Alternative Targeting Strategies Research Articles

Discovery of LC-MI-3: A Potent and Orally Bioavailable Degrader of Interleukin-1 Receptor-Associated Kinase 4 for the Treatment of Inflammatory Diseases.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target in inflammation-related diseases. However, the inhibition of IRAK4 kinase activity may lead to moderate anti-inflammatory efficacy owing to the dual role of IRAK4 as an active kinase and a scaffolding protein. Herein, we report the design, synthesis, and biological evaluation of an efficient and selective IRAK4 proteolysis-targeting chimeric molecule that eliminates IRAK4 scaffolding functions. The most potent compound, LC-MI-3, effectively degraded cellular IRAK4, with a half-maximal degradation concentration of 47.3 nM. LC-MI-3 effectively inhibited the activation of downstream nuclear factor-κB signaling and exerted more potent pharmacological effects than traditional kinase inhibitors. Furthermore, LC-MI-3 exerted significant therapeutic effects in lipopolysaccharide- and Escherichia coli-induced acute and chronic inflammatory skin models compared with kinase inhibitors in vivo. Therefore, LC-MI-3 is a candidate IRAK4 degrader in alternative targeting strategies and advanced drug development.

Synthesis and Bioevaluation of 3-(Arylmethylene)indole Derivatives: Discovery of a Novel ALK Modulator with Antiglioblastoma Activities.

Glioblastoma is the most common brain tumor, with high recurrence and low survival rates. An integrative bioinformatics analysis demonstrated that anaplastic lymphoma kinase (ALK) is a promising therapeutic target for glioblastoma. We designed and synthesized a series of 3-(arylmethylene)indole derivatives, which were further evaluated for antiproliferative activity using glioma cell lines. Among them, compound 4a significantly inhibited the viability of glioblastoma cells. With favorable pharmacokinetic characteristics and blood-brain barrier permeability, 4a improved the survival rate and inhibited the growth of orthotopic glioblastoma. The Phospho-Totum system revealed that ALK was a potential target for the antiglioblastoma activity of 4a. Further experiments indicated that 4a might be a novel ALK modulator, which interacted with the extracellular ligand-binding domain of ALK, thus selectively induced ERK-mediated autophagy and apoptosis. Our findings provide an alternative ALK-based targeting strategy and a new drug candidate for glioblastoma therapy.

Relaxing the production-conservation trade-off: Biodiversity spillover in the bioeconomic performance of ecological networks

Ecological networks (ENs) aim to accommodate production and conservation within landscapes by shaping the spatial scope of conservation policies based on ecological criteria. The environmental effectiveness of these networks has been extensively studied; however, it has rarely been linked to their economic cost. This paper investigates whether EN-based spatial targeting relaxes the production-conservation trade-off and, if so, what the processes underlying its performance may be. We design an EN at the national level (France), with common farmland birds defined as a conservation goal and grassland expansion defined as a conservation lever. A dynamic, mechanistic, ecological-economic model simulates policy scenarios up to 2050 with alternative targeting strategies, including the EN. The results reveal that EN targeting is almost twice as cost-effective as a nationally homogeneous policy and about as cost-effective as focusing on biodiversity reservoirs, but with higher biodiversity gains. These outcomes rely on higher initial bird abundance in targeted regions, as well as positive feedback and spillover supported by bird dispersal. However, the EN's superiority only appears in the medium term because of ecological inertia. These interdisciplinary insights on a tool from ecology and conservation biology echo policy needs for the design and implementation of sustainable landscape management strategies.

The ERK2-DBP domain opposes pathogenesis of a mouse JAK2V617F-driven myeloproliferative neoplasm

