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INTRODUCTION: EGFR-mutated NSCLC is minimally responsive to programmed cell death protein 1 or programmed death-ligand 1 blockade. We evaluated the safety, tolerability, and immunomodulatory effects of the EGFR tyrosine kinase inhibitor (TKI) afatinib in combination with the programmed cell death protein 1 antibody pembrolizumab in patients with EGFR-mutant NSCLC. METHODS: Patients with advanced EGFR-mutant NSCLC with progression (PD) on previous EGFR TKI(s), aged above or equal to 18 years, Eastern Cooperative Oncology Group performance status less than or equal to 1, acceptable organ function, no significant autoimmune disease, measurable disease, and controlled brain metastases were eligible. Primary end point was determination of the maximum tolerated dose and recommended phase 2 dose. Serial specimens were collected to assess for alterations in cytokines and immune cell subsets by quantitative immunofluorescence in tissue and Luminex and flow cytometry in the blood. RESULTS: A total of 11 patients were enrolled, six in dose finding and five in dose expansion. No dose-limiting toxicities were observed. The maximum tolerated dose was determined to be afatinib 40 mg orally daily and pembrolizumab 200 mg intravenously every 21 days. Four (36%) patients had immune-related adverse events (irAEs). Ten patients were assessable for response: two partial response, seven stable disease, and one PD. Peripheral natural killer and natural killer T-cells (p = 0.027, p = 0.01) increased and exhausted CD8+ T-cells decreased on treatment (p = 0.0035). Peripheral CD4/CD8 T-cells (area under the curve = 0.96, p = 0.042) and central memory T-cells (CD4/CD8) (area under the curve = 1.0, p = 0.0006) increased in patients who had disease control more than 6 months or partial response to afatinib/pembrolizumab as did CD3+ T-cells in a patient with progression-free survival more than 6 months after afatinib/pembrolizumab treatment. CONCLUSIONS: Afatinib and pembrolizumab were found to have modest activity associated with irAEs after PD on previous EGFR TKI setting. Proinflammatory changes in immune cell subsets in tissue and blood were detected and associated with antitumor activity and irAEs.

A long-standing question in the field of signal transduction is how distinct signaling pathways interact with each other to control cell behavior. Growth factor receptors and G protein-coupled receptors (GPCRs) are the two major signaling hubs in eukaryotes. Given that the mechanisms by which they signal independently have been extensively characterized, we investigated how they may cross-talk with each other. Using linear ion trap mass spectrometry and cell-based biophysical, biochemical, and phenotypic assays, we found at least three distinct ways in which epidermal growth factor affected canonical G protein signaling by the Gi-coupled GPCR CXCR4 through the phosphorylation of Gαi. Phosphomimicking mutations in two residues in the αE helix of Gαi (tyrosine-154/tyrosine-155) suppressed agonist-induced Gαi activation while promoting constitutive Gβγ signaling. Phosphomimicking mutations in the P loop (serine-44, serine-47, and threonine-48) suppressed Gi activation entirely, thus completely segregating growth factor and GPCR pathways. As expected, most of the phosphorylation events appeared to affect intrinsic properties of Gαi proteins, including conformational stability, nucleotide binding, and the ability to associate with and to release Gβγ. However, one phosphomimicking mutation, targeting the carboxyl-terminal residue tyrosine-320, promoted mislocalization of Gαi from the plasma membrane, a previously uncharacterized mechanism of suppressing GPCR signaling through G protein subcellular compartmentalization. Together, these findings elucidate not only how growth factor and chemokine signals cross-talk through the phosphorylation-dependent modulation of Gαi but also how such cross-talk may generate signal diversity.

Rationale & objectiveTubulointerstitial damage is a feature of early chronic kidney disease (CKD), but current clinical tests capture it poorly. Urine biomarkers of tubulointerstitial health may identify risk of CKD.Study designProspective cohort (Atherosclerosis Risk in Communities [ARIC]) and case-cohort (Multi-Ethnic Study of Atherosclerosis [MESA] and Reasons for Geographic and Racial Differences in Stroke [REGARDS]).Setting & participantsAdults with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and without diabetes in the ARIC, REGARDS, and MESA studies.ExposuresBaseline urine monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin (α1m), kidney injury molecule-1, epidermal growth factor, and chitinase-3-like protein 1.OutcomeIncident CKD or end-stage kidney disease.Analytical approachMultivariable Cox proportional hazards regression for each cohort; meta-analysis of results from all 3 cohorts.Results872 ARIC participants (444 cases of incident CKD), 636 MESA participants (158 cases), and 924 REGARDS participants (488 cases) were sampled. Across cohorts, mean age ranged from 60 ± 10 to 63 ± 8 years, and baseline eGFR ranged from 88 ± 13 to 91 ± 14 mL/min/1.73 m2. In ARIC, higher concentrations of urine MCP-1, α1m, and kidney injury molecule-1 were associated with incident CKD. In MESA, higher concentration of urine MCP-1 and lower concentration of epidermal growth factor were each associated with incident CKD. In REGARDS, none of the biomarkers were associated with incident CKD. In meta-analysis of all 3 cohorts, each 2-fold increase α1m concentration was associated with incident CKD (HR, 1.19; 95% CI, 1.08-1.31).LimitationsObservational design susceptible to confounding; competing risks during long follow-up period; meta-analysis limited to 3 cohorts.ConclusionsIn 3 combined cohorts of adults without prevalent CKD or diabetes, higher urine α1m concentration was independently associated with incident CKD. 4 biomarkers were associated with incident CKD in at least 1 of the cohorts when analyzed individually. Kidney tubule health markers might inform CKD risk independent of eGFR and albuminuria.

Background: Sepsis-associated encephalopathy (SAE) impairs hippocampal microglial efferocytosis, causing cognitive deficits. Previous research found that milk fat globule epidermal growth factor 8 protein (MFGE8) stimulates efferocytosis, reducing hippocampal inflammation in SAE rats. In this study, we explore MFGE8's role in alleviating cognitive impairment and its impact on neural activity using functional magnetic resonance imaging (fMRI). Methods: Sixty male Sprague Dawley rats were divided into four groups: Sham, cecal ligation and puncture (CLP), CLP+MFGE8, and CLP+MFGE8+CGT (Cilengitide). After CLP, CLP+MFGE8 rats received intracerebroventricular MFGE8 (3.3 µg), while CLP+MFGE8+CGT rats received intraperitoneal Cilengitide (10 mg/kg). We assessed cognitive function with the Morris water maze and open field test over five days. Eight days post-surgery, rats underwent T2-weighted magnetic resonance imaging (MRI) and resting state (rs)-fMRI scans. Brain tissues were collected for western blot, hematoxylin-eosin (HE) staining, and immunofluorescence. Statistical analysis employed one-way analysis of variance (ANOVA) followed by Tukey's post-test for multiple comparisons. Results: MFGE8 improved neurobehavioral performance in open field task (OFT) and morris water maze (MWM) tests. fMRI indicated a significant reduction in abnormal neural activity in the right hippocampal CA1, CA3, and dentate gyrus of SAE rats following MFGE8 treatment. Voxel-based morphometry (VBM) analysis revealed decreased high-signal areas in the hippocampus, along with reduced hippocampal volume due to alleviated neural edema. Western blot analysis demonstrated that MFGE8 enhanced ras-related C3 botulinum toxin substrate 1 (Rac1) and microtubule-associated protein 1A/1B-light chain 3 (LC3) expression in the rat hippocampus, while CGT reduced these protein levels. Behavioral experiments and fMRI results confirmed that CGT reversed the cognitive effects of MFGE8 by inhibiting microglial αVβ3/αVβ5 integrin receptors. Conclusions: Our findings show that MFGE8 reduced amplitude of low-frequency fluctuations (ALFF) values in the right hippocampal CA1, CA3, and the dentate gyrus, mitigating abnormal neural activity and decreasing hippocampal volume. This led to an improvement in cognitive dysfunction in SAE rats. These results suggest that MFGE8 enhances microglial efferocytosis by activating αVβ3 and αVβ5 integrin receptors on microglial surfaces, ultimately improving cognitive function in SAE rats. [ABSTRACT FROM AUTHOR]

