Secondary Mechanisms Research Articles

WRF-Chem quantification of transport events and emissions sensitivity in Korea during KORUS-AQ

To quantify the relative roles of long-range transport (LRT) versus locally emitted aerosol and ozone precursors during polluted periods in Korea, high-resolution (4 km) Weather Research and Forecasting with Chemistry model simulations were performed. The model was evaluated using surface and airborne observations collected during the KORea and United States Air Quality campaign. Ozone above 40 ppb had mean bias of −5.9 ppb. PM2.5 was biased high (8.2 µg/m3), with a relative bias of 30% given the mean observed value of 26.8 µg/m3. The absolute amounts and shifts between phases for all PM2.5 species except nitrate reasonably match observations across all 4 phases. Notable limitations include an underestimation of nighttime planetary boundary layer height. Transport versus domestic emissions influence was studied by model runs with perturbed emissions and by comparing east-west fluxes over the Yellow Sea to Korean emissions and other normalization metrics. Domestic anthropogenic emission contributions to surface air quality were quantified by location across Korea, segregated by synoptic meteorological phase. The largest contributions from Korean emissions were found under high-pressure stagnant conditions and the smallest for conditions with strong westerly winds. For example, at Seoul, domestic contributions of PM2.5 averaged 49% and 29% in the aforementioned meteorological phases, respectively. Surface concentrations of NOx and toluene in Seoul were over 85% due to domestic emissions. CO and black carbon had both local and remote contributions. Nitrate and ammonium contributions varied greatly by phases in Seoul, with 7%–51% nitrate and 42%–70% of ammonium from remote sources. Variation in direction (west-to-east vs. east-to-west) and magnitude of fluxes support the model sensitivity results. Analysis using fluxes facilitates the quantification of source contributions for secondary species and, in many cases, can be done using a single model run or reanalysis result. The analysis presented shows the importance of using models with high spatial resolution to capture pollutant transport and mixing around Korea. However, there remain uncertainties in secondary aerosol production mechanisms and indications that local production at times could be higher than those modeled in this analysis. Therefore, the results presented here should be viewed as an upper limit on the importance of LRT.

Separating Primary and Secondary Mechanisms for Seismicity Induced by Hydraulic Fracturing

ABSTRACT Hydraulic fracturing operations are generally associated with induced seismic events with magnitudes that are typically lower than those of tectonic-based earthquakes. Although fluid migration and the resulting pore-pressure increase appear to be the primary driving mechanisms, one must also understand fault activation and the secondary interevent triggering process(es) leading to the generation of aftershock sequences. This requires distinguishing between seismic events that are a direct consequence of fluid injections and those that predominantly arise because of secondary mechanisms such as static or dynamic stress triggering caused by preceding earthquakes. Focusing on a case study in the Montney area in western Alberta, Canada, where both surface array and borehole geophone data are available, we (1) establish the importance of secondary mechanisms and aftershock sequences in this area and (2) show that the statistical properties of the aftershock sequences can allow one to establish whether significant fault activation is at play and whether the activated fault zone was critically prestressed. Specifically, we find evidence for aftershock sequences using different statistical methodologies, although the presence of aftershocks in the studied hydraulic-fracturing-induced context is significantly less dominant compared with tectonic seismicity. The identified aftershock sequences are characterized by long-range spatial aftershock zones, setting them apart from other cases in fluid-driven settings but comparable to tectonic aftershock sequences and indicative of fault activation. Despite this observation, we find overall a strong dominance of smaller triggers for aftershock sequences and an aftershock production associated with large-magnitude events that is significantly lower than what has been observed in tectonic settings. This suggests that the activated fault zone as a whole was not critically prestressed, and the associated initial seismic hazard was significantly lower compared with tectonic cases.

Linear and Nonlinear Disturbance Evolution on the Frustum of Hypersonic Ogive Cylinders

Aspects of transition mechanisms on a 14° sharp-nosed ogive cylinder at Mach 6 are elucidated by considering linear and nonlinear disturbance evolution of freestream stochastic and wave packet forcing at different locations downstream of the ogive-cylinder junction. The spectral response of the stochastic forcing displays favorable agreement with experimental observations from Air Force Research Laboratory on which the configuration is based. Intermittent wave packets are generated from small-amplitude continuous freestream pressure forcing. Linear wave packet evolution reveals that Mack modes are the dominant primary instabilities, followed by relatively weaker first-mode waves. The nonlinear wavepacket displays a three-legged wall pressure perturbation signature, which is traced to spanwise curvature effects, and fundamental resonance is the dominant secondary instability mechanism. At higher amplitudes of excitation, weak signatures of subharmonic and oblique resonance phenomena are identified. Downstream placement of the small-amplitude disturbance diminishes amplification of first-mode waves; however, with high-amplitude forcing, the location of actuation does not significantly vary the disturbance evolution signature or the secondary instability mechanisms.

Mechanical loading of the ventricular wall as a spatial indicator for periventricular white matter degeneration

Progressive white matter degeneration in periventricular and deep white matter regions appears as white matter hyperintensities (WMH) on MRI scans. To date, periventricular WMHs are often associated with vascular dysfunction. Here, we demonstrate that ventricular inflation resulting from cerebral atrophy and hemodynamic pulsation with every heartbeat leads to a mechanical loading state of periventricular tissues that significantly affects the ventricular wall. Specifically, we present a physics-based modeling approach that provides a rationale for ependymal cell involvement in periventricular WMH formation. Building on eight previously created 2D finite element brain models, we introduce novel mechanomarkers for ependymal cell loading and geometric measures that characterize lateral ventricular shape. We show that our novel mechanomarkers, such as maximum ependymal cell deformations and maximum curvature of the ventricular wall, spatially overlap with periventricular WMH locations and are sensitive predictors for WMH formation. We also explore the role of the septum pellucidum in mitigating mechanical loading of the ventricular wall by constraining the radial expansion of the lateral ventricles during loading. Our models consistently show that ependymal cells are stretched thin only in the horns of the ventricles irrespective of ventricular shape. We therefore pose that periventricular WMH etiology is strongly linked to the deterioration of the over-stretched ventricular wall resulting in CSF leakage into periventricular white matter. Subsequent secondary damage mechanisms, including vascular degeneration, exacerbate lesion formation and lead to progressive growth into deep white matter regions.

