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IntroductionLung cancer is a leading cause of cancer-related deaths worldwide. Black/African American (B/AA) populations, in particular, exhibit the highest incidence and mortality rates of lung adenocarcinoma (LUAD) in the United States.MethodsThis study aims to explore gene expression patterns linked to LUAD in B/AA and case-matched white patients, with the goal of developing predictive models for prognosis. Leveraging RNA sequencing data from The Cancer Genome Atlas (TCGA) database, genes and pathways associated with overall survival (OS) were identified.ResultsThe OS-associated genes in B/AA patients were distinct from those in white patients, showing predominant enrichment in immune-related pathways. Furthermore, mRNA co-expression network analysis revealed that OS-associated genes in B/AA patients had higher levels of interaction with various pathways, including those related to immunity, cell-ECM interaction, and specific intracellular signaling pathways. Notably, a potential B/AA-specific biomarker, C9orf64, demonstrated significant correlations with genes involved in immune response. Unsupervised machine learning algorithms stratified B/AA patients into groups with distinct survival outcomes, while supervised algorithms demonstrated a higher accuracy in predicting survival for B/AA LUAD patients compared to white patients.DiscussionIn total, this study explored OS-associated genes and pathways specific for B/AA LUAD patients. Further validation and clinical application of these findings are warranted to address disparities and improve outcomes in diverse patient populations.

Abstract The high energy (Regge) limit provides a playground for understanding all loop structures of scattering amplitudes, and plays an important role in the description of many phenomenologically relevant cross-sections. While well understood in the planar limit, the structure of non-planar corrections introduces many fascinating complexities, for which a general organizing principle is still lacking. We study the structure of multi-reggeon exchanges in the context of the effective field theory for forward scattering, and derive their factorization into collinear operators (impact factors) and soft operators. We derive the structure of the renormalization group consistency equations in the effective theory, showing how the anomalous dimensions of the soft operators are related to those of the collinear operators, allowing us to derive renormalization group equations in the Regge limit purely from a collinear perspective. The rigidity of the consistency equations provides considerable insight into the all orders organization of Regge amplitudes in the effective theory, as well as its relation to other approaches. Along the way we derive a number of technical results that improve the understanding of the effective theory. We illustrate this collinear perspective by re-deriving all the standard BFKL equations for two-Glauber exchange from purely collinear calculations, and we show that this perspective provides a number of conceptual and computational advantages as compared to the standard view from soft or Glauber physics. We anticipate that this formulation in terms of collinear operators will enable a better understanding of the relation between BFKL and DGLAP in gauge theories, and facilitate the analysis of renormalization group evolution equations describing Reggeization beyond next-to-leading order.

Tumor microenvironments (TMEs) contain vast amounts of information on patient's cancer through their cellular composition and the spatial distribution of tumor cells and immune cell populations. Exploring variations in TMEs between patient groups, as well as determining the extent to which this information can predict outcomes such as patient survival or treatment success with emerging immunotherapies, is of great interest. Moreover, in the face of a large number of cell interactions to consider, we often wish to identify specific interactions that are useful in making such predictions. We present an approach to achieve these goals based on summarizing spatial relationships in the TME using spatial K functions, and then applying functional data analysis and random forest models to both predict outcomes of interest and identify important spatial relationships. This approach is shown to be effective in simulation experiments at both identifying important spatial interactions while also controlling the false discovery rate. We further used the proposed approach to interrogate two real data sets of Multiplexed Ion Beam Images of TMEs in triple negative breast cancer and lung cancer patients. The methods proposed are publicly available in a companion R package funkycells.

Summary: Lung cancer is the third most common cancer with Black/AA men showing higher risk and poorer outcomes than NHW men. Lung cancer disparities are multifactorial, driven by tobacco exposure, inequities in care access, upstream health determinants, and molecular determinants including biological and genetic factors. Elevated expressions of protein arginine methyltransferases (PRMTs) correlating with poorer prognosis have been observed in many cancers. Most importantly, our study shows that PRMT6 displays higher expression in lung cancer tissues of Black/AA men compared to NHW men. In this study, we investigated the underlying mechanism of PRMT6 and its cooperation with PRMT1 to form a heteromer as a driver of lung cancer. Disrupting PRMT1/PRMT6 heteromer by a competitive peptide reduced proliferation in non-small cell lung cancer cell lines and patient-derived organoids, therefore, giving rise to a more strategic approach in the treatment of Black/AA men with lung cancer and to eliminate cancer health disparities.

Abstract Using an effective field theory (EFT) formalism for forward scattering, we reconsider the factorization of 2 → 2 scattering amplitudes in the Regge limit. Expanding the amplitude in gauge invariant operators labelled by the number of Glauber exchanges, allows us to further factorize the standard impact factors into separate collinear and soft functions. The soft functions are universal, and describe radiative corrections to the Reggeized gluon states exchanged by the collinear projectiles. Remarkably, we find that the one-loop soft function for the single Reggeized gluon state is given to O $$ \mathcal{O} $$ (ϵ) in terms of the two-loop cusp and two-loop rapidity anomalous dimensions. We argue that this iterative structure follows from the simple action of crossing symmetry in the forward scattering limit, which in the EFT allows us to replace the divergent part of a soft loop by a much simpler Glauber loop. We use this correspondence to provide a simple calculation of the two-loop Regge trajectory using the EFT. We then explore its implications at higher perturbative orders, and derive the maximally matter dependent contributions to the Regge trajectory to all loop orders, i.e. the terms ∼ α s k + 1 n f k $$ \sim {\alpha}_s^{k+1}{n}_f^k $$ for any k, where n f is the number of massless flavors. These simplifications suggests that the EFT approach to the Regge limit will be helpful to explore and further understand the structure of the Regge limit.

Abstract Patients with non-small cell lung cancer (NSCLC) who have distant metastases have a poor prognosis. To determine which genomic factors of the primary tumor are associated with metastasis, we analyzed data from 759 patients originally diagnosed with stage I–III NSCLC as part of the AACR Project GENIE Biopharma Collaborative consortium. We found that TP53 mutations were significantly associated with the development of new distant metastases. TP53 mutations were also more prevalent in patients with a history of smoking, suggesting that these patients may be at increased risk for distant metastasis. Our results suggest that additional investigation of the optimal management of patients with early-stage NSCLC harboring TP53 mutations at diagnosis is warranted in light of their higher likelihood of developing new distant metastases.

