Irreversible Growth Research Articles

Porous Cyclodextrin PolymerEnablesDendrite-Free and Ultra-Long LifeSolid-State Zn-I 2 Batteries.

Zn-I2batteries have attracted attention due to their low cost, safety, and environmental friendliness. However, their performance is still limited by the irreversible growth of Zn dendrites, hydrogen evolution reactions, corrosion, and shuttle effect of polyiodide. In this work, we have prepareda newporous polymer (CD-Si) by nucleophilic reactionofβ-cyclodextrin with SiCl4, and CD-Si is applied to the solid polymer electrolyte (denoted PEO/PVDF/CD-Si) to solve above-mentioned problems. Through the anchoring of the CD-Si, a conductive network with dual transmission channels was successfully constructed. Due to the non-covalent anchoring effect, the ionic conductivity of the solid polymer electrolytes(SPE) can reach 1.64 × 10-3S cm-1at 25 ºC. The assembled symmetrical batteries can achieve highly reversible dendrite-free galvanizing/stripping (stable cycling for 7500 h at 5 mA cm-2and 1200 h at 20 mA cm-2). The solid-state Zn-I2battery shows anultra-long life of over 35,000 cycles at 2 A g-1. Molecular dynamics simulations are performed to elucidate the working mechanism of CD-Si in the polymer matrix. This work providesa novel strategy towards solid electrolytes for Zn-I2batteries.

Porous Cyclodextrin Polymer Enables Dendrite‐Free and Ultra‐Long Life Solid‐State Zn‐I2 Batteries

AbstractZn‐I2 batteries have attracted attention due to their low cost, safety, and environmental friendliness. However, their performance is still limited by the irreversible growth of Zn dendrites, hydrogen evolution reactions, corrosion, and shuttle effect of polyiodide. In this work, we have prepared a new porous polymer (CD‐Si) by nucleophilic reaction of β‐cyclodextrin with SiCl4, and CD‐Si is applied to the solid polymer electrolyte (denoted PEO/PVDF/CD‐Si) to solve above‐mentioned problems. Through the anchoring of the CD‐Si, a conductive network with dual transmission channels was successfully constructed. Due to the non‐covalent anchoring effect, the ionic conductivity of the solid polymer electrolytes (SPE) can reach 1.64×10−3 S cm−1 at 25 °C. The assembled symmetrical batteries can achieve highly reversible dendrite‐free galvanizing/stripping (stable cycling for 7500 h at 5 mA cm−2 and 1200 h at 20 mA cm−2). The solid‐state Zn‐I2 battery shows an ultra‐long life of over 35,000 cycles at 2 A g−1. Molecular dynamics simulations are performed to elucidate the working mechanism of CD‐Si in the polymer matrix. This work provides a novel strategy towards solid electrolytes for Zn‐I2 batteries.

A mechanistic model to predict saturated pool boiling Critical Heat Flux (CHF) in a confined gap

Boiling enables high rates of heat transfer from a surface made possible at a relatively low thermal resistance motivating the use of two-phase cooling for increasingly compact thermal management solutions. However, extreme geometrical confinement of the liquid above the boiling surfaces is known to have detrimental effects on maximum heat transfer rate by inducing premature onset of film boiling. Moreover, previously developed critical heat flux (CHF) models for confined geometries focused on triggering mechanisms associated with unconfined pool boiling and, thus, are not generalizable. This work proposes a new mechanistic model for predicting CHF during boiling within in narrow gap, specifically developed to account for confinement effects on the triggering mechanism. The model postulates that occurrence of CHF coincides with the irreversible growth of a dry spot on the boiling surface. Three competing forces govern the two-phase interface dynamics, namely vapor momentum, surface tension, and hydrostatic forces. Dryout is triggered when the vapor momentum force due to vaporization at the two-phase interface balances the combined surface tension and hydrostatic forces leading to irreversible growth of the dry spot. The present work offers a predictive confined CHF model that accounts for confined boiling surface shape, size, orientation, confinement gap spacing, and working fluid properties, with a single fluid-specific fitting coefficient that represents the ratio of vapor area to the confinement opening area near CHF conditions. Notably, the developed CHF model is also effective in predicting the threshold gap below which confinement reduces pool boiling CHF. The model is compared to 197 experimentally measured confined CHF data points available from 10 studies in the literature that represent 7 different working fluids and a range of boiling surface inclinations and shapes. The model predicts the confinement-reduced CHF values with a root mean square error of 21%, which is less than half of the error compared to all other available predictive models. This clarification of the triggering mechanism and improved prediction accuracy of CHF, as offered by the current study, will enable broader practical system implementation of compact two-phase cooling technologies.