AbstractAlthough Ras/mitogen-activated protein kinase (MAPK) signaling is activated in most human cancers, attempts to target this pathway using kinase-active site inhibitors have not typically led to durable clinical benefit. To address this shortcoming, we sought to test the feasibility of an alternative targeting strategy, focused on the ERK2 substrate binding domains, D and DEF binding pocket (DBP). Disabling the ERK2-DBP domain in mice caused baseline erythrocytosis. Consequently, we investigated the role of the ERK2-D and -DBP domains in disease, using a JAK2-dependent model of polycythemia vera (PV). Of note, inactivation of the ERK2-DBP domain promoted the progression of disease from PV to myelofibrosis, suggesting that the ERK2-DBP domain normally opposes progression. ERK2-DBP inactivation also prevented oncogenic JAK2 kinase (JAK2V617F) from promoting oncogene-induced senescence in vitro. The ERK2-DBP mutation attenuated JAK2-mediated oncogene-induced senescence by preventing the physical interaction of ERK2 with the transcription factor Egr1. Because inactivation of the ERK2-DBP created a functional ERK2 kinase limited to binding substrates through its D domain, these data suggested that the D domain substrates were responsible for promoting oncogene-induced progenitor growth and tumor progression and that pharmacologic targeting of the ERK2-D domain may attenuate cancer cell growth. Indeed, pharmacologic agents targeting the ERK2-D domain were effective in attenuating the growth of JAK2-dependent myeloproliferative neoplasm cell lines. Taken together, these data indicate that the ERK-D and -DBP domains can play distinct roles in the progression of neoplasms and that the D domain has the potential to be a potent therapeutic target in Ras/MAPK-dependent cancers.

Promoterless Gene Targeting Approach Combined to CRISPR/Cas9 Efficiently Corrects Hemophilia B Phenotype in Neonatal Mice.

Many inborn errors of metabolism require life-long treatments and, in severe conditions involving the liver, organ transplantation remains the only curative treatment. Non-integrative AAV-mediated gene therapy has shown efficacy in adult patients. However, treatment in pediatric or juvenile settings, or in conditions associated with hepatocyte proliferation, may result in rapid loss of episomal viral DNA and thus therapeutic efficacy. Re-administration of the therapeutic vector later in time may not be possible due to the presence of anti-AAV neutralizing antibodies. We have previously shown the permanent rescue of the neonatal lethality of a Crigler-Najjar mouse model by applying an integrative gene-therapy based approach. Here, we targeted the human coagulation factor IX (hFIX) cDNA into a hemophilia B mouse model. Two AAV8 vectors were used: a promoterless vector with two arms of homology for the albumin locus, and a vector carrying the CRISPR/SaCas9 and the sgRNA. Treatment of neonatal P2 wild-type mice resulted in supraphysiological levels of hFIX being stable 10 months after dosing. A single injection of the AAV vectors into neonatal FIX KO mice also resulted in the stable expression of above-normal levels of hFIX, reaching up to 150% of the human levels. Mice subjected to tail clip analysis showed a clotting capacity comparable to wild-type animals, thus demonstrating the rescue of the disease phenotype. Immunohistological analysis revealed clusters of hFIX-positive hepatocytes. When we tested the approach in adult FIX KO mice, we detected hFIX in plasma by ELISA and in the liver by western blot. However, the hFIX levels were not sufficient to significantly ameliorate the bleeding phenotype upon tail clip assay. Experiments conducted using a AAV donor vectors containing the eGFP or the hFIX cDNAs showed a higher recombination rate in P2 mice compared to adult animals. With this study, we demonstrate an alternative gene targeting strategy exploiting the use of the CRISPR/SaCas9 platform that can be potentially applied in the treatment of pediatric patients suffering from hemophilia, also supporting its application to other liver monogenic diseases. For the treatment of adult patients, further studies for the improvement of targeting efficiency are still required.

Targeting multidrug resistance-associated protein 1 (MRP1)-expressing cancers: Beyond pharmacological inhibition.

Resistance to chemotherapy remains one of the most significant obstacles to successful cancer treatment. While inhibiting drug efflux mediated by ATP-binding cassette (ABC) transporters is a seemingly attractive and logical approach to combat multidrug resistance (MDR), small molecule inhibition of ABC transporters has so far failed to confer clinical benefit, despite considerable efforts by medicinal chemists, biologists, and clinicians. The long-sought treatment to eradicate cancers displaying ABC transporter overexpression may therefore lie within alternative targeting strategies. When aberrantly expressed, the ABC transporter multidrug resistance-associated protein 1 (MRP1, ABCC1) confers MDR, but can also shift cellular redox balance, leaving the cell vulnerable to select agents. Here, we explore the physiological roles of MRP1, the rational for targeting this transporter in cancer, the development of small molecule MRP1 inhibitors, and the most recent developments in alternative therapeutic approaches for targeting cancers with MRP1 overexpression. We discuss approaches that extend beyond simple MRP1 inhibition by exploiting the collateral sensitivity to glutathione depletion and ferroptosis, the rationale for targeting the shared transcriptional regulators of both MRP1 and glutathione biosynthesis, advances in gene silencing, and new molecules that modulate transporter activity to the detriment of the cancer cell. These strategies illustrate promising new approaches to address multidrug resistant disease that extend beyond the simple reversal of MDR and offer exciting routes for further research.