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants in PKD1 or PKD2 genes that encode interacting transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations. Tolvaptan, a vasopressin receptor-2 antagonist that regulates cAMP pathway, is the only FDA-approved ADPKD therapeutic. Tolvaptan reduces renal cyst growth and kidney function loss, but it is not tolerated by many patients and is associated with idiosyncratic liver toxicity. Therefore, additional therapeutic options for ADPKD treatment are needed.MethodsAs drug repurposing of FDA-approved drug candidates can significantly decrease the time and cost associated with traditional drug discovery, we used the computational approach signature reversion to detect inversely related drug response gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database and identified compounds predicted to reverse disease-associated transcriptomic signatures in three publicly available Pkd2 kidney transcriptomic data sets of mouse ADPKD models. We focused on a pre-cystic model for signature reversion, as it was less impacted by confounding secondary disease mechanisms in ADPKD, and then compared the resulting candidates’ target differential expression in the two cystic mouse models. We further prioritized these drug candidates based on their known mechanism of action, FDA status, targets, and by functional enrichment analysis.ResultsWith this in-silico approach, we prioritized 29 unique drug targets differentially expressed in Pkd2 ADPKD cystic models and 16 prioritized drug repurposing candidates that target them, including bromocriptine and mirtazapine, which can be further tested in-vitro and in-vivo.ConclusionCollectively, these results indicate drug targets and repurposing candidates that may effectively treat pre-cystic as well as cystic ADPKD.Graphical

Graphene oxide reinforced chitosan/polyvinyl alcohol antibacterial coatings on stainless steel surfaces exhibit superior bioactivity without human cell cytotoxicity

The study proposes an alternative therapeutics to diminish bacterial attachment in biomedical implants by modifying their surface with passive coatings. A uniform, thin-film of chitosan/polyvinyl alcohol/graphene oxide (CS/PVA/GO) was coated on 316 L stainless steel (SS) surface through spread casting followed by solvent evaporation. The abundant anchoring sites available at macromolecular interfaces of chitosan/PVA matrix facilitated a smooth, dense loading of GO. The effect of GO content on physicochemical features, antibacterial potential, and biocompatibility of coatings was thoroughly studied. The hybrid films displayed good adhesion behavior, and UV-protection ability with desired mechanical and thermal stability when coated on SS surface. Coatings manifested a 1.5–1.7 fold rise in antibacterial efficacy against Staphylococcus epidermidis and Staphylococcus aureus and exhibited a permanent biocidal response after 6 h of contact-active behaviour. We investigated a 3-fold generation of reactive oxygen species as the predominant antibacterial mechanism, which diminishes bacterial integrity by inducing protein leakage (8.5–9 fold higher) and suppressing respiratory chain activity as two secondary mechanisms. All coatings with varying GO content appeared non-haemolytic (<2%) with ultra-low cytotoxicity (<29.08%) against human hepatocellular carcinoma (HepG2) and peripheral blood mononuclear cells. The degradation rate of coatings in simulated body fluid exhibited a higher stability, indicated by a lower weight loss (69–78%) and a decrease in pH values as the GO content in coatings increased from 0.05 to 0.15 wt%. Such anti-infective coating is a step forward in inhibiting bacterial colonization on SS surfaces to extend its lifespan.

Accumulation of Dystrophin-Positive Muscle Fibers and Improvement of Neuromuscular Junctions in mdx Mouse Muscles after Bone Marrow Transplantation under Different Conditions.

Duchenne muscular dystrophy (DMD) is a severe muscular disorder caused by mutations in the dystrophin gene. It leads to respiratory and cardiac failure and premature death at a young age. Although recent studies have greatly deepened the understanding of the primary and secondary pathogenetic mechanisms of DMD, an effective treatment remains elusive. In recent decades, stem cells have emerged as a novel therapeutic product for a variety of diseases. In this study, we investigated nonmyeloablative bone marrow cell (BMC) transplantation as a method of cell therapy for DMD in an mdx mouse model. By using BMC transplantation from GFP-positive mice, we confirmed that BMCs participate in the muscle restoration of mdx mice. We analyzed both syngeneic and allogeneic BMC transplantation under different conditions. Our data indicated that 3 Gy X-ray irradiation with subsequent BMC transplantation improved dystrophin synthesis and the structure of striated muscle fibers (SMFs) in mdx mice as well as decreasing the death rate of SMFs. In addition, we observed the normalization of neuromuscular junctions (NMJs) in mdx mice after nonmyeloablative BMC transplantation. In conclusion, we demonstrated that nonmyeloablative BMC transplantation could be considered a method for DMD treatment.

Current insights into the management of spinal cord injury

BackgroundTraumatic spinal cord injury (SCI) is a serious disorder that results in severe impairment of neurological function as well as disability, ultimately reducing a patient's quality of life. The pathophysiology of SCI involves a primary and secondary phase, which causes neurological injury. MethodsNarrative review on current clinical management of spinal cord injury and emerging therapies. ResultsThis review explores the management of SCI through early decompressive surgery, optimizing mean arterial pressure, steroid therapy and focused rehabilitation. These management strategies reduce secondary injury mechanisms to prevent the propagation of further neurological damage. The literature regarding emerging research is also explored in cell-based, gene, pharmacological and neuromodulation therapies, which aim to repair the spinal cord following the primary injury mechanism. ConclusionsOutcomes for patients with SCI can be enhanced and improved if primary and secondary phases of SCI can be addressed.

Investigation of the Formation and Further Development of Longitudinal Disturbances and Their Secondary Instability on the Flying Wing Model

Detailed investigation of two-dimensional roughness element influence on the flow behind three-dimensional roughness element was carried out. For the first time studies were conducted on the windward side of the flying wing in the range of free-stream 7,2 – 20 m/s in the favourable gradient region behind roughness elements. Secondary instability mechanisms of disturbances leading to turbulence stage were investigated. It was shown that longitudinal structure forming behind three-dimensional roughness element grows downstream and has its trajectory slightly bend. The longitudinal structure consists of two stationary disturbances different in size. This can be explained by presence of cross flow and secondary disturbances leading to the transition. On the straight wing model, influence of the distributed suction on the stationary disturbance development was investigated and quantitatively determined. It was shown that suction is able to relaminarize the flow and eliminate the separation of the boundary layer.

