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The article presents the discussion on seeking medical care. Topics include experiencing outstanding support or relief from the feelings and getting a graphic and detailed recollection of an event from the personal health memory bank; and leaning toward impressions from a scary radiology scan, painful lab draws and even shadowy images of routine childhood vaccinations and visits.

Background recognition of the multifactorial causes of delirium represents a clinical challenge. Objectives to develop and show proof of principle of a diagnostic support tool (DST) for identification of causes of delirium. Methods stage 1—development of the aetiology in delirium-diagnostic support tool (AiD-DST); stage 2—validation of the AiD-DST against reference standard diagnosis, based on clinical assessment from two independent consultant geriatricians. Results a series of eight steps AiD-DST were formulated by an expert group to identify possible causes of delirium. Forty inpatients admitted to a general medical unit with a consultant physician/geriatrician diagnosis of delirium were recruited, consented and reviewed against the AiD-DST. Mean age was 85.1 (standard deviation 7.9) years and 26 (65%) of participants were female. Participants had multiple chronic co-morbidities [median Charlson Comorbidity Index 7; interquartile range (IQR 6–9)] and median number of medications was 8 (IQR 6–11.75). Median number of causes of delirium detected on AiD-DST was 3 (IQR 3–4) versus 5 (IQR 3–6) using the reference standard diagnosis, with sensitivity of 88.8% (95% confidence interval, 81.6–93.9%) and specificity of 71.8% (63–79.5%). Conclusions the aetiology in delirium DST shows promise in the identification of cause(s) in delirium. [ABSTRACT FROM AUTHOR]

The article discusses that the Coronavirus disease 2019 (COVID-19) is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged out of Wuhan, China in late 2019. It mentions that the Public health efforts are oriented toward mitigation and limiting the rate of spread to prevent overextension of available health care resources such as ventilators by recommending wearing a mask, washing hands often, and practicing social distancing.

Case Presentation: A 54-year-old man presented with a 6-month history of progressive dyspnea occurring at rest and with minimal exertion. His medical history was notable for hypertension, non-insulin-dependent diabetes, coronary artery disease, and factor V Leiden heterozygosity. His social history was notable for a 43-pack-year smoking history but was otherwise unremarkable. [ABSTRACT FROM AUTHOR]

Opioid drug overdose is currently the leading cause of death in the United States. An estimated 91 Americans die from opioid overdoses every day. Opioids are a class of drugs that interact with opioid receptors in the body and brain; they are often used to treat pain. This webliography examines the three classes of opioids – prescription opioids, synthetic opioids like fentanyl, and heroin; reasons for the increased usage of opioids; and resources available to the public. The resources include ways to keep current on opioid-related legislation such as Good Samaritan Laws, information on medical guidelines and community support or treatment, and literature to halt the opioid epidemic. [ABSTRACT FROM PUBLISHER]

The current research examined how people form context-based trait impressions and why some of these impressions are stronger than others. This research drew from principles of attention theory (Kruschke, 1996, 2001) in order to account for the processes underlying impression formation in context. According to attention theory, the traits expressed by an individual target person in a rarely occurring context should be more strongly associated with that context than the traits expressed in a commonly occurring context are associated with the common context. That is, people form stronger impressions of others' behavior in rare compared to common contexts. Four experiments provide support for these predictions. The current study is one of the first to examine the cognitive mechanisms by which perceivers form trait impressions of individuals across different contexts and to explain why some of these impressions are stronger than others. Implications of the nature of these impression formation processes are discussed. [ABSTRACT FROM AUTHOR]

Early detection of cervical cancer is critical for a favorable prognosis. Standard cytological detection methods, such as Pap smear, are highly subjective and HPV detection is not a reliable marker for predicting the malignancy potential of cervical lesions. As a result, there is a demand for a diagnostic assay capable of sensitive and specific detection of cervical cancer. In this preclinical exploratory study, qRT-PCR and western blotting were used to assess expression levels of CIP2A and p16^{INK4a} in cervical tissue samples (n_{normal adjacent} = 23, n_{tumor} = 29). CIP2A was abundantly expressed in cervical cancer cell lines and was not expressed in normal epithelial cells. CIP2A mRNA levels were higher in cervical tumor tissues in comparison to the level of CIP2A mRNA in normal adjacent tissue from cervical cancer patients. CIP2A protein was specifically expressed in cervical tumor tissues at different cancer grades and stages, and was not observed in normal adjacent tissue. Elevated CIP2A mRNA levels in cervical tissues had a sensitivity of 80% and specificity of 91% and CIP2A protein expression detection had a sensitivity of 83% and specificity of 100%, similar to that of p16^{INK4a}, with no correlation of CIP2A expression with HPV infection, age, race, or other patient characteristics. However the number of samples analyzed in this preliminary study is limited and a large prospective cohort study is necessary to further evaluate CIP2A as a biomarker for cervical cancer. [ABSTRACT FROM AUTHOR]

