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The scaffold protein PEAK1 acts downstream of integrin adhesion complexes and the epidermal growth factor receptor, orchestrating signaling events that control cell proliferation and cytoskeletal remodeling. In this study we investigated the role of PEAK1 in colorectal carcinoma (CRC) progression using various in vitro and in vivo models to replicate the stepwise pathogenesis of CRC. While we observed a cell-type specific role for PEAK1 in the proliferation and in human CRC cell lines in vitro, our in vivo experiments using different CRC mouse models driven by loss of Apc, with or without oncogenic Kras or Pten loss suggest that PEAK1 does not significantly contribute to tumor formation in vivo. However, the survival time of Peak1−/− mice in the Apcfl/+ model appeared to be slightly increased. Furthermore, PEAK1 promotes EGF-induced Caco-2 cell proliferation and regulates spheroid polarization and lumenization. Given that the Caco-2 cells harbor mutations in the tumor suppressors APC and β-CATENIN, but not in other tumor suppressors or in proto-oncogenes, we conclude that the PEAK1's impact on colon carcinogenesis is limited, potentially playing a role in the initial stage of the adenoma to carcinoma progression. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and EGFR-TKI combination treatments have become the standard first-line treatments for EGFR-mutated non-small cell lung cancer (NSCLC) patients. However, the best option has yet to be determined. This study compares the efficacy and safety of various first-line EGFR-TKI monotherapies and combination treatments for advanced EGFR-mutated NSCLC. Methods: We searched PubMed, Embase, the Cochrane Central Register of Controlled Clinical Trials databases, and several international conferences to identify randomized controlled trials reporting on first-line EGFR-TKI treatments for patients with advanced EGFR-mutated NSCLC. The study quality was assessed using the revised tool for risk of bias in randomized trials. The efficacy and safety outcomes of the included treatments were compared by network meta-analysis based on a frequentist approach. Results: We identified 26 trials (8,359 patients) investigating 14 treatment groups, including first, second, and third-generation EGFR-TKIs and their combination treatments. Osimertinib plus chemotherapy and lazertinib plus amivantamab showed the highest efficacy in improving progression-free survival. New third-generation EGFR-TKIs demonstrated comparable efficacy to osimertinib alone but did not surpass it. Subgroup analyses revealed slight variation in treatment efficacy based on mutation types and patient demographics. Combination treatments were associated with a higher incidence of adverse events. Conclusion: These results reveal that osimertinib plus chemotherapy and lazertinib plus amivantamab are superior first-line options for patients with advanced EGFR-mutated NSCLC. However, these combinations are associated with higher adverse event rates. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aims Methods and Results Conclusion To prevent end‐stage renal disease caused by diabetic kidney disease, we created a predictive model for high‐risk patients using machine learning.The reference point was the time at which each patient's estimated glomerular filtration rate (eGFR) first fell below 60 mL/min/1.73 m2. The input period spanned the reference point to 1 year prior. The primary endpoint was a 50% decrease in eGFR from the mean of the input period over the 3 year evaluation period. We created predictive models for patients’ primary endpoints using time series data of various variables over the input period. Among 2,533 total patients, 1,409 had reference points, 31 had records for their input and evaluation periods and had reached their primary endpoints, and 317 patients had not. The area under the curve (AUC) of the predictive model peaked (0.81) when the minimum eGFR, the difference between maximum and minimum eGFR, and both maximum and minimum urinary protein values were included in the features.The accuracy of prognosis prediction can be improved by considering the variable components of urinary protein and eGFR levels. This model will allow us to identify patients whose renal functions are relatively preserved with eGFR of more than 60 mL/min/1.73 m2 and are likely to benefit clinically from immediate treatment intensification. [ABSTRACT FROM AUTHOR]

Introduction Method Results Discussion The epidermal growth factor receptor (EGFR; ErbB1), a membrane bound receptor tyrosine kinase, is hypothesized to have an inhibitory influence on peripheral nerve regeneration. This study examines the impact of EGFR inhibition on nerve regeneration using the commercially available small molecule inhibitor gefitinib.In vitro assays included neurite outgrowth of cultured dorsal root ganglion (DRG) neurons from adult C57Bl/6 wildtype mice on immobilized chondroitin sulfate proteoglycans (CSPG). Following forelimb median nerve injury, EGFR expression, number of regenerated neurons (using retrograde labeling) and myelination of motor and sensory neurons were compared between mice that received either gefitinib or vehicle. Functional recovery was assessed using grip strength.EGFR expression on DRG and spinal motor neurons was confirmed. Gefitinib significantly increased neurite outgrowth in medium sized (30–50 μm) DRG neurons, resulting in longer neurites (183 ± 36 μm) compared with CSPG alone (49 ± 9 μm). After median nerve injury, significantly greater numbers of sensory neurons (638 ± 112 vs. 301 ± 81), but not motor neurons (31 ± 12 vs. 42 ± 13) regenerated in animals treated with gefitinib compared with controls. Regenerated axons in gefitinib treated animals displayed significantly greater diameter and increased g‐ratio compared with controls. Grip strength recovered more quickly in animals receiving gefitinib compared with controls (27.6 vs. 19.1 g 18 days post‐injury).This study provides data supporting the role of EGFR as a negative regulator of sensory but not motor neuron regeneration. Further, it demonstrates versatile potential uses of existing pharmaceuticals. [ABSTRACT FROM AUTHOR]

Background: This is the first case report describing a patient with non-small cell lung cancer (NSCLC) harboring two rare human epidermal growth factor receptor 2 (HER2) exon 21 insertion mutations, who responded to furmonertinib treatment. Furmonertinib maybe one effective and economical treatment for NSCLC patients harboring HER2 mutations with minor side effects. Case description: We present a case report of a 49-year-old female diagnosed with stage IV lung adenocarcinoma who complained of irritating dry cough symptoms followed by chest tightness. Firstly, we describe the patient's treatment history, including failed third-line combination treatments of systemic chemotherapy with bevacizumab or carrelizumab or anlotinib, primary lung tumor recurrence, bilateral lung metastases progression, and new brain metastatic lesion detection. Next, we detail the patient's fourth-line treatment with radiotherapy for brain metastases and two cycles of bevacizumab plus Abraxane and cisplatin, however, the disease progressed and relapsed. After that, comprehensive genomic profiling revealed two HER2 exon 21 insertion mutations. Subsequently, the patient received targeted therapy with furmonertinib and achieved 11 months of progression-free survival. The patient received pyrrotinib therapy for 2 months after disease progression, but the disease continued to progress. In October 2023, the patient received therapy with furmonertinib again, and a month later, the disease went into partial remission. However, the patient died due to hypoproteinemia combined with severe pneumonia in December 2023. Conclusion: Furmonertinib may be effective for NSCLC patients with HER2 T8962A and L869R mutations and further studies are needed to confirm these results in prospective clinical trials. [ABSTRACT FROM AUTHOR]

Lung Cancer remains a significant health concern, necessitating the exploration of novel therapeutic avenues due to the limited efficacy and adverse effects of current treatments. In this study, we utilized a thorough in-silico and in-vitro methodology to develop prospective drugs for the treatment of lung cancer. The active components of Citrus latifolia were identified through the utilization of a variety of pharmacological instruments, such as Gene Ontology, GeneCards, DrugBank, the Chinese Traditional Drug Database, and GeneMANIA. Subsequent molecular docking studies using GOLD software revealed Hesperidin as the most promising candidate, exhibiting a remarkable binding affinity (GOLD score: 60.98 kcal/mol) towards the epidermal growth factor receptor (EGFR), a pivotal target in lung cancer therapy. Further validation through Schrodinger-Glide redocking reaffirmed the robust interaction between Hesperidin and EGFR. Pharmacokinetic profiling of top-scoring ligands indicated favorable drug-like properties, supporting their therapeutic potential. Molecular dynamics simulations employing Desmond software demonstrated the structural stability and persistence of the Hesperidin-EGFR complex over a 100-ns trajectory, corroborating its efficacy. Additionally, cytotoxicity analysis revealed a potent inhibitory effect of Hesperidin with an IC50 value of 34.25 µg/ml. Collectively, our findings underscore Hesperidin from Citrus latifolia as a promising candidate for lung cancer therapy, warranting further investigation through in-vivo studies for clinical translation. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) lacks expression of the oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu), has an aggressive tumor phenotype, shows only a partial response to chemotherapy, and lacks clinically established targeted therapies. Therefore, there is a need to develop more effective drugs for the treatment of TNBC. The ferrocenyl benzoxazine and α‐aminocresols class of compounds gave a potential source of multimodal inhibitors of cancer based on previous studies. In this study, a set of ferrocenyl benzoxazines and α‐aminocresols were screened and characterized as potential inhibitors of TNBC in vitro. A panel of 11 compounds was screened for selective cytotoxicity to cancer cells over normal cell equivalents. Focusing on the previously proposed modes of action of their building blocks, α‐aminocresols 3a and 3b exhibited significant DNA binding capabilities and caused robust DNA damage in TNBC cells. In addition, both compounds exhibited significant ROS generation capability; however, introducing a ROS quencher in a cell viability assay only partially rescued the cells from the cytotoxicity effects of the α‐aminocresols. This, together with the observation that compounds 3a and 3b triggered significant protein aggregation in HCC1806 cells, supports a mixed mode of action for these compounds. [ABSTRACT FROM AUTHOR]

