Failure Of Trials Research Articles

Abstract 2857: Patient-derived cells (PDCs) and organoids (PDOs) as platforms for screening novel therapeutics for NSCLC

Abstract Purpose: Patient-derived cells (PDCs) and organoids (PDOs) are constructed from patient tissue to mimic the biological features of patients. In cancer research, PDC/PDOs have been crucial as they can recapitulate tumor mutations. As heterogeneity between traditional cell lines and the human body leads to clinical trial failure, PDC/PDOs are widely used for predicting the preclinical drug efficacy. The aim of this study is to show that the PDC/PDOs can be used as effective tools for screening novel therapies on non-small cell lung cancer (NSCLC). Experimental design: PDC/PDO models from malignant effusions were established as following. We succeeded the establishment with samples which are positive for malignancy in cytology tests and tumor colony formation. Genotypes are analyzed by Sanger sequencing, Whole exome sequencing, or RNA-sequencing. Cell viability assay was performed using currently approved drugs or drugs in clinical development or their combinations. Results: A total of 46 PDCs and 150 PDOs was established from NSCLC patients, including models harboring sensitizing EGFR mutations, ALK fusions, ROS1 fusions, EGFR exon20 insertion, BRAF V600E, and those harboring various resistance mechanisms to EGFR-TKIs (T790M, C797S/C797G, MET amplification), to ALK-TKIs (G1202R), and to ROS1 TKI (G2032R). Osimertinib-resistant YU-1097 harboring EGFR resistance mutation (E19del/T790M/C797S) revealed sensitivity to BLU-945 (IC50, 108nM), a novel fourth-generation EGFR-TKI. A similar inhibition of cell viability was observed with repotrectinib (IC50, 21nM), a next-generation ROS1-TKI and lorlatinib (IC50, 9nM) in YU-1078 harboring CD74-ROS1, whereas more robust tumor regression was seen with repotrectinib in YU1078-derived xenograft model. Amivantamab, a EGFR-MET bispecific antibody, showed a robust activity in YU-1163 and YUO-036 in vitro and in vivo. YU-1077 harboring ALK G1202R solvent-front mutation showed sensitivity to NVL-655, a next-generation ALK-TKI, with a potency > 10-fold than that of lorlatinib. YUO-010 with MET amplification following osimertinib was sensitive to RGEN 5093-M114, a METxMET bispecific antibody-drug conjugate. Conclusions: PDC/PDO models can be utilized for evaluating activity of novel agents and will accelerate novel drug development in NSCLC. Citation Format: Yunjoo Joo, Sewon Park, Ju-hyeon Lee, Mi Ran Yun, Mi Ra Yu, Chun-Bong Synn, Seung Yeon Oh, Eun Ji Lee, Dong Kwon Kim, Seul Lee, Kyumin Lim, Min Hee Hong, Sun Min Lim, Chang Gon Kim, Ji Yun Lee, Jii Bum Lee, Byoung Chul Cho. Patient-derived cells (PDCs) and organoids (PDOs) as platforms for screening novel therapeutics for NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2857.

MP76-11 A NOVEL TURP SCORE FOR PREDICTING PERIOPERATIVE COMPLICATIONS

You have accessJournal of UrologyCME1 Apr 2023MP76-11 A NOVEL TURP SCORE FOR PREDICTING PERIOPERATIVE COMPLICATIONS Shanky Singh, Priyabrat Das, and Girdhar Bora Shanky SinghShanky Singh More articles by this author , Priyabrat DasPriyabrat Das More articles by this author , and Girdhar BoraGirdhar Bora More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003350.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: TURP complications significantly contribute for morbidity and hospital stay. Our objective was to prepare a score which can predict this complications preoperatively and help to take measures to reduce them. METHODS: A Prospective observational study was conducted. In the study variables used were- age, associated co morbidity (calculated by ASA–PS criteria), prostate size on USG, duration of treatment with 5-ἀ reductase inhibitors, serum PSA. Outcome variables measured were peri-operative bleeding, failed post catheter free trial, post operative electrolyte abnormality, long hospital stay and transient stress urinary incontinence. Each of study variables, based on their distribution were divided in to tertiles. The minimum value of the score being 5 and maximum 15. Based on the above findings we developed a scoring system as shown in Table 1 and an individual score was developed for each patients. RESULTS: We analyze 110 patients. Complications were bleeding in 11 (10.2%), electrolyte imbalance in 31 (29.5%), failure of catheter free trial in 5 (4.8%), longer hospital stay in (26) 25.7% and transient sress urinary incontinence in 6 (5.7%) patients were present. Factors and complications showed significant relation. The factors significantly associated with complications in Bivariate analysis were PSA value (p-0.008), age (p-0.049),prostate size (p-0.001), 5 alpha reductase (p-0.042) and not significant was ASA (p-0.431).Based on these findings we categorize patients in to three categories as CAT I with score of 5-7, CAT II with score of 8-11 and CAT III with a score of 12-15. The categorization predict the peri-opeartive complications according to groups so that effective measures can be taken before hand of the procedures. The sensitivity and specificity of the scoring system is as shown in below table. CONCLUSIONS: Our proposed scoring system based on the common pre operative parameters to predict the peri operative complication rate is easy to use which can reduce the morbidity of the patients. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1095 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shanky Singh More articles by this author Priyabrat Das More articles by this author Girdhar Bora More articles by this author Expand All Advertisement PDF downloadLoading ...