Several studies have shown that microsatellite changes can be profiled in urine for the detection of bladder cancer. The use of microsatellite analysis (MSA) for bladder cancer detection requires a comprehensive analysis of as many as 15 to 20 markers, based on the amplification and interpretations of many individual MSA markers, and it can be technically challenging. Here, to develop fast, more efficient, standardized, and less costly MSA for the detection of bladder cancer, we developed three multiplex-polymerase-chain-reaction-(PCR)-based MSA assays, all of which were analyzed via a genetic analyzer. First, we selected 16 MSA markers based on 9 selected publications. Based on samples from Johns Hopkins University (the JHU sample, the first set sample), we developed an MSA based on triplet, three-tube-based multiplex PCR (a Triplet MSA assay). The discovery, validation, and translation of biomarkers for the early detection of cancer are the primary focuses of the Early Detection Research Network (EDRN), an initiative of the National Cancer Institute (NCI). A prospective study sponsored by the EDRN was undertaken to determine the efficacy of a novel set of MSA markers for the early detection of bladder cancer. This work and data analysis were performed through a collaboration between academics and industry partners. In the current study, we undertook a re-analysis of the primary data from the Compass study to enhance the predictive power of the dataset in bladder cancer diagnosis. Using a four-stage pipeline of modern machine learning techniques, including outlier removal with a nonlinear model, correcting for majority/minority class imbalance, feature engineering, and the use of a model-derived variable importance measure to select predictors, we were able to increase the utility of the original dataset to predict the occurrence of bladder cancer. The results of this analysis showed an increase in accuracy (85%), sensitivity (82%), and specificity (83%) compared to the original analysis. The re-analysis of the EDRN study results using machine learning statistical analysis proved to achieve an appropriate level of accuracy, sensitivity, and specificity to support the use of the MSA for bladder cancer detection and monitoring. This assay can be a significant addition to the tools urologists use to both detect primary bladder cancers and monitor recurrent bladder cancer.

Abstract In the tumor microenvironment (TME), functional interactions among tumor, immune, and stromal cells and the extracellular matrix play key roles in tumor progression, invasion, immune modulation, and response to treatment. Intra‐tumor heterogeneity is ubiquitous not only at the genetic and transcriptomic levels but also in the composition and characteristics of TME. However, quantitative inference on spatial heterogeneity in the TME is still limited. Here, we propose a framework to use network graph‐based spatial statistical models on spatially annotated molecular data to gain insights into modularity and spatial heterogeneity in the TME. Applying the framework to spatial transcriptomics data from pancreatic ductal adenocarcinoma samples, we observed significant global and local spatially correlated patterns in the abundance score of tumor cells; in contrast, immune cell types showed dispersed patterns in the TME. Hypoxia, EMT, and inflammation signatures contributed to intra‐tumor spatial variations. Spatial patterns in cell type abundance and pathway signatures in the TME potentially impact tumor growth dynamics and cancer hallmarks. Tumor biopsies are integral to the diagnosis and clinical management of cancer patients; our data suggest that owing to intra‐tumor non‐genetic spatial heterogeneity, individual biopsies may underappreciate the extent of clinically relevant, functional variations across geographic regions within tumors.

Abstract Background Gestational diabetes mellitus (GDM) is a serious public health issue affecting 9–15% of all pregnancies worldwide. Recently, it has been suggested that extracellular vesicles (EVs) play a role throughout gestation, including mediating a placental response to hyperglycaemia. Here, we investigated the EV-associated miRNA profile across gestation in GDM, assessed their utility in developing accurate, multivariate classification models, and determined the signaling pathways in skeletal muscle proteome associated with the changes in the EV miRNA profile. Methods Discovery: A retrospective, case–control study design was used to identify EV-associated miRNAs that vary across pregnancy and clinical status (i.e. GDM or Normal Glucose Tolerance, NGT). EVs were isolated from maternal plasma obtained at early, mid and late gestation (n = 29) and small RNA sequencing was performed. Validation: A longitudinal study design was used to quantify expression of selected miRNAs. EV miRNAs were quantified by real-time PCR (cases = 8, control = 14, samples at three times during pregnancy) and their individual and combined classification efficiencies were evaluated. Quantitative, data-independent acquisition mass spectrometry was use to establish the protein profile in skeletal muscle biopsies from normal and GDM. Results A total of 2822 miRNAs were analyzed using a small RNA library, and a total of 563 miRNAs that significantly changed (p 90%. We identified a set of proteins in skeletal muscle biopsies from women with GDM associated with JAK-STAT signaling which could be targeted by the miRNA-92a-3p within circulating EVs. Interestingly, overexpression of miRNA-92a-3p in primary skeletal muscle cells increase insulin-stimulated glucose uptake. Conclusions During early pregnancy, differently-expressed, EV-associated miRNAs may be of clinical utility in identifying presymptomatic women who will subsequently develop GDM later in gestation. We suggest that miRNA-92a-3p within EVs might be a protected mechanism to increase skeletal muscle insulin sensitivity in GDM.

Metaplastic breast cancer (MBC) is a rare and aggressive subtype of breast cancer. Tumor characteristics typically feature estrogen receptor, progesterone receptor, and HER2-negative, triple-negative breast cancer (TNBC), with a poorer prognosis relative to pure invasive ductal or lobular disease. Resistance to chemotherapy often leads to local recurrence and distant metastasis. Genomic profiling has identified multiple molecular abnormalities that may translate to targetable therapies in MBC. These tumors are known to display higher PD-L1 expressivity than other subtypes of breast cancer, and disease control with pembrolizumab and chemotherapy has been documented. We identify a patient with metastatic, metaplastic TNBC, with mesenchymal components and osseous differentiation, who completed 2 years of pembrolizumab treatment and has remained without evidence of disease after 32 months of observation, while maintaining good quality of life. Future efforts should focus on immunotherapy response with respect to the various subtypes of MBC, and treatment should continue to be incorporated in clinical trials to maximize disease response.