In nanotechnology, biomolecular assemblies serve not only as model systems for the construction of nanodevices, but they can also be used directly as templates for the formation of nanostructures. Biological nano-building blocks can either be isolated as complete functional units from living cells or viruses (biological “Top down” approach) or formed by biomolecular assembly from recombinant or synthetic components (“Bottom up” approach). In both cases, rational design of nanostructures requires knowledge of the stoichiometry of the biological structures, which frequently occur as multimers, i.e., the morphological complex is composed of multiple copies of one or more macromolecules. In this paper, a method is described for the stoichiometric quantification of molecules in bio-nanostructures. The method is based on using dilution factors and relative concentrations rather than absolute quantities, which are often difficult to determine, especially in short-lived assembly intermediates. The approach exploits the fact that the larger the stoichiometry of the component is, the more dramatic is the influence of the dilution factor (decrease in concentration) on the reaction. We established and used the method to determine the stoichiometry of components of bacterial virus phi29. The log of dilution factors was plotted against the log of reaction yield. The stoichiometry Z was determined with the equation Z=−1.58+2.4193T−0.001746T2 [T ∈ (0,1000), or ∠α ∈ (0°, 89.9°)], where T is the slope of the curve (tangent of ∠α, which is the angle between the x-axis and the concentration dependent curve). Z can also be determined from a standard table given in this report. With the bacteriophage phi29 in vitro assembly system, up to 5×108 infectious virions per ml can be assembled from 11 purified components, giving our method a sensitivity of nine orders of magnitude. We confirmed the stoichiometries of phi29 components that were determined previously with microscopic approaches. The described method also responded to programmed stoichiometry changes, which were generated by assembling the phi29 DNA packaging motor from modified pRNA (DNA-packaging RNA) molecules forming a trimer of dimers or a dimer of trimers, instead of the wild-type hexamer. [Copyright &y& Elsevier]

All the well-defined DNA-packaging motors of the dsDNA viruses contain one pair of nonstructural DNA-packaging enzymes. Studies on the mechanism of virus DNA packaging have been seriously hampered by their insolubility. Phi29’s DNA-packaging enzyme, gp16, is also hydrophobic, insoluble, and self-aggregating. This article describes approaches to obtain affinity-purified, soluble, and highly active native gp16 with the aid of polyethylene glycol or acetone. The specific activity of this native gp16 was increased 3400-fold when compared with the traditional method. This unique approach made the ATP–gp16 interaction study feasible. Gp16 binds strongly to ATP, binds to ADP with a lower efficiency, and binds very weakly to AMP. The order of gp16-binding efficiency to the four ribonucleotides is, from high to low, ATP, GTP, CTP, and UTP. The ATP concentration level required to produce 50% of maximum virus yield exhibited during in vitro phi29 assembly is around 45 μM, which is close to the gp16 and ATP dissociation constant of 65 μM. Mutation studies revealed that changing only one conserved amino acid, whether R17, G24, G27, G29, K30, or I39, in the predicted Walker-A ATP motif of gp16 caused ATP hydrolysis and viral assembly to cease, while such mutation did not affect gp16’s binding to ATP. However, mutation on amino acids G248 and D256 did not affect the function of gp16 in DNA packaging. [Copyright &y& Elsevier]

All linear dsDNA viruses package their genome into a preformed procapsid via a ATP-driving motor involving two nonstructural enzymes or ATPase. This essential viral replication step has been investigated in the quest for new antiviral drugs. These DNA-packaging motors could be potential parts in nanotechnology. But both the low solubility and self-aggregation of all nonstructural enzymes have seriously hampered studies on these motors. Bacterial virus phi29 DNA-packaging motor has been well characterized. But the role of the nonstructural ATPase gp16 has not been well defined due to its hydrophobicity, low solubility, and self-aggregation. Here we report a novel approach to obtain affinity-purified, soluble, and highly active native gp16 with the aid of polyethylene glycol (PEG) or acetone. With several thousand-fold increase in specific activity in comparison to the traditional method, this unique approach has made the quantification of gp16 feasible. The basic functional unit of gp16 in solution was found to be a monomer, as determined by sedimentation and size exclusion chromatography. This result leads to a subsequent finding that the stoichiometry of gp16 for phi29 DNA-packaging was about 11±2. These findings will facilitate the study on this novel motor that involves three pRNA dimers and a 12-subunit connector. [Copyright &y& Elsevier]

