Brazilian Longitudinal Study of Adult Health cohort. We trained a logistic regression model for the risk of incident diabetes in 80% of the cohort using tenfold cross-validation, and tested the model in the remaining 20% of the cohort (test set). Variables included medical history and traits of the metabolic syndrome, followed by TRL-related measurements (plasma concentration, TRL particle diameter, cholesterol and triacylglycerol content). TRL features were measured using NMR spectroscopy. Discrimination was assessed using the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC). Results: Among 4463 at-risk individuals, there were 366 new cases of diabetes after a mean (±SD) of 3.7 (±0.63) years of follow-up. We derived an 18-variable model with a global AUROC of 0.846 (95% CI: 0.829, 0.869). Overall TRL-related markers were not associated with diabetes. However, TRL particle diameter increased the AUROC, particularly in individuals with HbA1c <39 mmol/mol (5.7%) (hold-out test set [n = 659]; training-validation set [n = 2638]), but not in individuals with baseline HbA1c 39–46 mmol/mol (5.7–6.4%) (hold-out test set [n = 233]; training-validation set [n = 933]). In the subgroup with baseline HbA1c <39 mmol/mol (5.7%), AUROC in the test set increased from 0.717 (95% CI 0.603, 0.818) to 0.794 (95% CI 0.731, 0.862), and AUPRC in the test set rose from 0.582 to 0.701 when using the baseline model and the baseline model plus TRL particle diameter, respectively. TRL particle diameter was highly correlated with obesity, insulin resistance and inflammation in those with impaired fasting glucose at baseline, but less so in those with HbA1c <39 mmol/mol (5.7%). Conclusions/interpretation: TRL particle diameter improves the prediction of diabetes, but only in individuals with HbA1c <39 mmol/mol (5.7%) at baseline. These data support TRL particle diameter as a risk factor that is changed early in the course of the pathophysiological processes that lead to the development of type 2 diabetes, even before glucose abnormalities are established. [ABSTRACT FROM AUTHOR]

Summary: Introduction Given the high level of uncertainty surrounding the outcomes of early phase clinical trials, whole genome and transcriptome analysis (WGTA) can be used to optimize patient selection and study assignment. In this retrospective analysis, we reviewed the impact of this approach on one such program. Methods Patients with advanced malignancies underwent fresh tumor biopsies as part of our personalized medicine program (NCT02155621). Tumour molecular data were reviewed for potentially clinically actionable findings and patients were referred to the developmental therapeutics program. Outcomes were reviewed in all patients, including those where trial selection was driven by molecular data (matched) and those where there was no clear molecular rationale (unmatched). Results From January 2014 to January 2018, 28 patients underwent WGTA and enrolled in clinical trials, including 2 patients enrolled in two trials. Fifteen patients were matched to a treatment based on a molecular target. Five patients were matched to a trial based upon single-gene DNA changes, all supported by RNA data. Ten cases were matched on the basis of genome-wide data (n = 4) or RNA gene expression only (n = 6). With a median follow-up of 6.7 months, the median time on treatment was 8.2 weeks. Discussion When compared to single-gene DNA-based data alone, WGTA led to a 3-fold increase in treatment matching. In a setting where there is a high level of uncertainty around both the investigational agents and the biomarkers, more data are needed to fully evaluate the impact of routine use of WGTA. [ABSTRACT FROM AUTHOR]

Background: At a young age, high-level youth footballers enter structured practice where they engage in regular training and matches. The academy system is considered fundamental to a young footballer's tactical, technical and physical development. Yet, with regular training and matches, high-level youth footballers may be exposed to the risk of injury. Objective: This systematic review analyses and summarises published scientific information on high-level youth football injury characteristics and calculates the risk of them sustaining an injury over the course of a typical season. Methods: The search was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Of the 1346 studies found, 23 fulfilled the inclusion criteria. Results: Quality assurance scores for the selected research articles ranged between two and five out of eight. A high degree of heterogeneity between studies was observed. The probability of sustaining a time-loss injury during a high-level youth season ranged between < 1% and 96% for under 9- to under 16-year age groups and 50% and 91% for under 18- to under 21-year age groups. Pooled estimates for total (training and match) incidence per 1000 h was 5.8 for youth players aged under 9 to under 21 years, 7.9 for older players (under 17–under 21 years) and 3.7 for younger aged players (under 9–under 16 years). Training injury incidence rate ranged from 0.69 to 7.9 per 1000 h for all age groups in youth football. Match injury incidence rate for high-level youth players ranged from 0.4 to 80.0 per 1000 h. Close to one-fifth (18%) of all high-level youth football injuries were classified as severe and required > 28 days recovery time. Muscle strain injury accounted for 37% of all injuries reported in youth football. High probabilities (> 90%) of sustaining a time-loss injury over one typical high-level football season were found. Conclusion: High-level youth players lose large portions of the seasonal development to injury, with players seemingly suffering long absences from training and matches, consequently affecting health and well-being and possibly burdening club/parental finances and healthcare systems. [ABSTRACT FROM AUTHOR]