Background: We describe two adult brothers with lower limb neuropathy and one with progressive optic neuropathy. One brother was found to have profound biotinidase deficiency by identifying biallelic pathogenic variants of the BTD gene by whole exome sequencing, which was confirmed by markedly decreased serum biotinidase activity. Case report and methods: The first brother had progressive optic atrophy and vision loss over 10 years and progressive peripheral neuropathy with weakness, pain, and fatigue for 20 years. Profound biotinidase deficiency was also identified in an older brother, who exhibited peripheral neuropathy since four years of age, but had no vision loss. Results: The first brother's vision loss and neuropathy improved markedly with biotin in six months. However, the neuropathy of the other brother did not improve with 16 months of biotin therapy. Conclusions: The first brother's neurological issues partially reversed with biotin. However, the longer-term symptoms of the other brother were irreversible. These cases emphasize the importance of considering biotinidase deficiency in the differential diagnosis of adolescents and adults with peripheral neuropathy with or without optic neuropathy/atrophy before symptoms become irreversible. Although WES initially identified the disorder in this family, measuring serum biotinidase activity was a necessary confirmatory step after WES and is less expensive than performing whole exome sequencing.

Cytotoxic T lymphocytes (CTLs) are thought to arrive at target sites either via random search or following signals by other leukocytes. Here, we reveal independent emergent behaviour in CTL populations attacking tumour masses. Primary murine CTLs coordinate their migration in a process reminiscent of the swarming observed in neutrophils. CTLs engaging cognate targets accelerate the recruitment of distant T cells through long-range homotypic signalling, in part mediated via the diffusion of chemokines CCL3 and CCL4. Newly arriving CTLs augment the chemotactic signal, further accelerating mass recruitment in a positive feedback loop. Activated effector human T cells and chimeric antigen receptor (CAR) T cells similarly employ intra-population signalling to drive rapid convergence. Thus, CTLs recognising a cognate target can induce a localised mass response by amplifying the direct recruitment of additional T cells independently of other leukocytes.

Background: Right sided tears or rupture are the most common injury to the heart after blunt chest trauma. The majority of these injuries are to the thin walled atrium. Reports of localized right atrial appendage rupture are rare. The classical features of Beck's triad are unreliable in the trauma bay. With the advent of EFAST (Focused assessment with sonography for trauma extended to thorax), Beck's triad should be considered but not used as the primary clinical tool for diagnosis of cardiac tamponade [1]. EFAST aids in rapid diagnosis and definitive care [3]. Case presentation: Our patient was a 17 year old male who presented with hypotension after a rollover motor vehicle accident. He presented with a grossly negative physical exam and positive EFAST for pericardial effusion with tamponade physiology. We performed an emergency pericardiocentesis and expedited transportation for operative exploration. A Right atrial appendage injury was identified and repaired and patient recovered uneventfully. Conclusion: EFAST examination aids in rapid diagnosis of cardiac tamponade in the trauma setting. Pericardiocentesis facilitates temporizing the hemodynamics in preparation for operative exploration.

Targeting defects in metabolism is an underutilized strategy for the treatment of cancer. Arginine auxotrophy resulting from the silencing of argininosuccinate synthetase 1 (ASS1) is a common metabolic alteration reported in a broad range of aggressive cancers. To assess the metabolic effects that arise from acute and chronic arginine starvation in ASS1-deficient cell lines, we performed metabolite profiling. We found that pharmacologically induced arginine depletion causes increased serine biosynthesis, glutamine anaplerosis, oxidative phosphorylation, and decreased aerobic glycolysis, effectively inhibiting the Warburg effect. The reduction of glycolysis in cells otherwise dependent on aerobic glycolysis is correlated with reduced PKM2 expression and phosphorylation and upregulation of PHGDH. Concurrent arginine deprivation and glutaminase inhibition was found to be synthetic lethal across a spectrum of ASS1-deficient tumor cell lines and is sufficient to cause in vivo tumor regression in mice. These results identify two synthetic lethal therapeutic strategies exploiting metabolic vulnerabilities of ASS1-negative cancers.

AimTo isolate and characterize oral extracellular vesicles from gingival crevicular fluid at 11-14 weeks and evaluate their capacity to identify patients at risk of developing gestational diabetes mellitus.MethodsA case-control study was conducted, including patients who developed gestational diabetes mellitus (n = 11) and healthy pregnant controls (n = 23). Obstetric and periodontal histories were recorded at 11-14 weeks of gestation, and samples of gingival crevicular fluid obtained. Extracellular vesicles were isolated from gingival crevicular fluid by ExoQuick. Nanoparticle tracking analysis, ELISA and transmission electron microscopy were used to characterize extracellular vesicles.ResultsTotal extracellular vesicles isolated from gingival crevicular fluid were significantly higher in patients who developed gestational diabetes mellitus later in pregnancy compared to normoglycemic pregnant women (6.3x109 vs 1.7 x1010, p value = 0.0026), and the concentration of the extracellular vesicles delivered an area under the ROC curve of 0.81. The distribution size of extracellular vesicles obtained using ExoQuick was around 148 ± 57 nm. There were no significant differences in the periodontal status between cases and controls. The exosome transmembrane protein CD63 was also detected in the extracellular vesicles of gingival crevicular fluid.ConclusionWe were able to isolate extracellular vesicles from gingival crevicular fluid using a method that is suitable to be applied in a clinical setting. Our results provide an insight into the potential capacity of first trimester oral extracellular vesicles as early biomarkers for the prediction of gestational diabetes mellitus in pre-symptomatic women.