Biologically excretable AIE nanoparticles wear tumor cell-derived “exosome caps” for efficient NIR-II fluorescence imaging-guided photothermal therapy

Nanoparticles (NPs) assisted photothermal therapy (PTT) is a promising cancer treatment modality and has attracted the attention of the scientific mainstream. However, developing bio-excretable NPs that exhibit efficient optical properties and specific tumor targeting capability simultaneously is difficult. Herein, we develop a kind of hybrid nanovesicles consisting of bio-excretable aggregation-induced emission (AIE) NPs and tumor cell-derived “exosome caps” (TT3-oCB NP@EXOs) with enhanced second near-infrared (NIR-II, 900–1700 nm) fluorescence property and PTT functionality via electroporation. Compared with TT3-oCB NPs, TT3-oCB NP@EXOs exhibit excellent biocompatibility, specific targeting ability in vitro, homing to homologous tumors in vivo, and prolonged circulation time. Furthermore, TT3-oCB NP@EXOs were utilized as biomimetic NPs for NIR-II fluorescence imaging-guided PTT of tumors, due to their high and stable photothermal conversion capacity under 808 nm irradiation. Therefore, with the validation of other AIE NPs with poor targeting property, the tumor cell-derived EXO/AIE NP hybrid nanovesicles may provide an alternative artificial targeting strategy for improving tumor diagnosis and PTT.

Cellular nanovesicles with bioorthogonal targeting enhance photodynamic/photothermal therapy in psoriasis

The interaction between over-proliferating keratinocytes and excessive activated immune cells contributes to the development and progression of psoriasis. Photodynamic therapy (PDT)/photothermal therapy (PTT) is a promising method to treat skin diseases due to their synergistic effect and low side effect. Cell membrane is an ideal cell-mediated drug delivery platform with inherent biocompatibility, but lacks of specific targeting properties to increase drug accumulation in the psoriatic site. Here, we develop a new PDT/PTT strategy to treat psoriasis, based on cell membrane functionalization by metabolic glycoengineering with unnatural sugars, which label cell membranes with chemical tags for subsequent targeting. In our study, in order to enhance the PDT/PTT effect, N3-labeled cell membrane-derived nanovesicles coated with IR-780 nanoparticals (N3-NV-INPs) are constructed, which can specifically recognize DBCO-modified psoriatic lesions through bioorthogonal click chemistry to achieve targeted PDT/PTT effect. The results showed that N3-NV-INPs could specifically target the psoriatic lesions, enhance the synergistic effect of PDT/PTT under the irradiation of near-infrared light, exhaust excessive proliferation of keratinocytes, regulate immunity, reduce the release of cytokines, such as IL-17, IL-22, TNF-α, improve epidermal hyperplasia, and effectively relieve the symptoms of psoriasis. Taken together, we constructed cellular nanovesicles based on an alternative artificial targeting strategy to enhance PDT/PTT effect in psoriasis, which shows great potential in clinical application. Statement of significanceThe major challenge in the treatment of psoriasis is how to effectively deliver drugs to the lesions to exhaust overproliferating keratinocytes and modulate immunity. A newly-developed cell membrane-coating technology combined with biorthogonal targeted delivery promotes more drug accumulation at the lesions of the disease. Incorporation of an effective photosensitizer into the lesions of psoriasis site results in exert PDT/PTT effect under the irradiation of near-infrared light. The synergistic PDT/PTT effect can effectively exhaust keratinocytes and immune cells in the epidermis and dermis, reduce the release of inflammatory cytokines, and relieve the symptoms of psoriasis. This unique functional cell membrane nanovesicles combined with bioorthogonal targeting is applied to enhance the PDT/PTT effect in psoriasis and may provide a solution for the clinical treatment of other inflammatory skin diseases.

Affimer-Based Europium Chelates Allow Sensitive Optical Biosensing in a Range of Human Disease Biomarkers.