Self-delivering mRNA inhibitors of MK2 improve outcomes after spinal cord injury

Functional recovery and tissue damage after spinal cord injury (SCI) are influenced by secondary damage mechanisms, including inflammation. The inflammatory response after SCI relies on a variety of cell types with both protective and cytotoxic functions. The macrophage derived MAPK-activated protein kinase 2 has been described as a critical regulator of inflammation with detrimental function after SCI. Targeted modification of inflammatory effector molecules after SCI faces challenges of optimal timing, dosage and location of administration. Modified RNA inhibitors, FANA antisense oligonucleotides, are promising inhibitors due to their stability, local penetration of cells and high efficacy in targeted suppression. Here, we describe the use of anti- MAPK-activated protein kinase 2 FANA antisense oligonucleotides in a mouse model of contusional SCI. The most efficient inhibitor was selected with in vitro and in vivo techniques and then applied via intrathecal injections after SCI. This treatment resulted in improved gait applying DigiGait assessments and tissue preservation, indicating the usefulness of the target and inhibition approach.

Secondary controls on the stratigraphic signature of the carbon isotope excursion marking the Paleocene-Eocene thermal maximum at Ocean Drilling Program Site 1135

The negative carbon isotope excursion (CIE) associated with an ancient global warming event referred to as the Paleocene Eocene thermal maximum (PETM, ca. 56 Ma) is commonly observed to have a smaller magnitude in marine records than in terrestrial records. This disparity has been attributed to secondary mechanisms that either attenuate or amplify the CIE magnitude in marine and terrestrial records, respectively. Here we investigate the effects of carbonate diagenesis and sediment mixing on the stratigraphic signature of the CIE in a PETM record recovered at Ocean Drilling Program (ODP) Site 1135 in the southern Indian Ocean. Comparison of parallel planktic foraminifer δ13C records constructed with two different analytical techniques – conventional gas source mass spectrometry (GSMS) measurements of individual whole shells versus in-situ microanalyses on subdomains inside individual foraminifer shells using secondary ion mass spectrometry (SIMS) – shows that both the δ13CGSMS and δ13CSIMS records capture the CIE. However, the δ13CSIMS records yield excursion magnitudes (acarininids = 5.3‰, morozovellids = 3.9‰) that are ~1.6‰ larger than in the whole-shell δ13CGSMS records. Patterns of intrashell δ13C variation delineated by the in-situ SIMS microanalyses indicate that the smaller CIE magnitude registered by δ13CGSMS records is chiefly due to incorporation of diagenetic calcite overgrowths by GSMS analyses of whole foraminifer shells. We also find that many foraminifer shells are infilled with fine-fraction carbonate (nannofossils) and posit that incorporation of non-CIE nannofossils into these infillings further bias whole-shell GSMS δ13C measurements toward more positive values over the CIE interval. We propose that 5.3‰ is the best estimate of the CIE in this deep-sea record, a near match to the average CIE magnitude published for terrestrial PETM records.

Antimicrobial Peptides and Small Molecules Targeting the Cell Membrane of Staphylococcus aureus.

Clinical management of Staphylococcus aureus infections presents a challenge due to the high incidence, considerable virulence, and emergence of drug resistance mechanisms. The treatment of drug-resistant strains, such as methicillin-resistant S. aureus (MRSA), is further complicated by the development of tolerance and persistence to antimicrobial agents in clinical use. To address these challenges, membrane disruptors, that are not generally considered during drug discovery for agents against S. aureus, should be explored. The cell membrane protects S. aureus from external stresses and antimicrobial agents, but membrane-targeting antimicrobial agents are probably less likely to promote bacterial resistance. Nontypical linear cationic antimicrobial peptides (AMPs), highly modified AMPs such as daptomycin (lipopeptide), bacitracin (cyclic peptide), and gramicidin S (cyclic peptide), are currently in clinical use. Recent studies have demonstrated that AMPs and small molecules can penetrate the cell membrane of S. aureus, inhibit phospholipid biosynthesis, or block the passage of solutes between the periplasm and the exterior of the cell. In addition to their primary mechanism of action (MOA) that targets the bacterial membrane, AMPs and small molecules may also impact bacteria through secondary mechanisms such as targeting the biofilm, and downregulating virulence genes of S. aureus. In this review, we discuss the current state of research into cell membrane-targeting AMPs and small molecules and their potential mechanisms of action against drug-resistant physiological forms of S. aureus, including persister cells and biofilms.

Performance-based design method for bolted stiffened end-plate connection under monotonic loading

Bolted stiffened end-plate connection is one of the solutions for steel beam to column connections in moment resisting frames implemented after the Northridge and Kobe earthquake incidents. The connection comprises a steel end-plate shop welded to the beam and field bolted to the column flange. In addition, the end-plate extensions are stiffened using angular stiffener plates. Out of the prevailing design codes and guidelines, Eurocode 3-1-8 [1] has provided specifications to design bolted end-plate connections using the equivalent T-stub method, but it does not incorporate the effect of end-plate stiffeners in the design of the connection, whereas AISC [2] design guidelines provide specifications to design the particular connection components. However, these design methods do not address the performance enhancement of the bolted stiffened connection.For these reasons, this study investigates a performance-based design method through numerical analyses to improve the performance of the bolted stiffened end-plate connection. This method is primarily based on the strong column and weak beam concept. Here, primary and secondary yield mechanisms are organized in a hierarchy so that the connection failure occurs in a predefined way by identifying the yield mechanisms and failure modes of the connection. Through this, the targeted performance characteristics of the connection identified as ductility and energy dissipation capacity can be improved. Thus, this performance-based design method is a better approach than the conventional load resisting design method proposed by the code of practice.