The role of staff involved with undergraduate admissions and recruitment has changed since the turn towards marketisation in higher education. This article focuses on the system in England following both a sharp rise in student fees and an associated tendency for the public university agenda and related social priorities, such as widening participation, to come up against more private and commercial priorities, such as business engagement, league table performance and internationalisation. Drawing on evidence from detailed interviews with admissions personnel, both academic and non-academic, across three disciplines within one higher prestige university, we revisit the notion of selectivity and the practice of selection. Tensions are revealed between two opposing approaches: a more traditional model of university admissions, as based on local knowledge and sensitivity towards underrepresented groups, and a purportedly merit-driven model, as driven by perceived market position. We explore the intricate and often unexpected ways in which staff reconcile their professed beliefs with their professional practices, and the complex identity work needed to renegotiate personal values in light of shifting institutional needs. Findings are offered as a microcosm for broader trends in the higher education sector. [ABSTRACT FROM AUTHOR]

The calculus concepts of concavity and inflection points are critical for a complete understanding of quantities' behavior, making them important topics of research for those interested in the intersections of STEM disciplines. This study seeks to provide insight into this area by reporting on trends in students' concept projections of these concepts in a range of real-world contexts, including temperature, economics, human height, and the universe's expansion. While the students mostly thought of concavity and inflection points in pure mathematics as shapes associated with graphs, the projections with the real-world contexts were based much more on changing rates of change. Pedagogically important student confusions were also evident in their attempts at applying concavity and inflection points to the real-world contexts, and this paper uses the concept projection perspective to identify possible sources of these confusions. [ABSTRACT FROM AUTHOR]

Zeolite-loaded aerogel (ZLA) getters were devised and developed for maintaining vacuum in the Seismic Experience for Interior Structure (SEIS) instrument on the NASA InSight mission to Mars. The ZLA are very lightweight compound materials (~ 0.1 g/cm3) with tunable density and high surface area (~ 500 m2/g), capable of maintaining high vacuum (HV, < 10−3 mbar) for extended periods of time at room temperature without any maintenance or consumption of power. Low temperatures, such as the surface environments on Mars and the icy worlds, enhance the ZLA adsorption by orders of magnitude, extending their capacity to the deep HV range sustainable over multi-year missions. Selective adsorption properties for species of interest can be further enhanced by cation exchange (Na+, Ca2+, Mg2+, Pd2+, etc.) prior to the zeolite incorporation in the material. The sol-gel process was formulated to produce homogeneously dispersed micron-sized zeolite particles embedded in the aerogel matrix. The ZLA liquid precursor can be cast in practically any shape prior to the formation of the solid wet gel, which is then dried supercritically. The resulting mesoporous aerogel network provides excellent molecular transport to the zeolite particles. For particle sensitive instruments such as SEIS, the ZLA adsorbers can be isolated by sub-micron filters without noticeable effects on their performance. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer (TNBC) subtypes are clinically aggressive and cannot be treated with targeted therapeutics commonly used in other breast cancer subtypes. The claudin-low (CL) molecular subtype of TNBC has high rates of metastases, chemoresistance and recurrence. There exists an urgent need to identify novel therapeutic targets in TNBC; however, existing models utilized in target discovery research are limited. Patient-derived xenograft (PDX) models have emerged as superior models for target discovery experiments because they recapitulate features of patient tumors that are limited by cell-line derived xenograft methods.Methods: We utilize immunohistochemistry, qRT-PCR and Western Blot to visualize tumor architecture, cellular composition, genomic and protein expressions of a new CL-TNBC PDX model (TU-BcX-2O0). We utilize tissue decellularization techniques to examine extracellular matrix composition of TU-BcX-2O0.Results: Our laboratory successfully established a TNBC PDX tumor, TU-BCX-2O0, which represents a CL-TNBC subtype and maintains this phenotype throughout subsequent passaging. We dissected TU-BCx-2O0 to examine aspects of this complex tumor that can be targeted by developing therapeutics, including the whole and intact breast tumor, specific cell populations within the tumor, and the extracellular matrix.Conclusions: Here, we characterize a claudin-low TNBC patient-derived xenograft model that can be utilized for therapeutic research studies. [ABSTRACT FROM AUTHOR]