A novel series of dihydropyrazolo‐[4′,3′:5,6]‐pyrano[3,2‐e][1,2,4]triazolo[4,3‐c]‐pyrimidine analogues were designed, synthesized, and their cytotoxic potential against four tumor cell lines assessed. HRMS, 1H NMR, and 13C NMR spectra analysis were used to describe the novel compounds. Compound 9c had noteworthy anticancer activity in vitro against the Hela, MCF‐7, A549, and A2780 cell lines, with IC50 values of 0.98 ± 0.26, 3.11 ± 0.18, 1.24 ± 0.88, and 2.62 ± 0.56 µM, in that order. The molecular docking and dynamics simulation studies revealed the lead molecule's action mechanism with EGFR target protein. [ABSTRACT FROM AUTHOR]

ABSTRACT This study compared the safety and efficacy of osimertinib, a third‐generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), with those of other TKIs and its use alongside bevacizumab in patients with EGFR mutation‐positive advanced non–small‐cell lung cancer. PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang, and VIP databases were used to conduct extensive searches for relevant randomized controlled trials until January 30, 2024. Osimertinib monotherapy favored disease control rate, whereas the comparator treatment arm favored overall survival. Using subgroup analysis, the objective response rate and progression‐free survival (PFS) were significantly elevated by Osimertinib monotherapy compared with pemetrexed combined with carboplatin or cisplatin. The comparator treatment arm receiving gefitinib or erlotinib significantly favored progression‐free survival and overall survival compared with osimertinib monotherapy. In patients treated with osimertinib monotherapy, the incidence of all adverse events (AEs) decreased compared with comparator treatment arm. Anemia was the only AE associated with osimertinib monotherapy. Pemetrexed combined with carboplatin or cisplatin resulted in greater loss of appetite than osimertinib monotherapy. The most associated AE of osimertinib monotherapy was diarrhea, according to network analysis. Although its efficacy is not consistent with other EGFR TKIs, osimertinib was associated with a decrease in AEs in patients with EGFR mutation‐positive advanced non–small‐cell lung cancer. [ABSTRACT FROM AUTHOR]

Ground-glass nodules (GGNs) are generally considered an early stage of lung cancer. The imaging characteristics and curative efficacy of multiple GGNs as metastases remain unclear. Microsatellite instability-high (MSI-H) is a biomarker for immunotherapy. The therapeutic effect and prognosis for patients with MSI-H and Epidermal Growth Factor Receptor (EGFR)-sensitive mutation stays uncertain. Here, we report a case of a lung adenocarcinoma patient presenting with ground-glass metastases, MSI-H, and EGFR-sensitive mutation and provide clinical data on the efficacy and prognosis. We describe the predictive significance of carcinoembryonic antigen (CEA) for disease progression when there is inconsistency between treatment effectiveness and CEA changes. [ABSTRACT FROM AUTHOR]

A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive microenvironment, which is densely populated by protumoral glioma-associated microglia and macrophages (GAMs). Myeloid immune checkpoint therapy targeting the CD47-signal regulatory protein alpha (SIRPα) axis induces GAM phagocytic function, but CD47 blockade monotherapy is associated with toxicity and low bioavailability in solid tumors. In this work, we engineer a CAR T cell against epidermal growth factor receptor variant III (EGFRvIII), constitutively secreting a signal regulatory protein gamma-related protein (SGRP) with high affinity to CD47. Anti-EGFRvIII-SGRP CAR T cells eradicate orthotopic EGFRvIII-mosaic GBM in vivo, promoting GAM-mediated tumor cell phagocytosis. In a subcutaneous CD19+ lymphoma mouse model, anti-CD19-SGRP CAR T cell therapy is superior to conventional anti-CD19 CAR T. Thus, combination of CAR and SGRP eliminates bystander tumor cells in a manner that could overcome main mechanisms of CAR T cell therapy resistance, including immune suppression and antigen escape. EGFRvIII-targeted CAR T cells have been proposed as a therapeutic option for patients with glioblastoma (GBM), however, clinical responses remain suboptimal. Here the authors engineer anti-EGFRvIII CAR T cells to secrete an optimized SIRPγ-derived CD47 blocker, showing that combining CAR T cell effector functions with enhanced macrophage-mediated tumor cell phagocytosis improves anti-tumor efficacy in preclinical models. [ABSTRACT FROM AUTHOR]

Frequent extreme heat events around the world not only pose a major threat to human health but also cause significant economic losses to the livestock industry. The existing management practices are insufficient to fully prevent heat stress with an urgent need to develop preventive medicines. The aim of this study was to develop an anti-heat stress Chinese herbal formula (CHF) via big data analysis techniques and to evaluate its anti-heat stress effect and mechanism of action via pharmacodynamic evaluation and network pharmacology analysis. Many anti-heat stress CHFs were collected from the Chinese National Knowledge Infrastructure (CNKI) database. Three alternative CHFs were obtained via unsupervised entropy hierarchical clustering analysis, and the most effective CHF against heat stress, Shidi Jieshu decoction (SJD), was obtained by screening in a mouse heat stress model. In dry and hot environments, SJD significantly improved the heat tolerance of AA broilers by 4–6°C. In a humid and hot environment, pretreatment with 2% SJD resulted in 100% survival of Wenchang chickens at high temperatures. The main active ingredients of SJD were identified as muntjacoside E, timosaponin C, macrostemonoside H and mangiferin via ultra-performance liquid chromatography/mass spectrometry (UPLC/MS) and database comparison. The active ingredients of SJD were found to target tumor necrosis factor-α (TNF-α), signal transducer activator of transcription 3 (STAT3) and epidermal growth factor receptor (EGFR). Finally, the safety of the new formulation was assessed in an acute oral toxicity study in rats. The SJDs developed in this study provide a new option for the prevention of heat stress in animal husbandry and offer new insights for further research on anti-heat stress. Highlights: 1. Shidi Jieshu decoction (SJD) increases the heat tolerance of animals. 2. SJD increased the survival rate of Wenchang chickens under heat stress to 100%. 3. SJD can be used to prevent heat stress in animals and humans. 4. EGFR and STAT3 may be novel anti-heat stress targets in addition to inflammation. [ABSTRACT FROM AUTHOR]

Introduction: The epidermal growth factor receptor (EGFR) presents a crucial target for combatting cancer mortality. Methods: This study employs a suite of computational techniques, including 3D-QSAR, ligand-based virtual screening, molecular docking, fingerprinting analysis, ADME, and DFT-based analyses (MESP, HOMO, LUMO), supplemented by molecular dynamics simulations and MMGB/PBSA free energy calculations, to explore the binding dynamics of quinazoline derivatives with EGFR. With strong q2 and r2 values from CoMFA and CoMSIA models, our 3D- QSAR models reliably predict EGFR inhibitors' efficacy. Results and Discussion: Utilizing a potent model compound as a reference, an E-pharmacophore model was developed to sift through the eMolecules database, identifying 19 virtual screening hits based on ShapeTanimoto, ColourTanimoto, and TanimotoCombo scores. These hits, assessed via 3D- QSAR, showed pIC50 predictions consistent with experimental data. Our analyses elucidate key features essential for EGFR inhibition, reinforced by ADME studies that reveal favorable pharmacokinetic profiles for most compounds. Among the primary phytochemicals examined, potential EGFR inhibitors were identified. Detailed MD simulation analyses on three select ligands—1Q1, 2Q17, and VS1—demonstrated their stability and consistent interaction over 200 ns, with MM/GBSA values corroborating their docking scores and highlighting 1Q1 and VS1's superior EGFR1 affinity. These results position VS1 as an especially promising lead in EGFR1 inhibitor development, contributing valuable insights towards crafting novel, effective EGFR1 inhibitors. [ABSTRACT FROM AUTHOR]

Somatic mutations in the epidermal growth factor receptor (EGFR) are a major cause of non-small cell lung cancer. Among these structurally diverse alterations, exon 20 insertions represent a unique subset that rarely respond to EGFR tyrosine kinase inhibitors (TKIs). Therefore, there is a significant need to develop inhibitors that are active against this class of activating mutations. Here, we conducted biochemical analysis of the two most frequent exon 20 insertion variants, V769_D770insASV (insASV) and D770_N771insSVD (insSVD) to better understand their drug sensitivity and resistance. From kinetic studies, we found that EGFR insASV and insSVD are similarly active, but have lower Km, ATP values compared to the L858R variant, which contributes to their lack of sensitivity to 1st-3rd generation EGFR TKIs. Biochemical, structural, and cellular studies of a diverse panel of EGFR inhibitors revealed that the more recently developed compounds BAY-568, TAS6417, and TAK-788 inhibit EGFR insASV and insSVD in a mutant-selective manner, with BAY-568 being the most potent and selective versus wild-type (WT) EGFR. Cocrystal structures with WT EGFR reveal the binding modes of each of these inhibitors and of poziotinib, a potent but not mutantselective inhibitor, and together they define interactions shared by the mutant-selective agents. Collectively, our results show that these exon20 insertion variants are not inherently inhibitor resistant, rather they differ in their drug sensitivity from WT EGFR. However, they are similar to each other, indicating that a single inhibitor should be effective for several of the diverse exon 20 insertion variants. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR)-activating mutations are critical factors in the development of EGFR-driven non-small-cell lung cancer (NSCLC), and molecular targeted therapies have focused on inhibiting these mutations. EGFR tyrosine kinase inhibitors (TKIs) have remarkable inhibitory effects on NSCLC with EGFR mutations. However, acquired resistance limits the clinical application of EGFR-TKIs, highlighting the need for discovery of novel therapeutic strategies. 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone is a natural product derived from Garcinia xanthochymus, has shown potential anti-tumor activity, but the underlying mechanism needs further elucidation. In this study, we developed Ba/F3 and NIH/3T3 cells harboring EGFR L858R/T790M/C797S mutation, and then found that 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone exerted inhibitory effects against cells with EGFR L858R/T790M/C797S mutation. Additionally, 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone exhibited potent anti-tumor activity against cells harboring the triple-mutant EGFR by promoting apoptosis and inducing changes in cell cycle distribution. Furthermore, 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone was found to significantly reduce tumor growth via suppressing the phosphorylation of EGFR in tumor tissues. These effects are associated with binding of 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone to EGFR resulting in the suppression of extracellular signal-regulated kinase (Erk) phosphorylation. In conclusion, our results suggest that 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone may be a potential novel candidate for further investigation and treatment of NSCLC with the triple-mutant EGFR. [ABSTRACT FROM AUTHOR]