HIV vaccine trial failure

HIV vaccine trial failure

The Role of Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure Management: The Continuing Challenge of Clinical Outcome Endpoints in Heart Failure Trials.

The introduction of sodium-glucose cotransporter-2 (SGLT2) inhibitors in the management of heart failure with preserved ejection fraction (HFpEF) may be regarded as the first effective treatment in these patients. However, this proposition must be evaluated from the perspective of the complexity of clinical outcome endpoints in heart failure. The major goals of heart failure treatment have been categorized as: (1) reduction in (cardiovascular) mortality, (2) prevention of recurrent hospitalizations due to worsening heart failure, and (3) improvement in clinical status, functional capacity, and quality of life. The use of the composite primary endpoint of cardiovascular death and hospitalization for heart failure in SGLT2 inhibitor HFpEF trials flowed from the assumption that hospitalization for heart failure is a proxy for subsequent cardiovascular death. The use of this composite endpoint was not justified since the effect of the intervention on both components was clearly distinct. Moreover, the lack of convincing and clinically meaningful effects of SGLT2 inhibitors on metrics of heart failure-related health status indicates that the effect of this class of drugs in HFpEF patients is essentially restricted to an effect on hospitalization for heart failure. In conclusion, SGLT2 inhibitors do not represent a substantial breakthrough in the management of HFpEF.

Immune evaluation of granulocyte-macrophage colony stimulating factor loaded hierarchically 3D nanofiber scaffolds in a humanized mice model.

Background: Immune evaluation of biomaterials for tissue regeneration is a critical preclinical evaluation. The current evaluation criterion (ISO 10993-1 or GB/T 16886) uses rodents to perform the immune evaluation. However, the immune system of rodents is different from humans, the obtained results may not be reliable, which could lead directly to the failure of clinical trials. Granulocyte-macrophage colony-stimulating factor (GM-CSF) shows a great potential application in tissue regeneration by regulating local immune responses. The presented work combines the advantages of GM-CSF (immunoregulation) and hierarchically 3D nanofiber scaffolds (tissue regeneration). Methods: Firstly, we fabricated GM-CSF loaded 3D radially aligned nanofiber scaffolds, and then subcutaneous implantation was performed in humanized mice. The whole scaffold and surrounding tissue were harvested at each indicated time point. Finally, the cell infiltration and local immune responses were detected by histological observations, including H&E and Masson staining and immunochemistry. Results: We found significant cell migration and extracellular matrix deposition within the 3D radially aligned nanofiber scaffold after subcutaneous implantation. The locally released GM-CSF could accelerate the expression of human dendritic cells (CD11c) only 3days after subcutaneous implantation. Moreover, higher expression of human cytotoxic T cells (CD3+/CD8+), M1 macrophages (CD68/CCR7) was detected within GM-CSF loaded radially aligned nanofiber scaffolds and their surrounding tissues. Conclusions: The 3D radially aligned scaffold can accelerate cell migration from surrounding tissues to regenerate the wound area. And the locally released GM-CSF enhances dendritic cell recruitment and activation of cytotoxic T cells and M1 macrophages. Taken together, the GM-CSF loaded 3D radially aligned nanofiber scaffolds have a promising potential for achieving tissue regeneration.

Autopsy of a failed trial part 1: A qualitative investigation of clinician's views on and experiences of the implementation of the DAISIES trial in UK-based intensive eating disorder services.