Many mathematical concepts may have prototypical images associated with them. While prototypes can be beneficial for efficient thinking or reasoning, they may also have self-attributes that may impact reasoning about the concept. It is essential that mathematics educators understand these prototype images in order to fully recognize their benefits and limitations. In this paper, I examine prototypes in a context in which they seem to play an important role: graphical representations of the calculus concept of the definite integral. I use student data to empirically describe the makeup of the definite integral prototype image, and I report on the frequency of its appearance among student, instructor, and textbook image data. I end by discussing the possible benefits and drawbacks of this particular prototype, as well as what the results of this study may say about prototypes more generally. [ABSTRACT FROM AUTHOR]

Previously we have reported that metastatic melanoma cell lines and tumor specimens have reduced expression of ADAR1 and consequently are impaired in their ability to perform A-to-I microRNA (miRNA) editing. The effects of A-to-I miRNAs editing on melanoma growth and metastasis are yet to be determined. Here we report that miR-378a-3p is undergoing A-to-I editing only in the non-metastatic but not in metastatic melanoma cells. The function of the edited form is different from its wild-type counterpart. The edited form of miR-378a-3p preferentially binds to the 3'-UTR of the PARVA oncogene and inhibits its expression, thus preventing the progression of melanoma towards the malignant phenotype. Indeed, edited miR-378a-3p but not its WT form inhibits melanoma metastasis in vivo. These results further emphasize the role of RNA editing in melanoma progression. [ABSTRACT FROM AUTHOR]

We report the implementation of molecular modeling approaches developed as a part of the 2016 Grand Challenge 2, the blinded competition of computer aided drug design technologies held by the D3R Drug Design Data Resource (). The challenge was focused on the ligands of the farnesoid X receptor (FXR), a highly flexible nuclear receptor of the cholesterol derivative chenodeoxycholic acid. FXR is considered an important therapeutic target for metabolic, inflammatory, bowel and obesity related diseases (Expert Opin Drug Metab Toxicol 4:523-532, 2015), but in the context of this competition it is also interesting due to the significant ligand-induced conformational changes displayed by the protein. To deal with these conformational changes we employed multiple simulations of molecular dynamics (MD). Our MD-based protocols were top-ranked in estimating the free energy of binding of the ligands and FXR protein. Our approach was ranked second in the prediction of the binding poses where we also combined MD with molecular docking and artificial neural networks. Our approach showed mediocre results for high-throughput scoring of interactions. [ABSTRACT FROM AUTHOR]

Purpose: We conducted a meta-analysis of randomized controlled trials (RCTs) and quasi-RCTs to synthesize evidence about the efficacy and safety of alternate-day vs daily dosing of statins. Methods: We searched selected databases through January 2, 2017 to identify relevant RCTs and quasi-RCTs. The primary outcome was change in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG), while secondary outcomes included adverse events and adherence. Results: Twelve RCTs and 1 quasi-RCT ( n = 1023 patients) were included in the analysis. Pooled analysis revealed no statistically significant difference between alternate-day and daily regimens of atorvastatin and rosuvastatin in terms of change in LDL-C (mean difference [MD] 6.79 mg/dL, 95% confidence interval [CI] −1.59, 15.17, p = 0.11, and 10.51 mg/dL, 95%CI −0.23, 21.26, p = 0.06, respectively) and TG ( p > 0.05). Daily regimens of atorvastatin and rosuvastatin were superior to alternate-day regimes in term of change in TC (MD 12.45 mg/L, 95%CI 8.14, 16.76, p < 0.00001, and 15.80 mg/dL, 95%CI 5.66, 25.95, p = 0.002, respectively). For all outcomes, there was no statistically significant difference between alternate-day and daily regimens for both fluvastatin and pravastatin ( p > 0.05). Both regimens of statins were generally well tolerated with good adherence. Conclusions: Alternate-day dosing of individual statins (especially atorvastatin and rosuvastatin) is as efficacious as daily dosing on LDL-C and TG. [ABSTRACT FROM AUTHOR]

