Tyrosine Kinase Research Articles

Abstract A106: Disparities in the presence of driver mutations and response to tyrosine kinase inhibitors in young patients with lung cancer

Abstract A106: Disparities in the presence of driver mutations and response to tyrosine kinase inhibitors in young patients with lung cancer

Abstract A105: Clinical characteristics of Hispanic patients ages 50 and younger with lung adenocarcinoma: A multi-center experience

Abstract Introduction: While uncommon, there has been an increase in non-small cell lung cancer (NSCLC) cases in patients under the age of 50 with little data on young Hispanic patients with NSCLC. This multicenter study describes the clinical characteristics of young Hispanic lung adenocarcinoma patients between two cities with a large Hispanic population. Methods: This retrospective study examined 90 Hispanic patients (18-50 years old) with metastatic lung adenocarcinoma treated at University of Miami (Miami) Sylvester Comprehensive Care Center (n=50), University of Southern California (USC) Norris Comprehensive Care Center/Los Angeles General Medical Center (n=26), and the Memorial Cancer Institute at West (Memorial) (n=14) from 2009-2023. We looked at age at diagnosis, sex, smoking history, stage at diagnosis, brain metastasis at diagnosis, mutations, tyrosine kinase inhibitor (TKI) exposure, and survival status at 24 months, 36 months, and 60 months. Fisher’s exact test was used to compare differences between USC (n=26) in Los Angeles, California, USA and Miami/Memorial (n=64) in Miami, Florida, USA. Results: 63.33% (n=57) of the patients were female. The median age at diagnosis was 41.5 years, including 8.89% (n=8) diagnosed from age 18-30, 33.33% (n=30) diagnosed from age 31-40, and 57.78% (n=52) diagnosed from age 41-50. 63.33% (n=57) identified as never smokers, 30.00% (n=27) identified as former smokers, and 6.67% (n=6) identified as current smokers. 85.56% (n=77) were found to have metastatic disease at diagnosis, including 34.44% (n=31) with brain metastasis at diagnosis. 28.89% (n=26) had an EGFR mutation, 28.89% (n=26) were ALK positive, and 8.89% (n=8) had a KRAS mutation. 55 (61.11%) had been exposed to a TKI. Between treatment sites, there was a greater prevalence of brain metastasis at USC versus Miami/Memorial (15/26, 57.69% vs. 16/64, 25.00%, p<0.01) and a trend towards greater prevalence of EGFR and KRAS mutations (EGFR: 11/26 (42.31%) vs. 15/64 (23.44%), p = 0.12; KRAS: 4/26 (15.38%) vs. 4/64 (6.25%), p = 0.22) and TKI exposure (19/26, 73.08% vs. 36/64, 56.25%, p=0.15) at USC versus Miami/Memorial. Regarding survival for stage IV patients, 37/61 (60.65%) of patients were alive at 24 months, 22/51 (43.1%) at 36 months, and 14/46 (30.4%) at 60 months with a trend towards more USC patients being alive at 36 months (10/18, 55.56% vs. 12/33, 36.36%) and 60 months (6/15, 40% vs. 8/31 25.8%). Conclusion: Young Hispanic lung adenocarcinoma patients are predominantly female, never smokers, diagnosed with metastatic disease, and enriched in EGFR and ALK mutations. There are differences in prevalence of brain metastasis, EGFR and KRAS mutations, TKI exposure, and survival between the USC and Miami/Memorial young lung adenocarcinoma patients. These notable frequencies may be attributed to the different Hispanic subgroups in the west coast versus southeastern USA. This study highlights the need for more attention towards Hispanic ethnicity in the young lung cancer population. Citation Format: Kyle Edwards, Darin Poei, Suset Almuinas de Armas, Coral Olazagasti, Zhonglin Hao, Jorge J. Nieva, Luis E Raez, Gilberto Lopes, Estelamari Rodriguez, Robert Hsu. Clinical characteristics of Hispanic patients ages 50 and younger with lung adenocarcinoma: A multi-center experience [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A105.

