Hepatic artery stenosis following adult liver transplantation: evaluation of different endovascular treatment approaches.

PURPOSE: To evaluate the efficacy and safety of hepatic artery interventions (HAI) versus extra-hepatic arterial interventions (EHAI) when managing clinically significant hepatic artery stenosis (HAS) after adult orthotopic liver transplantation. MATERIALS AND METHODS: A single-center retrospective cohort analysis was conducted on liver transplant patients who underwent intervention for clinically significant HAS from September 2012 to September 2021. The HAI treatment arm included hepatic artery angioplasty and/or stent placement while the EHAI treatment arm comprised of non-hepatic visceral artery embolization. Primary outcomes included peri-procedural complications and 1-year liver-related deaths. Secondary outcomes included biliary ischemic events, longitudinal trends in liver enzymes and ultrasound parameters pre-and post-intervention. RESULTS: The HAI arm included 21 procedures in 18 patients and the EHAI arm included 27 procedures in 22 patients. There were increased 1-year liver-related deaths (10% [2/21] vs 0% [0/27], p = 0.10) and complications (29% [6/21] vs 4% [1/27], p = 0.015) in the HAI group compared to the EHAI group. Both HAI and EHAI groups exhibited similar improvements in transaminitis including changes of ALT (-72 U/L vs -112.5 U/L, p = 0.60) and AST (-58 U/L vs -48 U/L, p = 0.56) at 1-month post-procedure. Both treatment arms demonstrated increases in post-procedural peak systolic velocity of the hepatic artery distal to the stenosis, while the HAI group also showed significant improvement in resistive indices following the intervention. CONCLUSION: Direct hepatic artery interventions remain the definitive treatment for clinically significant hepatic artery stenosis; however, non-hepatic visceral artery embolization can be considered a safe alternative intervention in cases of unfavorable hepatic anatomy.

MicroRNA, miR-501 regulate the V(D)J recombination in B cells.

The stringent regulation of RAGs (Recombination activating genes), the site-specific endonuclease responsible for V(D)J recombination, is important to prevent genomic rearrangements and chromosomal translocations in lymphoid cells. In the present study, we identify a microRNA, miR-501, which can regulate the expression of RAG1 in lymphoid cells. Overexpression of the pre-miRNA construct led to the generation of mature miRNAs and a concomitant reduction in RAG1 expression, whereas inhibition using anti-miRs resulted in its enhanced expression. The direct interaction of the 3'UTR of miR-501 with RAG1 was confirmed by the reporter assay. Importantly, overexpression of miRNAs led to inhibition of V(D)J recombination in B cells, revealing their impact on the physiological function of RAGs. Of interest is the inverse correlation observed for miR-501 with RAG1 in various leukemia patients and lymphoid cell lines, suggesting its possible use in cancer therapy. Thus, our results reveal the regulation of RAG1 by miR-501-3p in B cells and thus V(D)J recombination and its possible implications on immunoglobulin leukemogenesis.

Evaluation of potential role of R-loop and G-quadruplex DNA in the fragility of c-MYC during chromosomal translocation associated with Burkitt's lymphoma.

t(8;14) translocation is the hallmark of Burkitt's lymphoma and results in c-MYC deregulation. During the translocation, c-MYC gene on chromosome 8 gets juxtaposed to the Ig switch regions on chromosome 14. Although the promoter of c-MYC has been investigated for its mechanism of fragility, little is known about other c-MYC breakpoint regions. We have analyzed the translocation break points at the exon 1/intron 1 of c-MYC locus from patients with Burkitt's lymphoma. Results showed that the breakpoint region, when present on a plasmid, could fold into an R-loop confirmation in a transcription-dependent manner. Sodium bisulfite modification assay revealed significant single-strandedness on chromosomal DNA of Burkitt's lymphoma cell line, Raji, and normal lymphocytes, revealing distinct R-loops covering up to 100 bp region. Besides, ChIP-DRIP analysis reveals that the R-loop antibody can bind to the breakpoint region. Further, we show the formation of stable parallel intramolecular G-quadruplex on non-template strand of the genome. Finally, incubation of purified AID in vitro or overexpression of AID within the cells led to enhanced mutation frequency at the c-MYC breakpoint region. Interestingly, anti-γH2AX can bind to DSBs generated at the c-MYC breakpoint region within the cells. The formation of R-loop and G-quadruplex was found to be mutually exclusive. Therefore, our results suggest that AID can bind to the single-stranded region of the R-loop and G4 DNA, leading to the deamination of cytosines to uracil and induction of DNA breaks in one of the DNA strands, leading to double-strand break, which could culminate in t(8;14) chromosomal translocation.