Intraventricular SHH inhibition proves efficient in SHH medulloblastoma mouse model and prevents systemic side effects.

Medulloblastoma (MB) is the most common malignant brain tumor in children and requires intensive multimodal therapy. Long-term survival is still dissatisfying and, most importantly, survivors frequently suffer from severe treatment-associated morbidities. The sonic hedgehog pathway (SHH) in SHH MB provides a promising target for specific therapeutic agents. The small molecule Vismodegib allosterically inhibits SMO, the main upstream activator of SHH. Vismodegib has proven effective in the treatment of MB in mice and in clinical studies. However, due to irreversible premature epiphyseal growth plate fusions after systemic application to infant mice and children, its implementation to pediatric patients has been limited. Intraventricular Vismodegib application might provide a promising novel treatment strategy for pediatric medulloblastoma patients. Infant medulloblastoma-bearing Math1-cre::Ptch1Fl/Fl mice were treated with intraventricular Vismodegib in order to evaluate efficacy on tumor growth and systemic side effects. We show that intraventricular Vismodegib treatment of Math1-cre::Ptch1Fl/Fl mice leads to complete or partial tumor remission only 2 days after completed treatment. Intraventricular treatment also significantly improved symptom-free survival in a dose-dependent manner. At the same time, intraventricular application prevented systemic side effects in the form of anatomical or histological bone deformities. We conclude that intraventricular application of a SHH pathway inhibitor combines the advantages of a specific treatment agent with precise drug delivery and might evolve as a promising new way of targeted treatment for SHH MB patients.

Patterns, timing, and environmental drivers of growth in two coexisting green-stemmed Mediterranean alpine shrubs species.

The Mediterranean alpine is one of the most vulnerable ecosystems under future environmental change. Yet, patterns, timing and environmental controls of plant growth are poorly investigated. We aimed at an improved understanding of growth processes, as well as stem swelling and shrinking patterns, by examining two common coexisting green-stemmed shrub species. Using dendrometers to measure daily stem diameter changes, we separated these changes into water-related shrinking and swelling and irreversible growth. Implementing correlation analysis, linear mixed effects models, and partial least squares regression on time series of stem diameter changes, with corresponding soil temperature and moisture data as environmental predictors, we found species-specific growth patterns related to different drought-adaptive strategies. We show that the winter-cold-adapted species Cytisus galianoi uses a drought tolerance strategy combined with a high ecological plasticity, and is, thus, able to gain competitive advantages under future climate warming. In contrast, Genista versicolor is restricted to a narrower ecological niche using a winter-cold escape and drought avoidance strategy, which might be of disadvantage in a changing climate. Pregrowth environmental conditions were more relevant than conditions during growth, controlling the species' resource availability. Thus, studies focusing on current driver constellations of growth may fail to predict a species' ecological niche and its potential future performance.

Multi-omic profiling and real time ex vivo modelling of imatinib-resistant dermatofibrosarcoma protuberans with fibrosarcomatous transformation.

Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma, with the risk of aggressive fibro-sarcomatous transformation. Limited effective options are available for un-resectable or metastatic DFSP beyond targeting the oncogenic PDGF pathway with imatinib therapy. We established a patient-derived xenograft (PDX) and cell line model (designated MDFSP-S1) of imatinib-resistant DFSP with fibro-sarcomatous transformation. Whole genome sequencing identified high-level amplification at chromosomes 17 and 22, whilst homozygous deep deletion was demonstrated at chromosome 9 (CDKN2A, CDKN2B, MTAP). RNA sequencing followed by Sanger sequencing confirmed the pathognomonic COL1A1-PDGFB t (17;22) rearrangement in the original tumour, PDX and cell line model. Immunohistochemistry profiles of the PDX model were consistent with the patient's tumour sample (CD34 + /MIB1 + /SOX10- ). Gene set enrichment analysis highlighted top-scoring Hallmark gene sets in several oncogenic signalling pathways, including potentially targetable MTORC1 signalling and angiogenesis pathways. Antiangiogenic agents (sunitinib, regorafenib, pazopanib, axitinib) and the third-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib exhibited modest anti-proliferative activity in the cell line, with IC50 values between 1 and 10µM at 72h. No significant activity was observed with imatinib, palbociclib, everolimus, olaparib, gefitinib and erlotinib (IC50 all > 10µM). In conclusion, we established MDFSP-S1, a new PDX and cell line model of imatinib-resistant DFSP with fibro-sarcomatous transformation.

Determinant Analysis of Stunting Incidence in Toddlers in Lubuklinggau City

WHO defines stunting in the Global Nutrition Targets 2025 as an irreversible growth disorder primarily driven by inadequate nutritional intake and infections that occur repeatedly in the first 1000 days of life. Reducing stunting rates is the primary goal of the six goals in the 2025 Global Nutrition Targets. Stunting is also a vital indicator of the second goal of sustainable development, namely, no hunger. As many as 149.2 million toddlers (22%) worldwide were stunted in 2020. Southeast Asia has as many as 10.8 million toddlers (13.9%). This study analyzes the determinants of toddler stunting in Lubuklinggau City in 2022. The method used is an analytic observational research design with a case-control approach. Data were collected using a questionnaire on 71 stunted respondents and 71 respondents who were not stunted through the Cluster Random Sampling technique. The population to be studied was divided into sub-populations (clusters). A sample was selected for each cluster by random sampling. The results of the bivariate analysis showed that the variables Gender, Low Birth Weight, History of Exclusive Breastfeeding, Maternal Age at Birth, Parents' Income, History of ANC, and History of Infectious Diseases had a significant relationship affecting the incidence of stunting in toddlers in Lubuklinggau City in 2022. The results of the multivariate analysis test also show that parents' income is the most dominant factor influencing toddler stunting incidence in Lubuklinggau City in 2022.

Role of pelitinib in the regulation of migration and invasion of hepatocellular carcinoma cells via inhibition of Twist1

BackgroundOverexpression of Twist1, one of the epithelial-mesenchymal transition-transcription factors (EMT-TFs), is associated with hepatocellular carcinoma (HCC) metastasis. Pelitinib is known to be an irreversible epidermal growth factor receptor tyrosine kinase inhibitor that is used in clinical trials for colorectal and lung cancers, but the role of pelitinib in cancer metastasis has not been studied. This study aimed to investigate the anti-migration and anti-invasion activities of pelitinib in HCC cell lines.MethodsUsing three HCC cell lines (Huh7, Hep3B, and SNU449 cells), the effects of pelitinib on cell cytotoxicity, invasion, and migration were determined by cell viability, wound healing, transwell invasion, and spheroid invasion assays. The activities of MMP-2 and -9 were examined through gelatin zymography. Through immunoblotting analyses, the expression levels of EMT-TFs (Snail1, Twist1, and ZEB1) and EMT-related signaling pathways such as mitogen-activated protein kinases (MAPKs) and Akt signaling pathways were measured. The activity and expression levels of target genes were analyzed by reporter assay, RT-PCR, quantitative RT-PCR, and immunoblotting analysis. Statistical analysis was performed using one-way ANOVA with Dunnett's Multiple comparison tests in Prism 3.0 to assess differences between experimental conditions.ResultsIn this study, pelitinib treatment significantly inhibited wound closure in various HCC cell lines, including Huh7, Hep3B, and SNU449. Additionally, pelitinib was found to inhibit multicellular cancer spheroid invasion and metalloprotease activities in Huh7 cells. Further investigation revealed that pelitinib treatment inhibited the migration and invasion of Huh7 cells by inducing Twist1 degradation through the inhibition of MAPK and Akt signaling pathways. We also confirmed that the inhibition of cell motility by Twist1 siRNA was similar to that observed in pelitinib-treated group. Furthermore, pelitinib treatment regulated the expression of target genes associated with EMT, as demonstrated by the upregulation of E-cadherin and downregulation of N-cadherin.ConclusionBased on our novel finding of pelitinib from the perspective of EMT, pelitinib has the ability to inhibit EMT activity of HCC cells via inhibition of Twist1, and this may be the potential mechanism of pelitinib on the suppression of migration and invasion of HCC cells. Therefore, pelitinib could be developed as a potential anti-cancer drug for HCC.