Macromolecular Dexamethasone Prodrug Ameliorates Neuroinflammation and Prevents Bone Loss Associated with Traumatic Brain Injury (S28.001)

<h3>Objective:</h3> We hypothesized that systemically administered N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based dexamethasone (Dex) prodrugs (P-Dex) will target the brain trauma injury sites, substantially enhance the Glucocorticoid therapy efficacy, and improve its systemic safety. <h3>Background:</h3> Traumatic brain injury is (TBI) a leading cause of morbidity and mortality in children and adults. The pathology of TBI is heterogeneous, resulting from both primary and secondary injury mechanisms, the latter being attributed to the inflammatory response. Use of conventional glucocorticoid formulations (free DEX) leads to limited distribution to the brain, pulsatile brain tissue concentration and systemic side effects, with controversial benefit in being neuroprotective. Dex and prodrugs (P-Dex) passively target inflammation through the leaky vasculature associated with the underlying pathologies. Given the compromised blood brain barrier (BBB) and brain inflammation in the secondary injury phase of the TBI patients, we hypothesized that the systemically administrated P-Dex will passively target the brain trauma injury sites and reduce inflammation with least systemic side effects. <h3>Design/Methods:</h3> 30 mice were randomly assigned into 2 groups: TBI (Cortical impact model) and healthy mice. All mice received Saline, P-Dex or free Dex. They underwent optical imaging, Neurological severity score, Static weight bearing, Immunohistochemistry and Mico-CT analysis. <h3>Results:</h3> We found that P-Dex passively targeted the traumatic brain tissue and had sustained accumulation at the inflamed tissue for over 14 days. Histological evidence demonstrates the P-Dex’s therapeutic effect on the amelioration of neuroinflammation and prevention of neurodegeneration. Behaviorally, the P-Dex treated animals showed better recovery of the imbalance and better neurological severity score post-TBI. Higher bone mineral density and better bone microarchitecture was found in the skeletal tissues from P-Dex treated animals, comparing to the free Dex, and Saline treated animals, confirming the P-Dex bone protection effect. <h3>Conclusions:</h3> P-Dex can be a potential therapy targeting neuro-inflammation and preserving the neurons from death, avoiding bone loss post-TBI. <b>Disclosure:</b> Dr. Wei has nothing to disclose. Dr. Zhao has nothing to disclose. Jia Zhenshan has nothing to disclose. Zhao Zhifeng has nothing to disclose. Dr. Chen has nothing to disclose. Miss Sun has nothing to disclose. Dr. Kelso has received personal compensation for serving as an employee of Agilent Technologies. Dr. Kelso has stock in Agilent Technologies. Dr. Rathore has nothing to disclose. Dr. Wang has nothing to disclose.

Tackling Osimertinib Resistance in EGFR-Mutant Non-Small Cell Lung Cancer.

The current landscape of targeted therapies directed against oncogenic driver alterations in non-small cell lung cancer (NSCLC) is expanding. Patients with EGFR-mutant NSCLC can derive significant benefit from EGFR tyrosine kinase inhibitor (TKI) therapy, including the third-generation EGFR TKI osimertinib. However, invariably, all patients will experience disease progression with this therapy mainly due to the adaptation of cancer cells through primary or secondary molecular mechanisms of resistance. The comprehension and access to tissue and cell-free DNA next-generation sequencing have fueled the development of innovative therapeutic strategies to prevent and overcome resistance to osimertinib in the clinical setting. Herein, we review the biological and clinical implications of molecular mechanisms of osimertinib resistance and the ongoing development of therapeutic strategies to overcome or prevent resistance.

Axial Postural Abnormalities in Parkinsonism: Gaps in Predictors, Pathophysiology, and Management.