Preeclampsia is a pregnancy-specific disorder defined by the new onset of hypertension and proteinuria after 20 weeks of gestation. Although its precise etiology is still unknown, there is evidence suggesting that it may be a consequence of impaired decidual and stromal cell function. Recently, a stem cell population derived from endometrial tissue and isolated from menstrual effluent called menstrual stem cells (MenSCs) has been identified. MenSCs exhibit important angiogenic and inflammatory properties that may contribute to both normal and pathological complications of implantation and placentation, including preeclampsia. We hypothesized that the angiogenic and inflammatory activity of MenSCs is altered in women who have a past history of preeclampsia and that this phenotype persists postpartum. The primary outcome measures were stromal progenitor cell formation, in vitro induction of endothelial tube formation, and release of proinflammatory cytokines. MenSCs obtained from women with a previous normal or preeclamptic pregnancy displayed similar phenotypic characteristics, tri-differentiation capacity, and proliferation. MenSCs derived from women who had preeclampsia on their previous pregnancy had reduced angiogenic capacity (~30% fewer junctions and nodes, p

Early and innovative diagnostic strategies are required to predict the risk of developing pre-eclampsia (PE). The purpose of this study was to evaluate the performance of gingival crevicular fluid (GCF) placental alkaline phosphatase (PLAP) concentrations to correctly classify women at risk of PE. A prospectively collected, retrospectively stratified cohort study was conducted, with 412 pregnant women recruited at 11–14 weeks of gestation. Physical, obstetrical, and periodontal data were recorded. GCF and blood samples were collected for PLAP determination by ELISA assay. A multiple logistic regression classification model was developed, and the classification efficiency of the model was established. Within the study cohort, 4.3% of pregnancies developed PE. GCF-PLAP concentration was 3- to 6-fold higher than in plasma samples. GCF-PLAP concentrations and systolic blood pressure were greater in women who developed PE (p = 0.015 and p < 0.001, respectively). The performance of the multiparametric model that combines GCF-PLAP concentration and the levels of systolic blood pressure (at 11–14 weeks gestation) showed an association of systolic blood pressure and GCF-PLAP concentrations with the likelihood of developing PE (OR:1.07; 95% CI 1.01–1.11; p = 0.004 and OR:1.008, 95% CI 1.000–1.015; p = 0.034, respectively). The model had a sensitivity of 83%, a specificity of 72%, and positive and negative predictive values of 12% and 99%, respectively. The area under the receiver operating characteristic (AUC-ROC) curve was 0.77 and correctly classified 72% of PE pregnancies. In conclusion, the multivariate classification model developed may be of utility as an aid in identifying pre-symptomatic women who subsequently develop PE.

Healthcare is considered as one of the most promising application areas for artificial intelligence and analytics (AIA) just after the emergence of the latter. AI combined to analytics technologies is increasingly changing medical practice and healthcare in an impressive way using efficient algorithms from various branches of information technology (IT). Indeed, numerous works are published every year in several universities and innovation centers worldwide, but there are concerns about progress in their effective success. There are growing examples of AIA being implemented in healthcare with promising results. This review paper summarizes the past 5 years of healthcare applications of AIA, across different techniques and medical specialties, and discusses the current issues and challenges, related to this revolutionary technology. A total of 24,782 articles were identified. The aim of this paper is to provide the research community with the necessary background to push this field even further and propose a framework that will help integrate diverse AIA technologies around patient needs in various healthcare contexts, especially for chronic care patients, who present the most complex comorbidities and care needs.

Natural disasters increase the level population stress, including pregnant women, who can experience prenatal maternal stress, affecting the fetus and triggering perinatal complications, such as low birth weight, smaller head circumference, etc. However, little is known about effects of earthquake on perinatal outcomes.To evaluate the effect of earthquake occurred on February 27, 2010 and perinatal outcomes of Chilean pregnant women, and to examine these effects by timing of exposure during pregnancy and newborn gender.A register-based study was performed using data collected from women who had a vaginal delivery in a large private health center in Santiago, Chile, during 2009 and 2010. The study population was categorized according to exposure to earthquake and timing during gestation. Primary perinatal outcomes were gestational age at birth, birth weight, length and head circumference. Analyses adjusted for gender, gestational age at exposure, parity, maternal age and income.A total of 1,966 eligible vaginal deliveries occurred during 2009 and 2,110 in 2010. Birth weight was not affected by the trimester of exposure; however, length, head circumference and gestational age at birth were significantly different according to trimester of exposure and gender of newborn. In multivariable analysis, newborns were shorter by 2 mm, 5 mm and 4.5 mm, if they were exposed during their first, second and third trimester, respectively. Furthermore, newborns had a smaller head circumference by 1.2 mm and 1.5 mm if they were exposed during first and second trimester of gestation.In this cohort, exposure to the February 2010 earthquake resulted in earlier delivery and reduced length and head circumference in the offspring. This association varied according to trimester of exposure and fetal gender. Health workers should include exposed to high levels of stress associated with natural disasters when assessing pregnancy risk factors.

Leading institutions throughout the country have established Precision Medicine programs to support personalized treatment of patients. A cornerstone for these programs is the establishment of enterprise-wide Clinical Data Warehouses. Working shoulder-to-shoulder, a team of physicians, systems biologists, engineers, and scientists at Rutgers Cancer Institute of New Jersey have designed, developed, and implemented the Warehouse with information originating from data sources, including Electronic Medical Records, Clinical Trial Management Systems, Tumor Registries, Biospecimen Repositories, Radiology and Pathology archives, and Next Generation Sequencing services. Innovative solutions were implemented to detect and extract unstructured clinical information that was embedded in paper/text documents, including synoptic pathology reports. Supporting important precision medicine use cases, the growing Warehouse enables physicians to systematically mine and review the molecular, genomic, image-based, and correlated clinical information of patient tumors individually or as part of large cohorts to identify changes and patterns that may influence treatment decisions and potential outcomes.

Ovarian cancer is one of the most important causes of cancer-related death among women in the world. Despite advances in ovarian cancer treatment, 70–80% of women who initially respond to therapy eventually relapse and die. There is evidence that a small population of cells within the tumors called cancer stem cells (CSCs) could be responsible for treatment failure due to their enhanced chemoresistance and tumorigenicity. These cells reside in a niche that maintains the principal properties of CSCs. These properties are associated with the capacity of CSCs to interact with different cells of the tumor microenvironment including mesenchymal stem cells, endothelial cells, immune cells, and fibroblasts, promoting cancer progression. This interaction can be mediated by cytokines, growth factors, lipids, and/or extracellular vesicles released in the CSC niche. In this review, we will discuss how the interaction between ovarian CSCs and the tumor microenvironment can contribute to the maintenance of the CSC niche and consequently to tumor progression in ovarian cancer.