Optimizing the potential of intercalation on anode for long-cycle 420 Wh/kg Li-ion batteries

Utilization of novel cathode and anode materials is expected to achieve ultrahigh energy density of Li-ion batteries, but it usually suffers from a large capacity fade in full cells. Here we propose a strategy towards optimizing reversibility of intercalation/deintercalation in anode via regulating the negative/positive capacity ratio (N/P) ratios in full cells with Li-rich layered oxide cathode and SiOx@graphite anode. Compared with high N/P ratio, the cell with an optimal N/P ratio of 0.90 displays the best cycling performance. Some comprehensive characterizations such as in-situ pressure and electrochemical measurements reveal that the lower N/P ratio could reduce the polarization on this composite anode to maximize the utilization of the graphite component and minimize the irreversible pressure growth. On the basis of unraveled failure mechanisms, a 21 Ah multilayer pouch cell with low N/P ratio delivers the energy density up to 420 Wh kg−1 based on total mass of the cell and the capacity retention retains 82% after 300 cycles at 0.2 C. This work highlights the strong coupling between cell parameters and electrochemical performances, providing a new insight towards the dominant factor for irreversible Li-ion behavior during cycling besides the structural degradation of materials for high-energy-density Li-ion batteries.

Discovery and Structural Optimization of Novel Quinolone Derivatives as Potent Irreversible Pan-Fibroblast Growth Factor Receptor Inhibitors for Treating Solid Tumors.

Aberrant activation of fibroblast growth factor receptors (FGFRs) has been identified as an oncogenic driver force for multiple cancer types, making FGFRs a compelling target for anticancer therapy. Because of the renewed interest in irreversible inhibitors, considerable efforts have been made to find irreversible FGFR inhibitors. Herein, we discovered a series of novel quinolone-based covalent pan-FGFR inhibitors by further optimizing the lead compound (lenvatinib) under the guidance of molecular docking. The representative pan-FGFR inhibitor I-5 exhibited significant inhibitory potency against FGFR1-4 with nanomolar activity and effectively suppressed the proliferation of Huh-7 and Hep3B HCC cells. I-5 displayed high selectivity against a panel of 369 kinases at 1 μM. The irreversible binding to target proteins was characterized by liquid chromatography and tandem mass spectrometry (LC-MS/MS). Moreover, I-5 exhibited favorable PK properties in vivo and induced significant TGI in the Huh-7 and NCI-H1581 xenograft mouse models.

Characterizing microglial senescence: Tau as a key player.

The highest risk factor for the development of neurodegenerative diseases like tauopathies is aging. Many physiological decrements underlying aging are linked to cellular senescence. Senescent cells are characterized by an irreversible growth arrest and formation of a senescence-associated secretory phenotype (SASP), a proinflammatory secretome that modifies the cellular microenvironment and contributes to tissue deterioration. Microglia, the innate immune cells in the brain, can enter a senescent state during aging. In addition, senescent microglia have been identified in the brains of tau-transgenic mice and patients suffering from tauopathies. While the contribution of senescent microglia to the development of tauopathies and other neurodegenerative diseases is a growing area of research, the effect of tau on microglial senescence remains elusive. Here, we exposed primary microglia to 5 and 15 nanomolar (nM) of monomeric tau for 18 h, followed by a recovery period of 48 h. Using multiple senescence markers, we found that exposure to 15 nM, but not 5 nM of tau increased levels of cell cycle arrest and a DNA damage marker, induced loss of the nuclear envelope protein lamin B1 and the histone marker H3K9me3, impaired tau clearance and migration, altered the cell morphology and resulted in formation of a SASP. Taken together, we show that exposure to tau can lead to microglial senescence. As senescent cells were shown to negatively impact tau pathologies, this suggests the presence of a vicious circle, which should be further investigated in the future.