Axial postural abnormalities are common and disabling motor complications of Parkinson's disease (PD) and parkinsonism. They consist of abnormal trunk or neck postures in the upright position, often interfering with daily life activities.1-5 A high number of patients with PD may develop one or more axial postural abnormalities, which may begin as minor forms, almost universal in persons with parkinsonism (eg, minor flexed posture of the trunk and lower limbs), and progress to severe forms such as camptocormia, antecollis, or Pisa syndrome in over 20% of patients,1 although the definitions of severe axial postural abnormalities were purely based on subjective/expert opinion. Drug-induced parkinsonism or progressive supranuclear palsy may also present axial postural abnormalities, and in multiple system atrophy these symptoms are more frequent than in PD and occur earlier in the disease course.2, 6 Because axial postural abnormalities are associated with an increased risk of falling, pain, and diminished quality of life, their proper prevention and management is warranted.2, 4, 5, 7, 8 However, to date, recommendations for multidisciplinary management and prevention remain an unmet need.3 Diagnosis is typically based on a simple clinical examination, whereas treatments (eg, pharmacological, physical therapy, and surgical treatments) have been evaluated only in small single-center studies that failed to show consistent, long-lasting improvement.2, 5, 8-10 The absence of reliable protocols for the assessment, treatment, and prevention of axial postural abnormalities in parkinsonism is probably due to the largely obscure pathophysiology and uncertainty about prognostic factors needed to estimate beneficial responses to therapy (eg, duration of axial postural abnormalities).2, 5, 8, 11-13 The aim of this viewpoint is to critically analyze the literature on axial postural abnormalities, identify the current issues and gaps, and formulate proposals for current clinical management and future research exploration. Research on clinical predictors and risk factors for the onset of axial postural abnormalities in parkinsonism was mainly limited by the low quality of the methodology in the available literature (Supporting Information).2, 5, 8 Indeed, only a few studies were aimed primarily at the analysis of risk factors, and most studies were cross-sectional, lacking adequate longitudinal follow-up. In most cases the patient sample (usually PD) was heterogeneous for disease severity and stage. Clinical predictors were investigated for all axial postural abnormalities; however, the dependent variable in many studies was the presence of more than one axial postural abnormality, rather than a singular one. This approach renders it difficult to identify clinical predictors specific for each axial postural abnormality, which may vary between camptocormia, Pisa syndrome, and antecollis. Also, the cutoffs defining an axial postural abnormality differed across studies and were not stated in many cases. This generated possible bias in the prevalence rates due to differences in the clinical characteristics of patient samples. The identification of clinical predictors in patient samples presenting different degrees of trunk/neck flexion is challenging and limits interpretation of the study results. For example, patients with greater trunk flexion may also have more motor complications (ie, motor fluctuations) that make it difficult to identify the clinical predictors for mild axial forms (ie, anterior trunk flexion),3 which are of major clinical interest for prevention strategies. Finally, the variability in tools and reference bone points used for quantifying the degree of axial postural abnormalities renders comparison of study results arduous. The pathophysiology of axial postural abnormalities in PD is not clear, but several causes have been proposed,2, 5, 8 including central mechanisms (eg, imbalance in basal ganglia functioning leading to dystonia/rigidity, altered sensory–motor integration, higher cognitive function deficits) and/or peripheral mechanisms (ie, alteration in the musculoskeletal system).2, 5, 8 The main pathophysiological mechanisms considered in the literature are discussed here (Supporting Information). Dystonia, or a more general hyperactivity of paraspinal and nonparaspinal muscles, is the most common explanation for axial disability based on findings from electromyographic investigation.2, 5, 8, 9, 14-20 The hypothesis that dystonia underlies axial postural abnormalities is supported by three main findings: (1) the existence of drug-induced Pisa syndrome or camptocormia, (2) the (rare) existence of sensory tricks to alleviate some postural abnormalities, and (3) evidence of misalignment improvement by botulinum toxin type-A or lidocaine administration in some patients.2, 5, 8 However, in patients with Pisa syndrome, electromyography findings have been inconsistent concerning the side (ipsilateral or contralateral) of hyperactivity of paraspinal and nonparaspinal muscles in relation to trunk bending and PD asymmetry.16, 18, 19 Some studies suggested two different electromyographical patterns: (1) hyperactivity of lumbar and thoracic paraspinals ipsilateral to the trunk-leaning side during quiet stance and voluntary contralateral trunk flexion18, 21 and (2) hyperactivity of nonparaspinal muscles (eg, external oblique muscles, rectus femoris, and iliopsoas) ipsilaterally to the leaning side during quite stance and during voluntary contralateral trunk flexion.17 The paraspinal muscles contralateral to the side of flexion may have a compensatory action to further limit trunk bending.17 Other studies reported tonic and persistent activity in the paraspinal thoracic muscle and/or abdominal oblique muscles ipsilateral to the bending side and less-affected PD side, along with reduced/absent activity of the same muscles on the opposite side.19 In patients with camptocormia, studies suggested that the bilateral abdominal internal and the external oblique muscles, together with the rectus abdominis muscles, may be responsible for camptocormia with thoracic fulcrum,14 whereas rectus abdominis and iliopsoas hyperactivity could be more frequently involved in camptocormia with lumbar fulcrum.14, 20 Another study found hyperactivity of paraspinal muscles (ie, iliocostalis lumborum, longissimus, and multifidus) and, to a lesser extent, the rectus femoris but not rectus abdominis.15 It is probable that some hyperactivities observed in camptocormia, like those of paraspinal muscles that are spine erectors, are compensatory. Patients with antecollis showed hypertrophy and active spasms or hyperactivity in anterior (sternocleidomastoid muscles) and posterior (semispinalis, splenius capitis, trapezius, and levator scapulae) neck muscles.2 Passive head-up maneuvers may be limited by marked bilateral contractions of sternocleidomastoid muscles.2 The paucity of studies and objective measures to identify and quantify dystonia complicates the interpretation of these findings. Needle electromyography (EMG) has limited use because it is invasive and can be challenging when applied in deep muscles. Also, interpretation of needle EMG is relatively subjective as it is technically difficult to perform and has not been standardized for investigating axial muscles, and quantitative normative measures for activation of these muscle groups are not available. Finally, when EMG is performed in those with long-standing symptoms, it remains difficult to reliably separate primary abnormalities (ie, those causing postural abnormalities) from secondary ones (ie, resulting from the chronic changes in posture, or related to compensatory mechanisms). No studies have specifically and systematically evaluated rigidity in patients with axial postural abnormalities. During clinical examination in the supine position, patients demonstrate almost complete resolution of trunk bending, whereas when sitting or standing the paravertebral muscles may appear to have a wooden consistency.2, 15 The association between axial postural abnormalities and a more severe motor impairment and a rigid-akinetic phenotype makes rigidity a process worthy of investigation, albeit difficult to measure it empirically. Patients with PD have difficulty in properly controlling their postural stabilization and orientation (and also their interaction) based on sensory information from muscles and joints.2 PD patients with Pisa syndrome or camptocormia find it more difficult to achieve good postural alignment with gravity and display greater velocity of body sway than patients without axial postural abnormalities.22, 23 Patients with camptocormia with a lower fulcrum may have more severe gait and postural control deficits than patients with a thoracic fulcrum or patients without camptocormia.23 However, no studies have so far investigated the relationship between antecollis and postural instability. Postural control is a complex system involving the integration of different sensory inputs, including vestibular, visual, and proprioceptive. Some findings support the notion that proprioceptive function/kinesthesia is abnormal in PD.22, 23 Evidence was initially restricted to motor control of the limbs,24 but more recent studies22, 23 showed that proprioceptive defects might also affect axial motor control not only in the yaw plane (turning about the vertical axis)24 but also in the sagittal and coronal planes. Further studies are needed to understand the contribution of defective proprioceptive and kinesthesia in the pathophysiology of axial postural abnormalities.2, 24 Moreover, postural control depends on vestibular information. PD patients with Pisa syndrome may present with a central, peripheral, or mixed vestibular dysfunction2 along with a deviation in the subjective visual vertical,25 which was estimated to occur in about 67% of PD patients.26 A recent case–control study found worse performance on visuospatial ability tasks by PD patients with Pisa syndrome compared to PD controls without axial postural abnormalities.27 Visuospatial deficits are associated with dysfunctional subjective visual vertical, possibly contributing to altered perception of the trunk in space and the development of Pisa syndrome but not camptocormia.27 Whether visual spatial deficits and subjective visual vertical are defective and might also contribute to the development of antecollis has not been systematically investigated yet. Moreover, postural control demands complex motor–cognitive interactions that rely on high attentional resources and conserved executive functions. Some studies reported lower scores on tasks exploring executive functions (ie, divided attention, inhibitory control, and delayed free recall in verbal learning), perceptual visuospatial functions, and language for patients with Pisa syndrome compared to patients with PD without axial postural abnormalities.2, 5, 8, 28 Nevertheless, the association between kinesthetic/proprioceptive and cognitive deficits with axial postural abnormalities remains controversial. Without further details from pathophysiology studies, and also without intervention studies, three possibilities remain: (1) these deficits are a mere association (ie, they merely coincide with those with more severe disease), (2) these dysfunctions are not causal but rather a secondary manifestation (ie, they result as a consequence of the axial postural abnormalities), or (3) they are actually a contributing factor. The bulk of evidence from EMG (eg, fibrillation potentials, small polyphasic motor unit potentials, and weakness),5, 8, 14, 15, 17, 19, 29-34 muscle biopsy (eg, abnormal histology),5, 8, 29-32, 35 and muscle imaging (eg, fatty infiltration of muscles and muscle atrophy)5, 8, 9, 14, 17, 19, 29-31, 36 suggests myopathy as a contributing factor to the development of axial postural abnormalities. The cause of myopathy remains unclear, but ongoing research marks it as a secondary myopathic process, as a consequence of a chronically maintained abnormal posture.34 These phenomena probably reflect a continuum from early myopathic changes (ie, edema and partial swelling, contrast enhancement without degenerative muscle changes) in the early stages of camptocormia to progression to muscle atrophy and fatty degeneration in the end stage as shown by muscle magnetic resonance imaging (MRI) and biopsy. Although the exact cause of these muscular changes is unclear, they may arise due to muscle disuse or denervation secondary to chronic primary trunk misalignment. Camptocormia might be a consequence of overusing paraspinal muscles due to rigidity in patients with PD or a pronounced proprioceptive dysregulation in the context of underlying disease. Although a primary myopathy has been suggested to explain Pisa syndrome,19 no pathological studies have proven this hypothesis. Therefore, the observed muscular changes are probably caused by secondary mechanisms. The atrophy of paraspinal muscles ipsilateral to the bending side may be due to muscle disuse (excluded because of hyperactivity of nonparaspinal muscles) and cannot contribute to the development of Pisa syndrome; contralateral muscle atrophy instead might be secondary to the stress of prolonged stretching, as a consequence of muscle weakness, theoretically leading to Pisa syndrome.17 The mechanical efficiency of muscular activation of trunk extension (especially at the thoracic level) was markedly reduced in PD patients with camptocormia compared to those with PD without postural issues and to healthy controls, which suggests impairment of neuromuscular recruitment.34 The EMG of the paraspinal muscles is technically difficult, but this disadvantage is relative, as MRI and muscle biopsy can show the presence of myopathy. Although the finding of a monomorphic myopathy in the camptocormia of PD patients can be considered corroborated,35 the clarification of its cause remains an important task. Currently, the recording of myopathy with its subdivision into acute and chronic forms of muscle changes provides clues for therapeutic options.12 Postural improvement after high-frequency deep brain stimulation (DBS) of the bilateral subthalamic nuclei37 supports the notion that axial postural abnormalities may result from dysfunction of the basal ganglia. There is limited evidence for the presence of drug-induced axial postural abnormalities in persons with parkinsonism,2, 5, 8 with a dose reduction (or even complete withdrawal) or switching to another dopaminergic medication leading to improvement in posture.2, 8, 38 Finally, patients with axial postural abnormalities may present with a concomitant clinical history of back surgery (eg, laminectomy), degenerative spinal conditions, or trauma, which may have mechanical effects on bones or soft tissue (eg, muscles or fascia) and predisposing to their development.39 In clinical practice, the first step is to objectively measure the degree of trunk and/or neck flexion preferably while the patient is wearing only underwear (Fig. 1) during standing and walking.40 We suggest to investigate the possible presence of mild forms of axial postural abnormalities at each visit and inform and educate patients and caregivers on these symptoms; when actual axial postural abnormalities have been identified, clinicians could consider pharmacological and nonpharmacological interventions for their treatment. Figure 2 shows a practical road map as guidance for their clinical management. Four major issues may have limited the progress of research in this field: (1) different nosology and cutoffs to define axial postural abnormalities, (2) lack of common and objective assessment procedures, (3) heterogeneity of study design, and (4) heterogeneity of patient samples. Future research should focus on their clinical evaluation in terms of early detection and quantification using consensus-based criteria.3 Prospective, observational, long-term studies with large samples are immediately needed to explore the potential risk (causal) factors and pathophysiology involved in their development. From a therapeutic point of view, we call for well-controlled clinical trials: randomized trials using standard criteria for inclusion and endpoint measurement3 are needed to compare the efficacy of different pharmacological and nonpharmacological interventions and their combined effect (ie, botulinum toxin injections + physiotherapy). Such controlled studies could also focus on the merits of dopaminergic therapy withdrawal when these are suspected to have played a role in causing axial postural abnormalities. Moreover, we suggest researchers focus on a single postural abnormality per study, because risk factors, pathophysiology, and response to treatments may vary between camptocormia, Pisa syndrome, and antecollis. Finally, prevention programs using common diagnostic criteria3 should be investigated to study how the development of axial postural abnormalities can be avoided. Educate patients and their families to monitor possible improvement or worsening of posture. Adjustment of pharmacological therapy: remove the prescribed dopaminergic therapy potentially associated with the subacute onset of axial postural abnormality. The removal of therapy needs to be done very cautiously as this may also lead to a worsening of the underlying parkinsonism.8 Other expert opinion–based options include the following: botulinum toxin injection of hyperactive muscles should be cautiously considered for each patient based on EMG findings, in carefully selected patients, under the care of experts; avoiding injections of compensatory paraspinal and nonparaspinal muscles; prompt physiotherapy intervention to strengthen weak/compensatory trunk/neck muscles and improve balance and mobility; and prescription of walking aids (ie, high-frame walker) if needed. When a patient is suitable for DBS aimed at managing motor symptoms, camptocormia, and Pisa syndrome could also improve after surgery. Orthopedic surgery should be considered in very selected cases: patients should be properly counseled regarding the increased risk of operative complications and closely followed for incipient failure. We thank Rossella Targa (librarian) for her assistance in developing the literature search strategy. Open Access Funding provided by Universita degli Studi di Verona within the CRUI-CARE Agreement. (1) Writing of the first draft: C.G., M.T., C.A.A. (2) Data collection: C.G., C.A.A., J.N., C.A., D.G., M.L.D., D.S., Y.L., M.A.-W., M.S., R.W., V.T.L., G.I., and SC. (3) Review and critique: all authors. R.B. receives salary from Chulalongkorn University and stipend from the Royal Society of Thailand, has received consultancy and/or honoraria/lecture fees from Abbott, Boehringer-Ingelheim, Britannia, Ipsen, Novartis, Teva-Lundbeck, Takeda, and Otsuka pharmaceuticals; he has received research funding from the Newton Fund, the UK Government, Thailand Science and Research Innovation Bureau, Thailand Research Fund, Crown Property Bureau, Chulalongkorn University, and the National Science and Technology Development Agency; he holds patents for laser-guided walking stick, portable tremor device, nocturnal monitoring, and electronic Parkinson's disease symptom diary as well as copyright on Parkinson's mascot, dopamine lyrics and teaching video clips for common nocturnal and gastrointestinal symptoms for Parkinson's disease. A.F. reports the following: Consultancies from Abbvie, Medtronic, Boston Scientific, Sunovion, Ipsen, Merz; Advisory Boards of Abbvie, Boston Scientific, Ceregate, Inbrain, Ipsen, Medtronic, Jazz, Biogen/Sage; Honoraria from Abbvie, Medtronic, Boston Scientific, Sunovion, UCB, Ipsen; grants from University of Toronto, Weston foundation, Abbvie, Medtronic, Boston Scientific, Michael J Fox Foundation, European Union, MSA coalition, Dystonia Medical Research Foundation. L.L. reports the following: Consultancies and Honoraria from Bial, Zambon, Abbvie and Grants from University of Turin, Zambon, Abbvie. N.M. reports the following: dvisory Boards for Angelini, GW Pharmaceuticals and Grants from UCB Pharma, Desitin, Eisai, LivaNova, Angelini, GW Pharmaceuticals. M.M. reports the following: Consultant: St Jude/ Abbott, Honoraria: Glaxo Research grants: Glaxo, Allergan, TEVA. Royalties: Springer, Random House, Cambridge University press, Humana Press. Editor honorarium Wiley & Son. Movement Disorders Society.receives salary from Chulalongkorn University and stipend from the Royal Society of Thailand, has received consultancy and/or honoraria/lecture fees from Abbott, Boehringer-Ingelheim, Britannia, Ipsen, Novartis, Teva-Lundbeck, Takeda, and Otsuka pharmaceuticals; he has received research funding from the Newton Fund, the UK Government, Thailand Science and Research Innovation Bureau, Thailand Research Fund, Crown Property Bureau, Chulalongkorn University, and the National Science and Technology Development Agency; he holds patents for laser-guided walking stick, portable tremor device, nocturnal monitoring, and electronic Parkinson's disease symptom diary as well as copyright on Parkinson's mascot, dopamine lyrics and teaching video clips for common nocturnal and gastrointestinal symptoms for Parkinson's disease. A.F. reports the following: Consultancies from Abbvie, Medtronic, Boston Scientific, Sunovion, Ipsen, Merz; Advisory Boards of Abbvie, Boston Scientific, Ceregate, Inbrain, Ipsen, Medtronic, Jazz, Biogen/Sage; Honoraria from Abbvie, Medtronic, Boston Scientific, Sunovion, UCB, Ipsen; grants from University of Toronto, Weston foundation, Abbvie, Medtronic, Boston Scientific, Michael J Fox Foundation, European Union, MSA coalition, Dystonia Medical Research Foundation. L.L. reports the following: Consultancies and Honoraria from Bial, Zambon, Abbvie and Grants from University of Turin, Zambon, Abbvie. N.M. reports the following: dvisory Boards for Angelini, GW Pharmaceuticals and Grants from UCB Pharma, Desitin, Eisai, LivaNova, Angelini, GW Pharmaceuticals. M.M. reports the following: Consultant: St Jude/ Abbott, Honoraria: Glaxo Research grants: Glaxo, Allergan, TEVA. Royalties: Springer, Random House, Cambridge University press, Humana Press. Editor honorarium Wiley & Son. Movement Disorders Society. Data sharing not applicable to this article as no datasets were generated or analysed during the current study Data S1. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Polarity and functionality tailored conjugated microporous polymer coatings on silica microspheres for enhanced pollutant adsorption