The protein biomarker measurement has been well-established using ELISA (enzyme-linked immunosorbent assay), which offers good sensitivity and specificity, but remains slow and expensive. Certain clinical conditions, where rapid measurement or immediate confirmation of a biomarker is paramount for treatment, necessitate more rapid analysis. Biosensors offer the prospect of reagent-less, processing-free measurements at the patient’s bedside. Here, we report a platform for biosensing based on chelated Eu3+ against a range of proteins including biomarkers of cardiac injury (human myoglobin), stroke (glial fibrillary acidic protein (GFAP)), inflammation (C-reactive protein (CRP)) and colorectal cancer (carcinoembryonic antigen (CEA)). The Eu3+ ions are chelated by modified synthetic binding proteins (Affimers), which offer an alternative targeting strategy to existing antibodies. The fluorescence characteristics of the Eu3+ complex with modified Affimers against human myoglobin, GFAP, CRP and CEA were measured in human serum using λex = 395 nm, λem = 590 and 615 nm. The Eu3+-Affimer based complex allowed sensitive detection of human myoglobin, GFAP, CRP and CEA proteins as low as 100 fM in (100-fold) diluted human serum samples. The unique dependence on Eu3+ fluorescence in the visible region (590 and 615 nm) was exploited in this study to allow rapid measurement of the analyte concentration, with measurements in 2 to 3 min. These data demonstrate that the Affimer based Eu3+ complexes can function as nanobiosensors with potential analytical and diagnostic applications.

Predicting preventable hospital readmissions with causal machine learning.

To assess both the feasibility and potential impact of predicting preventable hospital readmissions using causal machine learning applied to data from the implementation of a readmissions prevention intervention (the Transitions Program). Electronic health records maintained by Kaiser Permanente Northern California (KPNC). Retrospective causal forest analysis of postdischarge outcomes among KPNC inpatients. Using data from both before and after implementation, we apply causal forests to estimate individual-level treatment effects of the Transitions Program intervention on 30-day readmission. These estimates are used to characterize treatment effect heterogeneity and to assess the notional impacts of alternative targeting strategies in terms of the number of readmissions prevented. 1539285 index hospitalizations meeting the inclusion criteria and occurring between June 2010 and December 2018 at 21 KPNC hospitals. There appears to be substantial heterogeneity in patients' responses to the intervention (omnibus test for heterogeneity p=2.23×10-7 ), particularly across levels of predicted risk. Notably, predicted treatment effects become more positive as predicted risk increases; patients at somewhat lower risk appear to have the largest predicted effects. Moreover, these estimates appear to be well calibrated, yielding the same estimate of annual readmissions prevented in the actual treatment subgroup (1246, 95% confidence interval [CI] 1110-1381) as did a formal evaluation of the Transitions Program (1210, 95% CI 990-1430). Estimates of the impacts of alternative targeting strategies suggest that as many as 4458 (95% CI 3925-4990) readmissions could be prevented annually, while decreasing the number needed to treat from 33 to 23, by targeting patients with the largest predicted effects rather than those at highest risk. Causal machine learning can be used to identify preventable hospital readmissions, if the requisite interventional data are available. Moreover, our results suggest a mismatch between risk and treatment effects.

Identification of Quinazolinone Analogs Targeting CDK5 Kinase Activity and Glioblastoma Cell Proliferation.

CDK5/p25 kinase plays a major role in neuronal functions, and is hyperactivated in several human cancers including glioblastoma and neurodegenerative pathologies such as Alzheimer's and Parkinson's. CDK5 therefore constitutes an attractive pharmacological target. Since the successful discovery and development of Roscovitine, several ATP-competitive inhibitors of CDK5 and peptide inhibitors of CDK5/p25 interface have been developed. However, these compounds suffer limitations associated with their mechanism of action and nature, thereby calling for alternative targeting strategies. To date, few allosteric inhibitors have been developed for successful targeting of protein kinases. Indeed, although this latter class of inhibitors are believed to be more selective than compounds targeting the active site, they have proven extremely difficult to identify in high throughput screens. By implementing a fluorescent biosensor that discriminates against ATP-pocket binding compounds to screen for allosteric inhibitors that target conformational activation of CDK5, we have identified a novel family of quinazolinones. Characterization of these hits and several of their derivatives revealed their inhibitory potential toward CDK5 kinase activity in vitro and to inhibit glioblastoma cell proliferation. The quinazolinone derivatives described in this study are the first small molecules reported to target CDK5 at a site other than the ATP pocket, thereby constituting attractive leads for glioblastoma therapeutics and providing therapeutic perspectives for neurodegenerative diseases. These compounds offer alternatives to conventional ATP-competitive inhibitors or peptides targeting CDK5/p25 interface with the potential of bypassing their limitations.