Printing 3D mesh-like grooves on zinc surface to enhance the stability of aqueous zinc ion batteries

Aqueous zinc ion batteries (AZIBs) are receiving broad attention owing to their high safety and low cost. However, the high mechanical strength and irreversible growth of zinc dendrites limit the practical application of AZIBs. Herein, regular mesh-like gullies are built on the surface of zinc foil (M150 Zn) by using simple model pressing method and stainless steel mesh as a mold. Due to the charge-enrichment effect, zinc ion deposition and stripping will be preferentially carried out in the grooves to keep the outer surface flat. In addition, zinc is exposed to 002 crystal surface in the gully after being pressed, and the deposited zinc is more inclined to grow at a small angle, so that it has a sedimentary morphology parallel to the basement. Consequently, at a current density of 0.5 mA cm−2, the M150 zinc anode has a voltage hysteresis of only 35 mV and a cycle life of up to 400 h (relative to a zinc foil of 96 mV and 160 h). Even more imposing is that the full cell has a capacity retention of approximately 100% after 1000 cycles at 2 A g−1 and a specific capacity of almost 60 mAh g−1 when activated carbon is used as the cathode. It is a promising method to improve the stable cycle performance of AZIBs by using a simple method to realize the non-prominent dendrites on the surface of zinc electrode.

The impact of cellular senescence in human adipose tissue.

In the last decades the prevalence of obesity has increased dramatically, and the worldwide epidemic of obesity and related metabolic diseases has contributed to an increased interest for the adipose tissue (AT), the primary site for storage of lipids, as a metabolically dynamic and endocrine organ. Subcutaneous AT is the depot with the largest capacity to store excess energy and when its limit for storage is reached hypertrophic obesity, local inflammation, insulin resistance and ultimately type 2 diabetes (T2D) will develop. Hypertrophic AT is also associated with a dysfunctional adipogenesis, depending on the inability to recruit and differentiate new mature adipose cells. Lately, cellular senescence (CS), an aging mechanism defined as an irreversible growth arrest that occurs in response to various cellular stressors, such as telomere shortening, DNA damage and oxidative stress, has gained a lot of attention as a regulator of metabolic tissues and aging-associated conditions. The abundance of senescent cells increases not only with aging but also in hypertrophic obesity independent of age. Senescent AT is characterized by dysfunctional cells, increased inflammation, decreased insulin sensitivity and lipid storage. AT resident cells, such as progenitor cells (APC), non-proliferating mature cells and microvascular endothelial cells are affected with an increased senescence burden. Dysfunctional APC have both an impaired adipogenic and proliferative capacity. Interestingly, human mature adipose cells from obese hyperinsulinemic individuals have been shown to re-enter the cell cycle and senesce, which indicates an increased endoreplication. CS was also found to be more pronounced in mature cells from T2D individuals, compared to matched non-diabetic individuals, with decreased insulin sensitivity and adipogenic capacity. Factors associated with cellular senescence in human adipose tissue.

Interfacial Engineering on Cathode and Anode with Iminated Polyaniline@rGO‐CNTs for Robust and High‐Rate Full Lithium–Sulfur Batteries

AbstractLithium–sulfur batteries (LSBs) currently suffer from severe polysulfide shuttling, slow redox kinetics at the sulfur cathode, and irreversible dendrite growth at the lithium anode. To address these issues, a dual interfacial engineering strategy on both the cathode and anode is proposed. For the cathode, iminated polyaniline (iPANI) is used to achieve energetic engineering to induce mid‐energy level to the adsorption of polysulfides, and catalyze the redox conversion of sulfur species, and realize morphological engineering via self‐assembly of iPANI onto a scaffold integrated by reduced graphene oxide (rGO) and carbon nanotubes (CNTs), namely iPANI@rGO‐CNTs. For the anode, the highly conductive and lithiophilic nature and porous nanostructure of the iPANI@rGO‐CNTs composite facilitates the uniform deposition of lithium‐ions, significantly preventing the growth of lithium dendrites. Density functional theory calculations suggest that the iminated functional group at the excited state in iPANI can significantly suppress the shuttling effect, catalyze the conversion of sulfur species, and enhance the conversion of the sulfur species on the sulfur cathode. With the synergic effects of the iPANI@rGO‐CNTs nanoreactors, the as‐prepared LSBs deliver an excellent rate capability and outstanding cycling life. This large‐scale production and application of the iPANI@rGO‐CNTs nanocomposite may lead to the eventual commercialization of LSBs.