Abstract C067: Immune thrombocytopenia induced by PD-1/PD-L1 inhibitors in a patient with non-small cell lung adenocarcinoma: A case report and literature review

Abstract Introduction: The introduction of immunotherapy, particularly programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors, has transformed the treatment paradigm for non-small cell lung adenocarcinoma (NSCLC), significantly improving patient survival rates. However, alongside their immune-activating effects, these agents can also lead to immune-related adverse events (irAEs), affecting various organ systems. Among these, immune thrombocytopenia (ITP) is a rare but potentially life-threatening complication characterized by the destruction of platelets by autoantibodies, resulting in decreased platelet counts and an increased risk of bleeding. While ITP has been identified as a complication of immunotherapy, particularly PD-1 or PD-L1 inhibitors, its incidence, clinical presentation, and management remain poorly understood. Case Presentation: The 73-year-old female with stage IIIA poorly differentiated NSCLC who received chemotherapy with Taxol/Carboplatin and concurrent radiation therapy followed by a right upper lobectomy, initiated on immunotherapy with durvalumab, a PD-L1 inhibitor, developed severe thrombocytopenia (grade 4) after receiving two cycles of durvalumab. Despite steroid treatment, her condition persisted, indicating immune-related adverse events (irAEs). After confirming the diagnosis through further investigation, including molecular analysis, the patient was treated with intravenous immunoglobulin (IVIG), which significantly increased her platelet counts. Durvalumab was discontinued, and fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, was initiated to manage the irAEs effectively. Discussion: ITP is recognized as an immune-related adverse event (irAE) associated with PD-1 or PD-L1 inhibitors, although it remains rare and poorly understood. Several case reports have highlighted the occurrence of ITP induced by these inhibitors, demonstrating varied clinical presentations and responses to treatment. Mechanisms underlying ITP induction by PD-1/PD-L1 inhibitors are not fully elucidated but may involve immune dysregulation, including CD4+ and CD8+ T cell activation, production of antiplatelet antibodies, and increased expression of PD-L1 on platelets. Management strategies for ITP induced by PD-1/PD-L1 inhibitors include steroids, intravenous immunoglobulin (IVIG) therapy, recombinant human thrombopoietin (TPO), interleukin-6 (IL-6) receptor antagonists, and immunosuppressive agents. However, the effectiveness of these treatments varies among patients, highlighting the need for individualized approaches and further research to optimize management strategies. Conclusion: The prompt recognition and management of ITP induced by PD-1/PD-L1 inhibitors are essential for ensuring favorable patient outcomes. Further research is needed to understand the underlying mechanisms and develop effective prevention and management strategies for this rare but serious immune-related adverse event. Citation Format: Aliya M Khan, Richa Dawar. Immune thrombocytopenia induced by PD-1/PD-L1 inhibitors in a patient with non-small cell lung adenocarcinoma: A case report and literature review [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C067.

Protein Tyrosine Kinase 7 (PTK7) in Breast Cancer: A Retrospective Analysis of Tumour Expression and Association with Clinical Outcome

Protein tyrosine kinase 7 (PTK7), originally known as colon carcinoma kinase (CCK4), is an evolutionary conserved, catalytically defective transmembrane receptor involved in Wnt signalling. PTK7 has been identified as a potential therapeutic target, and a PTK7 antibody drug conjugate (PF-06647020; cofetuzumab pelidotin) has been investigated in phase I clinical trials for triple-negative breast cancer, ovarian cancer, and non-small cell lung cancer. PTK7 protein expression was evaluated in 1136 early-stage invasive breast tumours by immunohistochemistry. In addition, PTK7 mRNA expression in the METABRIC (n = 1980) and the TCGA breast cancer cohorts (n = 1082) was evaluated. Associations between PTK7 expression and clinicopathological criteria and patient outcome were determined. No association between PTK7 protein expression and breast cancer-specific survival was observed; however, PTK7 mRNA expression in the METABRIC cohort was associated with breast cancer-specific survival (p < 0.001). PTK7 protein and mRNA expression were associated with breast cancer-specific survival of patients with a poor prognostic Nottingham Prognostic Index (NPI) and a moderate prognostic NPI, respectively. Taken together, these data indicate that PTK7 expression is associated with patient outcome in subgroups of breast cancer patients.

Hsa_circ_0006010 and hsa_circ_0002903 in peripheral blood serve as novel diagnostic, surveillance and prognostic biomarkers for disease progression in chronic myeloid leukemia