The DAISIES trial, comparing inpatient and stepped-care day patient treatment for adults with severe anorexia nervosa was prematurely terminated in March 2022 due to poor recruitment. This qualitative study seeks to understand the difficulties faced during the trial by investigating stakeholders' views on and experiences of its implementation. Semi-structured interview and focus group transcripts, and trial management and oversight group meeting minutes from May 2020-June 2022 were analysed using thematic analysis. Participants were 47 clinicians and co-investigators involved with the DAISIES trial. The Non-Adoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework was applied to the interpretive themes to classify barriers and facilitators to implementation. Five themes were identified: incompatible participation interests; changing standard practice; concerns around clinical management; systemic capacity and capability issues; and Covid-19 disrupting implementation. Applying the NASSS framework indicated the greatest implementation challenges to arise with the adopters (e.g. patients, clinicians), the organisational systems (e.g. service capacity), and the wider socio-political context (e.g. Covid-19 closing services). Our findings emphasise the top-down impact of systemic-level research implementation challenges. The impact of the Covid-19 pandemic accentuated pre-existing organisational barriers to trial implementation within intensive eating disorder services, further limiting the capacity for research.

Development on Animal Models for Drug/Chemical Induced Liver Injury

In the human body, the largest gland is the liver and does a lot of essential work of the body. Liver damage is the cause of mortality and increasing day by day. Liver disease is caused by multiple factors, such as an autoimmune condition, toxic chemical exposure, viral infection, and dietary factors. Drug-induced liver injury (DILI) is a critical issue in drug development because DILI causes failures in clinical trials and the withdrawal of approved drugs from the market and leading to pathological changes result, including increase in SGOT, SGPT and bilirubin as well as the free radical generation. In this review, contains the animal model of hepatotoxicity with a different cause, their action mech., and procedure with dose. These models include the toxicity caused by chemical, drug, radiation, metal, diet, and high-fat this will lead to pathological changes resulting in hepatotoxicity.

Differentiated approach to the pharmacotherapy of autism spectrum disorders: biochemical aspects

Autism Spectrum Disorders (ASD) are highly heterogeneous neurodevelopmental disorders caused by a complex interaction of numerous genetic and environmental factors and leading to deviations in the nervous system formation at very early developmental stages. Currently, there are no accepted pharmacological treatments for so-called core symptoms of ASD, such as social communication disorders and restricted and repetitive behavior patterns. The lack of knowledge about biological basis of ASD, the absence of clinically significant biochemical parameters reflecting abnormalities in signaling molecular cascades controlling the nervous system development and functioning, and the lack of methods for selection of clinically and biologically homogeneous subgroups are considered among the causes for the failure of clinical trials of ASD pharmacotherapy. This review considers the possibilities of applying a differentiated clinical and biological approach to the targeted search for ASD pharmacotherapy with an emphasis on biochemical markers associated with ASD and attempts to stratify patients by biochemical parameters. The use of approach such as “target-oriented therapy and assessment of the status of the target before and during the treatment to identify patients with a positive response to treatment” is discussed using the published results of clinical trials as examples. It is concluded that the identification of biochemical parameters for the identification of distinct subgroups among ASD patients requires research on large samples reflecting the clinical and biological diversity of patients with ASD, and the use of unified approaches for such studies. An integrated approach, including clinical observation, clinical-psychological assessment of patient behavior, study of anamnesis and description of individual molecular profiles should become a new strategy for stratifying and subgrouping patients with ASD for clinical pharmacotherapeutic trials, as well as for evaluating its efficiency.

A survey of neurophysiological differentiation across mouse visual brain areas and timescales.

Neurophysiological differentiation (ND), a measure of the number of distinct activity states that a neural population visits over a time interval, has been used as a correlate of meaningfulness or subjective perception of visual stimuli. ND has largely been studied in non-invasive human whole-brain recordings where spatial resolution is limited. However, it is likely that perception is supported by discrete neuronal populations rather than the whole brain. Therefore, here we use Neuropixels recordings from the mouse brain to characterize the ND metric across a wide range of temporal scales, within neural populations recorded at single-cell resolution in localized regions. Using the spiking activity of thousands of simultaneously recorded neurons spanning 6 visual cortical areas and the visual thalamus, we show that the ND of stimulus-evoked activity of the entire visual cortex is higher for naturalistic stimuli relative to artificial ones. This finding holds in most individual areas throughout the visual hierarchy. Moreover, for animals performing an image change detection task, ND of the entire visual cortex (though not individual areas) is higher for successful detection compared to failed trials, consistent with the assumed perception of the stimulus. Together, these results suggest that ND computed on cellular-level neural recordings is a useful tool highlighting cell populations that may be involved in subjective perception.