To investigate the DNA binding activity of the JC virus minor capsid protein, VP2, both wild-type and mutant VP2 were cloned and expressed in Escherichia coli. Southwestern blotting was employed for the DNA-binding assay. The results showed that VP2 was able to bind to DNA, except when either the last 13 or the last 29 amino acids were truncated. The results indicate that the DNA-binding domain of VP2 is located within the last 13 amino acids. Furthermore, we also demonstrated that Lys 332 and Lys 336 within the DNA-binding domain are crucial for DNA binding. The findings may provide further information for understanding the mechanism of virion assembly of the JC virus. [ABSTRACT FROM AUTHOR]

The number of known proteases is increasing at a tremendous rate as a consequence of genome sequencing projects. Although one can guess at the functions of these novel enzymes by considering sequence homology to known proteases, there is a need for new tools to rapidly provide functional information on large numbers of proteins. We describe a method for determining the cleavage site specificity of proteolytic enzymes that involves pooled sequencing of peptide library mixtures. The method was used to determine cleavage site motifs for six enzymes in the matrix metalloprotease (MMP) family. The results were validated by comparison with previous literature and by analyzing the cleavage of individually synthesized peptide substrates. The library data led us to identify the proteoglycan neurocan as a novel MMP-2 substrate. Our results indicate that a small set of libraries can be used to quickly profile an expanding protease family, providing information applicable to the design of inhibitors and to the identification of protein substrates. [ABSTRACT FROM AUTHOR]

Introduction:Almost half of veterans (44.6%) seen in the U.S. Department of Veterans Affairs outpatient setting are diagnosed with hypertension (HTN). Because of the widespread nature of HTN, use of virtual visits has the potential to improve blood pressure (BP) management. This evaluation assessed the effectiveness of video blood pressure visits (VBPVs) in the management of HTN in veterans enrolled in Veterans Health Administration primary care. Methods:The program was implemented within the existing veteran-centered medical home. VBPVs are scheduled where the nurse observes veterans taking their BP and provides teaching or counseling. A national training curriculum was delivered to local nurse champions through Microsoft Teams. We analyzed improvement in BP over a 2-year period. We also captured actions taken by nurses during the VBPV by searching the electronic notes. Ratings of training and comments were summarized using feedback forms completed after training. Results:In total, 81,476 veterans participated in VBPVs over 2 years. Of those, 44,682 veterans had an existing ICD-10 code related to HTN. Of the 18,078 veterans who had a pre- and post-VBPV BP, the average change to systolic measurement was −10.6 mm Hg (range −82 to 78). Average change to diastolic measurement was −4.61 mm Hg (range −59 to 55). Most interventions addressed medication management (77%). Nurses' evaluations of the program were positive. Conclusions:Video visits provide reliable and convenient veteran-centered care. Such visits enable care when unanticipated interruptions occur such as the coronavirus disease 2019 pandemic. In addition to medication management, nurse-led interventions such as counseling on lifestyle changes can be effective in HTN management. [ABSTRACT FROM AUTHOR]