BackgroundIn the era of tyrosine kinase inhibitor (TKI) treatment, the progression of chronic myeloid leukemia (CML) remains a significant clinical challenge, and genetic biomarkers for the early identification of CML patients at risk for progression are limited. This study explored whether essential circular RNAs (circRNAs) can be used as biomarkers for diagnosing and monitoring CML disease progression and assessing CML prognosis.MethodsPeripheral blood (PB) samples were collected from 173 CML patients (138 patients with chronic phase CML [CML-CP] and 35 patients with accelerated phase/blast phase CML [CML-AP/BP]) and 63 healthy controls (HCs). High-throughput RNA sequencing (RNA-Seq) was used to screen dysregulated candidate circRNAs for a circRNA signature associated with CML disease progression. Quantitative real-time PCR (qRT-PCR) was used for preliminary verification and screening of candidate dysregulated genes, as well as subsequent exploration of clinical applications. Receiver operating characteristic (ROC) curve analysis, Spearman’s rho correlation test, and the Kaplan-Meier method were used for statistical analysis.ResultsThe aberrant expression of hsa_circ_0006010 and hsa_circ_0002903 during CML progression could serve as valuable biomarkers for differentiating CML-AP/BP patients from CMP-CP patients or HCs. In addition, the expression levels of hsa_circ_0006010 and hsa_circ_0002903 were significantly associated with the clinical features of CML patients but were not directly related to the four scoring systems. Furthermore, survival analysis revealed that high hsa_circ_0006010 expression and low hsa_circ_0002903 expression indicated poor progression-free survival (PFS) in CML patients. Finally, PB hsa_circ_0006010 and hsa_circ_0002903 expression at diagnosis may also serve as disease progression surveillance markers for CML patients but were not correlated with PB BCR-ABL1/ABL1IS.ConclusionsOur study demonstrated that PB levels of hsa_circ_0006010 and hsa_circ_0002903 may serve as novel diagnostic, surveillance, and prognostic biomarkers for CML disease progression and may contribute to assisting in the diagnosis of CML patients at risk for progression and accurate management of advanced CML patients.

Targeted therapies, novel antibodies, and immunotherapies in advanced non-small cell lung cancer: clinical evidence and drug approval patterns.

Since 2011, the U.S. FDA has approved 30 new drugs for use in advanced non-small-cell lung cancer (NSCLC), mainly comprising tyrosine kinase inhibitors and immune checkpoint inhibitors. NSCLC with oncogene driver alterations is amenable to treatment with targeted drugs, usually small molecule inhibitors. In these cases, the demonstration of high overall response rates, coupled with a lasting duration of response, has allowed for accelerated approval in the U.S., based on single or multi-cohort trials. Confirmatory clinical evidence was subsequently provided through post-marketing trials. In NSCLC without such driver alterations, regulatory agencies in both the U.S. and the EU set clinical evidence expectations that foster the conduct of studies primarily focused on determining survival or event-free survival, based on randomized-controlled trial designs. This review analyzes the approval patterns of novel therapeutics for NSCLC with a focus on small molecule inhibitors that target driver alterations, as well as biologicals. The latter include monoclonal antibodies inhibiting immune checkpoints like PD-(L)1 or cell surface receptors, and antibody-drug conjugates, highly potent biologics linked to a cytotoxic compound. The differentiation of NSCLC into oncogene- and non-oncogene-addicted subtypes determines drug development strategies, the extent of the clinical development program, access to orphan drug development incentives, and regulatory approval strategies.

Repurposing Antiviral Drugs as Potential Anti-EGFR Agents in NSCLC: A Structure-Based Screening and Molecular Dynamics Analysis.

One of the problems resulting from recurrent hyperactivated or mutant epidermal growth factor receptors (EGFR) in non-small cell lung cancer (NSCLC) is therapeutic resistance. Consequently, this leads to increased expressionof oncogenicproteins and reduces the efficacy of EGFR tyrosine kinase inhibitors (TKIs). This study assessed antiviral drug efficacy as potential anti-EGFR agentsfor NSCLC. We used structure-based virtual screening to evaluate 66 antiviral drugs thoroughly. The top 6 antiviral drugs exhibiting impressive binding energies (i.e. surpassing a threshold of -8.5 kcalmol-1) were identified. Subsequent bioactivity analysis and ADMET profiling were performed to select the most promising candidates, followed by a molecular dynamic simulation. Among the selected antiviral regimens, dolutegravir demonstrated the highest docking score (-9.8 kcalmol-1), followed by rilpivirine and ensitrelvir, surpassing other candidates and our reference EGFR TKI. Further molecular dynamics simulations revealed promising dynamic interactions of dolutegravir, ensitrelvir, and rilpivirine with the EGFR target as compared with afatinib. Our findings highlight the repositioning potential of antiviral drugs for anti-EGFR drug discovery, supported by their robust docking scores, ADMET profiles, dynamic interactions, and binding free energies. The results open up new avenues for advanced NSCLC therapy. Further in vitro investigations are warranted to evaluate their efficacy and safety.