Past research in calculus education has shown that Riemann sum-based conceptions of the definite integral, such as the multiplicatively based summation (MBS) conception, can have important value in interpreting and making sense of certain types of definite integral expressions. However, additional research has shown that students tend to not draw on the MBS conception, even in situations where it would be advantageous to do so. In this study we examine how introductory instruction on integration, in which explicit attention is given to the Riemann sum and Riemann integral, may be related to students' tendency to not use the MBS conception. In particular, it appears that some calculus instructors may make instructional moves in their classrooms that directly undermine the time the instructors had spent developing the Riemann sum and Riemann integral concepts. In doing so, students may perceive these concepts only as calculational procedures, rather than as a potential source of conceptual meaning. [ABSTRACT FROM AUTHOR]

Introduction: Tamoxifen is a selective estrogen receptor modulator widely used in the treatment of breast cancer. Tamoxifen therapy is associated with lower circulating low-density lipoprotein cholesterol and increased triglycerides, but its effects on other lipids are less well studied. Aims: We aimed to investigate the effect of tamoxifen on circulating concentrations of lipoprotein(a) [Lp(a)] through a meta-analysis of available randomized controlled trials (RCTs) and observational studies. Methods: This study was registered in the PROSPERO database (CRD42016036890). Scopus, MEDLINE and EMBASE were searched from inception until 22 March 2016 to identify studies investigating the effect of tamoxifen on Lp(a) values in humans. Meta-analysis was performed using an inverse variance-weighted, random-effects model with standardized mean difference (SMD) as the effect size estimate. Results: Meta-analysis of five studies with 215 participants suggested a statistically significant reduction of Lp(a) levels following tamoxifen treatment (SMD −0.41, 95% confidence interval −0.68 to −0.14, p = 0.003). This effect was robust in the sensitivity analysis. Conclusions: Meta-analysis suggested a statistically significant reduction of Lp(a) levels following tamoxifen treatment. Further well-designed trials are required to validate these results. [ABSTRACT FROM AUTHOR]

Newly-established adsorption enthalpy and entropy values of 12 lanthanide hexafluoroacetylacetonates, denoted Ln[hfac], along with the experimental and theoretical methodology used to obtain these values, are presented for the first time. The results of this work can be used in conjunction with theoretical modeling techniques to optimize a large-scale gas-phase separation experiment using isothermal chromatography. The results to date indicate average adsorption enthalpy and entropy values of the 12 Ln[hfac] complexes ranging from −33 to −139 kJ/mol K and −299 to −557 J/mol, respectively. [ABSTRACT FROM AUTHOR]

The myocardial response to pressure overload involves coordination of multiple transcriptional, posttranscriptional, and metabolic cues. The previous studies show that one such metabolic cue, O-GlcNAc, is elevated in the pressure-overloaded heart, and the increase in O-GlcNAcylation is required for cardiomyocyte hypertrophy in vitro. Yet, it is not clear whether and how O-GlcNAcylation participates in the hypertrophic response in vivo. Here, we addressed this question using patient samples and a preclinical model of heart failure. Protein O-GlcNAcylation levels were increased in myocardial tissue from heart failure patients compared with normal patients. To test the role of OGT in the heart, we subjected cardiomyocyte-specific, inducibly deficient Ogt (i-cm Ogt ) mice and Ogt competent littermate wild-type (WT) mice to transverse aortic constriction. Deletion of cardiomyocyte Ogt significantly decreased O-GlcNAcylation and exacerbated ventricular dysfunction, without producing widespread changes in metabolic transcripts. Although some changes in hypertrophic and fibrotic signaling were noted, there were no histological differences in hypertrophy or fibrosis. We next determined whether significant differences were present in i-cm Ogt cardiomyocytes from surgically naïve mice. Interestingly, markers of cardiomyocyte dedifferentiation were elevated in Ogt-deficient cardiomyocytes. Although no significant differences in cardiac dysfunction were apparent after recombination, it is possible that such changes in dedifferentiation markers could reflect a larger phenotypic shift within the Ogt-deficient cardiomyocytes. We conclude that cardiomyocyte Ogt is not required for cardiomyocyte hypertrophy in vivo; however, loss of Ogt may exert subtle phenotypic differences in cardiomyocytes that sensitize the heart to pressure overload-induced ventricular dysfunction. [ABSTRACT FROM AUTHOR]