Management of Severe Allergic-Like Contrast Media Reactions: Pitfalls and Strategies, From the AJR Special Series on Contrast Media.

Adverse reactions to contrast media are often high-acuity events that are uncommon potentially life-threatening. Nonetheless, these events are treatable, and radiologists may be called upon to manage a contrast media reaction. However, because these events are infrequent, they are prone to management errors. This article highlights common pitfalls and practical tips for the management of acute contrast media reactions in children and adults. Recognition of frequent management errors and implementation of the mitigation strategies presented can ameliorate risk and improve patient outcomes. These measures include proper training on reaction management and medication administration, the prompt use of IM epinephrine autoinjectors whenever a severe allergic-like reaction is suspected, the use of visual aids for quick reference in the setting of a reaction, and the recognition of adverse events that are not allergic-like reactions, which commonly require only supportive care.

Integration of exome-seq and mRNA-seq using DawnRank, identified genes involved in innate immunity as drivers of breast cancer in the Indian cohort.

Genetic heterogeneity influences the prognosis and therapy of breast cancer. The cause of disease progression varies and can be addressed individually. To identify the mutations and their impact on disease progression at an individual level, we sequenced exome and transcriptome from matched normal-tumor samples. We utilised DawnRank to prioritise driver genes and identify specific mutations in Indian patients. Mutations in the C3 and HLA genes were identified as drivers of disease progression, indicating the involvement of the innate immune system. We performed immune profiling on 16 matched normal/tumor samples using CIBERSORTx. We identified CD8+ve T cells, M2 macrophages, and neutrophils to be enriched in luminal A and T cells CD4+naïve, natural killer (NK) cells activated, T follicular helper (Tfh) cells, dendritic cells activated, and neutrophils in triple-negative breast cancer (TNBC) subtypes. Weighted gene co-expression network analysis (WGCNA) revealed activation of T cell-mediated response in ER positive samples and Interleukin and Interferons in ER negative samples. WGCNA analysis also identified unique pathways for each individual, suggesting that rare mutations/expression signatures can be used to design personalised treatment.

Nanobiosensors: Concepts and emerging clinical applications.

Biosensors have been one of the most fascinating topics for scientists for a long time. This is because biological moieties are multifaceted and are unswervingly related to the presence of a healthy atmosphere. The biosensor approach has also endured profound changes in recent years. Biosensors have been emphasized for various applications, including food quality estimation, surveillance systems, and health and metabolic abnormality diagnostics. The advances in nanotechnology have led to a considerable potential to enhance biosensors' sensitivity, robustness, and anti-interference capabilities. Several new nanomaterials (such as nanoparticles, nanotubes, nanorods, and nanowires) have been fabricated due to the evolution of nanotechnology, and their unique features are gradually being identified, allowing for much faster detection and reproducibility. Biosensor performance has also been enhanced substantially as a result of their use. Because of their capacity to detect a wide range of compounds at deficient concentrations, nanobiosensors have sparked much interest. This article discusses biosensors based on various nanomaterials, their evolution, accompanying features, and their applications in multiple fields.

Neighborhood-Level Risk Factors for Severe Hyperglycemia among Emergency Department Patients without a Prior Diabetes Diagnosis.