GAS6 as a potential target to alleviate neuroinflammation during Japanese encephalitis in mouse models

Viral encephalitis is characterized by inflammation of the brain parenchyma caused by a variety of viruses, among which the Japanese encephalitis (JE) virus (JEV) is a typical representative arbovirus. Neuronal death, neuroinflammation, and breakdown of the blood brain barrier (BBB) constitute vicious circles of JE progression. Currently, there is no effective therapy to prevent this damage. Growth arrest specific gene 6 (GAS6) is a secreted growth factor that binds to the TYRO3, AXL, and MERTK (TAM) family of receptor tyrosine kinases and has been demonstrated to participate in neuroprotection and suppression of inflammation in many central nervous system (CNS) diseases which has great potential for JE intervention. In this study, we found that GAS6 expression in the brain was decreased and was reversely correlated with viral load and neuronal loss. Mice with GAS6/TAM signalling deficiency showed higher mortality and accelerated neuroinflammation during peripheral JEV infection, accompanied by BBB breakdown. GAS6 directly promoted the expression of tight junction proteins in bEnd.3 cells and strengthened BBB integrity, partly via AXL. Mice administered GAS6 were more resistant to JEV infection due to increased BBB integrity, as well as decreased viral load and neuroinflammation. Thus, targeted GAS6 delivery may represent a strategy for the prevention and treatment of JE especially in patients with impaired BBB.

Sequential vs. concurrent systemic therapies in combination with FOLFOX-HAIC for locally advanced hepatocellular carcinoma: a single-center, real-world cohort study

BackgroundTri-combination therapy based on hepatic arterial infusion chemotherapy (HAIC) of infusion fluorouracil, leucovorin, and oxaliplatin (FOLFOX-HAIC) plus immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the locally advanced hepatocellular carcinoma (HCC) patients have been proven effective. However, whether it was best for these HCC patients to start with the most potent therapeutic pattern was still under debate. This retrospective study evaluated the efficacy and safety of FOLFOX-HAIC combined with systemic therapies in the patterns of sequential and concurrent schedules.MethodsThis real-world study included 117 unresectable HCC patients who initially received either FOLFOX-HAIC monotherapy (HAIC group, n = 44) or concurrent ICIs and TKIs (ConHAIC group, n = 73) from March 2020 and June 2022, during the period of FOLFOX-HAIC monotherapy in HAIC group, patients in the HAIC group (n = 30) experienced progressive disease (PD) would have their treatment pattern converted from the FOLFOX-HAIC monotherapy to the combination of FOLFOX-HAIC plus ICIs and TKIs sequentially (SeqHAIC group). The progression-free survival (PFS) and overall survival (OS), as primary outcomes, were compared between patients in the SeqHAIC and ConHAIC groups.ResultsThe median follow-up time of the SeqHAIC group was 24.92 months (95% CI, 12.74–37.09 months) and of the ConHAIC group was 17.87 months (95% CI, 16.85–18.89 months) and no significant difference was observed in both PFS (HR, 1.572; 95% CI, 0.848–2.916; p = 0.151) and OS (HR, 1.212; 95% CI, 0.574–2.561; p = 0.614) between the SeqHAIC and the ConHAIC groups. As for the tumor responses, there was no significant difference between the two groups regarding tumor responses, overall response rates (p = 0.658) and disease control rates (p = 0.641) were 50.0%, 45.2%, and 83.3%, 89.0% for the SeqHAIC and the ConHAIC groups, respectively.ConclusionOur study revealed that sequential systemic ICIs and TKIs in combination with FOLFOX-HAIC provides similar long-term prognosis and better tolerability compared to concurrent therapy for locally advanced HCC patients. Prospective studies with a larger sample size and longer follow-up are required to validate these findings.

Research on the Improvement of Endothelial Cell Function and Trophoblast Apoptosis in Rats with Preeclampsia by Tanshinone IIA

Background Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of damage to another organ system, often the kidneys. Recent studies suggest that endothelial dysfunction and trophoblast apoptosis are involved in the pathogenesis of preeclampsia. Purpose To investigate the effects of tanshinone IIA (TIIA) on clinical symptoms, vascular endothelial function, and placental trophoblast apoptosis in preeclampsia rats. Materials and Methods Twenty-four pregnant Sprague-Dawley rats, between 8 and 10 weeks old, were randomly divided and allocated into three groups: Control, model, and treatment, with each group consisting of 8 rats. The control group received normal saline injections via the tail vein; the model group received NG-nitro-l-arginine methyl ester (l-NAME) to induce preeclampsia, followed by normal saline injections; and the treatment group received TIIA (10 mg/kg) via tail vein injection after preeclampsia induction with l-NAME. Various parameters were measured, including tail artery systolic pressure, 24-hour proteinuria, offspring and placental weight, levels of endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), placental growth factor (PLGF), and soluble FMS-like tyrosine kinase 1 (sFlt-1) in serum, and expression of B-cell lymphoma-2 (Bcl-2) and Bcl-2-related X protein (Bax) in placental trophoblasts. Results TIIA treatment led to decreased tail artery systolic pressure and 24-hour urine protein levels, increased body and placental weights of offspring, and favorable changes in serum levels of ET-1, sFlt-1, eNOS, and PLGF. Moreover, TIIA treatment resulted in decreased Bax levels and apoptosis in placental trophoblasts, along with increased Bcl-2 levels. Conclusion TIIA can improve the clinical symptoms of preeclampsia in rats induced by l-NAME, alleviate the apoptosis of placental trophoblast cells, and improve vascular endothelial function.