In the failing heart, iNOS is expressed by both macrophages and cardiomyocytes. We hypothesized that inflammatory cell-localized iNOS exacerbates left ventricular (LV) remodeling. Wild-type (WT) C57BL/6 mice underwent total body irradiation and reconstitution with bone marrow from iNOS mice (iNOSc) or WT mice (WTc). Chimeric mice underwent coronary ligation to induce large infarction and ischemic heart failure (HF), or sham surgery. After 28 days, as compared with WTc sham mice, WTc HF mice exhibited significant ( p < 0.05) mortality, LV dysfunction, hypertrophy, fibrosis, oxidative/nitrative stress, inflammatory activation, and iNOS upregulation. These mice also exhibited a ~twofold increase in circulating Ly6C pro-inflammatory monocytes, and ~sevenfold higher cardiac M1 macrophages, which were primarily CCR2 cells. In contrast, as compared with WTc HF mice, iNOSc HF mice exhibited significantly improved survival, LV function, hypertrophy, fibrosis, oxidative/nitrative stress, and inflammatory activation, without differences in overall cardiac iNOS expression. Moreover, iNOSc HF mice exhibited lower circulating Ly6C monocytes, and augmented cardiac M2 macrophages, but with greater infiltrating monocyte-derived CCR2 macrophages vs. WTc HF mice. Lastly, upon cell-to-cell contact with naïve cardiomyocytes, peritoneal macrophages from WT HF mice depressed contraction, and augmented cardiomyocyte oxygen free radicals and peroxynitrite. These effects were not observed upon contact with macrophages from iNOS HF mice. We conclude that leukocyte iNOS is obligatory for local and systemic inflammatory activation and cardiac remodeling in ischemic HF. Activated macrophages in HF may directly induce cardiomyocyte contractile dysfunction and oxidant stress upon cell-to-cell contact; this juxtacrine response requires macrophage-localized iNOS. [ABSTRACT FROM AUTHOR]

This study presents the first known detection of fission products commonly found in post-detonation nuclear debris samples using solid sample introduction and a uniquely coupled gas chromatography inductively-coupled plasma time-of-flight mass spectrometer. Rare earth oxides were chemically altered to incorporate a ligand that enhances the volatility of the samples. These samples were injected (as solids) into the aforementioned instrument and detected for the first time. Repeatable results indicate the validity of the methodology, and this capability, when refined, will prove to be a valuable asset for rapid post-detonation nuclear forensic analysis. [ABSTRACT FROM AUTHOR]

Purpose: Limited availability of specialist services places a considerable burden on caregivers of Persons with Dementia (PwD) in Low- and Middle-Income Countries (LMICs). There are limited qualitative data on coercive behavior towards PwD in an LMIC setting.Aim: The aim of this study was to find relevant themes of the lived experience of relatives as caregivers for PwD in view of their use of coercive measures in community setting in South India.Method: Primary caregivers (n = 13) of PwDs from the Mysore study of Natal effects on Ageing and Health (MYNAH) in South India were interviewed to explore the nature and impact of coercion towards community dwelling older adults with dementia. The narrative data were coded using an Interpretative Phenomenological Analysis (IPA) approach for thematic analysis and theory formation.Results: Caregivers reported feeling physical and emotional burn-out, a lack of respite care, an absence of shared caregiving arrangements, limited knowledge of dementia, and a complete lack of community support services. They reported restrictions on their lives through not being able take employment, a poor social life, reduced income and job opportunities, and restricted movement that impacted on their physical and emotional well-being. Inappropriate use of sedatives, seclusion and environmental restraint, and restricted dietary intake, access to finances and participation in social events, was commonly reported methods of coercion used by caregivers towards PwD. Reasons given by caregivers for employing these coercive measures included safeguarding of the PwD and for the management of behavioral problems and physical health.Conclusion: There is an urgent need for training health and social care professionals to better understand the use of coercive measures and their impact on persons with dementia in India. It is feasible to conduct qualitative research using IPA in South India. [ABSTRACT FROM AUTHOR]

In a patient suspected clinically to have Weaver syndrome, we ruled out mutations in EZH2 and NSD1, then identified a previously undescribed de novo mutation in EZH2's partner protein EED. Both proteins are members of the Polycomb Repressive Complex 2 that maintains gene silencing. On the basis of the similarities of the patient's phenotype to Weaver syndrome, which is caused by de novo mutations in EZH2, and on other lines of evidence including mouse Eed hypomorphs, we characterize this mutation as probably pathogenic for a Weaver-like overgrowth syndrome. This is the first report of overgrowth and related phenotypes associated with a constitutional mutation in human EED. [ABSTRACT FROM AUTHOR]

