Search

This review summarizes the framework behind global guidelines of coronary artery calcium (CAC) in atherosclerotic cardiovascular disease risk assessment, for applications in both the clinical setting and preventive therapy. By comparing similarities and differences in recommendations, this review identifies most notable common features for the application of CAC presented by different cardiovascular societies across the world. Guidelines included from North America are as follows: 1) the 2019 American College of Cardiology/American Heart Association Guideline on the Primary Prevention of Cardiovascular Disease; and 2) the 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for Prevention of Adult Cardiovascular Disease. The authors also included European guidelines: 1) the 2019 European Society for Cardiology/European Atherosclerosis Society Guidelines for the Management of Dyslipidemias; and 2) the 2016 National Institute for Health and Care Excellence Clinical Guidelines. In this comparison, the authors also discuss: 1) the Cardiac Society of Australia and New Zealand Guidelines on CAC; 2) the Chinese Society of Cardiology Guidelines; and 3) the Japanese Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases. Last, they include statements made by specialty societies including the National Lipid Association, Society of Cardiovascular Computed Tomography, and U.S. Preventive Services Task Force. Utilizing an in-depth review of clinical evidence, these guidelines emphasize the importance of CAC in the primary and secondary prevention of atherosclerotic cardiovascular disease. International guidelines all empower a dynamic clinician-patient relationship and advocate for individualized discussions regarding disease management and pharmacotherapy treatment. Some differences in precise coronary artery calcium score intervals, risk cut points, treatment thresholds, and stratifiers of specific patient subgroups do exist. However, international guidelines employ more similarities than differences from both a clinical and functional perspective. Understanding the parallels among international coronary artery calcium guidelines is essential for clinicians to correctly adjudicate personalized statin and aspirin therapy and further medical management.

Low-grade Oncocytic Tumor (LOT) of the kidney is a recently described entity with poorly understood pathogenesis. Using next-generation sequencing (NGS) and complementary approaches, we provide insight into its biology. We describe 22 LOT corresponding to 7 patients presenting with a median age of 75 years (range 63–86 years) and male to female ratio 2:5. All 22 tumors demonstrated prototypical microscopic features. Tumors were well circumscribed and solid. They were composed of sheets of tumor cells in compact nests. Tumor cells had eosinophilic cytoplasm, round to oval nuclei (without nuclear membrane irregularities), focal subtle perinuclear halos and occasional binucleation. Sharply delineated edematous stromal islands were often observed. Tumor cells were positive for PAX8, negative for CD117 and exhibited diffuse and strong cytokeratin-7 expression. Six patients presented with pT1 tumors and at a median follow-up of 29 months, 4 patients were alive without recurrence (3 patients had died from unrelated causes). All tumors were originally classified as chromophobe renal cell carcinoma, eosinophilic variant (chRCC-eo). While none of the patients presented with known syndromic features, one patient with multiple bilateral LOTs was subsequently found to have a likely pathogenic germline TSC1 mutation. Somatic, likely activating, mutations in MTOR and RHEB were identified in all other evaluable LOTs. As assessed by phospho-S6 and phospho-4E-BP1, mTOR complex 1 (mTORC1) was activated across all cases but to different extent. MTOR mutant LOT typically exhibited lower levels of mTORC1 activation, possibly related to mTORC1 dimerization and the preservation of a wild-type MTOR copy (retained chromosome 1). Supporting its distinction from related entities, gene expression analyses showed that LOT clustered separately from classic chRCC, chRCC-eo and RO. In summary, converging mTORC1 pathway mutations, mTORC1 complex activation and a distinctive gene expression signature along with characteristic phenotypic features support LOT designation as a distinct entity with both syndromic and non-syndromic cases associated with an indolent course.

In this study, the supersonic flow over strut cavities was experimentally studied to understand flow features. Instantaneous schlieren imaging in non-reacting flow experiments exhibited the seven types of waves associated with cavity pressure oscillations and the formation of unstable shear layers on both sides. The shear layers moved in and out in synchronous and asynchronous modes at the trailing edge of the strut cavities. The symmetrical wave structure appeared on both sides in the synchronous mode, whereas the shear layers appeared in different stages of the cavity pressure oscillation cycle in the asynchronous mode, resulting in an asymmetrical wave structure. The pressure waves generated at the trailing edge of the strut cavities perturbed the shear layers during their movement toward the leading edge, creating a wavy shear layer with alternate troughs and crests. The pressure oscillations of the strut cavities had high-amplitude cavity modes with broadband noises, and their amplitude decreased from the trailing edge to the leading edge. The estimated recovery factor using the time lag between the signals of the leading and trailing edges showed that the flow inside the strut cavities was low subsonic. The measured dominant pressure oscillation modes had a closer match with the Rossiter modes. The pressure coefficient demonstrated that fluid accumulation inside the cavity increased with an increase in the aspect ratio. Furthermore, a higher fluid mass accumulated at the trailing edge than at the leading edge, and the difference in fluid accumulation increased with an increase in the aspect ratio. Supersonic combustion experiments with strut cavities showed that the strut cavity stabilized the flame. Moreover, the addition of an acoustically open strut cavity ahead of the flame-stabilizing cavity advanced the heat release location upstream.