Enhanced Fyn-tau and NR2B-PSD95 interactions in epileptic foci in experimental models and human epilepsy

Abstract Epilepsy and Alzheimer’s Disease (AD) share some common pathologies such as neurodegeneration, seizures, and impaired cognition. However, the molecular mechanisms of these changes are still largely unknown. Fyn, a Src-family non-receptor tyrosine kinase (SFK), and its interaction with tau in mediating brain pathology in epilepsy and AD can be a potential therapeutic target for disease modification. Although Fyn and tau pathology occurs in both AD and epilepsy, the dynamics of Fyn-tau and PSD95-NR2B interactions affected by seizures and their impact on brain pathology in epilepsy have not been investigated. In this study, we demonstrate a significant increase of Fyn-tau interactions following seizure induction by kainate in both acute and chronic rodent models, and in human epilepsy. In the early phase of epileptogenesis, we show increased Fyn/tau/NR2B/PSD95/neuronal nitric oxide synthase (nNOS) complexes after status epilepticus and a post-synaptic increase of phosphorylated tau (pY18 and AT8), Fyn (pSFK-Y416), and NMDAR (pNR2B-Y1472), and nNOS. Hippocampal Proximity Ligation Assay and co-immunoprecipitation revealed a sustained increase of Fyn-tau and NR2B-PSD95 complexes/binding in rat chronic epilepsy at three months post-status epilepticus. Enhanced Fyn-tau complexes strongly correlated with the frequency of spontaneously recurring convulsive seizures and epileptiform spikes in the chronic epilepsy model. In human epileptic brains, we also identified increased Fyn-tau and NR2B-PSD95 complexes, tau phosphorylation (pY18 and AT8), and Fyn activation (pSFK-Y416), implying the translational and therapeutic potential of these molecular interactions. In tau knockout mice and in rats treated with a Fyn/SFK inhibitor saracatinib, we found a significant reduction of phosphorylated Fyn, tau (AT8 in saracatinib-treated), NR2B, and nNOS, and their interactions (Fyn-tau and NR2B-PSD95 in saracatinib-treated group; NR2B-PSD95 in tau knockout group). The reduction of Fyn-tau and NR2B-PSD95 interactions in the saracatinib-treated group, in contrast to the vehicle-treated group, correlated with the modification in seizure progression in the rat chronic epilepsy model. These findings from animal models and human epilepsy provide evidence for the role of Fyn-tau and NR2B-PSD95 interactions in seizure-induced brain pathology and suggest that blocking such interactions could modify the progression of epilepsy.

Inhibition of hTERT/telomerase/telomere mediates therapeutic efficacy of osimertinib in EGFR mutant lung cancer

The inevitable acquired resistance to osimertinib (AZD9291), an FDA-approved third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR activating or T790M resistant mutations, limits its long-term clinical benefit. Telomere maintenance via telomerase reactivation is linked to uncontrolled cell growth and is a cancer hallmark and an attractive cancer therapeutic target. Our effort toward understanding the action mechanisms, including resistance mechanisms, of osimertinib has led to the identification of a novel and critical role in maintaining c-Myc–dependent downregulation of hTERT, a catalytic subunit of telomerase, and subsequent inhibition of telomerase/telomere and induction of telomere dysfunction in mediating therapeutic efficacy of osimertinib. Consequently, osimertinib combined with the telomere inhibitor, 6-Thio-dG, which is currently tested in a phase II trial, effectively inhibited the growth of osimertinib-resistant tumors, regressed EGFRm NSCLC patient-derived xenografts, and delayed the emergence of acquired resistance to osimertinib, warranting clinical validation of this strategy to manage osimertinib acquired resistance.