A novel series of six [1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-(1,3-diphenyl-1H-pyrazol-4-yl)prop-2-en-1-ones (3a–3f) was designed and synthesized. They were characterized based on spectral and elemental analyses. In silico studies were also committed to provide insights and a better understanding of their structural features. The six compounds were screened for their antiproliferative activity using the MTT assay against five human cancer cell lines, namely, A549, HCT116, PC3, HT29, and MCF-7 in parallel with the non-cancerous human lung cell line WI-38. The results showed that 3e and 3f have potential cytotoxic activities, especially on A549 cells with IC50 = 2.3 µM and 1.15 µM, respectively. Meanwhile, they recorded a minimal cytotoxic effect on WI-38 cells. Concerning the molecular mechanism of action, the present study showed the inhibitory effect of the six compounds against total EGFR. The most potent EGFR inhibitors were 3e and 3f with IC50 = 0.031 µM and 0.023 µM, respectively. The selectivity index of 3f for EGFRT790M was 1.81 times more selective than that of lapatinib. In addition, 3e and 3f initiated cell cycle arrest at the G2/M and pre-G1 phases along with the downregulation of anti-apoptotic protein Bcl2 and the upregulation of pro-apoptotic proteins: p53, Bax, and caspases 3, 8, and 9. Further studies are recommended to evaluate animal models' promising anticancer activity and molecular mechanism of triazolo[3,4-a]isoquinoline derivatives 3e and 3f. [ABSTRACT FROM AUTHOR]

ABSTRACT Novel bioactive ternary nickel (II) complexes, [Ni(5BrSal‐Phe)(phen)] (1) and [Ni(5BrSal‐Tyr)(phen)] (2) (5BrSal‐Tyr: Schiff base derived from 5‐bromosalicylaldehyde and L‐tyrosine, 5BrSal‐Phe: Schiff base derived from 5‐bromosalicylaldehyde and L‐phenylalanine, phen: 1,10‐phenanthroline), have been synthesized and characterized by electronic absorption spectroscopy, CHN, FTIR, ESI‐MS and X‐ray crystallography techniques. Interaction of the complexes with biomolecules (calf thymus DNA (CT‐DNA) and bovine serum albumin (BSA)) has been investigated by electronic absorption and fluorescence spectroscopy. The results show that the complexes can bind to CT‐DNA via a minor groove binding mode. Moreover, the fluorescence quenching mechanism between the complexes and BSA is a static quenching process. The antiproliferative activities of the complexes against breast cancer cells (MCF‐7 and MDA‐MB‐231) and healthy breast epithelial cells (MCF‐10A) were investigated. The complex 2 was found to have promising antiproliferative activity in selected cell line, with lower IC50 values than cisplatin. Molecular docking studies suggest that the complexes may serve as potential chemotherapeutic agents. These complexes have been observed to interact with various targets within cells, including the epidermal growth factor receptor (EGFR), bovine serum albumin (BSA), and B‐DNA. Analyses indicate that these interactions are supported not only by conventional hydrogen bonds but also van der Waals forces and π‐π interactions. Additionally, determining binding constants and regions enhances our understanding of how the complexes interact with target molecules. The results emphasize the importance of the complexes in cancer therapy by highlighting the necessity of understanding their molecular‐level interactions with targets. [ABSTRACT FROM AUTHOR]

We have identified endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) as a poor prognostic indicator in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (EGFRMUT-NSCLC). In addition, comparison of high versus low ERO1A expression among cohorts of EGFRMUT-NSCLC primary samples revealed that ERO1A expression correlated with increased expression of proteins that regulate secretion. Using the CPTAC proteomic data set in lung adenocarcinoma we found that high ERO1A protein expression correlated with both extracellular matrix and matrix modifying enzymes. In this report, we found that ablating ERO1A expression was a determinant of clonogenicity, tumor sphere formation, spheroid growth and growth in vivo, as well as response to Osimertinib. We validated that ERO1A-knockout EGFRMUT-LUAD cell lines demonstrated a reduction in secretion of both laminin gamma 2 (LAMC2) and the collagen modifying enzyme lysyl oxidase-like 2 (LOXL2). Our work supports the role of ERO1A in modulating the tumor microenvironment that is likely to contribute to tumor progression. [ABSTRACT FROM AUTHOR]

Background: The advent of antibody-drug conjugates (ADCs) represents a landmark advance in cancer therapy, permitting targeted delivery of a potent cytotoxic agent to tumor cells with minimal damage to surrounding cells. Although ADCs can induce sustained therapeutic responses in heavily pretreated patients, they can also cause significant toxicity and thus require careful monitoring. The prototype ADC, ado-trastuzumab emtansine (T-DM1) is comprised of a humanized, monoclonal human epidermal growth factor receptor 2 (HER2)-directed antibody, trastuzumab, linked to the cytotoxic agent, DM1, and is used for the treatment of early-stage and advanced HER2-positive breast cancer. Liver toxicities, including transaminitis and nodular regenerative hyperplasia resulting in portal hypertension have been described. We report a case series of four patients who developed hepatopulmonary syndrome (HPS) during treatment with T-DM1. HPS is characterized by hypoxemia, portal hypertension, and intrapulmonary shunting, and it can be associated with severe hypoxic respiratory failure. HPS secondary to noncirrhotic portal hypertension occurring with long-term exposure to T-DM1 has not previously been reported. Case series presentation: Four patients who received T-DM1 in our institutional cohort (n=230) developed HPS, which can be associated with severe hypoxic respiratory failure. Each patient diagnosed with HPS received >50 doses of T-DM1. Only one patient at diagnosis had resting hypoxia, while the other three patients became hypoxic with exertion only. Discontinuation of T-DM1 led to clinical improvement in hypoxia in three of the four patients. The spectrum of liver injury that occurs with long-term use of T-DM1 remains incompletely defined. Conclusions: As T-DM1 is approved for use in the management of early-stage operable and advanced breast cancer, awareness of HPS as a potential complication of long-term administration of T-DM1 is necessary. The emergence of dyspnea alone or combined with low oxygen saturation and signs of hypoxemia (clubbing or elevated hemoglobin) should raise clinical suspicion and prompt evaluation for HPS. Cancer care team members should be vigilant regarding the potential for new and serious side effects associated with novel targeted therapies, which may emerge years beyond initial regulatory approval. [ABSTRACT FROM AUTHOR]

Background: Combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with chemotherapy (ETC) offers more advantages for patients with EGFR-positive non-small cell lung cancer (NSCLC) than using EGFR TKIs alone (ET). However, whether this conclusion applies to patients with brain metastases (BM) remains controversial. This meta-analysis was performed to evaluate the benefits and risks of the two groups. Methods: Six databases were systematically searched for relevant literatures comparing ETC versus ET in treating EGFR-positive NSCLC patients with BM. The primary outcome assessed was overall survival (OS), while secondary outcomes included progression-free survival (PFS), and central nervous system (CNS)-PFS, responses, progression status and safety. Results: Seven studies based on five randomized clinical trials with 550 patients were included. The ETC group exhibited better OS (hazard ratio [HR]: 0.64 [0.48, 0.87]), PFS (HR: 0.42 [0.34, 0.52]), and CNS-PFS (HR: 0.42 [0.31, 0.57]). The benefits in survival for OS, PFS, and CNS-PFS were validated in nearly all subgroups. Meanwhile, the overall objective response rate (ORR) (risk ratio [RR]: 1.25 [1.02, 1.52]) and CNS-ORR (RR: 1.19 [0.93, 1.51]) also tended to favor the ETC group. However, the addition of chemotherapy also brought about more grade 3-5/serious adverse events (AEs). The top five grade 3-5 AEs in the ETC group were alanine aminotransferase increase (11.25%), neutropenia (7.5%), nausea (7.5%), anorexia (5%), and diarrhea (5%). Conclusions: ETC appears to be better than ET in treating EGFR-positive NSCLC patients with BM, with better OS, PFS, CNS-PFS, and responses. However, its poorer safety profile also needs to be taken into consideration. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024551073. [ABSTRACT FROM AUTHOR]

Plasma membrane proteins play pivotal roles in receiving and transducing signals from other cells and from the environment and are vital for cellular functionality. Enzyme-based, proximity-dependent approaches, such as biotin identification (BioID), combined with mass spectrometry have begun to illuminate the landscape of proximal protein interactions within intracellular compartments. To extend the potential of these approaches to study the extracellular environment, we developed extracellular TurboID (ecTurboID), a method designed to profile the interactions between proteins on the surfaces of living cells over short timescales using the fast-acting biotin ligase TurboID. After optimizing our experimental and data analysis strategies to capture extracellular proximity interactions, we used ecTurboID to reveal the proximal interactomes of several plasma membrane proteins, including the epidermal growth factor receptor (EGFR). We found that EGF stimulation induced an association between EGFR and the low-density lipoprotein receptor (LDLR) and changed the interactome of LDLR by increasing its proximity with proteins that regulate EGFR signaling. The identification of this interaction between two well-studied and clinically relevant receptors illustrates the utility of our modified proximity labeling methodology for identifying dynamic extracellular associations between plasma membrane proteins. Editor's summary: Proximity labeling using the biotin ligase TurboID enables the identification of proteins that interact directly or indirectly inside cells. To extend the reach of this method to the extracellular side of the plasma membrane, Al Mismar et al. developed a form of TurboID optimized for use on the cell surface. The authors used it to identify the extracellular interactomes of several transmembrane proteins and ligand-dependent changes in the interaction partners of the epidermal growth factor receptor (EGFR). EGF stimulation induced EGFR to associate with the low-density lipoprotein receptor, demonstrating the utility of the method for detecting previously unknown interactions. —Annalisa M. VanHook [ABSTRACT FROM AUTHOR]