Although recent studies have shown that adenosine-to-inosine (A-to-I) RNA editing occurs in microRNAs (miRNAs), its effects on tumour growth and metastasis are not well understood. We present evidence of CREB-mediated low expression of ADAR1 in metastatic melanoma cell lines and tumour specimens. Re-expression of ADAR1 resulted in the suppression of melanoma growth and metastasis in vivo. Consequently, we identified three miRNAs undergoing A-to-I editing in the weakly metastatic melanoma but not in strongly metastatic cell lines. One of these miRNAs, miR-455-5p, has two A-to-I RNA-editing sites. The biological function of edited miR-455-5p is different from that of the unedited form, as it recognizes a different set of genes. Indeed, wild-type miR-455-5p promotes melanoma metastasis through inhibition of the tumour suppressor gene CPEB1. Moreover, wild-type miR-455 enhances melanoma growth and metastasis in vivo, whereas the edited form inhibits these features. These results demonstrate a previously unrecognized role for RNA editing in melanoma progression. [ABSTRACT FROM AUTHOR]

The pacemaking activity of specialized tissues in the heart and gut results in lifelong rhythmic contractions. Here we describe a new syndrome characterized by Chronic Atrial and Intestinal Dysrhythmia, termed CAID syndrome, in 16 French Canadians and 1 Swede. We show that a single shared homozygous founder mutation in SGOL1, a component of the cohesin complex, causes CAID syndrome. Cultured dermal fibroblasts from affected individuals showed accelerated cell cycle progression, a higher rate of senescence and enhanced activation of TGF-β signaling. Karyotypes showed the typical railroad appearance of a centromeric cohesion defect. Tissues derived from affected individuals displayed pathological changes in both the enteric nervous system and smooth muscle. Morpholino-induced knockdown of sgol1 in zebrafish recapitulated the abnormalities seen in humans with CAID syndrome. Our findings identify CAID syndrome as a novel generalized dysrhythmia, suggesting a new role for SGOL1 and the cohesin complex in mediating the integrity of human cardiac and gut rhythm. [ABSTRACT FROM AUTHOR]

Lipid measurement is one of the cornerstones of cardiovascular risk assessment and treatment. It is widely accepted that reduction of atherogenic lipids reduces risk of atherosclerotic cardiovascular disease. As the study of lipids has yielded deeper understanding of the pathophysiology of lipid metabolism, it has become clear that different techniques to quantify atherogenic lipids and lipoproteins could be complementary. For example, low-density lipoprotein cholesterol can exist in a range of forms from small, dense to large, buoyant, and therefore, discordance may arise between measures of its cholesterol content and particle concentration. In this article, we review the most recent literature on discordance in lipid measurements. We emphasize interesting and important new findings, and aim to bring the reader up-to-date on the topic. We submit that lipid discordances create an opportunity to better personalize the risk assessed for atherogenic cardiovascular disease and the care we give patients with dyslipidemia. We note that while prior research has often examined one lipid measure vs another in their abilities to predict the average risk in a population, recent studies are increasingly asking what lipid discordance in individual patients can tell us about risk. We propose that this latter approach asks the more clinically important question. The message from these studies is consistent: discordance matters. As the field moves forward, we propose standardization of methods for discordance research. In our view, this will best enable us to further clarify the clinical implications of the principle of discordance and best inform personalized cardiovascular care. [ABSTRACT FROM AUTHOR]

Amorphous TcO and NHTcO solubilized into 12 M HCl will spontaneously convert to hexachlorotechnetate (TcCl). This process is accelerated upon heating but species lower than Tc(IV) are not generated by this action. TcCl is kinetically unstable with regards to formation in solutions of low concentrations of HCl and will spontaneously convert back to soluble and insoluble forms of Tc(IV) in water. TcCl in 12 M HCl placed in contact with the reducing metal Zn at elevated temperatures (90 °C) forms a black precipitate that contains amorphous Tc metal, TcO, and oxy-chlorides of Tc. Powder X-ray diffraction indicates the presence of Tc metal after thermal treatment where X-ray absorption fine structure spectroscopy indicates the presence of hexagonal Tc metal and amorphous TcO in the precipitate after rinsing with 12 HCl but before thermal treatment. The resulting solution contains a mixture of Tc chlorides and oxy-chlorides following reduction where TcCl is completely consumed resulting primarily in TcOCl dominating the UV-visible spectra. Reducing the solution volume and reconstituting the products into 12 M HCl while boiling the mixed solution (>24 h) will slowly convert all soluble Tc back to TcCl. Expanding on previous efforts made in this laboratory to recover Tc metal from aqueous solution, we investigate its synthesis when Tc(IV) and Tc(VII) in 12 M HCl is placed in contact with the reducing metal (i.e., Zn) at elevated temperatures. [ABSTRACT FROM AUTHOR]