Intercellular delivery of bioorthogonal chemical receptors for enhanced tumor targeting and penetration

Targeted drug delivery using biological ligands can improve the precision of cancer therapy. However, this active targeting strategy is limited in tumor targeting and penetration abilities due to the paucity and heterogeneous distribution of targeted receptors in tumor cells, thus compromising the treatment outcomes. In this study, we developed an alternative active targeting strategy for enhanced tumor targeting and penetration through synthetic nanoparticle-mediated metabolic tumor ligand labeling for intercellular delivery of bioorthogonal chemical receptors combined with in vivo bioorthogonal click chemistry. Briefly, artificial azide-containing ligands were first labeled on perivascular tumor cells by nanoscale metabolic precursors (Az-NPs) via the enhanced permeability and retention (EPR) effect and metabolic engineering of the tumor cells. Through transport by extracellular vesicles (EVs) secreted by perivascular tumor cells, the azide-containing ligands can be autonomously transported intercellularly to adjacent cells and further spread throughout tumor tissues and label bioorthogonal ligands on cells that are not in proximity to blood vessels. Then, water-soluble dibenzocyclooctyne-modified chlorin e6 (DBCO-Ce6) was intravenously injected to react selectively, efficiently and irreversibly with the azide groups on the cell surface through an in vivo bioorthogonal click reaction. Enhanced tumor accumulation and penetration of DBCO-Ce6 was achieved through this strategy, resulting in improved therapeutic efficiency with laser irradiation for photodynamic therapy. Therefore, the artificial azide-containing ligand targeting strategy by nanoparticle-mediated metabolic labeling through the EPR effect combined with bioorthogonal click chemistry may provide an alternative strategy for enhanced tumor targeting and penetration with broad applications.

Catalytic Domain Plasticity of MKK7 Reveals Structural Mechanisms of Allosteric Activation and Diverse Targeting Opportunities

MKK7 (MEK7) is a key regulator of the JNK stress signaling pathway and targeting MKK7 has been proposed as a chemotherapeutic strategy. Detailed understanding of the MKK7 structure and factors that affect its activity is therefore of critical importance. Here, we present a comprehensive set of MKK7 crystal structures revealing insights into catalytic domain plasticity and the role of the N-terminal regulatory helix, conserved in all MAP2Ks, mediating kinase activation. Crystal structures harboring this regulatory helix revealed typical structural features of active kinase, providing exclusively a first model of the MAP2K active state. A small-molecule screening campaign yielded multiple scaffolds, including type II irreversible inhibitors a binding mode that has not been reported previously. We also observed an unprecedented allosteric pocket located in the N-terminal lobe for the approved drug ibrutinib. Collectively, our structural and functional data expand and provide alternative targeting strategies for this important MAP2K kinase.

Selective Targeting of Guanine-Vacancy-Bearing G-Quadruplexes by G-Quartet Complementation and Stabilization with a Guanine-Peptide Conjugate.

Stabilization of G-quadruplexes (G4s) formed in guanine-rich (G-rich) nucleic acids by small-molecule ligands has been extensively explored as a therapeutic approach for diseases such as cancer. Finding ligands with sufficient affinity and specificity toward G4s remains a challenge, and many ligands reported seemed to compromise between the two features. To cope with this challenge, we focused on targeting a particular type of G4s, i.e., the G-vacancy-bearing G-quadruplexes (GVBQs), by taking a structure complementation strategy to enhance both affinity and selectivity. In this approach, a G-quadruplex-binding peptide RHAU23 is guided toward a GVBQ by a guanine moiety covalently linked to the peptide. The filling-in of the vacancy in a GVBQ by the guanine ensures an exclusive recognition of GVBQ. Moreover, the synergy between the RHAU23 and the guanine dramatically improves both the affinity toward and stabilization of the GVBQ. Targeting a GVBQ in DNA by this bifunctional peptide strongly suppresses in vitro replication. This study demonstrates a novel and promising alternative targeting strategy to a distinctive panel of G4s that are as abundant as the canonical ones in the human genome.

New Advances in Targeting the Resolution of Inflammation: Implications for Specialized Pro-Resolving Mediator GPCR Drug Discovery.