The article in the JNCI: Journal of the National Cancer Institute celebrates Glenn Algire's 1945 pioneering contribution to antiangiogenic therapy for cancer. Algire's observations on tumor angiogenesis laid the foundation for Judah Folkman's idea in 1971 that angiogenesis inhibitors could be used to treat cancer. The article discusses the development of VEGF inhibitors and other antiangiogenic drugs, as well as the challenges and potential future directions in antiangiogenic cancer therapy. It emphasizes the complexity of tumor angiogenesis regulation and the need to explore new strategies beyond VEGF-targeted therapies to improve efficacy in cancer treatment. [Extracted from the article]

The human Atg8 family member GABARAP is involved in numerous autophagy‐related and ‐unrelated processes. We recently observed that specifically the deficiency of GABARAP enhances epidermal growth factor receptor (EGFR) degradation upon ligand stimulation. Here, we report on two putative LC3‐interacting regions (LIRs) within EGFR, the first of which (LIR1) is selected as a GABARAP binding site in silico. Indeed, in vitro interaction studies reveal preferential binding of LIR1 to GABARAP and GABARAPL1. Our X‐ray data demonstrate interaction of core LIR1 residues FLPV with both hydrophobic pockets of GABARAP suggesting canonical binding. Although LIR1 occupies the LIR docking site, GABARAP Y49 and L50 appear dispensable in this case. Our data support the hypothesis that GABARAP affects the fate of EGFR at least in part through direct binding. [ABSTRACT FROM AUTHOR]

Lung cancer remains the leading cause of cancer death in the United States, underscoring the critical need to optimize treatment strategies. Compared to conventional treatments such as surgical resection, radiotherapy, chemotherapy, and immunotherapy, targeted therapy stands out for its higher selectivity and minimal adverse effects. Among these, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the most widely used in targeted therapy for non-small-cell lung cancer (NSCLC). In our paper, we will conduct a comprehensive review of current literature on EGFR TKIs to contribute to advancements in molecular genomics and the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

A few studies have reported on the variability of the variant allele frequency (VAF) of gene mutations and the relationship between VAF and the therapeutic effect of molecular-targeted drugs. This joint study was conducted from May 2020 to January 2022 between St. Marianna University School of Medicine and the DNA Chip Research Institute. Cytology samples were used to verify the usefulness of a lung cancer compact panel test, which is a high-sensitivity next-generation sequencing (NGS) gene panel test. We analyzed the distribution of VAF and the duration of the initial molecular-targeted drug administration in patients with advanced-stage epidermal growth factor receptor (EGFR) mutations. Of the 196 patients diagnosed with non-small cell carcinoma (NSCLC), gene mutations were detected in 114 (58.2%) cases and in 68.7% of patients with adenocarcinomas (an increased detection rate). A VAF of 30% or more for DNA mutations was confirmed in 35 patients (33.7%), 10% to <30% in 38 (36.5%), and <10% in 31 (29.8%), including 18 patients (17.3%) with <6%, which is considered the lower limit of the LOD for other companion diagnostic kits. EGFR mutations were detected in 59 patients (30%), of whom 35 were in an advanced stage and received molecular-targeted drugs as their initial treatment. Groups A and B comprised patients with a VAF of ≥10% and <10%, respectively, with 27 patients (median VAF 30.6%, range 11.4–77%) in group A and 8 (median VAF 5.4%, range 0.1–8.5%) in group B. The duration of the administration of molecular-targeted drugs was 17 months (range 3–42 months) in group A and 14 months (range 1–45 months) in group B, with no statistically significant difference between the two groups (p-value = 0.7). Twenty-seven percent of patients had a VAF < 10%. Even in patients with a low VAF for gene mutations, sufficient therapeutic effects were observed with molecular-targeted drugs, suggesting the importance of detecting mutations using a highly sensitive method at initial diagnosis. Further prospective validation studies of a larger number of cases are warranted. [ABSTRACT FROM AUTHOR]

Molecular testing is recommended in patients with metastatic non-small cell lung cancer (NSCLC), but the extent of its use in Poland is unknown. The aim of the POL-MOL study was to investigate the frequency of using molecular testing in Polish patients with NSCLC. The invited Polish oncologists completed two questionnaires, and data for 1001 patients undergoing systemic treatment for NSCLC were collected. The use of molecular tests for the following genetic mutations was recorded: EGFR (del19, sub21), EGFR (other than del19/sub21), EGFR T790M, ALK (expression and rearrangement), RET, NTRK, ROS1, BRAF, HER2, and MET, as well as for immunochemical assessment of programmed cell death ligand 1 (PD-L1). Thanks to the weighting procedure, the results are representative of the population of Polish patients treated for NSCLC. Molecular tests were applied in 78% of patients with NSCL, 70% of patients with NSCLC not otherwise specified, and in 12% of patients with squamous cell carcinoma of the lung. The frequency of application increased with disease stage in all groups. In patients with squamous cell carcinoma, approximately 30% of tests for EGFR, ALK, and RET mutations were positive, which confirms the importance of testing at least a preselected subgroup of patients. [ABSTRACT FROM AUTHOR]

A 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. [ABSTRACT FROM AUTHOR]

Simple Summary: This study examined the real-world effectiveness of osimertinib, a third-generation tyrosine kinase inhibitor, on EGFR-mutated non-small-cell lung cancer. Osimertinib has shown promising results in clinical trials, but this research study looked at how it performs in real-world settings, where patients may have different characteristics than those typically included in trials. This study reviewed data from over 600 patients treated with osimertinib, either as their first (L1) or second metastatic line (L2) of treatment. The results showed that patients who took osimertinib as L1 experienced a median progression-free survival of 12.4 months, compared to 7.4 months for those treated in L2. The presence of brain metastases was associated with a poorer prognosis. Overall survival rates were lower than those reported in clinical trials, likely due to differences in patient conditions, such as older age and worse overall health. This study highlights the challenges of applying trial results to everyday medical practice and emphasizes the need for tailored treatment approaches for patients with advanced lung cancer. Background: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), demonstrated superior efficacy over first-generation TKIs in the FLAURA trial, resulting in its approval as first-line therapy for metastatic non-small-cell lung cancer (NSCLC). However, the real-world application of these trial results requires an evaluation of sequential therapeutic strategies. Methods: This retrospective, non-interventional study utilized data from the Epidemiological Strategy and Medical Economics (ESME) platform, which includes information on patients treated for lung cancer since 2015. Out of 39,974 patients in the database, 624 patients with EGFR-mutant advanced NSCLC treated with osimertinib as first-line (L1, n = 198) or second-line (L2, n = 426) treatment after first- or second-generation TKIs (n = 1262) were identified. Patient demographics, disease characteristics, treatment strategies, and disease progression were examined. Survival analyses were performed using Kaplan–Meier estimates and Cox proportional-hazards models. Results: In the study population (n = 624), 73.4% were female, with a median age of 70 years (range 28–93). Brain metastases at the start of osimertinib treatment were observed in 282 patients. ECOG PS-2 was reported in 29.4% of patients. The T790M mutation in exon 20 was identified in 257/426 patients (60.3%) receiving osimertinib in L2. Median progression-free survival (PFS) was 12.4 months (95% CI [10.7–14.7]) for L1 and 7.4 months (95% CI [6.2–8.7]) for L2. Median overall survival (OS) from advanced diagnosis was 28.5 months (95% CI [26.3–38.7]) for osimertinib L1 and 29.9 months (95% CI [28.6–31.8]) for osimertinib L2 (HR = 0.93; 95% CI [0.75–1.16]; p = 0.50). For L1, median OS was 27.1 months (95% CI [22.0–30.2]) for patients with cerebral metastases and 38.7 months (95% CI [26.3–52.8]) for those without (HR = 0.73; 95% CI [0.48–1.11]; p = 0.15). Discussion: Patients in the real-world ESME database exhibited a poorer prognosis compared to those in the FLAURA trial. The presence of cerebral metastases at diagnosis worsens the prognosis. [ABSTRACT FROM AUTHOR]

Introduction: Reactive oxygen species modulator 1 (Romo1) is a novel protein that is critically involved in the intracellular production of reactive oxygen species. Evidence has revealed that Romo1 is associated with treatment outcomes of various human malignancies, including lung cancer. However, the clinical implications of this protein in surgically resected lung cancers harboring epidermal growth factor receptor (EGFR) mutations have not been investigated. Methods: Data were collected from patients who underwent curative resection of EGFR-mutant lung adenocarcinoma. Romo1 protein expression levels were measured in the tumor tissue using immunohistochemical staining and evaluated semi-quantitatively using the histochemical score. Univariate and multivariate analyses were performed to identify the clinicopathological parameters that may be associated with clinical outcomes. Results: A total of 98 samples were analyzed. Using the cutoff H score of 200, the population was classified into low (n = 73) and high (n = 25) Romo1 groups. Romo1 expression was significantly higher in smokers, patients with stage III disease, and patients who experienced recurrence after surgery (all p < 0.05). Multivariate analyses showed that advanced-stage and poorly differentiated cancers were associated with shorter disease-free survival (DFS). In addition, high Romo1 expression was independently associated with poor DFS (hazard ratio = 2.18, 95% confidence interval: 1.10–4.32, p = 0.0261). Conclusions: Our data showed that Romo1 overexpression was significantly associated with early recurrence in patients with resected EGFR-mutant lung adenocarcinoma. Although large-scale studies are required, Romo1 may play a prognostic role in this patient population. [ABSTRACT FROM AUTHOR]