An improved biointerface was developed, dynamic layer-by-layer self-assembly surface (d-LbL), and utilized as a biologically-active substrate for platelet adhesion and aggregation. Possible clinical applications for this research include improved anti-coagulation surfaces. This work demonstrated the functionality of d-LbL biointerfaces in the presence of platelet-rich-plasma (PRP) with the addition of 20 μM adenosine diphosphate (ADP), a thrombus activator. The surface morphology of the experimental control, plain PRP, was compared to PRP containing additional ADP (PRP + ADP) and resulted in an expected increase of platelet adhesions along the fibrinogen d-LbL substrate. The d-LbL process was used to coat glass slides with fibrinogen, Poly (sodium 4-styrene-sulfonate), and Poly (diallydimethlyammonium chloride). Slides were exposed to PRP under flow and static conditions with and without 20 μM of ADP. Fluorescence microscopy (FM), phase contrast microscopy (PCM), atomic force microscopy (AFM), and field emission-scanning electron microscopy (FE-SEM) were used to evaluate platelet adhesions under the influence of varied shear conditions. PCM images illustrated differences between the standard LbL and d-LbL substrates. FM images provided percent surface coverage values. For high-shear conditions, percent surface coverage values increased when using ADP whereas plain PRP exposure displayed no significant increase. AFM scans also displayed higher mean peak height values and unique surface characteristics for PRP + ADP as opposed to plain PRP. FE-SEM images revealed platelet adhesions along the biointerface and unique characteristics of the d-LbL surface. In conclusion, PRP + ADP was more effective at increasing platelet aggregation, especially under high shear conditions, providing further validation of the improved biointerface. [ABSTRACT FROM AUTHOR]

The authors discuss the aspects of The Cancer Genome Atlas (TCGA) Research Network's Pan-Cancer scheme, which investigated a significant number of tumors to find molecular aberrations at the RNA, DNA, and protein levels. The project was introduced in Santa Cruz, California from October 26-27, 2013, and aims to gather coherent data sets of tumor types. The authors add that the TCGA Pan-Cancer papers provide an important contribution to cancer research.

Background: Nipple-sparing mastectomy (NSM) for both risk reduction and cancer is increasing. In the cancer setting, most studies suggest the use of both clinical and intraoperative biopsy criteria in patient selection. This study examines the use of both biopsy and clinical criteria in women undergoing total nipple-removing mastectomy. Methods: The study consisted of 58 patients undergoing total mastectomy without nipple sparing. Biopsies of the subareola tissue (SA), proximal nipple (NC) contents and radial sections of the residual nipple (NR) were examined microscopically. Tumor size and distance from the nipple were also noted. Results: Using clinical criteria alone, the false negative rate was 53.8 % and a false positive rate of 44.4 %. When adding subareola and nipple core biopsies to clinical criteria the false negative rate fell to 7.7 % but the false positive rate remained at 44.4 %. When using only SA and NC biopsies to predict occult nipple involvement, the false negative rate was 11.8 %. In 4 cases the NC was positive while the SA was negative for cancer and in 6 cases the SA was positive and NC negative. In 2 cases both the NC and SA biopsies were negative while the NR was positive. Conclusions: This study supports a more limited role in the use of clinical criteria for evaluating patients for NSM. This maximizes the number of patients who are candidates for NSM with minimal risk of nipple involvement. It was also noted that intraoperative biopsies are not totally reliable in predicting occult nipple involvement. [ABSTRACT FROM AUTHOR]

The YFF1 is a new universal molecular mechanic force field designed for drug discovery purposes. The electrostatic part of YFF1 has already been parameterized to reproduce ab initio calculated dipole and quadrupole moments. Now we report a parameterization of the van der Waals interactions (vdW) for the same atom types that were previously defined. The 6-12 Lennard-Jones potential terms were parameterized against homodimerization energies calculated at the MP2/6-31 G* level of theory. The Boys-Bernardi counterpoise correction was employed to account for the basis-set superposition error. As a source of structural information we used about 2,400 neutral compounds from the ZINC2007 database. About 6,600 homodimeric configurations were generated from this dataset. A special 'closure' procedure was designed to accelerate the parameters fitting. As a result, dimerization energies of small organic compounds are reproduced with an average unsigned error of 1.1 kcal mol. Although the primary goal of this work was to parameterize nonbonded interactions, bonded parameters were also derived, by fitting to PM6 semiempirically optimized geometries of approximately 20,000 compounds. [ABSTRACT FROM AUTHOR]