The human epidermal growth factor (hEGF) is a powerful mitogen used in medical treatment and cosmetics. However, the recovery of hEGF from natural sources is insufficient to meet market demands, thus recombinant protein production technology for recombinant hEGF (rhEGF) was developed. Among the heterologous expression systems used for rhEGF production, Escherichia coli is preferred due to its well-established advantages. In this review, we focus on the development of two rhEGF expression strategies (soluble rhEGF and rhEGF inclusion bodies), and discuss the design of fusion rhEGF protein and its cultivation strategies. We also explore downstream processes for rhEGF isolation and purification methods (with or without a column chromatography system), and the recovery of rhEGF from inclusion bodies through solubilisation and refolding. Lastly, methods of quantification, characterisation, and biological activity assays used to quantify and validate purified rhEGF are also listed. [Display omitted] • Recombinant human epidermal growth factor (rhEGF) is used for ulcer treatment and cosmetic applications. • rhEGF can be produced via soluble or insoluble (inclusion bodies) protein strategies. • Exploration on differences in fusion protein, cultivation conditions and purification for both rhEGF production strategies. • Method of analysis of produced rhEGF. [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]

Aim: To describe the microbiological composition of subgingival dental plaque and molecular profile of gingival crevicular fluid (GCF) of periodontal furcation‐involved defects. Materials and Methods: Fifty‐seven participants with periodontitis contributed with a degree II–III furcation involvement (FI), a non‐furcation (NF) periodontal defect and a periodontally healthy site (HS). Subgingival plaque was analysed by sequencing the V3–V4 region of the 16S rRNA gene, and a multiplex bead immunoassay was carried out to estimate the GCF levels of 18 GCF biomarkers. Aiming to explore inherent patterns and the intrinsic structure of data, an AI‐clustering method was also applied. Results: In total, 171 subgingival plaque and 84 GCF samples were analysed. Four microbiome clusters were identified and associated with FI, NF and HS. A reduced aerobic microbiota (p =.01) was detected in FI compared with NF; IL‐6, MMP‐3, MMP‐8, BMP‐2, SOST, EGF and TIMP‐1 levels were increased in the GCF of FI compared with NF. Conclusions: This is the first study to profile periodontal furcation defects from a microbiological and inflammatory standpoint using conventional and AI‐based analyses. A reduced aerobic microbial biofilm and an increase of several inflammatory, connective tissue degradation and repair markers were detected compared with other periodontal defects. [ABSTRACT FROM AUTHOR]

• The cytokine profile of cord blood tissue has not been extensively evaluated in the ASD population. • Increased G-CSF and lower IL-1α, IL-1β and IL-4 was found in the cord blood from children later diagnosed with ASD. • Inflammatory cytokines in children later diagnosed with ASD were linked to symptom severity, language, and behavioral assessment scores. In studies investigating the etiology and pathophysiology of autism spectrum disorder (ASD), immune dysregulation is commonly observed, with elevated levels of inflammatory cytokines frequently found in gestational tissues. However, studies investigating the relationship between early immune dysregulation within the umbilical cord blood (CB) compartment and neurodevelopmental outcomes remains limited. In this exploratory study, we utilized data from the prospective Markers for Autism Risk in Babies – Learning Early Signs (MARBLES) study to examine cytokine levels in the plasma fraction of CB in infants later diagnosed with ASD (n = 38) compared to infants typically developing (TD) at age 3 years (n = 103), using multiplex cytokine assays. Our findings reveal altered levels of several inflammatory cytokines in children later diagnosed with ASD, including increased granulocyte colony-stimulating factor (G-CSF) and decreased interleukin-1α (IL-1α), IL-1β, and IL-4 in CB. Furthermore, we identified several associations between behaviors and levels of cytokines, chemokines and growth factors. IL-1α, IL-17A, interferon γ-induced protein 10 (IP-10), and epidermal growth factor (EGF) were associated with worse scores on Autism Diagnostic Observation Schedule (ADOS) and the Mullen Scales of Early Learning (MSEL) assessments. In summary, our study demonstrates dysregulated levels of inflammatory cytokine mediators in the CB of children later diagnosed with ASD and that inflammatory mediators were associated with ASD severity, comorbid behaviors, and neurodevelopmental measures. These findings have important implications for the possible predictive value of early cytokine measures in neurodevelopmental outcomes and subsequent behavioral manifestations. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionsTalin-1 (TLN1) is crucial in cell migration, metastasis, and cancer development. This study evaluated Talin-1 expression and its clinical significance in gastric cancer (GC), along with human epidermal growth factor receptor-2 (HER-2) expression and its correlation with Talin-1.Bioinformatics analysis assessed the potential prognostic value of Talin-1 and HER-2 in GC patients. The study included 223 GC patients (Signet Ring Cells and Intestinal subtypes) and 29 non-malignant tissue samples. Immunohistochemistry (IHC) on tissue microarray slides evaluated Talin-1 and HER-2 expression and clinical significance. Receiver operating characteristic (ROC) curves assessed their diagnostic value.Bioinformatics identified Talin-1 as a potential prognostic factor and HER-2 as an oncogene in GC. Talin-1 and HER-2 expression increased in SRC-type GC samples compared to non-malignant tissues. High cytoplasmic Talin-1 expression inversely correlated with tumor expansion and invasion in SRC-type GC. Increased HER-2 expression positively correlated with metastasis. ROC curves showed significant diagnostic values for both proteins.Higher cytoplasmic Talin-1 expression is associated with less invasive tumor behavior, while increased membranous HER-2 expression is associated with metastasis in SRC-type GC. These findings suggest potential use in assessing diagnosis and screening high-risk cancer patients, particularly those with SRC-type GC. [ABSTRACT FROM AUTHOR]

Burn wound healing is a dynamic and interconnected process, with the complex status of the extracellular matrix (ECM) potentially leading to bacterial infections, drug resistance, or even fatality. However, it remains a grand challenge to assemble a skin‐like material showing similar biological properties as healthy ECM to accelerate burn healing. In this study, the ECM composition is closely mimicked and adaptive multifunctional artificial dermis is developed by leveraging Ag─S bonds, supramolecular interactions among recombinant proteins, Ag+, and hyaluronic acid (HA). The artificial dermis exhibits long‐lasting broad‐spectrum antibacterial activity, achieved though controlled Ag+ release via Ag─S bonds, supramolecular interactions, and recombinant protein‐guided multi‐level assembly, reaching a steady plateau of 83.7% in the later stage. It is found that inflammation is reduced by downregulating IL‐6 and TGF‐β expression. Furthermore, the epidermal growth factor (EGF) within the recombinant proteins stimulates Col1α, ELN, and CD31 upregulation, facilitating ECM remodeling. These adaptive multifunctional artificial dermis effectively address wound infections, accelerate collagen deposition, promote re‐epithelialization, and enhance angiogenesis in infected wounds, highlighting their potential to revolutionize burn wound treatment and offering a promising avenue to holistic care. [ABSTRACT FROM AUTHOR]