• Sclerocarya birrea fruit exocarp and Terminalia prunoides pods extracts have 24 poly phenolic metabolites including shikimic acid, gallic acid and quercetin-3-d-xyloside. • Sclerocarya birrea fruit exocarp, Terminalia prunoides extracts pod and their synergy inhibit the proliferation of HeLa cells. • Sclerocarya birrea fruit exocarp, Terminalia prunoides extracts pod and their synergy downregulate the expression of EGFR, VEGF, MACC1, and CYFRA 21-1 genes. • Sclerocarya birrea fruit exocarp, Terminalia prunoides extracts pod and their synergy downregulate the expression CD 95 gene. Cancer is one of the leading causes of death globally. Conventional drugs are expensive and have been reported to have side effects. This directs efforts in cancer research to search for inexpensive solutions with less or no side effects. This study aimed at screening for phytochemicals and the antiproliferative effects of Sclerocarya birrea fruit exocarp (SBFE) and Terminalia prunioides pods extracts (TPPE) on human cervical cancer cell line (HeLa). Extracts were qualitatively evaluated for their phytochemicals using HPLC and LC-MS/MS, and the antiproliferative effects by 4-[-3(4-Iodophenyl)-2-(4-nitro-phenyl)-2H-5-tetrazolio]-1,3-benzene sulfonate (WST-1) assay. HPLC and LC-MS/MS analysis led to identification and quantification of 24 polyphenolic metabolites amongst which shikimic acid (3.6014 mg g-1), gallic acid (40.8283 mg g-1), and quercetin-3-d-xyloside (3.4677 mg g-1) as the major metabolites. Results from antiproliferative effects of extracts were used to make 3 potential anticancer formulations. Furthermore, effects of extracts and formulations on the expressions of cervical cancer markers: Epidermal Growth Factor Receptor (EGFR), Metastasis-Associated in Colon Cancer 1 (MACC1), Vascular Endothelial Growth Factor (VEGF), Cytokeratin Fragment (CYFRA 21-1), and Cluster differentiation 95 (CD95) were evaluated by Reverse transcription quantitative Polymerase Chain Reaction (RT-qPCR). Methanol and ethyl acetate extracts of both plants tested positive for saponins, tannins, flavonoids, phenols, terpenoids, cardiac glycoside and steroids. Methanol extracts were the most effective with IC 50 values of 75 µg/mL and 190 µg/mL for SBFE and TPPE respectively. The formulations: M1E1M2E2 and M1M2 had IC 50 values of 77 µg/mL and 83 µg/mL respectively. All treatments downregulated mRNA expression of EGFR, VEGF, MACC1, CYFRA 21-1, and upregulated CD 95 mRNA expression. Formulations were more effective than individual extracts against HeLa cells. However, there is need for further testing for other possible mechanisms of action and isolation of phytocompounds. [ABSTRACT FROM AUTHOR]

Nowadays, the use of food additives, such as Sunset Yellow (SY), is growing, which attracted attention to the potential relationship between some diseases and food additives. The study aimed to investigate the role of Sunset Yellow during chemically-induced mammary gland carcinogenesis in Sprague–Dawley rats. Three groups of female rats were intraperitoneally administered with N-methyl-N-nitrosourea (MNU). Group 1 was set on a basal diet. Group 2 was treated with 161.4 mg\kg\day Sunset Yellow (SY). Group 3 was given SY at 80.7 mg\kg\day. Groups 4–6 were not administered MNU; Group 4 received vehicles only. Groups 5 and 6 were administered SY similarly to groups 2 and 3 respectively. Sunset Yellow at both doses exerted a significant dose-dependent increase in tumor incidences, multiplicities, volumes, and decreased tumor latency as compared with control. Immunolabeling indexes of the proliferating cell nuclear antigen, estrogen receptor alpha, and progesterone receptor were significantly increased after SY treatment. Oxidative stress markers, serum estrogen, progesterone, and prolactin levels were significantly modified by SY treatment. The mRNA expression of estrogen receptor alpha and epidermal growth factor was up-regulated in SY groups versus control. Collectively, SY has significantly promoted MNU-induced mammary tumors in rats with underlying mechanisms correlating SY consumption with estrogen disruption and subsequent antioxidative stress discrepancy. [Display omitted] • Sunset Yellow (SY) is a food coloring dye. • SY has significantly promoted MNU-induced mammary tumors in rats. • SY exaggerated tumor growth via estrogen disruption and subsequent antioxidative stress discrepancy. [ABSTRACT FROM AUTHOR]

Introduction: Comprehensive next-generation sequencing (NGS) of non-small-cell lung cancer specimens can identify oncogenic driver mutations and their corresponding targeted therapies. Plasma cell-free DNA (cfDNA) genotyping is easy to perform; however, false negatives cannot be overlooked. We explored malignant pleural effusion (MPE), a rich source of cfDNA, as a non-inferior alternative to tumor tissues for genotyping. Methods: We conducted a prospective trial including 39 patients with newly diagnosed stage IV lung adenocarcinoma who presented with MPE. Tissue tests matching hotspot variants, including EGFR, ALK, and ROS1, were compared with the AlphaLiquid100 of PE-cfDNA. Results: Among the 39 PE-cfDNA samples successfully sequenced, 32 (82.1%) had a PE cell-block tumor content of < 10%. Standard tissue or cell-block testing for EGFR, ALK, and ROS1 identified 20 mutations (51.3%), whereas PE cfDNA identified 25 mutations (64.1%). Five EGFR mutations were observed in PE cfDNA but not in Cobas EGFR owing to coverage or insufficient tumor content issues. The overall rate of oncogenic mutations identified in the PE cfDNA was 92.3%, and the mutation distribution was as follows: even with a very low cfDNA input, high detection rates could be achieved. Otherwise, most patients harbored co-mutations. Comparison of pleural fluid NGS with traditional testing revealed differences in accuracy. We also followed up with patients with EGFR-sensitizing mutations who had a treatment response rate of 97.2% after 3 months. Conclusions: Genotyping of MPE supernatant cfDNA is feasible in clinical practice, in addition to plasma and tumor testing, to improve diagnostic yield and extend patients' benefit from targeted therapies. [ABSTRACT FROM AUTHOR]

We aimed to generate a model of cancer-related fatigue (CRF) of clinical importance 2 years after diagnosis of breast cancer building on clinical and behavioral factors and integrating pre-treatment markers of systemic inflammation. Women with stage I-III hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer were included from the multimodal, prospective CANTO cohort (NCT01993498). The primary outcome was global CRF of clinical importance [European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 ≥40/100] 2 years after diagnosis (year 2). Secondary outcomes included physical, emotional, and cognitive CRF (EORTC QLQ-FA12). All pre-treatment candidate variables were assessed at diagnosis, including inflammatory markers [interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, interferon γ, IL-1 receptor antagonist, tumor necrosis factor-α, and C-reactive protein], and were tested in multivariable logistic regression models implementing multiple imputation and validation by 100-fold bootstrap resampling. Among 1208 patients, 415 (34.4%) reported global CRF of clinical importance at year 2. High pre-treatment levels of IL-6 (quartile 4 versus 1) were associated with global CRF at year 2 [adjusted odds ratio (aOR): 2.06 (95% confidence interval [CI] 1.40-3.03); P = 0.0002; area under the receiver operating characteristic curve = 0.74]. Patients with high pre-treatment IL-6 had unhealthier behaviors, including being frequently either overweight or obese [62.4%; mean body mass index 28.0 (standard deviation 6.3 kg/m2)] and physically inactive (53.5% did not meet World Health Organization recommendations). Clinical and behavioral associations with CRF at year 2 included pre-treatment CRF [aOR versus no pre-treatment CRF: 3.99 (95% CI 2.81-5.66)], younger age [aOR per 1-year decrement: 1.02 (95% CI 1.01-1.03)], current tobacco smoking [aOR versus never: 1.81 (95% CI 1.26-2.58)], and worse insomnia or pain [aOR per 10-unit increment: 1.08 (95% CI 1.04-1.13), and 1.12 (95% CI 1.04-1.21), respectively]. Secondary analyses indicated additional associations of IL-2 [aOR per log-unit increment: 1.32 (95% CI 1.03-1.70)] and IL-10 [0.73 (95% CI 0.57-0.93)] with global CRF and of C-reactive protein [1.42 (95% CI 1.13-1.78)] with cognitive CRF at year 2. Emotional distress was consistently associated with physical, emotional, and cognitive CRF. This study proposes a bio-behavioral framework linking pre-treatment systemic inflammation with CRF of clinical importance 2 years later among a large prospective sample of survivors of breast cancer. • 34.4% of 1208 stage I-III breast cancer survivors had cancer-related fatigue of clinical importance 2 years after diagnosis. • High pre-treatment levels of the pro-inflammatory cytokine IL-6 were associated with global fatigue 2 years later. • Individuals with high levels of IL-6 had higher BMI and were less physically active than those with lower levels. • Higher pre-treatment IL-2 and IL-10 were also associated with higher and lower likelihood of global fatigue, respectively. • Higher C-reactive protein was associated with higher likelihood of cognitive fatigue. [ABSTRACT FROM AUTHOR]

Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib–capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A—previously untreated BCBM, cohorts 4B and 4C—BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated. • T-DM1–neratinib is active for HER2+ BCBMs (radiation-naive, heavily pretreated, and T-DM1 exposed). • Approximately one-third of participants experienced a CNS partial response. • 38.1%-50.0% across study cohorts experienced stable disease for ≥6 months or response. • Our data provide further evidence for neratinib-based combinations for HER2+ BCBMs. • We believe this is the first trial to examine the activity of a T-DM1-inclusive combination after progression on T-DM1. [ABSTRACT FROM AUTHOR]

The activation of the Neuraminidase 3 (NEU3) enzyme has been associated with the hyperphosphoryla-tion of Epidermal Growth Factor Receptor (EGFR) in Nonsmall Cell Lung Carcinoma (NSCLC). Existing EGFR inhibitors (such as gefitinib, erlotinib, lapatinib, icotinib, afatinib and osimertinib) reduce the hyperactivation of downstream signaling pathways (Akt, Mapk, Jak-Stat, Plc) but fail to completely abolish EGFR hyperphosphorylation. Therefore, co-targeting NEU3 and EGFR presents a greater potential to be used as a combinatorial therapy for NSCLC. This study employs structure guided approaches to elucidate the binding hypothesis of NEU3 and EGFR inhibitors. Toward this, important 3D features associated with high inhibitory potency of NEU3, and EGFR modulators were identified through SAR. The triazole substitution in acetamide dihydropyran carboxylic acid derivatives is mainly responsible for improved inhibitory potency against NEU3. Therefore, the hydrophobic (ϕ -H) interaction with the benzene ring and hydrogen bonding with the hydroxyl group of triazole are critical for designing new NEU3 modulators. Molecular Dynamics (MD) simulation studies demonstrate the stability of hydrogen bonding interactions of highly active NEU3 inhibitors with Pro66, Gly199 and Glu410 residues. Similarly, pyrimidine ring of EGFR inhibitors forms stable hydrogen bonds with Lys721 and Asp831 residues, contributing to their inhibitory potency. Our findings suggest that incorporating these identified 3D features associated with triazole and pyrimidine substitutions into a suitable scaffold could be a valuable strategy for developing a new generation of NEU3 and EGFR modulators. This approach offers a potential multi-targeted therapy for NSCLC patients. This study explores co-targeting NEU3 and EGFR for treating NSCLC by identifying key 3D features that enhance inhibitor potency. The research highlights that triazole substitutions improve NEU3 inhibition, while pyrimidine rings contribute to EGFR inhibition through stable hydrogen bonding and hydrophobic interactions. By integrating the identified interactions associated with the potent triazole and pyrimidine substitutions into a new scaffold may provide a promising approach for developing multi-targeted therapies for NSCLC. [ABSTRACT FROM AUTHOR]

Background Inhibitors of epidermal growth factor receptor (EGFRi) or mitogen-activated kinase (MEKi) induce a folliculitis in 75–90% of patients, the pathobiology of which remains insufficiently understood. Objectives To characterize changes in the skin immune status and global transcriptional profile of patients treated with EGFRi; to investigate whether EGFRi affects the hair follicle's (HF) immune privilege (IP); and to identify early proinflammatory signals induced by EGFRi/MEKi in human scalp HFs ex vivo. Methods Scalp biopsies were taken from patients exhibiting folliculitis treated long term with EGFRi ('chronic EGFRi' group, n = 9) vs. healthy scalp skin (n = 9) and patients prior to commencing EGFRi treatment and after 2 weeks of EGFRi therapy ('acute EGFRi' group, n = 5). Healthy organ-cultured scalp HFs were exposed to an EGFRi (erlotinib, n = 5) or a MEKi (cobimetinib, n = 5). Samples were assessed by quantitative immunohistomorphometry, RNA sequencing (RNAseq) and in situ hybridization. Results The 'chronic EGFRi' group showed CD8+ T-cell infiltration of the bulge alongside a partial collapse of the HF's IP, evidenced by upregulated major histocompatibility complex (MHC) class I, β2-microglobulin (B2 M) and MHC class II, and decreased transforming growth factor-β1 protein expression. Healthy HFs treated with EGFRi/MEKi ex vivo also showed partial HF IP collapse and increased transcription of human leucocyte antigen (HLA)-A, HLA-DR and B2 M transcripts. RNAseq analysis showed increased transcription of chemokines (CXCL1, CXCL13, CCL18, CCL3, CCL7) and interleukin (IL)-26 in biopsies from the 'chronic EGFRi' cohort, as well as increased IL-33 and decreased IL-37 expression in HF biopsies from the 'acute EGFRi' group and in organ-cultured HFs. Conclusions The data show that EGFRi/MEKi compromise the physiological IP of human scalp HFs and suggest that future clinical management of EGFRi/MEKi-induced folliculitis requires HF IP protection and inhibition of IL-33. [ABSTRACT FROM AUTHOR]

BRAFV600E-mutant colorectal cancer (CRC) is resistant to most first-line therapeutics, including the BRAF inhibitor dabrafenib and epidermal growth factor receptor (EGFR) inhibitor cetuximab. Although copper depletion shows promise in reversing dabrafenib/cetuximab resistance in BRAFV600E-mutant CRC, its application is limited by the potential for excessive copper depletion in non-tumor objects. In this study, we have developed a hydrogel platform for confined copper depletion in BRAFV600E-mutant CRC cells, which effectively reverses dabrafenib/cetuximab resistance and enhancing therapeutic efficiency. The hydrogel platform enables precise intracellular copper depletion through localized administration, acidity-triggered drug release, and oxidized activation of a copper prochelator. The dosage of this prochelator is 37.5 μg/kg in mouse models, which is significantly lower than the commonly used tetrathiomolybdate. Furthermore, both dabrafenib and the prochelator are preloaded into acid-responsive nanoparticles before being embedded in the hydrogel matrix to facilitate efficient endocytosis and acid-activatable drug release. Confined copper depletion inhibits MEK1 signaling and suppresses the MAPK signaling pathway when combined with BRAF and EGFR inhibitors. Moreover, the hydrogel platform inhibits tumor growth and prolongs survival in subcutaneous and postsurgical models of BRAFV600E-mutant CRC. This study provides an innovative strategy for overcoming dabrafenib/cetuximab resistance in BRAFV600E-mutant CRC through precise intracellular copper depletion. A combinational therapeutic strategy was developed based on confined copper depletion to combat BRAFV600E-mutant colorectal cancer (CRC). Dabrafenib and a copper prochelator were loaded in acidity-responsive nanoparticles, and then loaded in peptide hydrogel along with cetuximab. The hydrogel platform conducted depletion of intracellular copper to block MAPK signaling pathway, thus reversing dabrafenib/cetuximab resistance in BRAFV600E-mutant CRC and improving therapeutic efficiency in mouse tumor models. [Display omitted] • Hydrogel platform enables confined copper depletion in BRAFV600E-mutant CRC. • Acidity-responsive nanoparticles deliver dabrafenib and copper prochelator to inhibit the MAPK signaling. • Hydrogel platform blocks MAPK signaling, reversing dabrafenib/cetuximab resistance. [ABSTRACT FROM AUTHOR]

High Epidermal growth factor receptor (EGFR) in Cutaneous Squamous Cell Carcinoma (cSCC) is associated with poor prognosis and advanced metastatic stages, severely impeding the efficacy of EGFR-targeting immunotherapy. This is commonly attributed to the combinatory outcomes of hypoxic tumor microenvironment (TME) and immunosuppressive effector cells together. Herein, a novel paradigm of EGFR-targeting oxygen-saturated nanophotosensitizers, designated as CHPFN-O 2 , has been specifically tailored to mitigate tumor hypoxia in EGFR-positive cSCC and achieve Cetuximab (CTX) - mediated immunotherapy (CIT). The conjugated CTX in CHPFN-O 2 serves to initiate immune responses by recruiting Fc receptor (FcR)-expressing immune effector cells towards tumor cells, thereby eliciting antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular trogocytosis (ADCT) and antibody-dependent cellular cytotoxicity (ADCC). Besides, CHPFN-O 2 can engender a shift from a tumor-friendly to a tumor-hostile one through improved tumor oxygenation, contributing to oxygen-elevated photodynamic therapy (oxPDT). Notably, the combination of oxPDT and CIT eventually promotes T-cell-mediated antitumor activity and successfully inhibits the growth of EGFR-expressing cSCC with good safety profiles. This comprehensive oxPDT/CIT integration aims not only to enhance therapeutic efficacy against EGFRhigh cSCC but also to extend its applicability to other EGFRhigh malignancies, thus delineating a new avenue for the highly efficient synergistic treatment of EGFR-expressing malignancies. EGFR-targeting oxygen-saturated nanophotosensitizers are meticulously designed to improve tumor selectivity, alleviate tumor hypoxia, reverse tumor immunosuppression, and recruit immune effector cells, thus resulting in the synergy of Cetuximab-based immunotherapy (CIT) and oxygen-elevated photodynamic therapy (oxPDT) for remarkably enhancing T cell-mediated antitumor efficacy against EGFR-expressing cSCC with great clinical value. [Display omitted] • CHPFN-O 2 demonstrates promising antitumor activity and high biosafety. • CHPFN-O 2 alleviates tumor hypoxia and initiates CIT-mediated immune responses. • CHPFN-O 2 presenting a new treatment paradigm of synergistic oxPDT/CIT. • CHPFN-O 2 improves the tumor microenvironment of EGFR-expressing cSCC. • The clinical prospects of CHPFN-O 2 can be extended to other forms of cSCC. [ABSTRACT FROM AUTHOR]