Background: Many low- and-middle-income countries are disproportionately burdened by cervical cancer, resulting in high morbidity and mortality. HPV-DNA testing coupled with treatment with thermal ablation is a recommended screening and precancer treatment strategy, but not enough is known about how this can be effectively implemented in the context of integrated services. The (Scale Up Cervical Cancer Elimination by Secondary prevention Strategy, (SUCCESS) project is conducting a study to understand this approach, integrated into existing women's health services in Burkina Faso, Cote d'Ivoire, Guatemala, and the Philippines (2020–2024). Methods: A hybrid effectiveness-implementation type III mixed-methods observational study design is used to assess feasibility, acceptability, and costs of integrated service delivery in 10 sites per country, selected considering urban/rural location, facility level, onsite/offsite laboratories, and health services type. In each country, a sample size of 2227 women aged 25–49 years will be enrolled with about 20% being women living with HIV. The primary outcome is proportion of HPV positive women completing precancer treatment, if eligible, within three months of screening. Data collection and analysis includes; facility and client exit surveys, key informant and client interviews, registries and project records extractions, and costing data analysis. Analysis includes descriptive statistics, context description, thematic analysis, and document analysis. Quantitative analyses will be stratified by participant's HIV status. Discussion: Recruitment of study participants started in April 2022 (Burkina Faso and Côte d'Ivoire) and August 2022 (Guatemala and the Philippines). Enrolment targets for women screened, client exit, in-depth and key informant interviews conducted were reached in Burkina Faso and Cote d'Ivoire in November 2022. Guatemala and Philippines are expected to complete enrolment by June 2023. Follow-up of study Participants 12-months post-treatment is ongoing and is expected to be completed for all countries by August 2024. In LMICs, integrating cervical cancer secondary prevention services into other health services will likely require specific rather than incidental recruitment of women for screening. Reconfiguration of laboratory infrastructure and planning for sample management must be made well in advance to meet induced demand for screening. Trail Registration ClinicalTrials.Gov ID: NCT05133661 (24/11/2021). Plain English Summary: Low- and middle-income countries bear a disproportionate burden of cervical cancer deaths and suffering from a disease that is preventable and treatable. Unitaid is funding and working collaboratively with the governments of Burkina Faso, Côte d'Ivoire, Guatemala, and the Philippines to implement Scale Up Cervical Cancer Elimination with Secondary prevention Strategy (SUCCESS) project. Significant advancements on cervical cancer management have been made in last four decades. However, the optimal approaches to translating available evidence into actionable screening and treatment implementation strategies in the context of mass-screening programmes is uncertain. SUCCESS project aims to generate evidence on how to deliver cervical cancer services in a way that promotes human papilloma virus (HPV) screening using newer diagnostic and treatment technologies available. This mixed methods study aims to contribute to the evidence on how HPV testing and treatment can be done in manner that is acceptable and feasible in the context of integrated service delivery. Quantitative and qualitative data will be collected over a period of 24 months (2022–2024) across the four countries. In each country, 2227 women aged 25–49 years will be enrolled and screened for HPV, with 20% of them being women living with HIV. In this study, HPV positive will be retested 12-months after initial screening and/or treatment. The findings of the study will add to the body of literature especially from low- and middle-income countries how to implement promising strategies for scaling up cervical cancer screening and treatment coverage. [ABSTRACT FROM AUTHOR]

Initial evaluations generalise to new contexts, whereas counter-attitudinal evaluations are context-specific. Counter-attitudinal information may not change evaluations in new contexts because perceivers fail to retrieve counter-attitudinal cue-evaluation associations from memory outside the counter-attitudinal learning context. The current work examines whether an additional, counter-attitudinal retrieval cue can enhance the generalizability of counter-attitudinal evaluations. In four experiments, participants learned positive information about a target person, Bob, in one context, and then learned negative information about Bob in a different context. While learning the negative information, participants wore a wristband as a retrieval cue for counter-attitudinal Bob-negative associations. Participants then made speeded as well as deliberate evaluations of Bob while wearing or not wearing the wristband. Internal meta-analysis failed to find a reliable effect of the counter-attitudinal retrieval cue on speeded or deliberate evaluations, whereas the context cues influenced speeded and deliberate evaluations. Counter to predictions, counter-attitudinal retrieval cues did not disrupt the generalisation of first-learned evaluations or the context-specificity of second-learned evaluations (Experiments 2–4), but the counter-attitudinal retrieval cue did influence evaluations in the absence of context cues (Experiment 1). The current work provides initial evidence that additional counter-attitudinal retrieval cues fail to disrupt the renewal and generalizability of first-learned evaluations. [ABSTRACT FROM AUTHOR]

The article reviews the web site on health education, Krames OneDemand, www.krames.com, from Stay Well.

The article highlights a study on characterization of the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in pancreatic ductal adenocarcinoma (PDAC) and indicated that the abundance of Schwann cells (TASc) was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. It concludes that depletion of TASc using a small-molecule inhibitor effectively sensitized PDAC to immunotherapy, signifying the roles of TASc in PDAC.