A person's place of residence is a strong risk factor for important diagnosed chronic diseases such as diabetes. It is unclear whether neighborhood-level risk factors also predict the probability of undiagnosed disease. The objective of this study was to identify neighborhood-level variables associated with severe hyperglycemia among emergency department (ED) patients without a history of diabetes. We analyzed patients without previously diagnosed diabetes for whom a random serum glucose value was obtained in the ED. We defined random glucose values ≥ 200 mg/dL as severe hyperglycemia, indicating probable undiagnosed diabetes. Patient addresses were geocoded and matched with neighborhood-level socioeconomic measures from the American Community Survey and claims-based surveillance estimates of diabetes prevalence. Neighborhood-level exposure variables were standardized based on z-scores, and a series of logistic regression models were used to assess the association of selected exposures and hyperglycemia adjusting for biological and social individual-level risk factors for diabetes. Of 77,882 ED patients without a history of diabetes presenting in 2021, 1,715 (2.2%) had severe hyperglycemia. Many geospatial exposures were associated with uncontrolled hyperglycemia, even after controlling for individual-level risk factors. The most strongly associated neighborhood-level variables included lower markers of educational attainment, higher percentage of households where limited English is spoken, lower rates of white-collar employment, and higher rates of Medicaid insurance. Including these geospatial factors in risk assessment models may help identify important subgroups of patients with undiagnosed disease.

Whole transcriptome sequencing reveals HOXD11-AGAP3, a novel fusion transcript in the Indian acute leukemia cohort.

Introduction: Acute leukemia is a heterogeneous disease with distinct genotypes and complex karyotypes leading to abnormal proliferation of hematopoietic cells. According to GLOBOCAN reports, Asia accounts for 48.6% of leukemia cases, and India reports ~10.2% of all leukemia cases worldwide. Previous studies have shown that the genetic landscape of AML in India is significantly different from that in the western population by WES. Methods: We have sequenced and analyzed 9 acute myeloid leukemia (AML) transcriptome samples in the present study. We performed fusion detection in all the samples and categorized the patients based on cytogenetic abnormalities, followed by a differential expression analysis and WGCNA analysis. Finally, Immune profiles were obtained using CIBERSORTx. Results: We found a novel fusion HOXD11-AGAP3 in 3 patients, BCR-ABL1 in 4, and KMT2A-MLLT3 in one patient. Categorizing the patients based on their cytogenetic abnormalities and performing a differential expression analysis, followed by WGCNA analysis, we observed that in the HOXD11-AGAP3 group, correlated co-expression modules were enriched with genes from pathways like Neutrophil degranulation, Innate Immune system, ECM degradation, and GTP hydrolysis. Additionally, we obtained HOXD11-AGAP3-specific overexpression of chemokines CCL28 and DOCK2. Immune profiling using CIBRSORTx revealed differences in the immune profiles across all the samples. We also observed HOXD11-AGAP3-specific elevated expression of lincRNA HOTAIRM1 and its interacting partner HOXA2. Discussion: The findings highlight population-specific HOXD11-AGAP3, a novel cytogenetic abnormality in AML. The fusion led to alterations in immune system represented by CCL28 and DOCK2 over-expression. Interestingly, in AML, CCL28 is known prognostic marker. Additionally, non-coding signatures (HOTAIRM1) were observed specific to the HOXD11-AGAP3 fusion transcript which are known to be implicated in AML.

Whole-exome sequencing of Indian prostate cancer reveals a novel therapeutic target: POLQ.

PURPOSE: Prostate cancer is the second most common cancer diagnosed worldwide and the third most common cancer among men in India. This study's objective was to characterise the mutational landscape of Indian prostate cancer using whole-exome sequencing to identify population-specific polymorphisms. METHODS: Whole-exome sequencing was performed of 58 treatment-naive primary prostate tumors of Indian origin. Multiple computational and statistical analyses were used to profile the known common mutations, other deleterious mutations, driver genes, prognostic biomarkers, and gene signatures unique to each clinical parameter. Cox analysis was performed to validate survival-associated genes. McNemar test identified genes significant to recurrence and receiver-operating characteristic (ROC) analysis was conducted to determine its accuracy. OncodriveCLUSTL algorithm was used to deduce driver genes. The druggable target identified was modeled with its known inhibitor using Autodock. RESULTS: TP53 was the most commonly mutated gene in our cohort. Three novel deleterious variants unique to the Indian prostate cancer subtype were identified: POLQ, FTHL17, and OR8G1. COX regression analysis identified ACSM5, a mitochondrial gene responsible for survival. CYLC1 gene, which encodes for sperm head cytoskeletal protein, was identified as an unfavorable prognostic biomarker indicative of recurrence. The novel POLQ mutant, also identified as a driver gene, was evaluated as the druggable target in this study. POLQ, a DNA repair enzyme implicated in various cancer types, is overexpressed and is associated with a poor prognosis. The mutant POLQ was subjected to structural analysis and modeled with its known inhibitor novobiocin resulting in decreased binding efficiency necessitating the development of a better drug. CONCLUSION: In this pilot study, the molecular profiling using multiple computational and statistical analyses revealed distinct polymorphisms in the Indian prostate cancer cohort. The mutational signatures identified provide a valuable resource for prognostic stratification and targeted treatment strategies for Indian prostate cancer patients. The DNA repair enzyme, POLQ, was identified as the druggable target in this study.