Abstract\nHIGHLIGHTSMilk fat globule-epidermal growth factor 8 (MFG-E8) is a multifunctional glycoprotein regulating intercellular interactions in various biological and pathological processes. This review summarizes the effects and mechanisms of MFG-E8 in neurodegenerative diseases (NDDs), emphasizing its roles in inflammation, apoptosis, and oxidative stress. In this review, will also explore the potential of MFG-E8 as a diagnostic biomarker and its therapeutic applications in neurodegenerative disorders. Recent studies have revealed intriguing characteristics of using MFG-E8 as a potential drug for treating various brain disorders. While the discovery, origin, expression, and physiological functions of MFG-E8 in various organs and tissues are well defined, its role in the brain remains less understood. This is particularly true for NDDs, indicating unmet medical needs. Elucidating its role in the brain could position MFG-E8 as a potential treatment for NDDs.The expression and regulation of MFG-E8 in neurodegenerative diseases.The role of MFG-E8 in the mechanisms of neurodegenerative diseases.Potential application challenges and strategies for MFG-E8 as a therapeutic target.The expression and regulation of MFG-E8 in neurodegenerative diseases.The role of MFG-E8 in the mechanisms of neurodegenerative diseases.Potential application challenges and strategies for MFG-E8 as a therapeutic target. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusions Patients with polypoidal choroidal vasculopathy (PCV) exhibit variability in response to anti‐VEGF therapy. This study aimed to analyse the aqueous humour proteomic profiles of PCV patients and provide preliminary insights for the identification of biomarkers associated with anti‐VEGF drug responsiveness.PCV patients who were treatment‐naïve or untreated for more than 3 months were prospectively recruited from two hospitals in Beijing and Tianjin. Based on the relative changes in central macular thickness (ΔCMT/baseline‐CMT) before and after anti‐VEGF treatment, the PCV patients were divided into a good response (GR) group (≤−25%) and a poor response (PR) group (>−25%). Aqueous humour proteomics was performed by the Data‐independent Acquisition‐Mass Spectrometry (DIA‐MS) method, and differentially expressed proteins (DEPs) analysis between the different PCV groups and the control group was conducted. Key DEPs were selected for preliminary validation in the aqueous humour using the Luminex method retrospectively.A total of 31 PCV patients (31 eyes) were included, 13 in the GR group and 18 in the PR group. A total of 414 DEPs were identified, including 36 significantly upregulated proteins, such as G protein regulatory factor 10 (RGS10), podocin (PODN) and epidermal growth factor (EGF), and 32 downregulated proteins, including RAB11FIP4 (Rab11 family‐interacting protein 4), α‐synuclein (SNCA), haemoglobin subunit δ (HBD) and interleukin 6 (IL6). Compared to the cataract control group (10 eyes), 134 proteins were significantly upregulated, and 72 were downregulated. KEGG pathway enrichment analysis revealed that the GR and PR groups differ in terms of cell communication, and cell signal transduction. Protein–protein interaction analysis revealed interactions between EGF and various DEPs. Validation of aqueous humour proteins using the Luminex method revealed that changes in the levels of EGF were associated with the anti‐VEGF treatment response in PCV patients.PCV patients with good or poor anti‐VEGF responses exhibit distinct aqueous humour proteomic profiles. Aqueous EGF may serve as a biomarker for the ‘precise treatment’ of PCV. [ABSTRACT FROM AUTHOR]

Background: There has been significant improvement in treating metastatic non–small-cell lung cancer (mNSCLC) over the past 2 decades. The aim of this study is to describe the use of tyrosine kinase inhibitors (TKIs) in Qatar. This study focuses on the objective response rate (ORR) and reported adverse drug events (ADEs) of TKIs used for the management of patients with mNSCLC. Methods: This is a descriptive retrospective cohort study. All non–small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations who received TKIs between 2015 and 2019 in Qatar were included. The TKIs used during this period include EGFR inhibitors such as afatinib, erlotinib, gefitinib, and osimertinib and ALK inhibitors such as alectinib and crizotinib. The response on each TKI was identified by reporting the ORR (as the sum of the complete response [CR] and the partial response [PR]), in addition stable disease (SD) and disease progression (DP) were reported. While ADEs were reported using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE). Results: A total of 63 patients were included, of which 36 cases (57.1%) expressed EGFR mutation, and 27 patients (42.9%) expressed ALK rearrangement. The ORR in EGFR inhibitors was as follows: osimertinib 40%, gefitinib 33%, afatinib 22%, and erlotinib 18%. However, the response to the ALK-targeted therapy was 43% with alectinib and 40% with crizotinib. A total of 112 ADEs were reported. They were distributed as 63.4% (71 of 112) with the anti-EGFR and 36.6% (41 of 112) ADEs with the ALK inhibitors. In the anti-EGFR group, the most common types of ADEs were dermatological toxicity 30%, whereas, in the anti-ALK group, gastrointestinal toxicity was the most common (29%). Conclusions: The EGFR-targeted and ALK-targeted therapies appear to have acceptable clinical response rate and safety profile in our population. Close and frequent monitoring of adverse events is advised to ensure a good quality of life and prevent serious complications. [ABSTRACT FROM AUTHOR]

Background: Venous thromboembolism (VTE) risk is higher among patients with non–small cell lung cancer (NSCLC) and specific subgroups, including the elderly, but little is known about the VTE risk of different generations of epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR‐TKIs) and whether the risk differs by demographic characteristics. This study aims to compare the risk of VTE (deep venous thromboembolism [DVT]; pulmonary embolism [PE]) between a third‐generation EGFR‐TKI and first/second‐generation EGFR‐TKIs and stratify VTE risk by sex, age, and race/ethnicity in third‐generation EGFR‐TKI users. Methods: Via the 2006–2019 Surveillance, Epidemiology, and End Results–Medicare database, this retrospective cohort study included older patients (aged ≥65 years) with advanced NSCLC who initiated on a third‐generation EGFR‐TKI (n = 493) and first/second‐generation EGFR‐TKIs (n = 1036). We estimated the hazard ratio (HR) and its 95% confidence interval (95% CI) with the Cox proportional hazards model. Results: A third‐generation EGFR‐TKI had a significantly higher VTE risk than first/second‐generation EGFR‐TKIs (HR, 1.26 [95% CI, 1.01–1.57]; p =.037), with an elevated risk in males (HR, 2.16 [95% CI, 1.47–3.19]; p <.001), patients aged ≥75 years (HR, 1.38 [95% CI, 1.04–1.83]; p =.026), and non‐Hispanic Whites (HR, 1.46 [95% CI, 1.10–1.95]; p =.010). Males consistently showed a significantly higher risk of DVT (HR, 2.49 [95% CI, 1.29–4.80]; p =.007) and PE (HR, 2.00 [95% CI, 1.29–3.11]; p =.002). A significantly higher risk of DVT (HR, 1.54 [95% CI, 1.00–2.37]; p =.050) and PE (HR, 1.47 [95% CI, 1.06–2.05]; p =.021) was shown in patients aged ≥75 years and non‐Hispanic Whites, respectively. Among third‐generation EGFR‐TKI users, non‐Hispanic Whites had a significantly higher risk of VTE (HR, 2.04 [95% CI, 1.03–4.02]; p =.041) and PE (HR, 2.88 [95% CI, 1.24–6.70]; p =.014) than non‐Hispanic Asian/Pacific Islanders. Conclusions: Close monitoring of VTE events in high‐risk patients is essential to promote early diagnosis and treatment. In older patients with non–small cell lung cancer, those treated with osimertinib (a third‐generation epidermal growth factor receptor–tyrosine kinase inhibitor [EGFR‐TKI]) had a significantly higher risk of venous thromboembolism (VTE) than those treated with traditional EGFR‐TKIs. The risk was elevated in patients who were male, aged ≥75 years, and non‐Hispanic White, which raises the need for close monitoring of VTE when using osimertinib. [ABSTRACT FROM AUTHOR]