The aging of the human immunodeficiency virus type 1 (HIV-1)-infected population obligates a focus on the interaction between aging, comorbid conditions, and HIV-1. We recruited a cohort of HIV-1-infected men aged ≤ 35 years or ≥ 50 years who were receiving fully suppressive antiretroviral therapy (ART). We analyzed plasma markers of inflammation; T-cell activation, exhaustion, proliferation; and innate cellular subsets and functional capacity. Levels of lipopolysaccharide and the plasma marker of chemokine (C-C motif) ligand 2 were significantly elevated in older HIV-infected men despite comparable cellular phenotypes. Compared with similarly age-stratified uninfected subjects, older HIV-1-infected adults were also more frequently in the upper quartile of soluble CD14 expression. [ABSTRACT FROM AUTHOR]

Canonical Wnt (cWnt) signaling through β-catenin regulates osteoblast proliferation and differentiation to enhance bone formation. We previously reported that osteogenic action of β-catenin is dependent on BMP signaling. Here, we further examined interactions between cWnt and BMP in bone. In osteoprogenitors stimulated with BMP2, β-catenin localizes to the nucleus, physically interacts with Smad4, and is recruited to DNA-binding transcription complexes containing Smad4, R-Smad1/5 and TCF4. Furthermore, Tcf/Lef-dependent transcription, Ccnd1 expression and proliferation all increase when Smad4, 1 or 5 levels are low, whereas TCF/Lef activities decrease when Smad4 expression is high. The ability of Smad4 to antagonize transcription of Ccnd1 is dependent on DNA-binding activity but Smad4-dependent transcription is not required. In mice, conditional deletion of Smad4 in osterix+ cells increases mitosis of cells on trabecular bone surfaces as well as in primary osteoblast cultures from adult bone marrow and neonatal calvaria. By contrast, ablation of Smad4 delays differentiation and matrix mineralization by primary osteoblasts in response to Wnt3a, indicating that loss of Smad4 perturbs the balance between proliferation and differentiation in osteoprogenitors. We propose that Smad4 and Tcf/Lef transcription complexes compete for β-catenin, thus restraining cWnt-dependent proliferative signals while favoring the matrix synthesizing activity of osteoblasts. [ABSTRACT FROM AUTHOR]

To examine interactions between bone morphogenic protein (BMP) and canonical Wnt signaling during skeletal growth, we ablated Smad4, a key component of the TGF-β-BMP pathway, in Osx1+ cells in mice. We show that loss of Smad4 causes stunted growth, spontaneous fractures and a combination of features seen in osteogenesis imperfecta, cleidocranial dysplasia and Wnt-deficiency syndromes. Bones of Smad4 mutant mice exhibited markers of fully differentiated osteoblasts but lacked multiple collagen-processing enzymes, including lysyl oxidase (Lox), a BMP2-responsive gene regulated by Smad4 and Runx2. Accordingly, the collagen matrix in Smad4 mutants was disorganized, but also hypomineralized. Primary osteoblasts from these mutants did not mineralize in vitro in the presence of BMP2 or Wnt3a, and Smad4 mutant mice failed to accrue new bone following systemic inhibition of the Dickkopf homolog Dkk1. Consistent with impaired biological responses to canonical Wnt, ablation of Smad4 causes cleavage of β-catenin and depletion of the low density lipoprotein receptor Lrp5, subsequent to increased caspase-3 activity and apoptosis. In summary, Smad4 regulates maturation of skeletal collagen and osteoblast survival, and is required for matrix-forming responses to both BMP2 and canonical Wnt. [ABSTRACT FROM AUTHOR]

The BvgAS virulence control system regulates the expression of type III secretion genes in Bordetella subspecies that infect humans and other mammals. We have identified five open reading frames, btrS, btrU, btrX, btrW and btrV, that are activated by BvgAS and encode regulatory factors that control type III secretion at the levels of transcription, protein expression and secretion. The btrS gene product bears sequence similarity to ECF ( extra cytoplasmic function) sigma factors and is required for transcription of the bsc locus. btrU, btrW and btrV encode proteins predicted to contain PP2C-like Ser phosphatase, HPK ( His protein kinase)-like Ser kinase and STAS anti-sigma factor antagonist domains, respectively, which are characteristic of Gram-positive partner switching proteins in Bacillus subtilis. BtrU and BtrW are required for secretion of proteins that are exported by the bsc type III secretion system, whereas BtrV is specifically required for protein synthesis and/or stability. Bordetella species have thus evolved a unique cascade to differentially regulate type III secretion that combines a canonical phosphorelay system with an ECF sigma factor and a set of proteins with domain signatures that define partner switchers, which were traditionally thought to function only in Gram-positive bacteria. The presence of multiple layers and mechanisms of regulation most likely reflects the need to integrate multiple signals in controlling type III secretion. The bsc and btr loci are nearly identical between broad-host-range and human-specific Bordetella. Comparative analysis of Bordetella subspecies revealed that, whereas bsc and btr loci were transcribed in all subspecies, only broad-host-range strains expressed a functional type III secretion system in vitro. The block in type III secretion is post-transcriptional in human-adapted strains, and signal recognition appears to be a point of divergence between subspecies. [ABSTRACT FROM AUTHOR]