Genome-wide differential DNA methylation analysis of MDA-MB-231 breast cancer cells treated with curcumin derivatives, ST08 and ST09.

ST08 and ST09 are potent curcumin derivatives with antiproliferative, apoptotic, and migrastatic properties. Both ST08 and ST09 exhibit in vitro and in vivo anticancer properties. As reported earlier, these derivatives were highly cytotoxic towards MDA-MB-231 triple-negative breast cancer cells with IC50 values in the nanomolar (40-80nM) range.In this study,we performed whole-genome bisulfite sequencing(WGBS) of untreated (control), ST08 and ST09 (treated) triple-negative breast cancer cell line MDA-MB-231 to unravel epigenetic changes induced by the drug. We identified differentially methylated sites (DMSs) enriched in promoter regions across the genome. Analysis of the CpG island promoter methylation identified 12 genes common to both drugs, and 50% of them are known to be methylated in patient samples that were hypomethylated by drugs belonging to the homeobox family transcription factors.Methylation analysis of the gene body revealed 910 and 952 genes to be hypermethylatedin ST08 and ST09 treated MDA-MB-231 cells respectively. Correlation of the gene body hypermethylation with expression revealed CACNAH1 to be upregulated in ST08 treatment and CDH23 upregulation in ST09.Further, integrated analysis of the WGBS with RNA-seq identified uniquely altered pathways - ST08 altered ECM pathway, and ST09 cell cycle, indicating drug-specific signatures.

Nonamer dependent RAG cleavage at CpGs can explain mechanism of chromosomal translocations associated to lymphoid cancers.

Chromosomal translocations are considered as one of the major causes of lymphoid cancers. RAG complex, which is responsible for V(D)J recombination, can also cleave non-B DNA structures and cryptic RSSs in the genome leading to chromosomal translocations. The mechanism and factors regulating the illegitimate function of RAGs resulting in oncogenesis are largely unknown. Upon in silico analysis of 3760 chromosomal translocations from lymphoid cancer patients, we find that 93% of the translocation breakpoints possess adjacent cryptic nonamers (RAG binding sequences), of which 77% had CpGs in proximity. As a proof of principle, we show that RAGs can efficiently bind to cryptic nonamers present at multiple fragile regions and cleave at adjacent mismatches generated to mimic the deamination of CpGs. ChIP studies reveal that RAGs can indeed recognize these fragile sites on a chromatin context inside the cell. Finally, we show that AID, the cytidine deaminase, plays a significant role during the generation of mismatches at CpGs and reconstitute the process of RAG-dependent generation of DNA breaks both in vitro and inside the cells. Thus, we propose a novel mechanism for generation of chromosomal translocation, where RAGs bind to the cryptic nonamer sequences and direct cleavage at adjacent mismatch generated due to deamination of meCpGs or cytosines.

ST08 Altered NF-κB Pathway in Breast Cancer Cells In Vitro as Revealed by miRNA-mRNA Analysis and Enhanced the Effect of Cisplatin on Tumour Reduction in EAC Mouse Model.