Overexpression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-XL) is associated with drug resistance and disease progression in numerous cancers. The compelling nature of this protein as a therapeutic target prompted efforts to develop selective small-molecule BCL-XL inhibitors. Although efficacious in preclinical models, we report herein that selective BCL-XL inhibitors cause severe mechanism-based cardiovascular toxicity in higher preclinical species. To overcome this liability, antibody-drug conjugates were constructed using altered BCL-XL-targeting warheads, unique linker technologies, and therapeutic antibodies. The epidermal growth factor receptor-targeting antibody-drug conjugate AM1-15 inhibited growth of tumor xenografts and did not cause cardiovascular toxicity nor dose-limiting thrombocytopenia in monkeys. While an unprecedented BCL-XL-mediated toxicity was uncovered in monkey kidneys upon repeat dosing of AM1-15, this toxicity was mitigated via further drug-linker modification to afford AM1-AAA (AM1-25). The AAA drug-linker has since been incorporated into mirzotamab clezutoclax, the first selective BCL-XL-targeting agent to enter human clinical trials. [ABSTRACT FROM AUTHOR]

Compartmentalization and differential distribution of proteins within a cell maintain cellular function and viability. CapG is a gelsolin-related actin-binding protein that distributes in steady state diffusively throughout cytoplasm and cell nucleus. To detect changes in CapG's nucleocytoplasmic shuttling in response to external stimuli on the single cell level, we established repeated FRAP experiments of one and the same breast cancer cell. With this experimental set up, we found that ATP-depletion reversibly decreased CapG's shuttling into the cell nucleus. The addition of epidermal growth factor (EGF) increased CapG's nuclear shuttling within minutes. Serum-starvation doubled the number of breast cancer cells from 40 to 80% displaying increased CapG shuttling in response to EGF. Testing five different potential CapG phosphorylation sites, we found that serine 70 mediates the increase in CapG's nuclear shuttling triggered by EGF. Thus, repeated FRAP of CapG in the cell nucleus can be used as functional readout of signaling cascades in the same single live breast cancer cell. [ABSTRACT FROM AUTHOR]

Retinal neurovascular unit (NVU) is a multi-cellular structure that consists of the functional coupling between neural tissue and vascular system. Disrupted NVU will result in the occurrence of retinal and choroidal vascular diseases, which are characterized by the development of neovascularization, increased vascular permeability, and inflammation. This pathological entity mainly includes neovascular age-related macular degeneration (neovascular-AMD), diabetic retinopathy (DR) retinal vein occlusion (RVO), and retinopathy of prematurity (ROP). Emerging evidences suggest that the angopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Ang/Tie) signaling pathway is essential for the development of retinal and choroidal vascular. Tie receptors and their downstream pathways play a key role in modulating the vascular development, vascular stability, remodeling and angiogenesis. Angiopoietin 1 (Ang1) is a natural agonist of Tie2 receptor, which can promote vascular stability. On the other hand, angiopoietin 2 (Ang2) is an antagonist of Tie2 receptor that causes vascular instability. Currently, agents targeting the Ang/Tie signaling pathway have been used to inhibit neovascularization and vascular leakage in neovascular-AMD and DR animal models. Particularly, the AKB-9778 and Faricimab have shown promising efficacy in improving visual acuity in patients with neovascular-AMD and DR. These experimental and clinical evidences suggest that activation of Ang/Tie signaling pathway can inhibit the vascular permeability, neovascularization, thereby maintaining the normal function and structure of NVU. This review seeks to introduce the versatile functions and elucidate the modulatory mechanisms of Ang/Tie signaling pathway. Recent pharmacologic therapies targeting this pathway are also elaborated and summarized. Further translation of these findings may afford a new therapeutic strategy from bench to bedside. [ABSTRACT FROM AUTHOR]

Background: Primary breast lymphoma (PBL) is a rare type of extranodal lymphoma, the diagnostic process for which presents significant challenges owing to an overlap in clinical and pathological features with those observed in triple-negative breast cancer (TNBC). However, the current literature reveals a paucity of information regarding the ramifications of potential diagnostic errors, particularly in the context of emergent therapeutic strategies for TNBC. Thus, we present a unique report of a case of PBL. Case presentation: A 76-year-old female with no past medical or family history presented to the hospital with the chief complaint of a mass in the right breast. Two masses were palpated in the right breast: one 56 mm mass (No. 1) located at 10 o'clock, and a 21 mm large, elastic, hard mass (No. 2) at 4 o'clock. Needle biopsy was performed only on the larger 56 mm mass (No. 1). The results showed invasive carcinoma that was negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2. The preoperative diagnosis was right breast cancer (T3N0M0 Stage IIB) of the TNBC subtype. The patient refused the preoperative chemotherapy recommended by the treatment team; therefore, right breast mastectomy and sentinel lymph-node biopsy were performed instead. The histopathological diagnosis of the first mass was diffuse large B-cell lymphoma (DLBCL); that of the second mass (No. 2) was an invasive breast carcinoma of no special type. Postoperative treatment consisted of endocrine therapy (letrozole) for breast cancer, while the DLBCL was treated with chemotherapy and three courses of intrathecal chemotherapy. At the time of this report, the patient is still living, and neither tumor had recurred in the 2 years following surgery. Conclusions: On rare occasions, PBL can preoperatively mimic TNBC. While this case did not lead to serious consequences, because surgery was eventually selected as the first therapy, clinicians should be aware that the diagnosis of PBL is challenging using only a core-needle biopsy and can often be misdiagnosed as TNBC. [ABSTRACT FROM AUTHOR]

Wounds that become infected can lead to serious illness or even death if left untreated. Unfortunately, current wound healing treatments don't always work well. Achieving optimal wound healing involves the coordination of diverse cellular events facilitated by numerous growth factors, cytokines, and chemokines. One potential solution for addressing the wound healing process is using lyophilized-secretome gel from human Wharton's Jelly Mesenchymal Stem Cells (hWJMSCs-Sec). This gel, called lyophilized-hWJMSCs-Sec gel (LSG) is created by mixing carbomer gel with hWJMSCs-Sec, then freeze-dry it into a powder to maintain its quality and stability. The quality testing of the topical gel formulation is conducted by measuring. The gel is tested for pH, viscosity, consistency, and its appearance. It's also tested for antioxidant activity using 2,2-Diphenyl-1-picrylhydrazyl (DPPH), and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays were employed to identify the antioxidant activities of the lyophilized-gel. Proteins level of Tissue Inhibitor of Metalloproteinases-2 (TIMP-2), Epidermal Growth Factor (EGF), basic Fibroblast Growth Factor (bFGF), Interleukin-6 (IL-6), and IL-4 were also measured with the ELISA method. The LSG has a soft and non-sticky texture with clarity, a pandan-like aroma, and excellent adhesion and spreadability. It contains proteins and antioxidants that help wound healing. The lyophilized-Sec gel contained TIMP-2, EGF, bFGF, IL-6, and IL-4 as well as stronger antioxidant properties compared to un-lyophilized-hWJMSCs-Sec gel, and showed promise as an effective remedy for wound healing. [ABSTRACT FROM AUTHOR]