Gaze direction, a cue of both social and spatial attention, is known to modulate early neural responses tofaces e.g. N170. However, findings in the literature have been inconsistent, likely reflecting differences in stimulus characteristics and task requirements. Here, we investigated the effect of task on neural responses to dynamic gaze changes: away and toward transitions (resulting or not in eye contact). Subjects performed, in random order, social (away/toward them) and non-social (left/right) judgment tasks on these stimuli. Overall, in the non-social task, results showed a larger N170 to gaze aversion than gaze motion toward the observer. In the social task, however, this difference was no longer present in the right hemisphere, likely reflecting an enhanced N170 to gaze motion toward the observer. Our behavioral and event-related potential data indicate that performing social judgments enhances saliency of gaze motion toward the observer, even those that did not result in gaze contact. These data and that of previous studies suggest two modes of processing visual information: a 'default mode' that may focus on spatial information; a 'socially aware mode' that might be activated when subjects are required to make social judgments. The exact mechanism that allows switching from one mode to the other remains to be clarified. [ABSTRACT FROM AUTHOR]

ABSTRACT Disability following spinal cord injury is due to failure of axon regeneration, which has been ascribed to environmental factors in the central nervous system and a developmental loss of intrinsic growth capacity in neurons. Recently, the receptor-like protein tyrosine phosphatases, protein tyrosine phosphatase σ (PTPσ) and leukocyte common antigen-related phosphatase (LAR), have been identified as specific receptors for the regeneration-inhibiting matrix molecules chondroitin sulfate proteoglycans (CSPGs). After spinal cord transection in lampreys, axons of the large, identified reticulospinal neurons have heterogeneous regenerative abilities. The bad-regenerating neurons also undergo a delayed form of axotomy-induced apoptosis. In the present study, a lamprey genomic database was used to identify homologs of CSPGs, clone PTPσ and LAR, and examine their mRNA expression. CSPG immunoreactivity was increased significantly near the lesion at 2 weeks post transection, and decreased thereafter. Both receptors were expressed selectively in the bad-regenerating neurons and had overlapping cellular distributions. PTPσ was upregulated with age (LAR was not evaluated). By 2 weeks post transection, neurons expressing PTPσ also showed caspase activation, suggesting apoptosis. The probability of axon regeneration for individual identified neurons was negatively correlated with the expression level of PTPσ in both control and spinal cord-transected lampreys. In an animal 7 weeks post transection, regenerated axons were labeled retrogradely from beyond the transection. PTPσ expression and caspase labeling was seen only in neurons whose axon had not regenerated. These results are consistent with a possible role for PTPσ (and LAR) in both retrograde neuronal death and the poor intrinsic regenerative ability of bad-regenerating neurons. J. Comp. Neurol. 522:2209-2229, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

[Display omitted] We describe our efforts to introduce structural diversity to a previously described triazole-containing N1-carboline series of bromodomain and extra-terminal (BET) inhibitors. N9 carbolines were designed to retain favorable binding interactions that the N1-carbolines possess. A convergent synthetic route enabled modifications to reduce clearance, enhance physicochemical properties, and improve the overall in vitro profile. This work led to the identification of a potent BET inhibitor, (S)-2‐{8‐fluoro‐5‐[(3‐fluoropyridin‐2‐yl)(oxan‐4‐yl)methyl]‐7‐[4‐(2H 3)methyl‐1‐methyl‐1 H ‐1,2,3‐triazol‐5‐yl]‐5 H ‐pyrido[3,2‐b]indol‐3‐yl}propan‐2‐ol (10), a compound with enhanced oral exposure in mice. Subsequent evaluation in a mouse triple-negative breast cancer tumor model revealed efficacy at 4 mg/kg of N9-carboline 10. [ABSTRACT FROM AUTHOR]