Single-leg medial drop landing with trunk lean includes improper body mechanics related to anterior cruciate ligament injury risk: A comparison of body mechanics between successful trials and failed trials in the drop landing test among female basketball athletes

Improper body mechanics during landing is a typical risk factor of anterior cruciate ligament injury. Drop landing test is used to evaluate landing mechanics by observing not only successful trials but also failed trials. Leaning of the trunk, which is frequently observed during failed trials, may lead to improper body mechanics related to anterior cruciate ligament injury. This study aimed to elucidate the mechanisms of landing with trunk lean that may underlie the risks of anterior cruciate ligament injury by comparing body mechanics between failed and successful trials. Participants were 72 female basketball athletes. The athletic task was single-leg medial drop landing, and the body mechanics was recorded by a motion capture system and force plate. Participants fixed the landing pose for ≥3s in successful trials but failed to do so in failed trials. Failed trials included the large lean of trunk. There were significant changes in thoracic and pelvic leans at initial contact in failed trials with medial trunk lean (p<0.05). Kinematics and kinetics during the landing phase in failed trials were associated with the risks of anterior cruciate ligament injury. These findings suggest that landing mechanics with trunk lean involves many biomechanical factors related to anterior cruciate ligament injury and demonstrates the inappropriate pose of trunk from the dropping phase. Exercise programs aimed at the landing manoeuver without trunk lean may contribute to reduce the risks of anterior cruciate ligament injury in female basketball athletes.

Immune-mediated myogenesis and acetylcholine receptor clustering promote a slow disease progression in ALS mouse models

BackgroundAmyotrophic lateral sclerosis (ALS) is a heterogeneous disease in terms of onset and progression rate. This may account for therapeutic clinical trial failure. Transgenic SOD1G93A mice on C57 or 129Sv background have a slow and fast disease progression rate, mimicking the variability observed in patients.Based on evidence inferring the active influence of skeletal muscle on ALS pathogenesis, we explored whether dysregulation in hindlimb skeletal muscle reflects the phenotypic difference between the two mouse models.MethodsEx vivo immunohistochemical, biochemical, and biomolecular methodologies, together with in vivo electrophysiology and in vitro approaches on primary cells, were used to afford a comparative and longitudinal analysis of gastrocnemius medialis between fast- and slow-progressing ALS mice.ResultsWe reported that slow-progressing mice counteracted muscle denervation atrophy by increasing acetylcholine receptor clustering, enhancing evoked currents, and preserving compound muscle action potential. This matched with prompt and sustained myogenesis, likely triggered by an early inflammatory response switching the infiltrated macrophages towards a M2 pro-regenerative phenotype. Conversely, upon denervation, fast-progressing mice failed to promptly activate a compensatory muscle response, exhibiting a rapidly progressive deterioration of muscle force.ConclusionsOur findings further pinpoint the pivotal role of skeletal muscle in ALS, providing new insights into underestimated disease mechanisms occurring at the periphery and providing useful (diagnostic, prognostic, and mechanistic) information to facilitate the translation of cost-effective therapeutic strategies from the laboratory to the clinic.

GENDER-RELATED VARIATIONS IN PATHOPHYSIOLOGICAL RESPONSES TO METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS PNEUMONIA AND SEPSIS.

In preclinical studies, the protective effects of female sex hormones and the immunosuppressive effects of male sex hormones were demonstrated. However, gender-related differences in multiorgan failure and mortality in clinical trials have not been consistently explained. This study aims to investigate gender-related differences in the development and progression of sepsis using a clinically relevant ovine model of sepsis. Adult Merino male (n=7) and female (n=7) sheep were surgically prepared with multiple catheters before the study. To induce sepsis, bronchoscopy instilled methicillin-resistant Staphylococcus aureus into sheep's lungs. The time from the bacterial inoculation until the modified Quick Sequential Organ Failure Assessment (q-SOFA) score became positive was measured and analyzed primarily. We also compared the SOFA score between these male and female sheep over time. Survival, hemodynamic changes, the severity of pulmonary dysfunction, and microvascular hyperpermeability were also compared. The time from the onset of bacterial inoculation to the positive q-SOFA in male sheep was significantly shorter than in female sheep. Mortality was not different between these sheep (14% vs. 14%). There were no significant differences in hemodynamic changes and pulmonary function between the two groups at any time point. Similar changes in hematocrit, urine output, and fluid balance were observed between females and males. The present data indicate that the onset of multiple organ failure and progression of sepsis is faster in male sheep than in female sheep, even though the severity of cardiopulmonary function is comparable over time. Further studies are warranted to validate the above results.