ST08 is a novel curcumin derivative that exhibited apoptotic and anti-migratory activity in MDA-MB-231, triple-negative breast cancer cells reported earlier. In this study, we further explored the anticancer properties of ST08. ST08 reduced tumor burden in vivo and induced apoptosis through the mitochondrial pathway both in vitro and in vivo. ST08 potentiated the effect of cisplatin in vitro and in vivo in mouse EAC breast cancer models with minimal toxicity. ST08 induced alterations in the gene expression were studied by parallel analysis of miRNA and mRNA. 74 differentially expressed miRNA regulated 114 mRNA in triple-negative (MDA-MB-231) cancer cells. Pathway related to the ECM was altered in mesenchymal MDA-MB-231 cells. We constructed a unique miRNA-mRNA interaction network, and one of the pathways regulated by miRNA was NF-κB. Targets of NF-κB like MMP1, PTX3, and MMP2 were downregulated in MDA-MB-231 in response to ST08 treatment. PMA induced cell proliferation was abrogated by ST08 treatment, and no additional cell cytotoxicity was observed when used in combination with IKK-16 indicating ST08 regulation of NF-κB pathway in MDA-MB-231 cells.

MiRAGDB: A Knowledgebase of RAG Regulators.

RAG1 and RAG2 genes generate diversity in immunoglobulin and TCR genes by initiating the process of V-D-J recombination. RAGs recognize specific sequences (heptamer-nonamer) to generate a diversity of immunoglobulins. RAG expression is limited to early B and T cell developmental stages. Aberrant expression of RAG can lead to double strand breaks and translocations as observed in leukemia and lymphoma. The expression of RAG is tightly regulated at the transcriptional and posttranscriptional levels. MicroRNAs (miRNAs) are small non-coding RNAs that are involved in the post-transcriptional regulation of gene expression. This study aimed to identify and catalog RAG regulation by miRNA during normal development and cancer. NGS data from normal B-cell and T-cell developmental stages and blood cancer samples have been analyzed for the expression of miRNAs against RAG1 (1,173 against human RAG1 and 749 against mouse RAG1). The analyzed data has been organized to retrieve the miRNA and mRNA expression of various RAG regulators (10 transcription factors and interacting partners) in normal and diseased states. The database allows users to navigate through the human and mouse RAG regulators, visualize and plot expression. miRAGDB is freely available and can be accessed at http://52.4.112.252/shiny/miragdb/.

Curcumin alters distinct molecular pathways in breast cancer subtypes revealed by integrated miRNA/mRNA expression analysis.

BACKGROUND: Curcumin is well known for its anticancer properties. Its cytotoxic activity has been documented in several cancer cell lines, including breast cancer. The pleiotropic activity of curcumin as an antioxidant, an antiangiogenic, antiproliferative, and pro-apoptotic, is due to its diverse targets, such as signaling pathways, protein/enzyme, or noncoding gene. AIM: This study aimed to identify key miRNAs and mRNAs induced by curcumin in breast cancer cells MCF7, T47D (hormone positive), versus MDA-MB231 (hormone negative) using comparative analysis of global gene expression profiles. METHODS: RNA was isolated and subjected to mRNA and miRNA library sequencing to study the global gene expression profile of curcumin-treated breast cancer cells. The differential expression of gene and miRNA was performed using the DESeq R package. The enriched pathways were studied using cluster profileR, and integrated miRNA-mRNA analysis was carried out using miRtarvis and miRmapper tools. RESULTS: Curcumin treatment led to upregulation of 59% TSGs in MCF7, 21% in MDA-MB-231 cells, and 36% TSGs in T47D, and downregulation of 57% oncogenes in MCF7, 76% in MDA-MB-231, and 91% in T47D. Similarly, curcumin treatment led to upregulation of 32% TSmiRs in MCF7, 37.5% in MDA-MB231, and 62.5% in T47D, and downregulation of 77% oncomiRs in MCF7, 50% in MDA-MB231 and 28.6% in T47D. Integrated analysis of miRNA-mRNA led to the identification of a common NFKB pathway altered by curcumin in all three cell lines. Analysis of uniquely enriched pathway revealed non-integrin membrane-ECM interactions and laminin interactions in MCF7; extracellular matrix organization and degradation in MDA-MB-231 and cell cycle arrest and G2/M transition in T47D. CONCLUSION: Curcumin regulates miRNA and mRNA in a cell type-specific manner. The integrative analysis led to the detection of miRNAs and mRNAs pairs, which can be used as biomarkers associated with carcinogenesis, diagnostic, and treatment response in breast cancer.