Evaluation of the Cytochrome P450 3A and P-glycoprotein Drug-Drug Interaction Potential of Futibatinib.

Futibatinib, a selective, irreversible fibroblast growth factor receptor 1-4 inhibitor, is being investigated for tumors harboring FGFR aberrations and was recently approved for the treatment of FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma. In vitro studies identified cytochrome P450 (CYP) 3A as the major CYP isoform in futibatinib metabolism and indicated that futibatinib is likely a P-glycoprotein (P-gp) substrate and inhibitor. Futibatinib also showed time-dependent inhibition of CYP3A in vitro. Phase I studies investigated the drug-drug interactions of futibatinib with itraconazole (a dual P-gp and strong CYP3A inhibitor), rifampin (a dual P-gp and strong CYP3A inducer), or midazolam (a sensitive CYP3A substrate) in healthy adult participants. Compared with futibatinib alone, coadministration of futibatinib with itraconazole increased futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 51% and 41%, respectively, and coadministration of futibatinib with rifampin lowered futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 53% and 64%, respectively. Coadministration of midazolam with futibatinib had no effect on midazolam pharmacokinetics compared with midazolam administered alone. These findings suggest that concomitant use of dual P-gp and strong CYP3A inhibitors/inducers with futibatinib should be avoided, but futibatinib can be concomitantly administered with other drugs metabolized by CYP3A. Drug-drug interaction studies with P-gp-specific substrates and inhibitors are planned.

Modeling Ratchet Growth as Porosity Creep

Irreversible thermal cycling growth (or ratchet growth) of insensitive explosive formulations has been known for years. Traditionally it’s attributed to material texture and to anisotropic thermal expansion. Although this understanding has been accepted for a long time, we’re not aware of any model on the macroscale that connects these material properties to ratchet growth behavior. Thompson et al. [1] have observed that they get growth not just from thermal cycling, but also from a long hold time of the material sample at high temperature, and that such growth resembles creep response. Following their findings we propose here a predictive model for ratchet growth on the macroscale, where we assume that when temperature is increased, growth comes about by porosity (or volume) creep. We model ratchet growth by assuming that: 1) increasing temperature decreases strength in tension (negative pressure), causing the porosity in the part of the material that is in tension to creep (slowly increase in volume); and 2) increasing temperature increases the internal pressure/tension fluctuations caused by thermal expansion anisotropy, thereby enhancing the rate of porosity creep and ratchet growth. We write down equations for porosity creep and the resulting ratchet growth, and we demonstrate that our modeled ratchet growth results are similar to test data. We do not calibrate the free parameters of our model to reproduce specific data, as we do not own such data

Abstract 3499: Inhibition of SOS1 by MRTX0902 augments the anti-tumor response of the targeted EGFR inhibitor osimertinib in NSCLC