Long non-coding RNAs (lncRNAs) have been recognized as key players in transcriptional regulation. We show that the lncRNA steroid receptor RNA activator (SRA) participates in regulation through complex formation with trithorax group (TrxG) and polycomb repressive complex 2 (PRC2) complexes. Binding of the SRA-associated RNA helicase p68 preferentially stabilizes complex formation between SRA and a TrxG complex but not PRC2. In human pluripotent stem cells NTERA2, SRA binding sites that are also occupied by p68 are significantly enriched for H3K4 trimethylation. Consistent with its ability to interact with TrxG and PRC2 complexes, some SRA binding sites in human pluripotent stem cells overlap with bivalent domains. CTCF sites associated with SRA appear also to be enriched for bivalent modifications. We identify NANOG as a transcription factor directly interacting with SRA and co-localizing with it genome-wide in NTERA2. Further, we show that SRA is important for maintaining the stem cell state and for reprogramming of human fibroblasts to achieve the pluripotent state. Our results suggest a mechanism whereby the lncRNA SRA interacts with either TrxG or PRC2. These complexes may then be recruited by various DNA binding factors to deliver either activating or silencing signals, or both, to establish bivalent domains.

Este experimento teve como objetivo comparar os efeitos do desmame temporário (DT) por 72 horas associado ou não ao uso de Norgestomet (NOR) e estradiol na fertilidade do estro induzido e no período reprodutivo de vacas de corte acíclicas no pós-parto. O grupo DT (n= 38) era constituído por vacas que tiveram os terneiros separados por 72 horas. O grupo NOR (n= 29) foi constituído por vacas que receberam (dia 0) um implante subcutâneo de Norgestomet e uma aplicação de Valerato de estradiol (5mg) e Norgestomet (3mg), intramuscular. No momento da retirada dos implantes (dia 9), os terneiros foram separados por 72 horas. O intervalo desmame-estro foi significativamente mais curto (P0,05) entre os grupos. O grupo NOR apresentou uma menor incidência (P

No presente trabalho, são apresentados dados sobre o diagnóstico de gestação realizado por ultra-sonografia em 45 rebanhos ovinos, durante seis períodos reprodutivos. Foram examinadas 27.089 ovelhas de rebanhos comerciais, acasaladas durante o outono. A porcentagem de prenhez(PP) variou de 77,3 a 89,9%, com uma PP média de 81,6%. Rebanhos de raças de carne (Hampshire Down, Suffolk e Texel) mostram em média a PP mais elevada que foi de 85,6%, seguidos de ovelhas cruzas, com PP de 82,9% e finalmente ovelhas de raças de lã (Merino Australiano, Corriedale e Ideal) com PP média de 80,8%. Prováveis causas de baixas PP observadas em alguns rebanhos são apresentadas e discutidas.

Hemitruncus arteriosus is a rare congenital deformity that results in early infant mortality. Persistence into adulthood is very unusual and is associated with pulmonary hypertension. We report a case in an adult male with the associated clinical issues.

In vitro and in vivo models are widely used in cancer research. Characterizing the similarities and differences between a patient's tumor and corresponding in vitro and in vivo models is important for understanding the potential clinical relevance of experimental data generated with these models. Towards this aim, we analyzed the genomic aberrations, DNA methylation and transcriptome profiles of five parental tumors and their matched in vitro isolated glioma stem cell (GSC) lines and xenografts generated from these same GSCs using high-resolution platforms. We observed that the methylation and transcriptome profiles of in vitro GSCs were significantly different from their corresponding xenografts, which were actually more similar to their original parental tumors. This points to the potentially critical role of the brain microenvironment in influencing methylation and transcriptional patterns of GSCs. Consistent with this possibility, ex vivo cultured GSCs isolated from xenografts showed a tendency to return to their initial in vitro states even after a short time in culture, supporting a rapid dynamic adaptation to the in vitro microenvironment. These results show that methylation and transcriptome profiles are highly dependent on the microenvironment and growth in orthotopic sites partially reverse the changes caused by in vitro culturing.

Age is a powerful predictor of survival in glioblastoma multiforme (GBM) yet the biological basis for the difference in clinical outcome is mostly unknown. Discovering genes and pathways that would explain age-specific survival difference could generate opportunities for novel therapeutics for GBM. Here we have integrated gene expression, exon expression, microRNA expression, copy number alteration, SNP, whole exome sequence, and DNA methylation data sets of a cohort of GBM patients in The Cancer Genome Atlas (TCGA) project to discover age-specific signatures at the transcriptional, genetic, and epigenetic levels and validated our findings on the REMBRANDT data set. We found major age-specific signatures at all levels including age-specific hypermethylation in polycomb group protein target genes and the upregulation of angiogenesis-related genes in older GBMs. These age-specific differences in GBM, which are independent of molecular subtypes, may in part explain the preferential effects of anti-angiogenic agents in older GBM and pave the way to a better understanding of the unique biology and clinical behavior of older versus younger GBMs.

Abstract Background Despite major advances in drug development, effective cardiovascular therapies and suitable cardiovascular biomarkers remain limited. The aim of this study was to leverage mass spectrometry (MS) based peptide profiling strategies to identify changes that occur in peptidomic profiles of rat plasma following coronary artery ligation generated myocardial infarction (MI). Methods One week after MI, rats were randomized to receive either an ACE inhibitor (ramipril, Ram‐1 mg/kg/day), or vehicle (Veh) for 12 weeks. Echocardiography and hemodynamic measurements were made before sacrifice and plasma collection. High abundance proteins were depleted with affinity capture before MS profiling. Differentially expressed peptide ions were identified using proprietary software (ClinProtTools). Results MI increased heart/body weight (18%), lung/body weight (56%), and left ventricular (LV) end diastolic pressure (LVEDP, 247%); and significantly reduced percentage fractional shortening (FS, 75%) and rate of pressure rise in the LV (dP/dtmax, 20%). Ram treatment significantly attenuated the changes in LVEDP (61%) and FS (27%). Analysis of MALDI‐ToF generated mass spectra demonstrated that peptide ions 1271, 1878, 1955, 2041 and 2254 m/z were consistently decreased by Ram treatment (p

As the societal and economic burdens of Alzheimer's disease (AD) continue to mount, so does the need for therapies that slow the progression of the illness. Beta amyloid has long been recognized as the pathologic hallmark of AD, and the past decade has seen significant progress in the development of various immunotherapeutic approaches targeting beta amyloid. This paper reviews active and passive approaches aimed at beta amyloid, with a focus on clinical trial data.