Multidimensional Mutational Profiling of the Indian HNSCC Sub-Population Provides IRAK1, a Novel Driver Gene and Potential Druggable Target.

Head and neck squamous cell carcinomas (HNSCC) include heterogeneous group of tumors, classified according to their anatomical site. It is the sixth most prevalent cancer globally. Among South Asian countries, India accounts for 40% of HNC malignancies with significant morbidity and mortality. In the present study, we have performed exome sequencing and analysis of 51 Head and Neck squamous cell carcinoma samples. Besides known mutations in the oncogenes and tumour suppressors, we have identified novel gene signatures differentiating buccal, alveolar, and tongue cancers. Around 50% of the patients showed mutation in tumour suppressor genes TP53 and TP63. Apart from the known mutations, we report novel mutations in the genes AKT1, SPECC1, and LRP1B, which are linked with tumour progression and patient survival. A highly curated process was developed to identify survival signatures. 36 survival-related genes were identified based on the correlation of functional impact of variants identified using exome-seq with gene expression from transcriptome data (GEPIA database) and survival. An independent LASSO regression analysis was also performed. Survival signatures common to both the methods led to identification of 4 dead and 3 alive gene signatures, the accuracy of which was confirmed by performing a ROC analysis (AUC=0.79 and 0.91, respectively). Also, machine learning-based driver gene prediction tool resulted in the identification of IRAK1 as the driver (p-value = 9.7 e-08) and also as an actionable mutation. Modelling of the IRAK1 mutation showed a decrease in its binding to known IRAK1 inhibitors.

MicroRNA miR-29c regulates RAG1 expression and modulates V(D)J recombination during B cell development.

Recombination activating genes (RAGs), consisting of RAG1 and RAG2, are stringently regulated lymphoid-specific genes, which initiate V(D)J recombination in developing lymphocytes. We report the regulation of RAG1 through a microRNA (miRNA), miR-29c, in a B cell stage-specific manner in mice and humans. Various lines of experimentation, including CRISPR-Cas9 genome editing, demonstrate the target specificity and direct interaction of miR-29c to RAG1. Modulation of miR-29c levels leads to change in V(D)J recombination efficiency in pre-B cells. The miR-29c expression is inversely proportional to RAG1 in a B cell developmental stage-specific manner, and miR-29c null mice exhibit a reduction in mature B cells. A negative correlation of miR-29c and RAG1 levels is also observed in leukemia patients, suggesting the potential use of miR-29c as a biomarker and a therapeutic target. Thus, our results reveal the role of miRNA in the regulation of RAG1 and its relevance in cancer.

LL-00066471, a novel positive allosteric modulator of α7 nicotinic acetylcholine receptor ameliorates cognitive and sensorimotor gating deficits in animal models: Discovery and preclinical characterization.

α7 nicotinic acetylcholine receptor (α7 nAChR) is an extensively validated target for several neurological and psychiatric conditions namely, dementia and schizophrenia, owing to its vital roles in cognition and sensorimotor gating. Positive allosteric modulation (PAM) of α7 nAChR represents an innovative approach to amplify endogenous cholinergic signaling in a temporally restricted manner in learning and memory centers of brain. α7 nAChR PAMs are anticipated to side-step burgeoning issues observed with several clinical-stage orthosteric α7 nAChR agonists, related to selectivity, tolerance/tachyphylaxis, thus providing a novel dimension in therapeutic strategy and pharmacology of α7 nAChR ion-channel. Here we describe a novel α7 nAChR PAM, LL-00066471, which potently amplified agonist-induced Ca2+ fluxes in neuronal IMR-32 neuroblastoma cells in a α-bungarotoxin (α-BTX) sensitive manner. LL-00066471 showed excellent oral bioavailability across species (mouse, rat and dog), low clearance and good brain penetration (B/P ratio > 1). In vivo, LL-00066471 robustly attenuated cognitive deficits in both procognitive and antiamnesic paradigms of short-term episodic and recognition memory in novel object recognition task (NORT) and social recognition task (SRT), respectively. Additionally, LL-00066471 mitigated apomorphine-induced sensorimotor gating deficits in acoustic startle reflex (ASR) and enhanced antipsychotic efficacy of olanzapine in conditioned avoidance response (CAR) task. Further, LL-00066471 corrected redox-imbalances and reduced cortico-striatal infarcts in stroke model. These finding together suggest that LL-00066471 has potential to symptomatically alleviate cognitive deficits associated with dementias, attenuate sensorimotor gating deficits in schizophrenia and correct redox-imbalances in cerebrovascular disorders. Therefore, LL-00066471 presents potential for management of cognitive impairments associated with neurological and psychiatric conditions.