A Novel Rat Model of Embolic Cerebral Ischemia Using a Cell-Implantable Radiopaque Hydrogel Microfiber.

The failure of neuroprotective treatment-related clinical trials, including stem cell therapies, may be partially due to a lack of suitable animal models. We have developed a stem cell-implantable radiopaque hydrogel microfiber that can survive for a long time in vivo. The microfiber is made of barium alginate hydrogel containing zirconium dioxide, fabricated in a dual coaxial laminar flow microfluidic device. We aimed to develop a novel focal stroke model using this microfiber. Using male Sprague-Dawley rats (n=14), a catheter (inner diameter, 0.42 mm; outer diameter, 0.55 mm) was navigated from the caudal ventral artery to the left internal carotid artery using digital subtraction angiography. A radiopaque hydrogel microfiber (diameter, 0.4 mm; length, 1 mm) was advanced through the catheter by slow injection of heparinized physiological saline to establish local occlusion. Both 9.4-T magnetic resonance imaging at 3 and 6 h and 2% 2,3,5-triphenyl tetrazolium chloride staining at 24 h after stroke model creation were performed. Neurological deficit score and body temperature were measured. The anterior cerebral artery-middle cerebral artery bifurcation was selectively embolized in all rats. Median operating time was 4 min (interquartile range [IQR], 3-8 min). Mean infarct volume was 388 mm3 (IQR, 354-420 mm3) at 24 h after occlusion. No infarction of the thalamus or hypothalamus was seen. Body temperature did not change significantly over time (P = 0.204). However, neurological deficit scores before and at 3, 6, and 24 h after model creation differed significantly (P < 0.001). We present a novel rat model of focal infarct restricted to the middle cerebral artery territory using a radiopaque hydrogel microfiber positioned under fluoroscopic guidance. By comparing the use of stem cell-containing versus non-containing fibers in this stroke model, it would be possible to determine the efficacy of "pure" cell transplantation in treating stroke.

Differentiated Approach to Pharmacotherapy of Autism Spectrum Disorders: Biochemical Aspects

Autism Spectrum Disorders (ASD) are highly heterogeneous neurodevelopmental disorders caused by a complex interaction of numerous genetic and environmental factors and leading to deviations in the nervous system formation at the very early developmental stages. Currently, there are no accepted pharmacological treatments for the so-called core symptoms of ASD, such as social communication disorders and restricted and repetitive behavior patterns. Lack of knowledge about biological basis of ASD, absence of the clinically significant biochemical parameters reflecting abnormalities in the signaling cascades controlling the nervous system development and functioning, and lack of methods for selection of clinically and biologically homogeneous subgroups are considered as causes for the failure of clinical trials of ASD pharmacotherapy. This review considers the possibilities of applying differentiated clinical and biological approaches to the targeted search for ASD pharmacotherapy with emphasis on biochemical markers associated with ASD and attempts to stratify patients by biochemical parameters. The use of such approach as "the target-oriented therapy and assessment of the target status before and during the treatment to identify patients with a positive response to treatment" is discussed using the published results of clinical trials as examples. It is concluded that identification of biochemical parameters for selection of the distinct subgroups among the ASD patients requires research on large samples reflecting clinical and biological diversity of the patients with ASD, and use of unified approaches for such studies. An integrated approach, including clinical observation, clinical-psychological assessment of the patient behavior, study of medical history and description of individual molecular profiles should become a new strategy for stratifying patients with ASD for clinical pharmacotherapeutic trials, as well as for evaluating their efficiency.

Neutrophil Heterogeneity and its Roles in the Inflammatory Network after Ischemic Stroke.