Histone methylation regulates normal stem cell fate decisions through a coordinated interplay between histone methyltransferases and demethylases at lineage specific genes. Malignant transformation is associated with aberrant accumulation of repressive histone modifications, such as polycomb mediated histone 3 lysine 27 (H3K27me3) resulting in a histone methylation mediated block to differentiation. The relevance, however, of histone demethylases in cancer remains less clear. We report that JMJD3, a H3K27me3 demethylase, is induced during differentiation of glioblastoma stem cells (GSCs), where it promotes a differentiation-like phenotype via chromatin dependent (INK4A/ARF locus activation) and chromatin independent (nuclear p53 protein stabilization) mechanisms. Our findings indicate that deregulation of JMJD3 may contribute to gliomagenesis via inhibition of the p53 pathway resulting in a block to terminal differentiation.

The Partners HealthCare system′s Clinical Fellowship in Pathology Informatics (Boston, MA, USA) faces ongoing challenges to the delivery of its core curriculum in the forms of: (1) New classes of fellows annually with new and varying educational needs and increasingly fractured, enterprise-wide commitments; (2) taxing electronic health record (EHR) and laboratory information system (LIS) implementations; and (3) increasing interest in the subspecialty at the academic medical centers (AMCs) in what is a large health care network. In response to these challenges, the fellowship has modified its existing didactic sessions and piloted both a network-wide pathology informatics lecture series and regular "learning laboratories". Didactic sessions, which had previously included more formal discussions of the four divisions of the core curriculum: Information fundamentals, information systems, workflow and process, and governance and management, now focus on group discussions concerning the fellows′ ongoing projects, updates on the enterprise-wide EHR and LIS implementations, and directed questions about weekly readings. Lectures are given by the informatics faculty, guest informatics faculty, current and former fellows, and information systems members in the network, and are open to all professional members of the pathology departments at the AMCs. Learning laboratories consist of small-group exercises geared toward a variety of learning styles, and are driven by both the fellows and a member of the informatics faculty. The learning laboratories have created a forum for discussing real-time and real-world pathology informatics matters, and for incorporating awareness of and timely discussions about the latest pathology informatics literature. These changes have diversified the delivery of the fellowship′s core curriculum, increased exposure of faculty, fellows and trainees to one another, and more equitably distributed teaching responsibilities among the entirety of the pathology informatics asset in the network. Though the above approach has been in place less than a year, we are presenting it now as a technical note to allow for further discussion of evolving educational opportunities in pathology informatics and clinical informatics in general, and to highlight the importance of having a flexible fellowship with active participation from its fellows.

Background: Pathology informatics is both emerging as a distinct subspecialty and simultaneously becoming deeply integrated within the breadth of pathology practice. As specialists, pathology informaticians need a broad skill set, including aptitude with information fundamentals, information systems, workflow and process, and governance and management. Currently, many of those seeking training in pathology informatics additionally choose training in a second subspecialty. Combining pathology informatics training with molecular pathology is a natural extension, as molecular pathology is a subspecialty with high potential for application of modern biomedical informatics techniques. Methods and Results: Pathology informatics and molecular pathology fellows and faculty evaluated the current fellowship program′s core curriculum topics and subtopics for relevance to molecular pathology. By focusing on the overlap between the two disciplines, a structured curriculum consisting of didactics, operational rotations, and research projects was developed for those fellows interested in both pathology informatics and molecular pathology. Conclusions: The scope of molecular diagnostics is expanding dramatically as technology advances and our understanding of disease extends to the genetic level. Here, we highlight many of the informatics challenges facing molecular pathology today, and outline specific informatics principles necessary for the training of future molecular pathologists.

RNA is subject to a multitude of different chemical modifications that collectively represent the epitranscriptome. Individual RNA modifications including N6-methyladenosine (m 6 A) on mRNA play essential roles in the posttranscriptional control of gene expression. Recent technological advances have enabled the transcriptome-wide mapping of certain RNA modifications, to reveal their broad relevance and characteristic distribution patterns. However, convenient methods that enable the simultaneous mapping of multiple different RNA marks within the same sample are generally lacking. Here we present EpiPlex RNA modification profiling, a bead-based proximity barcoding assay with sequencing readout that expands the scope of molecular recognition-based RNA modification detection to multiple targets, while providing relative quantification and enabling low RNA input. Measuring signal intensity against spike-in controls provides relative quantification, indicative of the RNA mod abundance at each locus. We report on changes in the modification status of HEK293T cells upon treatment with pharmacological inhibitors separately targeting METTL3, the dominant m 6 A writer enzyme, and the EIF4A3 component of the exon junction complex (EJC). The treatments resulted in decreased or increased m 6 A levels, respectively, without effect on inosine levels. Inhibiting the helicase activity of EIF4A3 and EIF4A3 knockdown both cause a significant increase of m 6 A sites near exon junctions, consistent with the previously reported role of EIF4A3 in shaping the m 6 A landscape. Thus, EpiPlex offers a reliable and convenient method for simultaneous mapping of multiple RNA modifications to facilitate epitranscriptome studies.

N 6 -methyladenosine (m 6 A) is the most abundant chemical modification in mRNA and plays important roles in human and mouse embryonic stem cell pluripotency, maintenance, and differentiation. We have recently reported that m 6 A is involved in the postnatal control of β-cell function in physiological states and in type 1 and 2 diabetes. However, the precise mechanisms by which m 6 A acts to regulate the development of human and mouse pancreas are unexplored. Here, we show that the m 6 A landscape is dynamic during human pancreas development, and that METTL14, one of the m 6 A writer complex proteins, is essential for the early differentiation of both human and mouse pancreatic cells., (© 2024. The Author(s).)