Hepsin as a potential therapeutic target for alleviating acetaminophen-induced hepatotoxicity via gap-junction regulation and oxidative stress modulation

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver damage, highlighting the limitations of current emergency treatments that primarily involve administering the glutathione precursor N-acetylcysteine and supportive therapy. This study highlights the essential protective role of the type II transmembrane serine protease (TTSP), hepsin, in mitigating acetaminophen-induced liver injury, particularly through its regulation of gap junction (GJ) abundance in response to reactive oxygen stress in the liver. We previously reported that reduced levels of activated hepatocyte growth factor and the c-Met receptor tyrosine kinase—both of which are vital for maintaining cellular redox balance—combined with increased expression of GJ proteins in hepsin-deficient mice. Here, we show that hepsin deficiency in mice exacerbates acetaminophen toxicity compared to wild-type mice, leading to more severe liver pathology, elevated oxidative stress, and greater mortality within 6 h after exposure. Administering hepsin had a protective effect in both mouse models, reducing hepatotoxicity by modulating GJ abundance. Additionally, transcriptome analysis and a functional GJ inhibitor have highlighted hepsin's mechanism for managing oxidative stress. Combining hepsin with relatively low doses of N-acetylcysteine had a synergistic effect that was more efficacious than high-dose N-acetylcysteine alone. Our results illustrate the crucial role of hepsin in modulating the abundance of hepatic GJs and reducing oxidative stress, thereby offering early protection against acetaminophen-induced hepatotoxicity and a new, combination approach. Emerging as a promising therapeutic target, hepsin holds potential for combination therapy with N-acetylcysteine, paving the way for novel approaches in managing drug-induced liver injury.Graphical 1. Hepsin−/− mice exhibit exacerbated APAP toxicity, resulting in more severe liver damage, elevated oxidative stress, and higher mortality.2. Hepsin is crucial in protecting against APAP-induced liver injury by regulating gap junctions and reducing oxidative stress.3. Combining hepsin with low doses of N-acetylcysteine provides greater protection against APAP-induced hepatotoxicity than high-dose NAC alone.

Reduction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infection by blocking the epidermal growth factor receptor (EGFR) pathway.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants presents challenges in global efforts to transition from the pandemic to an endemic stage. The spike protein of the SARS-CoV-2 virus, which is pivotal for cell entry, exhibits significant mutations in its variants, potentially affecting infectivity and therapeutic efficacy. Recent findings indicate upregulation of the epidermal growth factor receptor (EGFR) pathway, a key target in cancer therapy, by the spike protein of SARS-CoV-2. This study aimed to investigate the activity of the EGFR pathway against SARS-CoV-2 variants and to assess the inhibitory effects of EGFR inhibitors using SARS-CoV variant pseudoviral particles to guide future therapeutic strategies. Omicron variant SARS-CoV pseudoviral particles exhibited heightened infectivity in human angiotensin-converting enzyme 2 (hACE2)-expressing HEK293 and A549 lung cancer cells accompanied by increased EGFR pathway activation in infected cells. Using the EGFR tyrosine kinase inhibitor, osimertinib, we observed a reduction in viral infection rates in hACE2-HEK293 and A549 cells infected with the SARS-CoV-2 variant pseudoviral particles. We conducted further experiments to confirm that the reduction in infection efficacy with osimertinib treatment was not associated to a decrease in cell viability. Furthermore, this inhibitory effect of osimertinib in cell lines was corroborated in a spheroid cell culture model derived from hACE2-A549 cells. These findings suggest the potential application of EGFR-targeted antiviral therapy against highly infectious SARS-CoV-2 variants.IMPORTANCEThe emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is concerning as vaccines designed for one variant need not essentially protect against other novel variants. Therefore, there is an urgent need to identify therapies that can act against multiple novel variants that have heightened virulence compared with the wild type. It has been reported that the spike protein of the SARS-CoV-2 virus elicits an increased expression of the epidermal growth factor receptor (EGFR) pathway. We used this information and examined whether treatment with an EGFR inhibitor, osimertinib, which is already approved for clinical use in cancer therapy, can reduce the infection caused by SARS-CoV-2, wild type, and Omicron and Delta variants, in two cell lines and one spheroid model. The results showed that osimertinib treatment successfully reduced infection efficacy, particularly in variants, and that this effect was not related to a reduction in cell viability, making this a promising strategy for treating SARS-CoV-2 infections.