Chronic inflammation is a component of numerous diseases including autoimmune, metabolic, neurodegenerative, and cancer. The discovery and characterization of specialized pro-resolving mediators (SPMs) critical to the resolution of inflammation, and their cognate G protein-coupled receptors (GPCRs) has led to a significant increase in the understanding of this physiological process. Approximately 20 ligands, including lipoxins, resolvins, maresins, and protectins, and 6 receptors (FPR2/ALX, GPR32, GPR18, chemerin1, BLT1, and GPR37) have been identified highlighting the complex and multilayered nature of resolution. Therapeutic efforts in targeting these receptors have proved challenging, with very few ligands apparently progressing through to preclinical or clinical development. To date, some knowledge gaps remain in the understanding of how the activation of these receptors, and their downstream signaling, results in efficient resolution via apoptosis, phagocytosis, and efferocytosis of polymorphonuclear leukocytes (mainly neutrophils) and macrophages. SPMs bind and activate multiple receptors (ligand poly-pharmacology), while most receptors are activated by multiple ligands (receptor pleiotropy). In addition, allosteric binding sites have been identified signifying the capacity of more than one ligand to bind simultaneously. These fundamental characteristics of SPM receptors enable alternative targeting strategies to be considered, including biased signaling and allosteric modulation. This review describes those ligands and receptors involved in the resolution of inflammation, and highlights the most recent clinical trial results. Furthermore, we describe alternative mechanisms by which these SPM receptors could be targeted, paving the way for the identification of new therapeutics, perhaps with greater efficacy and fidelity.

Catalytic Domain Plasticity of MKK7 Reveals Structural Mechanisms of Allosteric Activation and New Targeting Opportunities

MKK7 (MEK7) is a key regulator of the JNK stress signaling pathway and targeting MKK7 has been proposed as a chemotherapeutic strategy. Detailed understanding of the MKK7 structure and factors that impact its activity is therefore of critical importance. Here, we present a comprehensive set of MKK7 crystal structures revealing insights into catalytic domain plasticity and the role of the N-terminal regulatory helix, conserved in all MAP2Ks, mediating kinase activation. Crystal structures harboring this regulatory helix revealed typical structural features of active kinase, providing exclusively a first model of the MAP2K active state. A small molecule screening campaign yielded multiple scaffolds, including type-II irreversible inhibitors a binding mode that has not been reported previously. We also observed an unprecedented allosteric pocket located in the N-terminal lobe for the approved drug ibrutinib. Collectively, our structural and functional data expand and provide alternative targeting strategies for this important MAP2K kinase.

T Cell Membrane Mimicking Nanoparticles with Bioorthogonal Targeting and Immune Recognition for Enhanced Photothermal Therapy.

Due to specific immune recognition receptors on the surface of T cells, their membranes are promising mimic nanocarriers for delivering drugs to tumor lesions. However, this single targeting strategy potentially compromises therapy efficacy for tumor targeting due to inter‐ and intra‐heterogeneity of tumors. Azide (N3) or bicyclo [6.1.0] nonyne (BCN) modified unnatural sugars can be successfully incorporated into surface glycans of various tumor cells as artificial receptors, which is expected to overcome the insufficiency of single targeting. Based on this artificial tumor targeting strategy, indocyanine green nanoparticles (INPs) coated with N3‐labeled T cell membrane (N3‐TINPs) are constructed, which can specifically target the natural antigen and BCN artificial receptors on tumors through immune recognition and bioorthogonal chemistry, respectively. The results show that the fluorescence intensity in the tumors of mice treated with N3‐TINPs is 1.5 fold compared with that of the mice treated with unlabeled TINPs. The accumulated N3‐TINPs in the tumor significantly increase the photothermal therapeutic effect without adverse effect. Therefore, this T cell membrane mimicking nanoparticles based bioorthogonal chemistry may provide an alternative artificial targeting strategy for further tumor targeting photothermal therapy.

Molecular and epigenetic profiles of BRCA1-like hormone-receptor-positive breast tumors identified with development and application of a copy-number-based classifier