The epitranscriptome includes a diversity of RNA modifications that influence gene expression. N3-methylcytidine (m 3 C) mainly occurs in the anticodon loop (position C32) of certain tRNAs yet its role is poorly understood. Here, using HAC-Seq, we report comprehensive METTL2A/2B-, METTL6-, and METTL2A/2B/6-dependent m 3 C profiles in human cells. METTL2A/2B modifies tRNA-arginine and tRNA-threonine members, whereas METTL6 modifies the tRNA-serine family. However, decreased m 3 C32 on tRNA-Ser-GCT isodecoders is only observed with combined METTL2A/2B/6 deletion. Ribo-Seq reveals altered translation of genes related to cell cycle and DNA repair pathways in METTL2A/2B/6-deficient cells, and these mRNAs are enriched in AGU codons that require tRNA-Ser-GCT for translation. These results, supported by reporter assays, help explain the observed altered cell cycle, slowed proliferation, and increased cisplatin sensitivity phenotypes of METTL2A/2B/6-deficient cells. Thus, we define METTL2A/2B/6-dependent methylomes and uncover a particular requirement of m 3 C32 tRNA modification for serine codon-biased mRNA translation of cell cycle, and DNA repair genes., (© 2024. The Author(s).)

Upstream open reading frames (uORFs) are typically defined as translation sites located within the 5' untranslated region upstream of the main protein coding sequence (CDS) of messenger RNAs (mRNAs). Although uORFs are prevalent in eukaryotic mRNAs and modulate the translation of downstream CDSs, a comprehensive resource for uORFs is currently lacking. We developed Ribo-uORF (http://rnainformatics.org.cn/RiboUORF) to serve as a comprehensive functional resource for uORF analysis based on ribosome profiling (Ribo-seq) data. Ribo-uORF currently supports six species: human, mouse, rat, zebrafish, fruit fly, and worm. Ribo-uORF includes 501 554 actively translated uORFs and 107 914 upstream translation initiation sites (uTIS), which were identified from 1495 Ribo-seq and 77 quantitative translation initiation sequencing (QTI-seq) datasets, respectively. We also developed mRNAbrowse to visualize items such as uORFs, cis-regulatory elements, genetic variations, eQTLs, GWAS-based associations, RNA modifications, and RNA editing. Ribo-uORF provides a very intuitive web interface for conveniently browsing, searching, and visualizing uORF data. Finally, uORFscan and UTR5var were developed in Ribo-uORF to precisely identify uORFs and analyze the influence of genetic mutations on uORFs using user-uploaded datasets. Ribo-uORF should greatly facilitate studies of uORFs and their roles in mRNA translation and posttranscriptional control of gene expression., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Chemical modifications of RNA have key roles in many biological processes 1-3 . N 7 -methylguanosine (m 7 G) is required for integrity and stability of a large subset of tRNAs 4-7 . The methyltransferase 1-WD repeat-containing protein 4 (METTL1-WDR4) complex is the methyltransferase that modifies G46 in the variable loop of certain tRNAs, and its dysregulation drives tumorigenesis in numerous cancer types 8-14 . Mutations in WDR4 cause human developmental phenotypes including microcephaly 15-17 . How METTL1-WDR4 modifies tRNA substrates and is regulated remains elusive 18 . Here we show,  through structural, biochemical and cellular studies of human METTL1-WDR4, that WDR4 serves as a scaffold for METTL1 and the tRNA T-arm. Upon tRNA binding, the αC region of METTL1 transforms into a helix, which together with the α6 helix secures both ends of the tRNA variable loop. Unexpectedly, we find that the predicted disordered N-terminal region of METTL1 is part of the catalytic pocket and essential for methyltransferase activity. Furthermore, we reveal that S27 phosphorylation in the METTL1 N-terminal region inhibits methyltransferase activity by locally disrupting the catalytic centre. Our results provide a molecular understanding of tRNA substrate recognition and phosphorylation-mediated regulation of METTL1-WDR4, and reveal the presumed disordered N-terminal region of METTL1 as a nexus of methyltransferase activity., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

N6-methyladenosine (m 6 A), the most abundant modification of mRNA, is essential for normal development and dysregulation promotes cancer. m 6 A is highly enriched in the 3' untranslated region (UTR) of a large subset of mRNAs to influence mRNA stability and/or translation. However, the mechanism responsible for the observed m 6 A distribution remains enigmatic. Here we find the exon junction complex shapes the m 6 A landscape by blocking METTL3-mediated m 6 A modification close to exon junctions within coding sequence (CDS). Depletion of EIF4A3, a core component of the EJC, causes increased METTL3 binding and m 6 A modification of short internal exons, and sites close to exon-exon junctions within mRNA. Reporter gene experiments further support the role of splicing and EIF4A3 deposition in controlling m 6 A modification via the local steric blockade of METTL3. Our results explain how characteristic patterns of m 6 A mRNA modification are established and uncover a role of the EJC in shaping the m 6 A epitranscriptome., (© 2022. The Author(s).)

tRNAs are key adaptor molecules that decipher the genetic code during translation of mRNAs in protein synthesis. In contrast to the traditional view of tRNAs as ubiquitously expressed housekeeping molecules, awareness is now growing that tRNA-encoding genes display tissue-specific and cell type-specific patterns of expression, and that tRNA gene expression and function are both dynamically regulated by post-transcriptional RNA modifications. Moreover, dysregulation of tRNAs, mediated by alterations in either their abundance or function, can have deleterious consequences that contribute to several distinct human diseases, including neurological disorders and cancer. Accumulating evidence shows that reprogramming of mRNA translation through altered tRNA activity can drive pathological processes in a codon-dependent manner. This Review considers the emerging evidence in support of the precise control of functional tRNA levels as an important regulatory mechanism that coordinates mRNA translation and protein expression in physiological cell homeostasis, and highlights key examples of human diseases that are linked directly to tRNA dysregulation., (© 2022. Springer Nature Limited.)

High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we showed that LIN28B expression was associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7-independent enrichment of transcripts encoding components of the translational and ribosomal apparatus and depletion of transcripts of neuronal developmental programs. We further observed that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrated that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a posttranscriptional driver of the metastatic phenotype.