Adjuvant treatment for renal cell carcinoma: current status and future

Purpose of review Renal cell carcinoma (RCC) is resistant to chemotherapy. Adjuvant interferon and tyrosine kinase inhibitors were ineffective. Immune checkpoint inhibitors (ICIs), however, have shed new hope in this setting. In the current review, updated evidence of adjuvant therapy in RCC is summarized. Recent findings KEYNOTE-564 demonstrated survival benefits of adjuvant Pembrolizumab in RCC. EAU guidelines now recommend adjuvant pembrolizumab to ccRCC patients at an increased risk of recurrence, as defined in the study. At a median follow-up of 24 months, the disease-free survival (DFS) was significantly longer for the Pembrolizumab group than placebo group [DFS 77.3 vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval (95% CI), 0.53–0.87; P = 0.002]. From its updated analysis, at median follow up of 57.2 months, overall survival (OS) benefit of Pembrolizumab was demonstrated (hazard ratio for death, 0.62; 95% CI, 0.44–0.87; P = 0.005). A number of other adjuvant ICI trials have though been negative. Summary Pembrolizumab is currently the only adjuvant therapy for RCC showing survival benefits, amid a number of negative trials on adjuvant immunotherapy. Currently, there is no role for adjuvant tyrosine-kinase inhibitors and radiotherapy for RCC. Meanwhile, a multidisciplinary approach and shared decision-making should be adopted.

Philadelphia-like B-cell acute lymphoblastic Leukaemia: Disease features and outcomes in the era of immunotherapy.

Philadelphia chromosome (Ph)-like acute lymphoblastic leukaemia (ALL) is a high-risk subtype with a gene expression profile similar to Ph-positive ALL, due to activation of tyrosine kinase signalling. To understand the clinical implications of Ph-like ALL, this single-centre retrospective study evaluates outcomes in 268 adults, largely Hispanic ALL patients treated between 2013 and 2024, with a subgroup analysis of 139 haematopoietic stem cell transplantation (HSCT) patients. ALL subtypes included 68 (25.4%) Ph-like, 89 (33.2%) Ph-positive, and 111 (41.4%) Ph-negative. Ph-like patients were the youngest age at diagnosis (p = 0.007), most likely to have refractory disease (p < 0.001), and least likely to achieve minimal residual disease (MRD) negativity after induction (p = 0.031). Relative to Ph-negative ALL, Ph-like achieved worse event-free survival (EFS) (HR = 1.66; 95% CI 1.12-2.46; p = 0.012), whereas Ph-positive had improved EFS (HR = 0.60; 95% CI 0.38-0.93; p = 0.024) and cumulative incidence of relapse (CIR) (HR = 0.59; 95% CI 0.35-0.99; p = 0.046). Within the transplant subgroup, Ph status did not impact disease-free survival (DFS), CIR, or overall survival (OS). However, patients who received blinatumomab within 1-year pre-HSCT had improved DFS (HR = 0.43; 95% CI 0.20-0.94; p = 0.034) and CIR (HR = 0.26; 95% CI 0.09-0.75; p = 0.13). In conclusion, our data suggest that Ph-like is less likely to respond to standard induction therapy and HSCT may result in similar survival outcomes to Ph-negative ALL.

Detection of Circulating Tumor Cells and EGFR Mutation in Pulmonary Vein and Arterial Blood of Lung Cancer Patients Using a Newly Developed Immunocytology-Based Platform

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are powerful molecular targeted therapeutic agents for lung cancer. We recently developed an original immunocytology and glass slide-based circulating tumor cell (CTC) detection platform for both CTC enumeration and EGFR mutation analysis with DNA extracted from CTCs. Methods: Using this platform, we conducted a pilot clinical study for CTC enumeration in peripheral blood (PB), pulmonary arterial blood (PA), and pulmonary venous blood (PV) from 33 patients with lung cancer (Stage I–III) who underwent surgery, followed by digital PCR-based EGFR mutation analysis of CTCs in PV from 12 patients. Results: The results showed that CTC levels were significantly higher in PV and PA than in PB (p &lt; 0.05, p &lt; 0.01. respectively), with a notably greater number of small and large CTC clusters (p &lt; 0.01). Genetic analysis of EGFR mutations of CTCs from PV (n = 12) revealed six mutations, including three Exon19del and three L856R, in CTCs and eight EGFR mutations, including five Exon19del and three L856R, in lung tumor tissue. CTC mutation status matched that of tissue samples in nine patients, was unmatched in two patients, and controversial in one patient, indicating a sensitivity of 0.75 (6/8) and specificity of 1.0 (4/4) with some false-negative results for the mutation analysis of CTCs. Conclusions: This immunocytology-based CTC detection platform is a convenient method for detecting both CTC number and EGFR mutation status under microscopy, suggesting its potential as a liquid biopsy tool in the hospital for patients with lung cancer in some clinical settings.