Abstract Osimertinib is a third generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor recommended as a first line therapy in patients with advanced non-small lung cancer (NSCLC) characterized by EGFR activating mutations (exon 19 deletions and exon 21 L858R) and the resistance associated exon 20 T790M mutation, which is present in approximately 40-55% of patients following treatment with first generation EGFR-targeting inhibitors. Unfortunately, osimertinib monotherapy inevitably leads to both EGFR-dependent and EGFR-independent resistance mechanisms that reactivate RTK/MAPK pathway signaling. Thus, exploration of new combination strategies that target RTK/MAPK-mediated bypass of EGFR dependence may circumvent or delay therapeutic resistance are a key research focus. Preclinically, it has been shown that EGFR-mutant NSCLC cell lines are sensitive to inhibition of an upstream node of the MAPK pathway, the Son of Sevenless homolog 1 (SOS1) protein, which functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases. MRTX0902 is a selective and potent SOS1 inhibitor currently in Phase 1 clinical trials and functions by disrupting the KRAS/SOS1 protein-protein interaction to prevent SOS1-mediated nucleotide exchange on KRAS, ultimately leading to downregulation of KRAS-MAPK pathway signaling. Here we demonstrate that dual inhibition of SOS1 and mutant EGFR by osimertinib results in greater anchorage-independent (3D) cell death and further downregulation of MAPK and PI3K/AKT pathway signaling compared to single agent osimertinib treatment. In our current study, we characterized the anti-tumor effects of SOS1 inhibition by MRTX0902 as a monotherapy and in combination with osimertinib in EGFR mutant models of NSCLC. While single agent MRTX0902 treatment effectively inhibited EGFR mutant cell survival, combination treatment of MRTX0902 with osimertinib resulted in (1) deeper and sustained inhibition of MAPK and PI3K/AKT pathway signaling, (2) enhanced inhibition of 3D cell viability and increased apoptosis, and (3) increased anti-tumor efficacy compared to osimertinib monotherapy in EGFR mutant CDX models in vivo. These studies uncover the potential clinical application of combined vertical inhibition of RTK/MAPK pathway signaling by osimertinib and MRTX0902 and ultimately aide in the understanding of EGFR and RAS biology in targeted cancer therapy. Citation Format: Shilpi Khare, Niranjan Sudhakar, Jade Laguer, David M. Briere, Larry Yan, Allan Hebbert, Andrew Calinisan, Lars D. Engstrom, Fadia Qiryaqos, Peter Olson, James G. Christensen, Jacob R. Haling. Inhibition of SOS1 by MRTX0902 augments the anti-tumor response of the targeted EGFR inhibitor osimertinib in 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 3499.

Modelling intra-annual tree stem growth with a distributional regression approach for Gaussian process responses

Abstract High-resolution circumference dendrometers measure the irreversible growth and the reversible shrinking and swelling due to the water content of a tree stem. We propose a novel statistical method to decompose these measurements into a permanent and a temporary component, while explaining differences between the trees and years by covariates. Our model embeds Gaussian processes with parametric mean and covariance functions as response structures in a distributional regression framework with structured additive predictors. We discuss different mean and covariance functions, connections with other model classes, Markov chain Monte Carlo inference, and the efficiency of our sampling scheme.

Intervertebral disc cell fate during aging and degeneration: apoptosis, senescence, and autophagy

Degenerative disc disease, a major cause of low back pain and associated neurological symptoms, is a global health problem with the high morbidity, workforce loss, and socioeconomic burden. The present surgical strategy of disc resection and/or spinal fusion results in the functional loss of load, shock absorption, and movement; therefore, the development of new biological therapies is demanded. This achievement requires the understanding of intervertebral disc cell fate during aging and degeneration. Literature review was performed to clarify the current concepts and future perspectives of disc cell fate, focused on apoptosis, senescence, and autophagy. The intervertebral disc has a complex structure with the nucleus pulposus (NP), annulus fibrosus (AF), and cartilage endplates. While the AF arises from the mesenchyme, the NP originates from the notochord. Human disc NP notochordal phenotype disappears in adolescence, accompanied with cell death induction and chondrocyte proliferation. Discs morphologically and biochemically degenerate from early childhood as well, thereby suggesting a possible involvement of cell fate including age-related phenotypic changes in the disease process. As the disc is the largest avascular organ in the body, nutrient deprivation is a suspected contributor to degeneration. During aging and degeneration, disc cells undergo senescence, irreversible growth arrest, producing proinflammatory cytokines and matrix-degradative enzymes. Excessive stress ultimately leads to programmed cell death including apoptosis, necroptosis, pyroptosis, and ferroptosis. Autophagy, the intracellular degradation and recycling system, plays a role in maintaining cell homeostasis. While the incidence of apoptosis and senescence increases with age and degeneration severity, autophagy can be activated earlier, in response to limited nutrition and inflammation, but impaired in aged, degenerated discs. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) is a signal integrator to determine disc cell fate. Cell fate and microenvironmental regulation by modulating PI3K/Akt/mTOR signaling is a potential biological treatment for degenerative disc disease.