In the present article, a new adsorbent synthesized from Salvadora persica (miswak) powder with chemical activation has been applied to remove Acid Violet 17 dye from aqueous solution. Characterization of the synthesized adsorbent was carried out using the techniques of FTIR, SEM, BET, zeta potential and DLS. The effect of pH, adsorbent dose, contact time, initial dye concentration and temperature were assessed in batch operation. Maximum removal was favored at pH of 2, adsorbent dose of 2 g/L and temperature as 333 K. Chemical activation has increased surface area of raw adsorbent from 58.38 to 124.99 m2/g. Nonlinear regression has been applied for the model fitting of the experimental data. Kinetic data was well described by pseudo-second-order model. Weber-Morris model established involvement of multiple steps in governing the adsorption mechanism. Isotherm data was well described by Freundlich model. Root mean square error analysis was also applied to check the best model fitting. Maximum adsorption capacity values were obtained as 74.28 and 141.30 mg/g for raw adsorbent and activated adsorbent, respectively. Thermodynamic calculations established endothermic and feasible nature of the adsorption. The obtained removal of 97.24 ± 0.69% for simulated solution reduced to 91.17 ± 0.86% in case of real effluent containing 100 mg/L of dye solution as attributed to other compounds present in the actual industrial effluent which can compete on adsorption sites along with the targeted dye. Reusability study performed using ethanol as an eluent confirmed suitability of synthesized adsorbent for dye removal from wastewater. The obtained maximum adsorption capacity along with good reusability results depicted that activated Salvadora persica could be used as an efficient adsorbent for sequestration of Acid Violet 17 from the aqueous phase.

While population studies have demonstrated that high density lipoprotein cholesterol (HDL-C) and the ratio of total cholesterol to HDL (TC/HDL) improve cardiovascular risk prediction, the mechanism by which these parameters protect the cardiovascular system remains uncertain.To investigate the relationship between the HDL-C level and the total cholesterol to HDL (TC/HDL) ratio with the morphology of coronary artery plaque as determined by coronary computed tomography angiography (CCTA).This is a cross-sectional study involving 190 subjects with stable coronary artery disease. Semi-automated plaque analysis software was utilized to quantify plaque and plaque volumes are presented as total atheroma volume normalized (TAVOf the 190 subjects the average (SD) age was 58.9 (9.8) years, with 63% being male. After adjustment for cardiovascular risk factors, HDL- C (40 mg/dl) is inversely associated with fibrous (p = 0.003), fibrous fatty (p = 0.007), low attenuation plaque (LAP) (p = 0.007), total non-calcified plaque (TNCP) (p = 0.002) and total plaque (TP)(p = 0.004) volume. Furthermore, the TC/HDL ratio (4.0) is associated with fibrous (p = 0.047) and total non-calcified plaque (p = 0.039), but not with fibrofatty, LAP, dense calcified plaque, or TP volume.There is a strong association between low HDL-C levels and increasing TC/HDL ratio with certain types of coronary plaque characteristics, independent of traditional risk factors. The findings of this study suggest mechanistic evidence supporting the protective role of HDL-C and the TC/HDL ratio's clinical relevance in coronary artery disease management.

A large body of work has revealed fundamental principles of HIV integration into the human genome, but the effect of the integration site to viral transcription has so far remained elusive. Here, we generate and combine large-scale datasets including epigenetics, transcriptome, and 3D genome architecture to interrogate the chromatin states, transcription activity, and nuclear sub-compartments around HIV integrations in CD4+ T cells to decipher human genome codes shaping HIV expression. Using Hidden Markov and Machine-learning Logistic Regression Models, we defined nuclear sub-compartments and chromatin states contributing to genomic architecture, transcriptional activity, and nucleosome density of regions neighboring the integration site, as additive features influencing HIV expression. Surprisingly, no single feature nor combination of features accurately predicted HIV expression likely reflecting the underlying heterogeneity of HIV placement. While human genes are “precisely” positioned for accurate transcriptional responses, HIV “random” positions dictate the heterogeneous responses as a consequence of the diversity of regulatory features surrounding integration sites.

Gas in thermally mature shale reservoirs is considered to exist as adsorbed volume in organic matter and free gas within pores and voids in natural fractures. Gas in-place is derived from summation of aforementioned volumes. Although industry has adopted laboratory-based adsorption isotherms, quantification is still uncertain and questions on recoverability still linger. This study reevaluated in-place adsorbed gas and post-stimulation recovery. Two proprietary laboratories, using small and large mesh sizes, generated different adsorption isotherms for comparable samples of a Middle East source rock. In addition, review of published experimental studies led to the realization that confining pressures as those in situ were seldomy replicated and derived isotherms exhibited wide variability. A hypothetical scenario, using benchmarked adsorption isotherms illustrated impacts of unreliable adsorbed volume quantification on total gas in-place. From analysis of well production for three shales, matrix transient linear flow persisted for extended periods without indicating influence of boundaries. The flow regime is often matched by considering only free gas porosity. Using a sector model with 1.0 nanodarcy (nD) system permeability in reservoir simulation, a considerable proportion of the adopted grid remained above a benchmarked average critical desorption pressure after long-term post-stimulation drainage. Thus, desorption could be of limited significance in shale production if the flow model was appropriate. This study illustrated uncertainties in traditional concepts for shale gas storage and recovery. Realistic quantification of in-place adsorbed gas was found to require tailoring of laboratory protocols to account for crushed sample sizes and confinement that should match subsurface conditions such as effective vertical stress.