As the first peripheral immune cells to enter the brain after ischemic stroke, neutrophils are important participants in stroke-related neuroinflammation. Neutrophils are quickly mobilized from the periphery in response to a stroke episode and cross the blood-brain barrier to reach the ischemic brain parenchyma. This process involves the mobilization and activation of neutrophils from peripheral immune organs (including the bone marrow and spleen), their chemotaxis in the peripheral blood, and their infiltration into the brain parenchyma (including disruption of the blood-brain barrier, inflammatory effects on brain tissue, and interactions with other immune cell types). In the past, it was believed that neutrophils aggravated brain injuries through the massive release of proteases, reactive oxygen species, pro-inflammatory factors, and extracellular structures known as neutrophil extracellular traps (NETs). With the failure of early clinical trials targeting neutrophils and uncovering their underlying heterogeneity, our view of their role in ischemic stroke has become more complex and multifaceted. As neutrophils can be divided into N1 and N2 phenotypes in tumors, neutrophils have also been found to have similar phenotypes after ischemic stroke, and play different roles in the development and prognosis of ischemic stroke. N1 neutrophils are dominant during the acute phase of stroke (within three days) and are responsible for the damage to neural structures via the aforementioned mechanisms. However, the proportion of N2 neutrophils gradually increases in later phases, and this has a beneficial effect through the release of anti-inflammatory factors and other neuroprotective mediators. Moreover, the N1 and N2 phenotypes are highly plastic and can be transformed into each other under certain conditions. The pronounced differences in their function and their high degree of plasticity make these neutrophil subpopulations promising targets for the treatment of ischemic stroke.

Abstract Number ‐ 128: Predictors of the effects of flow diversion in very large and giant aneurysms

Introduction The treatment paradigm for very large and giant aneurysms recently changed to flow diversion, in light of the results of the Pipeline for Uncoilable or Failed Aneurysms trial. However, the effects of flow diversion was definitely unknown. We explored this topic and identified predictors of such effects. Methods We retrospectively reviewed 51 patients with unruptured aneurysms admitted to our institution for flow diversion between February 2014 and August 2019. Patients were categorized into an effect group (no filling or remnant entry) and a no‐effect group (subtotal or total filling). We evaluated aneurysm size and shape, incorporation vessel, parent artery stenosis and curvature, stagnation of contrast medium within the aneurysm, use or not of balloon angioplasty, and intra‐aneurysm thrombus, as potential predictors of the effects of flow diversion. Results The effect group comprised 34 patients (66.7%, 34/51; no filling [35.3%, 18/51] and remnant entry [31.4% 16/51]). The no‐effect group comprised 17 patients (33.3%, 17/51; subtotal filling [29.4%, 15/51] and total filling [3.9% 2/51]). The presence of an incorporation vessel (odds ratio 0.13, p = 0.021) and balloon angioplasty (odds ratio 0.05, p = 0.004) were independent risk factors for poor flow diversion (no‐effect group) in multivariate logistic regression analyses. Conclusions Flow diversion is effective for very large and giant aneurysms but the outcomes require further improvement. The results of this study show that an incorporated vessel and excessive balloon angioplasty might compromise flow diversion. Considering this finding can help improve the outcomes of flow diversion.

Translating precision medicine for autism spectrum disorder: A pressing need.

Autism spectrum disorder (ASD) is a heterogenous group of neurodevelopmental disorders (NDDs) with a high unmet medical need. Currently, ASD is diagnosed according to behavior-based criteria that overlook clinical and genomic heterogeneity, thus repeatedly resulting in failed clinical trials. Here, we summarize the scientific evidence pointing to the pressing need to create a precision medicine framework for ASD and other NDDs. We discuss the role of omics and systems biology to characterize more homogeneous disease subtypes with different underlying pathophysiological mechanisms and to determine corresponding tailored treatments. Finally, we provide recent initiatives towards tackling the complexity in NDDs for precision medicine and cost-effective drug discovery.

Recent Advances in Psychopharmacology: From Bench to Bedside Novel Trends in Schizophrenia.