Many sources of pollution that are generated by modern society are not addressable by conventional methods. Especially organic compounds, like pharmaceutics, are particularly hard to remove from waterbodies. Herein, a new approach is presented using conjugated microporous polymers (CMPs) to coat silica microparticles yielding specifically tailored adsorbents. The CMPs are generated with three different monomers: 2,6-dibromonaphthalene (DBN), 2,5-dibromoaniline (DBA) and 2,5-dibromopyridine (DBPN) respectively coupled to 1,3,5-triethynylbenzene (TEB) via Sonogashira coupling. By optimizing the polarity of the silica surface, all three CMPs were converted into microparticle coatings. The resulting hybrid materials feature the advantages of being adjustable in polarity and functionality, as well as morphology. Sedimentation allows facile removal of the coated microparticles after the adsorption. Further, the expansion of the CMP to a thin coating increases the accessible surface area compared to the bulk material. These effects were demonstrated by the adsorption of the model drug diclofenac. Thereby, the aniline-based CMP proved to be most advantageous due to a secondary crosslinking mechanism of amino and alkyne functionalities. An outstanding adsorption capacity of 228 mg diclofenac per gram of the aniline CMP within the hybrid material was achieved. This represents a five-fold increase compared to the value obtained by the pure CMP material underlining the advantages of the hybrid material.