Deconvolution of regulatory mechanisms that drive transcriptional programs in cancer cells is key to understanding tumor biology. Herein, we present matched transcriptome (scRNA-seq) and chromatin accessibility (scATAC-seq) profiles at single-cell resolution from human ovarian and endometrial tumors processed immediately following surgical resection. This dataset reveals the complex cellular heterogeneity of these tumors and enabled us to quantitatively link variation in chromatin accessibility to gene expression. We show that malignant cells acquire previously unannotated regulatory elements to drive hallmark cancer pathways. Moreover, malignant cells from within the same patients show substantial variation in chromatin accessibility linked to transcriptional output, highlighting the importance of intratumoral heterogeneity. Finally, we infer the malignant cell type-specific activity of transcription factors. By defining the regulatory logic of cancer cells, this work reveals an important reliance on oncogenic regulatory elements and highlights the ability of matched scRNA-seq/scATAC-seq to uncover clinically relevant mechanisms of tumorigenesis in gynecologic cancers.

The pluripotency of embryonic stem cells (ESCs) relies on appropriate responsiveness to developmental cues. Promoter-proximal pausing of RNA polymerase II (Pol II) has been suggested to play a role in keeping genes poised for future activation. To identify the role of Pol II pausing in regulating ESC pluripotency, we have generated mouse ESCs carrying a mutation in the pause-inducing factor SPT5. Genomic studies reveal genome-wide reduction of paused Pol II caused by mutant SPT5 and further identify a tight correlation between pausing-mediated transcription effect and local chromatin environment. Functionally, this pausing-deficient SPT5 disrupts ESC differentiation upon removal of self-renewal signals. Thus, our study uncovers an important role of Pol II pausing in regulating ESC differentiation and suggests a model that Pol II pausing coordinates with epigenetic modification to influence transcription during mESC differentiation.

Background and Aim: This retrospective cohort study examined the effects of yoga-treatment in rural Indian settings in achieving composite treatment goals set forth by the American Diabetes Association (ADA) for Type 2 Diabetes. Research Design and Methods: The study was a multicentre retrospective study. Records of 146 type 2 diabetes patients who received treatment under the "Apollo Total Health Programme" for rural diabetes management between November 2016 to April 2017 were extracted. Treatment based two equal groups (n=73 each) were assigned; non-yoga group with only usual care and experiment group with yoga as an adjunct treatment to the usual care. Comparative efficacy of 6 months of adjunct yoga treatment vs. usual care was evaluated against attainment of defined composite scores. Findings: Compared to usual care, 6 months adjunct yoga treatment was found to significantly facilitate the attainment of composite score by ~12-fold (OR=12.07, 95% CI= 0.89-163.76), individual treatment goals; A1c

Summary Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms., Graphical Abstract, Highlights • In vivo screen identifies drivers of antiandrogen resistance in prostate cancer • CHD1 loss establishes a state of chromatin dysregulation and lineage plasticity • Heterogeneous mechanisms were enabled to escape from luminal lineage and therapy • Patients with reduced tumor CHD1 levels have a shorter response to antiandrogen, Performing an in vivo shRNA screen, Zhang et al. identify that CHD1 loss confers antiandrogen resistance. Low CHD1 levels correlate with shorter clinical responses to enzalutamide. CHD1 loss induces global chromatin changes, increasing expression of transcription factors that contribute to antiandrogen resistance.

PARP inhibitors (PARPi) prevent cancer cell growth by inducing synthetic lethality with DNA repair defects (e.g., in BRCA1/2 mutant cells). We have identified an alternative pathway for PARPi-mediated growth control in BRCA1/2-intact breast cancer cells involving rDNA transcription and ribosome biogenesis. PARP-1 binds to snoRNAs, which stimulate PARP-1 catalytic activity in the nucleolus independent of DNA damage. Activated PARP-1 ADP-ribosylates DDX21, an RNA helicase that localizes to nucleoli and promotes rDNA transcription when ADP-ribosylated. Treatment with PARPi or mutation of the ADP-ribosylation sites reduces DDX21 nucleolar localization, rDNA transcription, ribosome biogenesis, protein translation, and cell growth. The salient features of this pathway are evident in xenografts in mice and human breast cancer patient samples. Elevated levels of PARP-1 and nucleolar DDX21 are associated with cancer-related outcomes. Our studies provide a mechanistic rationale for efficacy of PARPi in cancer cells lacking defects in DNA repair whose growth is inhibited by PARPi.