Research in the field of psychopharmacology is ongoing to develop novel compounds which can revolutionize the treatment of psychiatric disorders. The concept of bench-to-bedside is a tedious process, transforming the initial research performed in the laboratories into novel treatment options. Schizophrenia (SCZ) is a chronic psychiatric illness with significant morbidity and mortality. SCZ not only presents with psychotic symptoms including hallucinations and delusions but also with negative and cognitive symptoms. The negative symptoms include the diminished ability to express emotions, loss of pleasure, and motivation with minimal social interactions. Conventional antipsychotics primarily target positive symptoms with minimal therapeutic benefits for negative and cognitive symptoms along with metabolic side effects. Researchers have explored novel targets to develop new compounds to overcome the above limitations. The glutamatergic system has provided new hope in treating schizophrenia by targeting negative and cognitive symptoms. Other receptor modulators, including serotonergic, phosphodiesterase, trans-amine-associated receptors, etc., are novel targets for developing new compounds. Future research is required in this field to explore novel compounds and establish their efficacy and safety for the treatment of schizophrenia. Last but not least, pharmacogenomics has effectively utilized genetic information to develop novel compounds by minimizing the risk of failure of the clinical trials and enhancing efficacy and safety.

Ultrasound-Assisted Synthesis of Piperidinyl-Quinoline Acylhydrazones as New Anti-Alzheimer's Agents: Assessment of Cholinesterase Inhibitory Profile, Molecular Docking Analysis, and Drug-like Properties.

Alzheimer's disease (AD) is one of the progressive neurological disorders and the main cause of dementia all over the world. The multifactorial nature of Alzheimer's disease is a reason for the lack of effective drugs as well as a basis for the development of new structural leads. In addition, the appalling side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with the marketed treatment modalities and many failed clinical trials significantly limit the use of drugs and alarm for a detailed understanding of disease heterogeneity and the development of preventive and multifaceted remedial approach desperately. With this motivation, we herein report a diverse series of piperidinyl-quinoline acylhydrazone therapeutics as selective as well as potent inhibitors of cholinesterase enzymes. Ultrasound-assisted conjugation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes (4a,b) and (un)substituted aromatic acid hydrazides (7a-m) provided facile access to target compounds (8a-m and 9a-j) in 4-6 min in excellent yields. The structures were fully established using spectroscopic techniques such as FTIR, 1H- and 13C NMR, and purity was estimated using elemental analysis. The synthesized compounds were investigated for their cholinesterase inhibitory potential. In vitro enzymatic studies revealed potent and selective inhibitors of AChE and BuChE. Compound 8c showed remarkable results and emerged as a lead candidate for the inhibition of AChE with an IC50 value of 5.3 ± 0.51 µM. The inhibitory strength of the optimal compound was 3-fold higher compared to neostigmine (IC50 = 16.3 ± 1.12 µM). Compound 8g exhibited the highest potency and inhibited the BuChE selectively with an IC50 value of 1.31 ± 0.05 µM. Several compounds, such as 8a-c, also displayed dual inhibitory strength, and acquired data were superior to the standard drugs. In vitro results were further supported by molecular docking analysis, where potent compounds revealed various important interactions with the key amino acid residues in the active site of both enzymes. Molecular dynamics simulation data, as well as physicochemical properties of the lead compounds, supported the identified class of hybrid compounds as a promising avenue for the discovery and development of new molecules for multifactorial diseases, such as Alzheimer's disease (AD).

Strategy toward Kinase-Selective Drug Discovery.

Kinase drug selectivity is the ground challenge in cancer research. Due to the structurally similar kinase drug pockets, off-target inhibitor toxicity has been a major cause for clinical trial failures. The pockets are similar but not identical. Here, we describe a transformation invariant protocol to identify distinct geometric features in the drug pocket that can distinguish one kinase from all others. We integrate available experimental structures with the artificial intelligence-based structural kinome, performing a kinome-wide structural bioinformatic analysis to establish the structural principles of kinase drug selectivity. We generate the structural landscape from the experimental kinase-ligand complexes and propose a binary network that encapsulates the information. The results show that all kinases contain binary units that are shared by less than seven other kinases in the kinome. 331 kinases contain unique binary units that may distinguish them from all others. The structural features encoded by these binary units in the network represent the inhibitor-accessible geometric space that may capture the kinome-wide selectivity. Our proposed binary network with the unsupervised clustering can serve as a general structural bioinformatic protocol for extracting the distinguishing structural features for any protein from their families. We apply the binary network to epidermal growth factor receptor tyrosine kinase inhibitor selectivity by targeting the gate area and the AKT1 serine/threonine kinase selectivity by binding to the αC-helix region and the allosteric pocket. Finally, we develop the cross-platform software, KDS (Kinase Drug Selectivity), for customized visualization and analysis of the binary networks in the human kinome (https://github.com/CBIIT/KDS).