The epidermis, the most superficial layer of the human skin, serves a critical barrier function, protecting the body from external pathogens and allergens. Dysregulation of epidermal differentiation contributes to barrier dysfunction and has been implicated in the pathology of various dermatological diseases, including atopic dermatitis (AD). Mucopolysaccharide polysulphate (MPS) is a moisturising agent used to treat xerosis in patients with AD. However, its mechanism of action on keratinocytes, the main constituents of the epidermis, remains unclear. In this study, we investigated the effect of MPS on keratinocytes by subjecting adult human epidermal and three‐dimensional cultured keratinocytes to MPS treatment, followed by transcriptome analysis. The analysis revealed that MPS treatment enhances keratinocyte differentiation and suppresses proliferation. We focused on amphiregulin (AREG), a membrane protein that belongs to the epidermal growth factor (EGF) family and possesses a heparin‐binding domain, as a significant target among the genes altered by MPS. MPS exerted an inhibitory effect directly on AREG, rather than on EGF receptors or other members of the EGF family. Furthermore, AREG leads to a reduction in epidermal barrier function, whereas MPS contributes to barrier enhancement via AREG inhibition. Collectively, these findings suggest that MPS modulates barrier function through AREG inhibition, offering insights into potential therapeutic strategies for skin barrier restoration. [ABSTRACT FROM AUTHOR]

Microglia are resident immune cells in the central nervous system(CNS), it play an important role in both physiological and pathological conditions of the CNS, and can be activated by a variety of physicochemical factors to produce pro-inflammatory phenotype (M1 type) and anti-inflammatory phenotype (M2 type). Milk fat globule epidermal growth factor 8(MFG-E8) is closely related to the biological function of microglia, which can regulate microglia neuroprotective effects such as promoting phagocytosis, anti-inflammatory, and inhibiting oxidative stress in CNS related diseases. It also regulates microglia pro-tumor effect, which in turn affects the outcome of the disease. This article reviews the role of targeting MFG-E8 in regulating the function of microglia, and provides a basis for finding therapeutic targets for CNS related diseases in the future. [ABSTRACT FROM AUTHOR]

Ramucirumab (RAM) has been approved for the treatment of non‐small cell lung cancer (NSCLC). Here, we report two cases of RAM‐induced ascites with epidermal growth factor receptor‐mutant NSCLC. Patient 1, a 72‐year‐old man, developed ascites 20 months after erlotinib (ERL) and RAM administration, which resolved after their discontinuation and performing paracentesis. Patient 2, an 83‐year‐old woman, developed ascites 9 months after ERL and RAM administration, which resolved after RAM discontinuation and furosemide administration. Ramucirumab administration can cause ascites due to increased hepatic sinusoidal pressure. Clinicians should be aware of RAM‐induced ascites in patients with NSCLC and should appropriately manage it. [ABSTRACT FROM AUTHOR]

Background: Although several cell culture systems have been developed to investigate the function of the mammary gland in dairy livestock, they have potential limitations, such as the loss of alveolar structure or genetic and phenotypic differences from their native counterparts. Overcoming these challenges is crucial for lactation research. Development of protocols to establish lactating organoid of livestock represents a promising goal for the future. In this study, we developed a protocol to establish a culture system for mammary organoids in dairy goats to model the mammary gland development and lactation process. Results: The organoids cultured within an extracellular matrix gel maintained a bilayer structure that closely resembled the native architecture of mammary tissue. The expansion of mammary organoids was significantly promoted by growth factors containing epidermal growth factor and fibroblast growth factor 2 whereas the proliferative index of the organoids was significantly inhibited by the treatment with WNT inhibitors. Upon stimulation with a lactogenic medium containing prolactin, the mammary organoids exhibited efficient lactation, characterized by the accumulation of lipid droplets in the lumen space. The lactation could be sustained for more than 3 weeks. Importantly, the expression patterns of genes related to fatty acid synthesis and milk proteins in lactating organoids closely mirrored those observed in mammary tissues. These observations were confirmed by data from proteomic analysis that the bulk of milk proteins was produced in the lactating organoids. Conclusion: This study is the first to establish a mammary organoid culture system modeling the mammary gland development and lactation process in ruminants. The efficient induction of lactation in ruminant mammary organoids holds promises for advancing the field of cell-based milk bio-manufacture in the food industry. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does medroxyprogesterone acetate (MPA) exposure in progestin-primed ovarian stimulation (PPOS) cycles cause molecular perturbations in the steroidogenic function and gonadotropin responsiveness of the granulosa cells? SUMMARY ANSWER PPOS cycles are identical to traditional GnRH antagonist cycles not only for clinical IVF characteristics but also for gonadotropin receptor expression, response to gonadotropins, and steroidogenic function at the molecular level. WHAT IS KNOWN ALREADY PPOS is increasingly used as an alternative to GnRH antagonists due to the inhibitory effect of progesterone on LH release by reducing GnRH pulsatility at the hypothalamic level. Although a growing body of evidence from clinical studies did not indicate significant differences between PPOS and antagonist protocols for IVF cycle characteristics and obstetrical outcomes, it is still unknown whether exposure of the antral follicle cohort to progesterone or its synthetic derivatives during ovarian stimulation causes any subtle molecular aberrations in terms of steroidogenesis and gonadotropin responsiveness. To address this issue, detailed comparative molecular analyses were conducted in the luteinized mural granulosa cells (GCs) obtained from normal responding IVF patients undergoing PPOS and antagonist cycles. STUDY DESIGN, SIZE, DURATION A clinical translational research study was conducted with IVF patients. PARTICIPANTS/MATERIALS, SETTING, METHODS This study included 55 normal responding IVF patients who underwent ovarian stimulation with either PPOS using MPA (5 mg twice daily) or GnRH antagonist cetrorelix acetate. Recombinant forms of FSH and hCG were used for ovarian stimulation and ovulation triggering, respectively. Luteinized mural GCs obtained during the oocyte retrieval procedure were used for the experiments. Cell culture, quantitative real-time PCR, immunoblotting, confocal time-lapse live cell imaging, and hormone assays were used. MAIN RESULTS AND THE ROLE OF CHANCE Demographic and IVF cycle characteristics of the patients undergoing ovarian stimulation with PPOS and GnRH antagonist were similar, including ovarian response, mature oocyte yield, and fertilization rates. Molecular analyses revealed that the expression of the enzymes involved in sex-steroid synthesis (StAR, SCC, 3β-HSD, 17β-HSD, aromatase) and the uptake/storage/utilization of cholesterol (LDL receptor, Hormone-sensitive lipase, hydroxy-methyl glutaryl Co-enzyme-A reductase, and Sterol O-acyltransferase1) in the GCs of the PPOS cycles were comparable to those of the antagonist cycles. The expression of the receptors for gonadotropins, estrogen, and progesterone hormones was also similar. Basal and hCG-induced increases in 3β-HSD expression and progesterone production and basal and FSH-induced increases in aromatase expression and E2 output of the GCs from PPOS patients did not exhibit any meaningful differences when compared with GCs from antagonist cycles. Furthermore, basal and hCG-induced up-regulation in the LDL receptor expression and cholesterol uptake did not differ between the groups. Confocal imaging also revealed similar patterns of expression for the steroidogenic enzymes and their co-localization with mitochondria. Lastly, the expression of the other important genes regulating cumulus expansion, ovulation, and luteal function [Relaxin, ADAMTS-1, and epidermal growth factor (EGF)-like growth factor amphiregulin] in the GCs of the PPOS and antagonist cycles were similar. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Caution should be exercised when interpreting our data which was derived from normally responding patients whose ovulation was triggered with hCG. It is unclear whether the molecular parameters assessed vary according to infertility etiologies, magnitude of ovarian response, mode of trigger, and any other underlying ovarian pathologies or systemic diseases. MPA was the progestin used for PPOS and whether these findings can be generalized to other progestins is unknown. WIDER IMPLICATIONS OF THE FINDINGS This study provides reassuring molecular evidence that exposure of antral follicle cohorts to MPA during the follicular growth phase does not have any detrimental effects on steroidogenic, ovulatory, and luteal functions when compared with GnRH antagonist cycles. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the School of Medicine, the Graduate School of Health Sciences of Koc University and Koç University Research Center for Translational Medicine (KUTTAM), and equally funded by the Republic of Turkey Ministry of Development Research Infrastructure Support Program. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the efficacy of ethanol extracts of Cornus alba (ECA) against benign prostatic hyperplasia (BPH) in vitro and in vivo. Materials and Methods: The prostate stromal cells (WPMY-1) and epithelial cells (RWPE-1) were used to examine the action mechanism of ECA in BPH in vitro. ECA efficacy was evaluated in vivo using a testosterone propionate (TP)-induced BPH rat model. Results: Treatment with ECA inhibited the proliferation of prostate cells by inducing G1-phase cell cycle arrest through the regulation of positive and negative proteins. Treatment of prostate cells with ECA resulted in alterations in the mitogen-activated protein kinases and protein kinase B signaling pathways. The transcriptional binding activity of the NF-κB motif was suppressed in both ECA-treated prostate cells. In addition, treatment with ECA altered the level of BPH-associated axis markers (5α-reductase, fibroblast growth factor-2, androgen receptor, epidermal growth factor, Bcl-2, and Bax) in both cell lines. Finally, the administration of ECA attenuated the enlargement of prostatic tissues in the TP-induced BPH rat model, accompanied by histology, immunoblot, and serum dihydrotestosterone levels. Conclusions: These results demonstrated that ECA exerted beneficial effects on BPH both in vitro and in vivo and might provide valuable information in the development of preventive or therapeutic agents for improving BPH. [ABSTRACT FROM AUTHOR]