Background: Diabetic kidney disease (DKD) is a microvascular complication of diabetes mellitus and is the main cause of end-stage renal failure. Suoquan pills (SQP) has a variety of pharmacological activities and multiple therapeutic effects, and it is used clinically as a basic formula for the treatment of DKD. Methods: Public databases were used to identify SQP compounds and the potential targets of SQP and DKD. A drug-component-therapeutic target network was constructed. Protein-protein interaction network analysis, Gene Ontology functional analysis, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were used to analyse the potential molecular mechanisms of SQP based on common targets of drugs and diseases. Molecular docking simulations were conducted to confirm the binding abity of the core compounds to key targets. The efficacy and predicted molecular mechanisms of SQP were validated using cell counting kit-8 assay, flow cytometry, and western blotting with HK-2 cells as a model. Results: Network pharmacology analysis showed that 26 compounds and 207 potential targets of SQP were involved in the treatment of DKD; boldine, denudatin B, pinocembrin, kaempferoid, and quercetin were considered core compounds, and epidermal growth factor receptor (EGFR) and proto-oncogene, non-receptor tyrosine kinase (SRC) were considered key targets. Gene Ontology enrichment analysis indicated that protein phosphorylation and negative regulation of apoptotic processes are important biological processes in the treatment of DKD by SQP. Molecular docking confirmed the excellent binding abilities of boldine, denudatin B, kaempferide, and quercetin to EGFR and SRC. The results of in vitro experiments showed that treatment with an ethanolic extract of SQP significantly protected HK-2 cells from high glucose-induced cell damage. In addition, the SQP ethanol extract inhibited the phosphorylation of EGFR and SRC, suppressed the apoptosis rate, and regulated apoptosis-related proteins in HK-2 cells under high glucose stress. Conclusion: This study systematically and intuitively illustrated the possible pharmacological mechanisms of SQP against DKD through multiple components, targets, and signalling pathways, especially the inhibition of EGFR and SRC phosphorylation and apoptosis. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) remains one of the most common malignant diseases affecting female patients, and it can metastasize to nearly every part of the body. BC is rare in men, and therefore men rarely develop BC liver metastases (BCLMs). However, the present study reports a 55-year-old male patient who underwent surgery 5 years ago for BC. After treatment, the patient was actively followed up regularly. Recently, the patient was examined for chest tightness, and liver space-occupying lesions were found. The upper abdominal enhanced computed tomography images of the patient showed that the liver density was not uniform and that the liver had a mass. A crude needle biopsy was used to examine the liver tumour under the guidance of ultrasound. The pathology revealed that the patient was positive for E-cadherin, oestrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, GATA binding protein 3 and CK7. The patient was subsequently diagnosed with BCLM. The patient was treated with doxorubicin hydrochloride, cyclophosphamide, Docetaxel and followed up regularly. The present case report emphasizes that BC is found not only in women but also in an increasing number of men, and that liver metastasis can occur in males with BC. BCLM is a complex process, and therefore it is hoped this case report will improve the understanding of male BCLM and the mechanism of this disease. [ABSTRACT FROM AUTHOR]

The current evidence for the use of nanoparticle albumin-bound paclitaxel (nab-PTX) for adjuvant breast cancer chemotherapy is insufficient. The present study aimed to assess the efficacy and toxicity of nab-PTX in comparison with solvent-based paclitaxel (sb-PTX) in postoperative adjuvant breast cancer treatment. A total of 345 patients were included in the study and separated into nab-PTX (n=289) and sb-PTX (n=56) groups based on the type of taxane used in the adjuvant chemotherapy regimen. The study evaluated the baseline characteristics in both groups and the risk factors for postoperative recurrence of mammary cancer. Furthermore, data concerning disease-free survival (DFS) and adverse effects were obtained and analyzed, and group confounding variables were addressed using 1:2 propensity score matching (PSM). Comparisons before PSM revealed significant differences in baseline characteristics including age, underlying disease, lymph node involvement, vascular invasion, human epidermal growth factor receptor 2 and axillary surgery (P<0.05). Following PSM, there were 90 patients in the nab-PTX group and 56 in the sb-PTX group, with no significant differences in the baseline differences (P>0.05). Before PSM, the 73-month DFS rate was 97.9% in the nab-PTX group compared with 91.1% in the sb-PTX group. However, there were no significant differences between the groups before or after PSM (P=0.15 and P=0.49, respectively). Additionally, Cox regression analysis demonstrated a significantly lower chance of recurrence in patients aged >45 years [hazard ratio (HR), 0.197; 95% confidence interval (CI), 0.052-0.753; P=0.018], whereas underlying disease (HR, 5.352; 95% CI, 1.310-21.854; P=0.019) and lymph node infiltration (HR, 8.930; 95% CI, 1.121-71.161; P=0.039) significantly increased the risk of recurrence. Regarding safety, the sb-PTX group had a significantly greater incidence of anaphylaxis, whereas the nab-PTX group had significantly increased rates of anemia and peripheral neuropathy (P<0.05). In summary, the 73-month DFS rate of the nab-PTX cohort exceeded that of the sb-PTX cohort, but no significant difference was detected between them. Underlying disease, lymph node metastasis and an age of ≤45 years are significant predictors of postoperative recurrence of breast cancer. [ABSTRACT FROM AUTHOR]

Treatment options for epidermal growth factor receptor (EGFR)-mutant advanced non-small cell lung cancer (NSCLC) following tyrosine kinase inhibitor (TKI) failure are limited, and platinum-based chemotherapy remains the main treatment. The development of effective immunotherapy for this disease has been challenging. In the present study, 37 patients with EGFR-mutant advanced NSCLC who were treated with programmed cell death-1 (PD-1) inhibitor-based combinations after TKI failure were reviewed. The total cohort had a median progression-free survival (mPFS) of 5.2 months (95% CI, 4.077-6.323 months) and a median overall survival (mOS) of 18.3 months (95% CI, 12.932-23.668 months). Patients with Eastern Cooperative Oncology Group performance-status (ECOG-PS) scores of 0 or 1 had longer mPFS than those with ECOG-PS scores of 2 (5.4 vs. 2.4 months; P=0.006). In addition, a PFS benefit was observed in patients with EGFR T790M-negative compared with EGFR T790M-positive tumors (mPFS 6.2 vs. 4.4 months; P=0.041). Patients treated with immunotherapy-based combinations as a front-line therapy had a longer mPFS than those in which the combinations were used as a late-line therapy (6.2 vs. 2.4 months; P<0.001). PD-1 inhibitor combined with chemotherapy and bevacizumab did not show a clear advantage over PD-1 inhibitor combined with chemotherapy alone (mPFS, 6.2 vs. 4.4 months; P=0.681), although it resulted in an improved overall response rate (ORR) and disease control rate. Notably, the 7 patients with a programmed cell death ligand-1 (PD-L1) tumor proportion score of ≥50% had an ORR of 100% and an mPFS of 8.3 months. Therefore, it is suggested that PD-1 inhibitor-based combinations should be a priority treatment option in selective populations, such as those with low ECOG-PS scores, T790M-negative status or high PD-L1 expression in EGFR-mutant NSCLC after TKI failure. The use of immunotherapy and chemotherapy in combination with antiangiogenic agents appears to be a promising combination therapy for such patients. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) mutations have emerged as the most well-studied oncogenic alterations in advanced non-small cell lung cancer. The presence of single common or rare EGFR mutations and extra complex EGFR mutations correlates with the response sensitivity to EGFR tyrosine kinase inhibitors. Therefore, given the lack of evidence for the emergence of rare EGFR mutation types, the pathogenic mechanisms of uncommon EGFR mutations and the optimal treatment strategies remain to be explored further. The present study describes the case of a patient diagnosed with lung adenocarcinoma (LUAD) carrying two rare EGFR exon 18 indel/G719C and exon 19 L747S mutations, in which persistent lesion shrinkage was exhibited within 16 months of osimertinib treatment. Given the paucity of clinical trials for the treatment of LUAD harboring complex EGER mutations, the present detailed case description may provide clinicians with effective clinical experience in treating patients. [ABSTRACT FROM AUTHOR]

Background: Between 5 and 50% of atypical hemolytic uremic syndrome (aHUS) cases in children are caused by autoantibodies against complement factor H (CFH). Given the acquired autoimmune nature of the disease, plasma exchange (PE) and various immunosuppressive treatments have been used. More recently, eculizumab has been proposed. Methods: In this multicenter, retrospective study, we report outcomes of 12 children with anti-FH antibody-associated HUS treated with eculizumab associated with various immunosuppressive regimens. Results: Patients were treated with eculizumab for 15.5 [9.5;23.0] months and 3 received PE or IgG adsorption. Three patients received mycophenolate mofetil (MMF) alone, 1 patient received MMF and steroids, 1 patient received MMF and rituximab, 3 patients received MMF/steroids and rituximab, and 4 patients did not receive any immunosuppression. Anti-FH antibody levels significantly decreased but no difference was observed based on the immunosuppressive regimen. Eculizumab was discontinued in 7/10 patients after 11 [7.5;15.5] months and MMF in 6/8 patients after 36 [35;40] months. Anti-FH titers at MMF discontinuation ranged from 257 to 3425 UI/L. None of these patients relapsed and eGFR at last follow-up was above 70 mL/min/1.73 m2 in all patients. Conclusions: Eculizumab is effective and safe in inducing and maintaining remission in aHUS secondary to anti-FH antibodies and renders reduction of anti-FH titers less urgent. Anti-FH antibody titers decreased in most patients irrespective of the immunosuppressive treatment chosen, so that a strategy consisting of combining eculizumab with MMF monotherapy seems sufficient at least in non-Indian or less severe forms of anti-FH antibody-associated HUS. [ABSTRACT FROM AUTHOR]