BackgroundBRCA1-mutated cancers exhibit deficient homologous recombination (HR) DNA repair, resulting in extensive copy number alterations and genome instability. HR deficiency can also arise in tumors without a BRCA1 mutation. Compared with other breast tumors, HR-deficient, BRCA1-like tumors exhibit worse prognosis but selective chemotherapeutic sensitivity. Presently, patients with triple negative breast cancer (TNBC) who do not respond to hormone endocrine-targeting therapy are given cytotoxic chemotherapy. However, more recent evidence showed a similar genomic profile between BRCA1-deficient TNBCs and hormone-receptor-positive tumors. Characterization of the somatic alterations of BRCA1-like hormone-receptor-positive breast tumors as a group, which is currently lacking, can potentially help develop biomarkers for identifying additional patients who might respond to chemotherapy.MethodsWe retrained and validated a copy-number-based support vector machine (SVM) classifier to identify HR-deficient, BRCA1-like breast tumors. We applied this classifier to The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast tumors. We assessed mutational profiles and proliferative capacity by covariate-adjusted linear models and identified differentially methylated regions using DMRcate in BRCA1-like hormone-receptor-positive tumors.ResultsOf the breast tumors in TCGA and METABRIC, 22% (651/2925) were BRCA1-like. Stratifying on hormone-receptor status, 13% (302/2405) receptor-positive and 69% (288/417) triple-negative tumors were BRCA1-like. Among the hormone-receptor-positive subgroup, BRCA1-like tumors showed significantly increased mutational burden and proliferative capacity (both P < 0.05). Genome-scale DNA methylation analysis of BRCA1-like tumors identified 202 differentially methylated gene regions, including hypermethylated BRCA1. Individually significant CpGs were enriched for enhancer regions (P < 0.05). The hypermethylated gene sets were enriched for DNA and chromatin conformation (all Bonferroni P < 0.05).ConclusionsTo provide insights into alternative classification and potential therapeutic targeting strategies of BRCA1-like hormone-receptor-positive tumors we developed and applied a novel copy number classifier to identify BRCA1-like hormone-receptor-positive tumors and their characteristic somatic alteration profiles.

Identification of potential drugs targeting L,L-diaminopimelate aminotransferase of Chlamydia trachomatis: An integrative pharmacoinformatics approach.

Chlamydia trachomatis (C.t) is a gram-negative obligate intracellular bacteria, which is a major causative of infectious blindness and sexually transmitted diseases. A surge in multidrug resistance among chlamydial species has posed a challenge to adopt alternative drug targeting strategies. Recently, in C.t, L,L-diaminopimelate aminotransferase (CtDAP-AT) is proven to be a potential drug target due its essential role in cell survival and host nonspecificity. Hence, in this study, a multilevel precision-based virtual screening of CtDAP-AT was performed to identify potential inhibitors, wherein, an integrative stringent scoring and filtration were performed by coupling, glide docking score, binding free energy, ADMET (absorption, distribution, metabolism, and excretion, toxicity) prediction, density functional theory (quantum mechanics), and molecular dynamics simulation (molecular mechanics). On cumulative analysis, NSC_5485 (1,3-bis((7-chloro-4-quinolinyl)amino)-2-propanol) was found to be the most potential lead, as it showed higher order significance in terms of binding affinity, bonded interactions, favorable ADMET, chemical reactivity, and greater stabilization during complex formation. This is the first report on prioritization of small molecules from National Cancer Institute (NCI) and Maybridge data sets (341 519 compounds) towards targeting CtDAP-AT. Thus, the proposed compound shall aid in effective combating of a broad spectrum of C.t infections as it surpassed all the levels of prioritization.

Active Redesign of a Medicaid Care Management Strategy for Greater Return on Investment: Predicting Impactability.

Care management of high-cost/high-needs patients is an increasingly common strategy to reduce health care costs. A variety of targeting methodologies have emerged to identify patients with high historical or predicted health care utilization, but the more pertinent question for program planners is how to identify those who are most likely to benefit from care management intervention. This paper describes the evolution of complex care management targeting strategies in Community Care of North Carolina's (CCNC) work with the statewide non-dual Medicaid population, culminating in the development of an “Impactability Score” that uses administrative data to predict achievable savings. It describes CCNC's pragmatic approach for estimating intervention effects in a historical cohort of 23,455 individuals, using a control population of 14,839 to determine expected spending at an individual level, against which actual spending could be compared. The actual-to-expected spending difference was then used as the dependent variable in a multivariate model to determine the predictive contribution of a multitude of demographic, clinical, and utilization characteristics. The coefficients from this model yielded the information required to build predictive models for prospective use. Model variables related to medication adherence and historical utilization unexplained by disease burden proved to be more important predictors of impactability than any given diagnosis or event, disease profile, or overall costs of care. Comparison of this approach to alternative targeting strategies (emergency department super-utilizers, inpatient super-utilizers, or patients with highest Hierarchical Condition Category risk scores) suggests a 2- to 3-fold higher return on investment using impactability-based targeting.