Background: Adenosine deaminases acting on RNA (ADARs) modify many cellular RNAs by catalyzing the conversion of adenosine to inosine (A-to-I), and their deregulation is associated with several cancers. We recently showed that A-to-I editing is elevated in thyroid tumors and that ADAR1 is functionally important for thyroid cancer cell progression. The downstream effectors regulated or edited by ADAR1 and the significance of ADAR1 deregulation in thyroid cancer remain, however, poorly defined., Methods: We performed whole transcriptome sequencing to determine the consequences of ADAR1 deregulation for global gene expression, RNA splicing and editing. The effects of gene silencing or RNA editing were investigated by analyzing cell viability, proliferation, invasion and subnuclear localization, and by protein and gene expression analysis., Results: We report an oncogenic function for CDK13 in thyroid cancer and identify a new ADAR1-dependent RNA editing event that occurs in the coding region of its transcript. CDK13 was significantly over-edited (c.308A > G) in tumor samples and functional analysis revealed that this editing event promoted cancer cell hallmarks. Finally, we show that CDK13 editing increases the nucleolar abundance of the protein, and that this event might explain, at least partly, the global change in splicing produced by ADAR1 deregulation., Conclusions: Overall, our data support A-to-I editing as an important pathway in cancer progression and highlight novel mechanisms that might be used therapeutically in thyroid and other cancers., (© 2021. The Author(s).)

The emerging "epitranscriptomics" field is providing insights into the biological and pathological roles of different RNA modifications. The RNA methyltransferase METTL1 catalyzes N7-methylguanosine (m 7 G) modification of tRNAs. Here we find METTL1 is frequently amplified and overexpressed in cancers and is associated with poor patient survival. METTL1 depletion causes decreased abundance of m 7 G-modified tRNAs and altered cell cycle and inhibits oncogenicity. Conversely, METTL1 overexpression induces oncogenic cell transformation and cancer. Mechanistically, we find increased abundance of m 7 G-modified tRNAs, in particular Arg-TCT-4-1, and increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon. Accordingly, Arg-TCT expression is elevated in many tumor types and is associated with patient survival, and strikingly, overexpression of this individual tRNA induces oncogenic transformation. Thus, METTL1-mediated tRNA modification drives oncogenic transformation through a remodeling of the mRNA "translatome" to increase expression of growth-promoting proteins and represents a promising anti-cancer target., Competing Interests: Declaration of interests R.I.G. and F.J.S. are co-founders and scientific advisory board members of 28-7 Therapeutics. R.I.G. is a co-founder and scientific advisory board member of Theon Therapeutics. E.Y. is co-funded by STORM Therapeutics., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The most prevalent post-transcriptional mRNA modification, N 6 -methyladenosine (m 6 A), plays diverse RNA-regulatory roles, but its genetic control in human tissues remains uncharted. Here we report 129 transcriptome-wide m 6 A profiles, covering 91 individuals and 4 tissues (brain, lung, muscle and heart) from GTEx/eGTEx. We integrate these with interindividual genetic and expression variation, revealing 8,843 tissue-specific and 469 tissue-shared m 6 A quantitative trait loci (QTLs), which are modestly enriched in, but mostly orthogonal to, expression QTLs. We integrate m 6 A QTLs with disease genetics, identifying 184 GWAS-colocalized m 6 A QTL, including brain m 6 A QTLs underlying neuroticism, depression, schizophrenia and anxiety; lung m 6 A QTLs underlying expiratory flow and asthma; and muscle/heart m 6 A QTLs underlying coronary artery disease. Last, we predict novel m 6 A regulators that show preferential binding in m 6 A QTLs, protein interactions with known m 6 A regulators and expression correlation with the m 6 A levels of their targets. Our results provide important insights and resources for understanding both cis and trans regulation of epitranscriptomic modifications, their interindividual variation and their roles in human disease., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

MicroRNAs (miRNAs) have essential functions during embryonic development, and their dysregulation causes cancer 1,2 . Altered global miRNA abundance is found in different tissues and tumours, which implies that precise control of miRNA dosage is important 1,3,4 , but the underlying mechanism(s) of this control remain unknown. The protein complex Microprocessor, which comprises one DROSHA and two DGCR8 proteins, is essential for miRNA biogenesis 5-7 . Here we identify a developmentally regulated miRNA dosage control mechanism that involves alternative transcription initiation (ATI) of DGCR8. ATI occurs downstream of a stem-loop in DGCR8 mRNA to bypass an autoregulatory feedback loop during mouse embryonic stem (mES) cell differentiation. Deletion of the stem-loop causes imbalanced DGCR8:DROSHA protein stoichiometry that drives irreversible Microprocessor aggregation, reduced primary miRNA processing, decreased mature miRNA abundance, and widespread de-repression of lipid metabolic mRNA targets. Although global miRNA dosage control is not essential for mES cells to exit from pluripotency, its dysregulation alters lipid metabolic pathways and interferes with embryonic development by disrupting germ layer specification in vitro and in vivo. This miRNA dosage control mechanism is conserved in humans. Our results identify a promoter switch that balances Microprocessor autoregulation and aggregation to precisely control global miRNA dosage and govern stem cell fate decisions during early embryonic development.

Cellular RNAs are subject to a myriad of different chemical modifications that play important roles in controlling RNA expression and function. Dysregulation of certain RNA modifications, the so-called 'epitranscriptome', contributes to human disease. One limitation in studying the functional, physiological, and pathological roles of the epitranscriptome is the availability of methods for the precise mapping of individual RNA modifications throughout the transcriptome. 3-Methylcytidine (m3C) modification of certain tRNAs is well established and was also recently detected in mRNA. However, methods for the specific mapping of m3C throughout the transcriptome are lacking. Here, we developed a m3C-specific technique, Hydrazine-Aniline Cleavage sequencing (HAC-seq), to profile the m3C methylome at single-nucleotide resolution. We applied HAC-seq to analyze ribosomal RNA (rRNA)-depleted total RNAs in human cells. We found that tRNAs are the predominant m3C-modified RNA species, with 17 m3C modification sites on 11 cytoplasmic and 2 mitochondrial tRNA isoacceptors in MCF7 cells. We found no evidence for m3C-modification of mRNA or other non-coding RNAs at comparable levels to tRNAs in these cells. HAC-seq provides a novel method for the unbiased, transcriptome-wide identification of m3C RNA modification at single-nucleotide resolution, and could be widely applied to reveal the m3C methylome in different cells and tissues., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)