[Display omitted] Breast cancers that overexpress human epidermal growth factor receptor 2 (HER2) have poor prognosis. Moreover, available chemotherapies cause numerous side effects due to poor selectivity. To advance more effective and safer therapies for HER2-positive breast cancer, we explored the fusion of drug delivery technology and immunotherapy. Our research led to the design of immunocubosomes loaded with panobinostat and functionalized with trastuzumab antibodies, enabling precise targeting of breast cancer cells that overexpress HER2. We characterised the nanostructure of cubosomes using small-angle X-ray scattering (SAXS), cryo-transmission electron microscopy (cryo-TEM), and dynamic light scattering (DLS). Moreover, we confirmed the integrity of the trastuzumab antibodies on the immunocubosomes by Fourier-transform infrared spectroscopy (FTIR) and sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Additionally, we found that panobinostat-loaded immunocubosomes were more cytotoxic, and in an uptake-dependant manner, towards a HER2-positive breast cancer cell line (SKBR3) compared to a cell line representing healthy cells (L929). These results support that the functionalization of cubosomes with antibodies enhances both the effectiveness of the loaded drug and its selectivity for targeting HER2-positive breast cancer cells. [ABSTRACT FROM AUTHOR]

Early tumor response prediction can help avoid overtreatment with unnecessary chemotherapy sessions. It is important to determine whether multiple apparent diffusion coefficient indices (S index, ADC‐diff) are effective in the early prediction of pathological response to neoadjuvant chemotherapy (NAC) in breast cancer (BC). Patients with stage II and III BCs who underwent T1WI, diffusion‐weighted imaging (DWI), and dynamic contrast‐enhanced MRI using a 3 T system were included. They were divided into two groups: major histological responders (MHRs, Miller–Payne G4/5) and nonmajor histological responders (nMHRs, Miller–Payne G1–3). Three b values were used for DWI to derive the S index; ADC‐diff values were obtained using b = 0 and 1000 s/mm2. The different interquartile ranges of percentile S‐index and ADC‐diff values after treatment were calculated and compared. The assessment was performed at baseline and after two and four NAC cycles. A total of 59 patients were evaluated. There are some correlations of interquartile ranges of S‐index parameters and ADC‐diff values with histopathological prognostic factors (such as estrogen receptor and human epidermal growth factor receptor 2 expression, all p < 0.05), but no significant differences were found in some other interquartile ranges of S‐index parameters or ADC‐diff values between progesterone receptor positive and negative or for Ki‐67 tumors (all P > 0.05). No differences were found in the dynamic contrast‐enhanced MRI characteristics between the two groups. HER‐2 expression and kurtosis of the S‐index distribution were screened out as independent risk factors for predicting MHR group (p < 0.05, area under the curve (AUC) = 0.811) before NAC. After early NAC (two cycles), only the 10th percentile S index was statistically significant between the two groups (p < 0.05, AUC = 0.714). No significant differences were found in ADC‐diff value at any time point of NAC between the two groups (P > 0.1). These findings demonstrate that the S‐index value may be used as an early predictor of pathological response to NAC in BC; the value of ADC‐diff as an imaging biomarker of NAC needs to be further confirmed by ongoing multicenter prospective trials. [ABSTRACT FROM AUTHOR]

Introduction: Until recently, the available human receptor epidermal growth factor 2 (HER2) targeted agents were ineffective for treating patients with HER2-low expressing breast cancer (defined as immunohistochemical expression of 1+ or 2+ without amplification). The development of novel and potent HER2-directed antibody-drug conjugates, affective at treating HER2-low expressing breast cancers, have changed the way we think about HER2-low expression and expanded the treatment options for many patients with advanced disease. Areas covered: In this review, we summarize the current management of HER2-low breast cancer and commonly encountered challenges such as treatment sequencing and toxicity management. Expert opinion: trastuzumab deruxtecan (T-DXd) is a treatment option for patients with advanced, HER2-low breast cancer, irrespective of the hormone receptor status. The current optimal place in treatment algorithms is after the first line of chemotherapy, both in HR-positive and triple-negative breast cancer; however, other agents are available in this setting and risks and benefits for each should be considered in shared decision making. Up to 10–15% of patients receiving T-DXd develop interstitial lung disease. Patient and clinician education are key to safely implement T-DXd in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: To explore the specific pharmacological molecular mechanisms of Laoke Formula (LK) on treating advanced non-small cell lung cancer (NSCLC) based on clinical application, network pharmacology and experimental validation. Methods: Kaplan-Meier method and Cox regression analysis were used to evaluate the survival benefit of Chinese medicine (CM) treatment in 296 patients with NSCLC in Tianjin Medical University Cancer Institute and Hospital from January 2011 to December 2015. The compounds of LK were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and the corresponding targets were performed from Swiss Target Prediction. NSCLC-related targets were obtained from Therapeutic Target Database and Comparative Toxicogenomics Database. Key compounds and targets were identified from the compound-target-disease network and protein-protein interaction (PPI) network analysis, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis were used to predict the potential signaling pathways involved in the treatment of advanced NSCLC with LK. The binding affinities between key ingredients and targets were further verified using molecular docking. Finally, A549 cell proliferation and migration assay were used to evaluate the antitumor activity of LK. Western blot was used to further verify the expression of key target proteins related to the predicted pathways. Results: Kaplan-Meier survival analysis showed that the overall survival of the CM group was longer than that of the non-CM group (36 months vs. 26 months), and COX regression analysis showed that LK treatment was an independent favorable prognostic factor (P=0.027). Next, 97 components and 86 potential targets were included in the network pharmacology, KEGG and GO analyses, and the results indicated that LK was associated with proliferation and apoptosis. Moreover, molecular docking revealed a good binding affinity between the key ingredients and targets. In vitro, A549 cell proliferation and migration assay showed that the biological inhibition effect was more obvious with the increase of LK concentration (P<0.05). And decreased expressions of nuclear factor κB1 (NF-κB1), epidermal growth factor receptor (EGFR) and AKT serine/threonine kinase 1 (AKT1) and increased expression of p53 (P<0.05) indicated the inhibitory effect of LK on NSCLC by Western blot. Conclusion: LK inhibits NSCLC by inhibiting EGFR/phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, NFκB signaling pathway and inducing apoptosis, which provides evidence for the therapeutic mechanism of LK to increase overall survival in NSCLC patients. [ABSTRACT FROM AUTHOR]

The purpose of this study is to explore the potential molecular mechanism of Bidentis Bipinnatae Herba against gastric cancer by using network pharmacology methods, molecular docking, and cellular experimental validation. Medicinal plants related to gastric cancer were queried through TCMSP, SymMap, and Herb databases. The TCSMP database (drug-likeness ≥ 0.18) was used to retrieve the bioactive constituents. TCSMP, SwissTargetPrediction, and Herb databases were used to retrieve the target genes, and Cytoscape software was used to construct the "active ingredient-target" network. After protein interaction analysis using String 11.0 platform, the hub genes were screened using CytoHubba. The obtained hub genes were uploaded to the cBioPortal for pathway enrichment. The genes involved in gastric cancer-related RTK-RAS pathway were molecularly docked and experimentally validated. Bidentis Bipinnatae Herba was common to TCMSP, SymMap, and Herb databases. A total of nine active ingredients were obtained in Bidentis Bipinnatae Herba, acting on 192 targets. Seven hub genes were obtained from these target genes and enriched in the RTK-RAS pathway in gastric cancer. MAPK1 and EGFR had good molecular docking results with their corresponding chemicals. Cellular experiments showed that the treatment of luteolin, quercetin, and Okanin reduced the expression of EGFR in AGS cells; the treatment of luteolin and quercetin could reduce the expression of MAPK1. Bidentis Bipinnatae Herba contained active components, which may be anti-gastric cancer in a multi-target (MAPK1 and EGFR) manner. [ABSTRACT FROM AUTHOR]

It has been shown that the high expression of human epididymis protein 4 (HE4) in most lung cancers is related to the poor prognosis of patients, but the mechanism of pathological transformation of HE4 in lung cancer is still unclear. The current study is expected to clarify the function and mechanism of HE4 in the occurrence and metastasis of lung adenocarcinoma (LUAD). Immunoblotting evaluated HE4 expression in lung cancer cell lines and biopsies, and through analysis of The Cancer Genome Atlas (TCGA) dataset. Frequent HE4 overexpression was demonstrated in LUAD, but not in lung squamous cell carcinoma (LUSC), indicating that HE4 can serve as a biomarker to distinguish between LUAD and LUSC. HE4 knockdown significantly inhibited cell growth, colony formation, wound healing, and invasion, and blocked the G1-phase of the cell cycle in LUAD cell lines through inactivation of the EGFR signaling downstream including PI3K/AKT/mTOR and RAF/MAPK pathways. The first-line EGFR inhibitor gefitinib and HE4 shRNA had no synergistic inhibitory effect on the growth of lung adenocarcinoma cells, while the third-line EGFR inhibitor osimertinib showed additive anti-proliferative effects. Moreover, we provided evidence that HE4 regulated EGFR expression by transcription regulation and protein interaction in LUAD. Our findings suggest that HE4 positively modulates the EGFR signaling pathway to promote growth and invasiveness in LUAD and highlight that targeting HE4 could be a novel strategy for LUAD treatment. [ABSTRACT FROM AUTHOR]