Subclinical coronary artery disease (CAD) is widespread and under-diagnosed. Preventive efforts are required to reduce the burden of this disease and its complications. Imaging of coronary artery calcium (CAC) with cardiac computed tomography is highly specific for the diagnosis of subclinical CAD and can also facilitate treatment decisions in preventive cardiology. Indeed, CAC testing has been recommended by the American Heart Association for asymptomatic patients at intermediate risk for future cardiac events (as defined by clinical risk factors) to refine existing risk estimates. However, the optimal follow-up of those patients who have already undergone CAC testing remains unclear, particularly with regards to repeat CAC testing. The existing literature points to two major considerations for the use of CAC progression in the management of subclinical CAD. On one hand, CAC progression has been used as a surrogate marker to test the efficacy of cardiac preventive medications in halting or regressing CAD. To date, study results have been mostly disappointing and CAC progression appears resistant to medications such as statins. On the other hand, however, CAC progression has potential as a clinical indicator of underlying CAD activity. This may facilitate optimization or up-titration of preventive medications by using CAC progression as a marker of subclinical disease activity. We believe that the data, thus far, argues against the use of a CAC progression as a clinical surrogate marker of preventive therapy efficacy. Further studies with non-statin medications and with concomitant outcome data are needed. However, CAC progression has potential for monitoring subclinical CAD in some patients and may facilitate treatment decisions. In this review we will provide recommendations for repeat CAC testing and discuss when repeat CAC testing may be helpful to assess coronary artery disease progression. [ABSTRACT FROM AUTHOR]

Background: The objectives of this study were to determine: (1) the incidence permanent hypothyroidism after thyroid lobectomy (TL), (2) whether asymptomatic patients with mildly elevated thyrotropin (TSH) levels can be managed without thyroid hormone replacement, and (3) if the degree of lymphocytic infiltration (LI) and germinal center (GC) formation in the resected thyroid lobe correlates with the development of post-TL hypothyroidism. Methods: Subjects undergoing TL between January 2006 and January 2008 at 2 centers were enrolled in the study and thyroid function was followed prospectively based on a previously published algorithm. The histology of each resected thyroid lobe was examined, and the degree of LI and GC was quantified. Results: The study cohort consisted of 117 patients. Early postoperative TSH levels were significantly increased over preoperative levels ( P < .001). TSH measured at 6 months to 1 year postoperatively, while still significantly increased over preoperative levels ( P < .001), was also significantly reduced ( P = .006) compared with early postoperative levels. Of the patients who presented with early postoperative hypothyroidism, 69.2% recovered to normal levels without intervention. The overall incidence of early postoperative hypothyroidism was 21.6%, and permanent hypothyroidism was 7.8%. A high degree of LI and GC correlated with a significantly higher mean TSH level ( P = .003). Conclusions: The incidence of hypothyroidism following TL is low, and a significant proportion of individuals who become biochemically hypothyroid will demonstrate only a transient elevation in their TSH levels. As well, individuals with LI, or GC formation, within their resected thyroid lobe may be at increased risk for post-TL hypothyroidism. [ABSTRACT FROM AUTHOR]

Chromosomal translocations are critically involved in the molecular pathogenesis of B-cell lymphomas, and highly recurrent and specific rearrangements have defined distinct molecular subtypes linked to unique clinicopathological features. In contrast, several well-characterized lymphoma entities still lack disease-defining translocation events. To identify novel fusion transcripts resulting from translocations, we investigated two Hodgkin lymphoma cell lines by whole-transcriptome paired-end sequencing (RNA-seq). Here we show a highly expressed gene fusion involving the major histocompatibility complex (MHC) class II transactivator CIITA (MHC2TA) in KM-H2 cells. In a subsequent evaluation of 263 B-cell lymphomas, we also demonstrate that genomic CIITA breaks are highly recurrent in primary mediastinal B-cell lymphoma (38%) and classical Hodgkin lymphoma (cHL) (15%). Furthermore, we find that CIITA is a promiscuous partner of various in-frame gene fusions, and we report that CIITA gene alterations impact survival in primary mediastinal B-cell lymphoma (PMBCL). As functional consequences of CIITA gene fusions, we identify downregulation of surface HLA class II expression and overexpression of ligands of the receptor molecule programmed cell death 1 (CD274/PDL1 and CD273/PDL2). These receptor-ligand interactions have been shown to impact anti-tumour immune responses in several cancers, whereas decreased MHC class II expression has been linked to reduced tumour cell immunogenicity. Thus, our findings suggest that recurrent rearrangements of CIITA may represent a novel genetic mechanism underlying tumour-microenvironment interactions across a spectrum of lymphoid cancers. [ABSTRACT FROM AUTHOR]