Organocatalytic[3 + 2]Cycloaddition: Synthesis of Quinazoline Containing Sulfonyl 1,2,3‐Triazoles as Potent EGFR Targeting Anti‐Breast Cancer Agents

ABSTRACTA general strategy was developed for the synthesis of new fully decorated 1,2,3‐triazoles (4a–4m and 5a–5g) containing quinazolines from 1‐(4‐nitrophenyl)‐2‐(quinazolin‐8‐ylsulfonyl) ethan‐1‐one and several azides using Ramachary organocatalytic azide‐ketone cycloaddition method. This reaction is reported for the synthesis of fully substituted sulfonyl‐1,2,3‐triazolyl quinazolins at a temperature of 100°C and the yields of the products produced are satisfactory to excellent. In vitro anticancer activity of all these derivatives demonstrated that six compounds, 4d, 4f, 4i, 4j, 5d, and 5e, were effective against two human breast cancer cell lines, MCF‐7 and MDA‐MB‐231. Compounds 4f, 4j, and 5d had more action against both cell lines than Erlotinib. Later, the findings of inhibitory assays of potent compounds 4d, 4f, 4i, 4j, 5d, and 5e against the tyrosine kinase EGFR revealed that compound 5d proved more potent than the reference erlotinib, while 4f and 4j had comparable efficacy. In silico molecular docking studies were also performed on six strong medicines to identify interactions with the EGFR receptor, and the energy estimations were shown to be comparable with the observed IC50 values. Ultimately, using SWISS/ADME and pkCSM, the in silico pharmacokinetic profile of potent compounds 4d, 4f, 4i, 4j, 5d, and 5e was predicted. All of the compounds precisely followed the principles established by Lipinski, Veber, Egan, and Muegge.

Forecasting the Pharmacological Mechanisms of Plumbago zeylanica and Solanum xanthocarpum in Diabetic Retinopathy Treatment: A Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation Study

(1) Background: Diabetic retinopathy (DR) is a major complication of diabetes, marked by abnormal angiogenesis, microaneurysms, and retinal hemorrhages. Traditional Ayurvedic medicine advocates multi-target strategies for DR management. However, the mechanisms by which Solanum xanthocarpum (SX) and Plumbago zeylanica (PZ) exert therapeutic effects are not well understood; (2) Methods: To investigate these mechanisms, we employed network pharmacology and molecular docking techniques. Phytochemicals from SX and PZ were identified using the IMPPAT database and Swiss Target Prediction tool. DR-related protein targets were sourced from the GeneCards database, and common targets were identified through Venn diagram analysis. STRING and Cytoscape were used to construct and analyze protein–protein interaction networks. Pathway enrichment was performed with Gene Ontology and KEGG databases; (3) Results: We identified 28 active phytoconstituents, targeting proteins such as EGFR, SRC, STAT3, AKT1, and HSP90AA1. Molecular docking and dynamics simulations confirmed the strong binding affinities of these compounds to their targets; (4) Conclusions: The study highlights the multi-target activity of SX and PZ, particularly in pathways related to EGFR tyrosine kinase inhibitor resistance and PI3K–AKT signaling. These findings provide valuable insights into their therapeutic potential for DR, suggesting the effective modulation of key molecular pathways involved in the disease.

Measurement of adhesion and traction of cells at high yield reveals an energetic ratchet operating during nephron condensation

Developmental biology-inspired strategies for tissue-building have extraordinary promise for regenerative medicine, spurring interest in the relationship between cell biophysical properties and morphological transitions. However, mapping gene or protein expression data to cell biophysical properties to physical morphogenesis remains challenging with current techniques. Here, we present multiplexed adhesion and traction of cells at high yield (MATCHY). MATCHY advances the multiplexing and throughput capabilities of existing traction force and cell-cell adhesion assays using microfabrication and a semiautomated computation scheme with machine learning-driven cell segmentation. Both biophysical assays are coupled with serial downstream immunofluorescence to extract cell type/signaling state information. MATCHY is especially suited to complex primary tissue-, organoid-, or biopsy-derived cell mixtures since it does not rely on a priori knowledge of cell surface markers, cell sorting, or use of lineage-specific reporter animals. We first validate MATCHY on canine kidney epithelial cells engineered for rearranged during transfection (RET) tyrosine kinase expression and quantify a relationship between downstream signaling and cell traction. We then use MATCHY to create a biophysical atlas of mouse embryonic kidney primary cells and identify distinct biophysical states along the nephron differentiation trajectory. Our data complement expression-level knowledge of adhesion molecule changes that accompany nephron differentiation with quantitative biophysical information. These data reveal an "energetic ratchet" that accounts for spatial trends in nephron progenitor cell condensation as they differentiate into early nephron structures, which we validate through agent-based computational simulation. MATCHY offers semiautomated cell biophysical characterization at >10,000-cell throughput, an advance benefiting fundamental studies and new synthetic tissue strategies for regenerative medicine.