Discovery of Novel, Potent, Brain-Permeable, and Orally Efficacious Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptor [4-(5-(4-Chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide]: Structure-Activity Relationship and Preclinical Characterization.

The discovery of a series of thiophenephenylsulfonamides as positive allosteric modulators (PAM) of α7 nicotinic acetylcholine receptor (α7 nAChR) is described. Optimization of this series led to identification of compound 28, a novel PAM of α7 nicotinic acetylcholine receptor (α7 nAChR). Compound 28 showed good in vitro potency, with pharmacokinetic profile across species with excellent brain penetration and residence time. Compound 28 robustly reversed the cognitive deficits in episodic/working memory in both time-delay and scopolamine-induced amnesia paradigms in the novel object and social recognition tasks, at very low dose levels. Additionally, compound 28 has shown excellent safety profile in phase 1 clinical trials and is being evaluated for efficacy and safety as monotherapy in patients with mild to moderate Alzheimer's disease.

G-quadruplex Structures Contribute to Differential Radiosensitivity of the Human Genome.

DNA, the fundamental unit of human cell, generally exists in Watson-Crick base-paired B-DNA form. Often, DNA folds into non-B forms, such as four-stranded G-quadruplexes. It is generally believed that ionizing radiation (IR) induces DNA strand-breaks in a random manner. Here, we show that regions of DNA enriched in G-quadruplex structures are less sensitive to IR compared with B-DNA in vitro and inside cells. Planar G-quartet of G4-DNA is shielded from IR-induced free radicals, unlike single- and double-stranded DNA. Whole-genome sequence analysis and real-time PCR reveal that genomic regions abundant in G4-DNA are protected from radiation-induced breaks and can be modulated by G4 stabilizers. Thus, our results reveal that formation of G4 structures contribute toward differential radiosensitivity of the human genome.

Δ-9-Tetrahydrocannabinol and Cannabidiol produce dissociable effects on prefrontal cortical executive function and regulation of affective behaviors.

The use of cannabis for therapeutic and recreational purposes is growing exponentially. Nevertheless, substantial questions remain concerning the potential cognitive and affective side-effects associated with cannabis exposure. In particular, the effects of specific marijuana-derived phytocannabinoids on neural regions such as the prefrontal cortex (PFC) are of concern, given the role of the PFC in both executive cognitive function and affective processing. The main biologically active phytocannabinoids, ∆-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), interact with multiple neurotransmitter systems important for these processes directly within the PFC. Considerable evidence has demonstrated that acute or chronic THC exposure may induce psychotomimetic effects, whereas CBD has been shown to produce potentially therapeutic effects for both psychosis and/or anxiety-related symptoms. Using an integrative combination of cognitive and affective behavioral pharmacological assays in rats, we report that acute intra-PFC infusions of THC produce anxiogenic effects while producing no impairments in executive function. In contrast, acute infusions of intra-PFC CBD impaired attentional set-shifting and spatial working memory, without interfering with anxiety or sociability behaviors. In contrast, intra-PFC CBD reversed the cognitive impairments induced by acute glutamatergic antagonism within the PFC, and blocked the anxiogenic properties of THC, suggesting that the therapeutic properties of CBD within the PFC may be present only during pathologically aberrant states within the PFC. Interestingly, the effects of PFC THC vs. CBD were found to be mediated through dissociable CB1 vs. 5-HT1A-dependent receptor signaling mechanisms, directly in the PFC.