Factor XII (FXII), the zymogen of the protease FXIIa, contributes to pathologic processes such as bradykinin-dependent angioedema and thrombosis through its capacity to convert the homologs prekallikrein and factor XI to the proteases plasma kallikrein and factor XIa. FXII activation and FXIIa activity are enhanced when the protein binds to a surface. Here, we review recent work on the structure and enzymology of FXII with an emphasis on how they relate to pathology. FXII is a homolog of pro-hepatocyte growth factor activator (pro-HGFA). We prepared a panel of FXII molecules in which individual domains were replaced with corresponding pro-HGFA domains and tested them in FXII activation and activity assays. When in fluid phase (not surface bound), FXII and prekallikrein undergo reciprocal activation. The FXII heavy chain restricts reciprocal activation, setting limits on the rate of this process. Pro-HGFA replacements for the FXII fibronectin type 2 or kringle domains markedly accelerate reciprocal activation, indicating disruption of the normal regulatory function of the heavy chain. Surface binding also enhances FXII activation and activity. This effect is lost if the FXII first epidermal growth factor (EGF1) domain is replaced with pro-HGFA EGF1. These results suggest that FXII circulates in blood in a "closed" form that is resistant to activation. Intramolecular interactions involving the fibronectin type 2 and kringle domains maintain the closed form. FXII binding to a surface through the EGF1 domain disrupts these interactions, resulting in an open conformation that facilitates FXII activation. These observations have implications for understanding FXII contributions to diseases such as hereditary angioedema and surface-triggered thrombosis, and for developing treatments for thrombo-inflammatory disorders. [ABSTRACT FROM AUTHOR]

Vasculitides are a set of pathologies that can affect one or several organs, in the short and long term. They are associated with various etiologies, among which paraneoplastic syndromes and medications stand out. Although everyday cancer therapies are more directed against a therapeutic target, their use can cause a wide spectrum of complications. Some treatments against human epidermal growth factor 2 (HER2) have been associated with cutaneous and pulmonary vasculitis. We present the first case of Henoch-Schönlein purpura associated with the use of T-DM1 in a patient with HER2 breast cancer. [ABSTRACT FROM AUTHOR]

Polyscias fulva (Hiern) Harms. (Araliaceae) is a medicinal plant used in the treatment of various types of illness including infectious diseases and cancers. The present chapter aimed at compiling the ethnopharmacological uses, the phytochemistry, and the cytotoxicity of this plant. P. fulva has many pharmacological properties including antioxidant, anti-inflammatory, antivenereal, antibacterial, antifungal, and anticancer activities. Botanicals from this plant had cytotoxic effects on several human cancer cell lines, including multidrug-resistant phenotypes such as P-glycoprotein overexpressing CEM/ADR5000 leukemia cells, breast cancer resistance protein-transfected (BCRP) MDA-MB-231-BCRP breast cancer cells, Tumor suppressor p53 knockout cells (HCT116 p53-/-) colon cancer cells, and mutation-activated epidermal growth factor receptor-transfected U87MG. ΔEGFR glioblastoma cells. P. fulva selectively showed antiproliferative effects against breast, prostate, colon, lung, stomach, and ovarian cancer, and hematological cancer cell lines. The cytotoxic phytochemicals identified in this plant include oleanolic acid, alpha-hederin, quercetin, β-sitosterol, and β-sitosterol-β-D-glucoside. Finally, P. fulva as well as its constituents may be useful in the development of novel drugs to fight cancer including the refractory phenotypes. [ABSTRACT FROM AUTHOR]

Objective: Hard-to-heal (chronic) wounds are treated differently at varying healing stages and often require long periods of time to heal completely. Therefore, it is often very difficult to achieve this primary endpoint in clinical trials with wound products which are used temporarily. Thus, it seems reasonable to use valid wound healing parameters determined at an early stage, such as the percentage (wound) area reduction (PAR), as surrogates for predicting complete wound healing. Method: To identify studies on the association between potential surrogate endpoints and complete wound healing, a systematic literature search in MEDLINE, Embase and the Cochrane Library databases was performed. The findings of the studies were summarised qualitatively. Results: A total of 23 publications with a focus on hard-to-heal wounds (n=10 diabetic foot ulcers (DFUs), n=10 venous leg ulcers (VLUs), n=3 other ulcers) and various wound care regimens were identified. All studies showed a high bias potential. The available clinical evidence confirmed that the PAR at week 4 showed a good discriminatory capacity to predict which wounds would eventually heal and which would not. The chance to achieve complete wound healing was significantly higher for wounds achieving a PAR of >40% (VLU) or ≥50% (DFU) at week 4. Conclusion: The PAR thresholds of 40% (VLU) and 50% (DFU) can be used to identify the proportion of the wounds that will heal, and those that will not heal, to compare the efficacy of different wound dressings as early as week 4 in the setting of clinical trials. The available evidence may be limited by a potential risk of bias. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most common primary brain tumor. Although there have been significant advances in surgical techniques, chemo and immunotherapies, and radiation therapy, outcomes continue to be devastating for these patients with minimal improvements in survival. Chimeric antigen receptor T cell therapy is a revolutionary approach that is a new pillar in the treatment of cancer. CAR T cell therapy has produced remarkable results in hematological malignancies; however, multiple limitations currently prevent it from being a first-line therapy, especially for solid tumors. Epidermal growth factor receptor is classically amplified in glioblastoma, and a variant, EGFR variant III, is expressed on glioblastoma, making it an exciting potential target for CAR T cell therapy. Although preclinical has exciting potential, clinical data has been heterogeneous. In this review, we assess the state of field of EGFR-targeted CAR T cells. [ABSTRACT FROM AUTHOR]