Abstract OT2-14-01: Pyrotinib after trastuzumab-based adjuvant therapy in high-risk early human epidermal growth factor receptor 2-positive breast cancer: a multicenter phase 2 trial

Abstract Objective: Trastuzumab-based adjuvant therapy was demonstrated to improve the prognosis of early human epidermal growth factor receptor 2 (HER-2) positive breast cancer, while about 10% of patients showed primary resistance. ExteNET study showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, after trastuzumab-based adjuvant therapy significantly improved invasive disease-free survival (iDFS) in women with HER2-positive breast cancer. Besides, for patients with early hormone receptor positive breast cancer within 1 year of prior trastuzumab with residual disease after neoadjuvant therapy, extended adjuvant neratinib showed prolonged overall survival, which suggested the potential benefit of extended adjuvant therapy for high-risk patients. Pyrotinib is an oral irreversible pan-HER receptor tyrosine kinase inhibitor targeting epidermal growth factor receptor, HER2, and HER4, which showed promising efficacy and manageable safety profiles in the treatment of HER-2 positive advanced breast cancer. In this study, we aimed to evaluate the efficacy and safety of extended adjuvant pyrotinib following trastuzumab-based adjuvant therapy in patients with high-risk early HER-2 positive breast cancer. Methods: In this ongoing multicenter, open-label, phase II trial at 23 centers in China, women with operable high-risk early HER-2 positive breast cancer and known hormone receptor status, who have completed trastuzumab-based adjuvant therapy within 6 months were enrolled. High-risk patients must meet one of the following criteria: N stage ≥1; T stage ≥2; did not achieve pathological complete response (pCR) after neoadjuvant therapy; had pCR after neoadjuvant therapy but with tumor size ≥ 5cm or N stage ≥2; or tumor size less than 2cm but with high Ki67, histologic grade 3 or with lymph node micrometastasis. Eligible patients were assigned to receive 6 month or 1 year of oral pyrotinib 400mg/day. The primary endpoint was the 2-year iDFS rate. Results: Between January, 2019 and February, 2022, a total of 142 eligible women were enrolled and assigned to receive pyrotinib, with a median age of 50 (range: 25-72) years old. Ninety-seven patients had a T stage ≥2. A total of 108 patients (76.1%) had node-positive disease, and 64 (45.1%) were hormone receptor positive. Twenty-five patients used neoadjuvant therapy previously, and all of them did not receive pCR (Table 1). After a median follow-up of 20 (range: 0.25-41) months, the 2-year iDFS rate was not available. Two and four patients reported invasive disease events after 6-month and 1-year of follow-up, with the 6-month and 1-year iDFS rates of 98.6% and 97.2%, respectively. The most common adverse events reported was diarrhea (78.2%), followed by fatigue (36.6%), lymphocyte count decreased (36.6%), nausea (33.1%) and hand-foot syndrome (33.1%). Forty-three patients experienced grade 3 diarrhea, and no grade 4 or higher adverse event was reported (Table 2). Adverse event leading to treatment discontinuation occurred in 12 (8.5%) patients. Conclusion: Extended adjuvant pyrotinib administrated after trastuzumab-based adjuvant therapy was well-tolerated and showed potential efficacy in high-risk early HER-2 positive breast cancer. The follow-up is ongoing to determine the long-term benefit of extended adjuvant pyrotinib. Table 1. Baseline characteristics of patients ER: estrogen receptor; PR: progesterone receptor. Table 2. Treatment-emergent adverse event occurring in at least 10% of the patients Citation Format: Feilin Cao, Zhaosheng Ma, Guinv Hu, Xiaotao Zhu, Shuguang Li, Shuzheng Chen, Binglie Chen, Zhanwen Li, Weizhu Wu, Xiaochun Ji, Jingde Shu, Deyou Tao, Xiaoqing Hu, Min Zheng, Ouchen Wang, Qingjing Feng, Jing Hao, Xujun Li. Pyrotinib after trastuzumab-based adjuvant therapy in high-risk early human epidermal growth factor receptor 2-positive breast cancer: a multicenter phase 2 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-14-01.