Identification of a GABAergic neural circuit governing leptin signaling deficiency-induced obesity.

The hormone leptin is known to robustly suppress food intake by acting upon the leptin receptor (LepR) signaling system residing within the agouti-related protein (AgRP) neurons of the hypothalamus. However, clinical studies indicate that leptin is undesirable as a therapeutic regiment for obesity, which is at least partly attributed to the poorly understood complex secondary structure and key signaling mechanism of the leptin-responsive neural circuit. Here, we show that the LepR-expressing portal neurons send GABAergic projections to a cohort of α3-GABAA receptor expressing neurons within the dorsomedial hypothalamic nucleus (DMH) for the control of leptin-mediated obesity phenotype. We identified the DMH as a key brain region that contributes to the regulation of leptin-mediated feeding. Acute activation of the GABAergic AgRP-DMH circuit promoted food intake and glucose intolerance, while activation of post-synaptic MC4R neurons in the DMH elicited exactly opposite phenotypes. Rapid deletion of LepR from AgRP neurons caused an obesity phenotype which can be rescued by blockage of GABAA receptor in the DMH. Consistent with behavioral results, these DMH neurons displayed suppressed neural activities in response to hunger or hyperglycemia. Furthermore, we identified that α3-GABAA receptor signaling within the DMH exerts potent bi-directional regulation of the central effects of leptin on feeding and body weight. Together, our results demonstrate a novel GABAergic neural circuit governing leptin-mediated feeding and energy balance via a unique α3-GABAA signaling within the secondary leptin-responsive neural circuit, constituting a new avenue for therapeutic interventions in the treatment of obesity and associated comorbidities.