Background: The human endometrium, lining the inner uterus, regenerates over 400 times uniquely during a woman's reproductive life. Endometrial stem cells (eSCs) enrich the tissue, resulting in a dense vascular network, significant angiogenic potential, and effective regeneration power. Being of natural angiogenic properties and proven effective in the treatment of vascular disorders, eSCs can be considered safe, reliable, and superior to other post-natal stem cells. Cluster of Differentiation 146 (CD146) has emerged as a pivotal marker associated with pericytes and endothelial cells for promoting angiogenesis. Endometrial cells with high CD146 expression could proliferate and differentiate into multiple lineages. This study will explore the role of CD146 in eSCs, focusing on the potential to boost the angiogenic and regenerative functions of the cells. The novelty of this study lies in the investigation of CD146 on eSC function, which may open new possibilities for eSC-based therapy in regenerative medicine and vascular disorders. Methods: The study involved obtaining endometrial biopsies from active reproducing women to isolate and cultivate eSCs. eSCs were assessed for growth factor secretion pattern, characterized for their mesenchymal properties. Finally, eSCs were tested for their angiogenic potential by angiogenic gene expression profile and in-ovo chick embryo model. As aimed, to check the role of CD146 in eSC angiogenesis, CD146+ cells were magnetically sorted and cultured. The sorted cells underwent various analyses, including flowcytometry to identify mesenchymal markers and human growth factor panel to analyze growth factor secretion profiles The study evaluated the angiogenic potential of CD146 + cells using functional assays, including ring formation, endothelial differentiation, and wound scratch assays, to evaluate cell migration and healing capabilities. Molecular insights were obtained through chemokine and cytokine investigations In-ovo Chick model assay was conducted to check the angiogenic potential and evaluated through macroscopic as well as through immunohistochemistry. Result: Endometrial stem cells (eSCs) were successfully isolated using a combination of mechanical and enzymatic digestion, followed by culturing in complete DMEM media. The secretion profile of eSCs revealed significant production of various angiogenic growth factors, including Granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), Vascular endothelial growth factor (VEGF), Fibroblast growth factors (FGF), and Platelet derived growth factor AA (PDGF-AA). The angiogenic gene profile indicated upregulation of several angiogenic genes in eSCs. The mesenchymal nature of eSCs was demonstrated through surface marker analysis (Cluster of differentiation 73, Cluster of differentiation 90, Cluster of differentiation 105) and trilineage differentiation. The in-ovo chick model confirmed the angiogenic potential of eSCs. CD146+ cells, isolated via magnetic sorting, exhibited enhanced angiogenic potential. These cells secreted significant levels of angiogenic growth factors such as VEGF. In Matrigel assays, CD146+ cells formed endothelial ring structures more rapidly and persistently than unsorted eSCs. Semi-quantitative PCR confirmed their endothelial differentiation. CD146+ cells express various angiogenic chemokines such as CXCL5, CXCL8, CCL3, and CCL20 and cytokines such as GM-CSF, Interleukin-1β (IL-1β), Interleukin-6 (IL-6), PDGF AA/BB, Epidermal growth factor (EGF), Endothelin 1, Angiopoietin. In-ovo chick model assay showed that CD146+ cells had superior angiogenesis, with more nodes, junctions, and segments compared to eSCs and controls. Immunohistochemistry confirmed increased expression of endothelial markers (Cluster of differentiation 31, VEGF, Vascular associated protein (VAP), Von Willebrand factor (vWF) in CD146+ cells. Conclusion: The study highlights the angiogenic potential of endometrial stem cells, particularly the CD146+ cell population. These cells promote angiogenesis, secreting growth factors and forming stable blood vessel structures. CD146+ cells have higher expression levels of VEGF and TGF-α, key factors in angiogenesis. This suggests CD146+ eSCs may be promising for therapeutic applications in vascular diseases requiring angiogenesis. Further research is needed. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effect and potential mechanism of evodiamine (EVO) on proliferation and apoptosis of nasopharyngeal carcinoma (NPC) cells. EVO inhibited proliferation, blocked cell cycle progression, and induced apoptosis of NPC cells. There are 27 known anti-NPC targets of EVO, of which eight are core targets, namely SRC, ERBB2, STAT3, MAPK8, NOS3, CXCL8, APP, and HDAC1. Molecular docking analysis showed that the binding of EVO with its key targets (SRC, ERBB2) was good. EVO also reduced the expression of SRC and ERBB2, the key proteins p-MEK and p-ERK1/2 of the MAPK/ERK signaling pathway, and the downstream proteins PCNA and XIAP. EVO inhibited the growth of NPC xenografts in nude mice and reduced the expression levels of SRC, ERBB2, ERK1/2, p-ERK1/2, PCNA and XIAP in NPC tissue. When the MAPK/ERK signaling pathway was activated by epidermal growth factor (EGF), the expression levels of PCNA and XIAP increased, the cell proliferation index increased, and the apoptosis rate decreased in the EGF + EVO treatment group compared to treatment with EVO alone. These changes indicated that the inhibitory effect of EVO on proliferation and apoptosis of NPC cells was related to the down-regulation of SRC and ERBB2 expression, and further inhibition of the MAPK/ERK signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Patients with pathologic complete response (pCR) to neoadjuvant chemotherapy for invasive breast cancer (BC) have better outcomes, potentially warranting less extensive surgical and systemic treatments. Early prediction of treatment response could aid in adapting therapies. Methods: On-treatment biopsies from 297 patients with invasive BC in three randomized, prospective neoadjuvant trials were assessed (GeparQuattro, GeparQuinto, GeparSixto). BC quantity, tumor-infiltrating lymphocytes (TILs), and the proliferation marker Ki-67 were compared to pre-treatment samples. The study investigated the correlation between residual cancer, changes in Ki-67 and TILs, and their impact on pathologic complete response (pCR) and disease-free survival (DFS). Results: Among the 297 samples, 138 (46%) were hormone receptor-positive (HR+)/human epidermal growth factor 2-negative (HER2−), 87 (29%) were triple-negative (TNBC), and 72 (24%) were HER2+. Invasive tumor cells were found in 70% of on-treatment biopsies, with varying rates across subtypes (HR+/HER2−: 84%, TNBC: 62%, HER2+: 51%; p < 0.001). Patients with residual tumor on-treatment had an 8% pCR rate post-treatment (HR+/HER2−: 3%, TNBC: 19%, HER2+: 11%), while those without any invasive tumor had a 50% pCR rate (HR+/HER2−: 27%; TNBC: 48%, HER2+: 66%). Sensitivity for predicting residual disease was 0.81, with positive and negative predictive values of 0.92 and 0.50, respectively. Increasing TILs from baseline to on-treatment biopsy (if residual tumor was present) were linked to higher pCR likelihood in the overall cohort (OR 1.034, 95% CI 1.013–1.056 per % increase; p = 0.001) and with a longer DFS in TNBC (HR 0.980, 95% CI 0.963–0.997 per % increase; p = 0.026). Persisting or increased Ki-67 was associated with with lower pCR probability in the overall cohort (OR 0.957, 95% CI 0.928–0.986; p = 0.004) and shorter DFS in TNBC (HR 1.023, 95% CI 1.001–1.047; p = 0.04). Conclusion: On-treatment biopsies can predict patients unlikely to achieve pCR post-therapy. This could facilitate therapy adjustments for TNBC or HER2 + BC. They also might offer insights into therapy resistance mechanisms. Future research should explore whether standardized or expanded sampling enhances the accuracy of on-treatment biopsy procedures. Trial registration GeparQuattro (EudraCT 2005-001546-17), GeparQuinto (EudraCT 2006-005834-19) and GeparSixto (EudraCT 2011-000553-23). [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer is a heterogeneous disease comprising various molecular subtypes, including Luminal A, Luminal B, human epidermal growth factor receptor-2 (HER2) positive, and triple negative types, each with distinct biological characteristics and behaviors. Triple negative breast cancer (TNBC) remains a particularly challenging subtype worldwide. Our study aims to evaluate whether Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) parameters, clinical pathological features, and biochemical indicators serve as prognostic risk factors for TNBC. Additionally, we explore correlations between biochemical indicators and 18F-FDG PET/CT parameters. Methods: We conducted a retrospective analysis of 95 TNBC patients who underwent preoperative 18F-FDG PET/CT examinations at Tianjin Medical University Cancer Institute and Hospital from 2013 to 2018. Collected data included 18F-FDG PET/CT parameters, clinical and pathological features, and biochemical indicators. We used Kaplan-Meier survival analysis and multivariate Cox regression analysis to evaluate associations between 18F-FDG PET/CT parameters/biochemical indicators and disease free survival (DFS)/overall survival (OS). The log-rank test determined significant differences in survival curves, and the Spearman correlation coefficient analyzed correlations between quantitative variables. Visualization and analysis were performed using R packages. Results: Among 95 TNBC patients, mean standardized uptake value (SUVmean) was significantly correlated with DFS. Fasting blood glucose (FBG), a-L-fucosylase (AFU) and Creatine kinase (CK) were independent predictors of DFS, while Precursor albumin (PALB) and CK were independent predictors of OS. FBG showed correlations with SUVpeak and SUVmean, and CK was correlated with peak standardized uptake value (SUVpeak). Our results indicated that 18F-FDG PET/CT parameters and biochemical indicators may constitute a new prognostic model for TNBC patients post-surgery. Discussion: We found that SUVmean, FBG, AFU and CK are predictive factors for DFS in TNBC patients post-surgery, while PALB and CK are predictive factors for OS, which prompts us to pay more attention to these indicators in clinical practice. Also 18F-FDG PET/CT parameters and biochemical indicators have potential utility in constituting a new prognostic model for TNBC patients postsurgery. [ABSTRACT FROM AUTHOR]