Abstract 940: Comprehensive characterization of MET exon 14 skipping mutations in non-small cell lung cancer

Abstract Background: MET exon 14 skipping mutation (METΔex14) is a key driver event in non-small cell lung cancer (NSCLC), and can be acquired following drug resistance to MET, EGFR or ALK inhibitors. Clinical and genomic features of METΔex14 in NSCLC remain to be further characterized. Methods: A total of 556 baseline samples, 54 MET inhibitor-resistant samples and 16 EGFR/ALK inhibitor-resistant samples from 586 METΔex14 NSCLC patients were included in the analysis. Tissue and/or plasma samples were subjected to targeted next-generation sequencing (NGS) using Geneseeq’s 139/425 cancer-relevant gene panels. Results: The overall frequency of METΔex14 was 1.1%, with a total of 266 distinct variants detected. Of these, 40.2% were base substitutions in the intronic non-coding region immediately adjacent to the splice acceptor site, followed by indels (25.6%) and base substitutions (4.5%) in the splice donor site, and indels (21.4%) and base substitutions (2.3%) in the splice acceptor site, etc. No associations with clinical features were found among different variants. At baseline, METΔex14 commonly co-occurred with TP53 mutations (40.8%), and CDK4 (15.8%) and MET (7.9%) amplifications. In 42 (7.6%) patients, concurrent oncogenic mutations in EGFR, KRAS, ALK, RET, BRAF, and ERBB2 were also detected. Such patients displayed a different spectrum of METΔex14 variants compared with those without concurrent oncogenic mutations (P=0.08). In patients treated with MET inhibitors, no difference in survival was seen among different METΔex14 variants (P=0.38). Notably, activation of EGFR or MET (kinase domain mutations/amplification) conferred primary resistance to savolitinib and crizotinib. In addition, patients with high chromosomal instability or low intratumoral heterogeneity had unfavorable PFS. Secondary resistance to MET-TKI included MET activation (D1228N/H, Y1230C/S, amplification), EGFR activating mutations/amplification, KRAS G12V, as well as FGFR2/4 amplification. Surprisingly, we identified a FGFR3-TACC3 fusion as a previously unreported secondary resistance mechanism to savolitinib in the second line setting. Finally, we found that MET exon 14 skipping mutation might be a rare secondary resistance mechanism to EGFR/ALK inhibitors. Conclusion: In this study, we characterized METΔex14 in a large cohort of NSCLC patients and explored potential primary and secondary resistance mechanisms to savolitinib and crizotinib, which may facilitate drug development and help inform clinical actions. Citation Format: Xue Wu, Yaru Zhang, Jiaohui Pang, Li Lin, Jiani C. Yin, Haimeng Tang, Yang Shao. Comprehensive characterization of MET exon 14 skipping mutations in non-small cell lung cancer [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 940.

Abstract 4010: Inhibition of PERK by HC-5404 sensitizes clear cell renal cell carcinoma tumor models to anti-angiogenic tyrosine kinase inhibitors

Abstract Anti-angiogenic agents form the backbone of standard of care for advanced clear cell renal cell carcinoma (ccRCC), but their clinical impact is limited by primary and secondary resistance mechanisms that remain a critical problem. Furthermore, the approvals for VEGFR-targeting receptor tyrosine kinase inhibitors (VEGFR-TKIs), cabozantinib in second-line, and tivozanib in third-line RCC patients were based on modest objective response rates and median progression-free survival. There is an urgent need for novel mechanisms that target adaptive tumor responses that drive resistance to these agents, as well as combination drug partners that improve outcomes for patients. As part of their mechanism, VEGFR-TKIs induce oxygen- and nutrient-deprivation that drives ER stress. Tumors can evade deleterious ER stress by activating PERK branch of the integrated stress response, which arrests global translation and restores homeostasis. We hypothesized that inhibiting PERK would enhance the anti-tumor activity of VEGFR-TKIs in vivo and tested this using HC-5404, a potent and selective PERK inhibitor currently in Ph1 clinical testing (NCT04834778). Here, we present preclinical evidence that supports combining HC-5404 with VEGFR-TKIs in ccRCC. We demonstrate that axitinib, cabozantinib, lenvatinib, and sunitinib all activate PERK in 786-O ccRCC xenografts in a dose-responsive manner. The addition of HC-5404 significantly enhanced the tumor growth inhibition (TGI) of VEGFR-TKIs across multiple ccRCC tumor models, resulting in tumor stasis or regression in combination groups. Expression profiling and IHC analysis of tumor sections revealed that HC-5404 enhanced the anti-angiogenic effects of axitinib and lenvatinib in 786-O tumors, highlighting the protective role of PERK in response to anti-angiogenics. To evaluate whether the combination treatments could benefit a diverse patient population, sensitivity to HC-5404 and axitinib was evaluated across a panel of patient-derived xenograft (PDX) models. This experiment confirmed widespread responsiveness to the combination treatment that in some cases achieved &amp;gt;50% tumor regression. As tumor progression on VEGFR-TKIs limits the success of these agents in the clinic, we evaluated the effect of adding HC-5404 to tumors that have previously progressed on axitinib. In this study, 786-O xenografts were treated with axitinib for 2-weeks and non-responders were rerandomized into groups of either single agent or combination of HC-5404 and axitinib. The combination treatment significantly improved TGI relative to either monotherapy, resulting in tumor regression of ~20%. Taken together, these findings highlight that by disrupting an adaptive stress response evoked by VEGFR-TKIs, HC-5404 presents a clinical opportunity to enhance the anti-tumor effects of well-established standard of care therapies in ccRCC. Citation Format: Michael E. Stokes, Veronica Calvo, Crissy Dudgeon, Sho Fujisawa, Sharon Huang, Leyi Shen, Nupur Ballal, Joe McGinley, David Liu, Mark J. Mulvihill, Alan C. Rigby, Nandita Bose, Eric S. Lightcap, David Surguladze. Inhibition of PERK by HC-5404 sensitizes clear cell renal cell carcinoma tumor models to anti-angiogenic tyrosine kinase inhibitors. [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 4010.