Background: Patients with non‐small cell lung cancer (NSCLC) with liver metastasis have a poor prognosis, and there are no reliable biomarkers for predicting disease progression. Currently, no recognized and reliable prediction model exists to anticipate liver metastasis in NSCLC, nor have the risk factors influencing its onset time been thoroughly explored. Methods: This study conducted a retrospective analysis of 434 NSCLC patients from two hospitals to assess the association between the risk and timing of liver metastasis, as well as several variables. Results: The patients were divided into two groups: those without liver metastasis and those with liver metastasis. We constructed a nomogram model for predicting liver metastasis in NSCLC, incorporating elements such as T stage, N stage, M stage, lack of past radical lung cancer surgery, and programmed death ligand 1 (PD‐L1) levels. Furthermore, NSCLC patients with wild‐type EGFR, no prior therapy with tyrosine kinase inhibitors (TKIs), and no prior radical lung cancer surgery showed an elevated risk of early liver metastasis. Conclusion: In conclusion, the nomogram model developed in this study has the potential to become a simple, intuitive, and customizable clinical tool for assessing the risk of liver metastasis in NSCLC patients following validation. Furthermore, it provides a framework for investigating the timing of metachronous liver metastasis. [ABSTRACT FROM AUTHOR]

The mitogen-activated protein kinase (MAPK) pathway is an important intracellular signaling cascade that plays a key role in various cellular processes. Understanding the regulatory mechanisms of this pathway is essential for developing effective interventions and targeted therapies for related diseases. Recent advances in single-cell proteomic technologies have provided unprecedented opportunities to investigate the heterogeneity and noise within complex, multi-signaling networks across diverse cells and cell types. Mathematical modeling has become a powerful interdisciplinary tool that bridges mathematics and experimental biology, providing valuable insights into these intricate cellular processes. In addition, statistical methods have been developed to infer pathway topologies and estimate unknown parameters within dynamic models. This review presents a comprehensive analysis of how mathematical modeling of the MAPK pathway deepens our understanding of its regulatory mechanisms, enhances the prediction of system behavior, and informs experimental research, with a particular focus on recent advances in modeling and inference using single-cell proteomic data. [ABSTRACT FROM AUTHOR]

In this study, we investigated the effect of biphasic microcurrent electrical stimulation (b‐MES) on the epidermal healing process using a rat model of skin abrasion. We analyzed the expression levels of growth factors [fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF)] and keratin subtypes (K10) in both the b‐MES and control groups at different time points after wounding. The b‐MES group showed a significantly accelerated healing process of the epithelial tissue, resulting in more consistent healing as compared to the control group. A molecular biological analysis showed that the FGF2 mRNA expression level on Day 2 after wounding was significantly higher in the b‐MES group, whereas the EGF mRNA expression level on Days 1, 2, and 4 after wounding was significantly lower in the b‐MES group. Additionally, the K10 mRNA expression level on Days 1 and 2 after wounding was significantly higher in the b‐MES group. Our study findings suggest that b‐MES facilitates wound healing by regulating the growth factors. However, the precise mechanisms underlying these effects remain to be fully elucidated. Further research is needed to fully understand the therapeutic potential of b‐MES and its applications in clinical setting. Clinically, m‐MES requires shunting due to residual electrical charge at the application site. However, b‐MES alternates polarity, leaving no charge at the site of application. Therefore, b‐MES also has the advantage of being safer and allowing treatment for longer periods of time. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD‐1)/programmed cell death 1 ligand 1 (PD‐L1) pathway have transformed urothelial cancer (UC) therapy. The correlation between PD‐L1 expression and ICI effectiveness is uncertain, leaving the role of PD‐L1 as a predictive marker for ICI efficacy unclear. Among several ways to enhance the efficacy of ICI, trials are exploring combining ICIs with serine/threonine‐protein kinase mTOR (mTOR) inhibitors in different tumor types. The potential interaction between mTOR inhibitors and PD‐L1 expression in UC has not been well characterized. In our study, we investigated how phosphoinositide 3‐kinase (PI3K)/AKT/mTOR pathway inhibitors (TAK‐228, everolimus and TAK‐117) affect PD‐L1 expression and function in preclinical bladder cancer cell models. TAK‐228 increased cell surface levels of glycosylated PD‐L1 in all but one of the seven cell lines, regardless of baseline levels. TAK‐228 promoted the secretion of epidermal growth factor (EGF) and interferon‐β (IFNβ), both linked to PD‐L1 protein induction. Blocking EGF and IFNβ receptors reversed the TAK‐228‐induced PD‐L1 increase. Additionally, TAK‐228 enhanced IFN‐γ‐induced PD‐L1 expression and intracellular HLA‐I levels in some cells. TAK‐228‐treated bladder cancer cells exhibited resistance to the cytotoxic effects of peripheral blood mononuclear cells (PBMCs) and cluster of differentiation 8 (CD8)+ T cells. The addition of an anti‐PD‐L1 antibody diminished this resistance in T24 cells. Increased expression of PD‐L1 under TAK‐228 exposure was confirmed in patient‐derived explants (PDEs) treated ex vivo. These preclinical findings suggest that mTOR inhibition with TAK‐228 can increase PD‐L1 levels, potentially impacting the specific immune response against UC cells. This highlights the rationale for exploring the combination of mTOR inhibitors with ICIs in patients with advanced UC. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is a malignant neoplasm which is classified into various types defined by underlying molecular factors such as estrogen receptor positive (ER+), progesterone receptor positive (PR+), human epidermal growth factor positive (HER2+) and triple negative (TNBC). Early detection of ER+ and TNBC is crucial in the choice of diagnosis and appropriate treatment strategy. Here we report the key genes associated to ER+ and TNBC using RNA-Seq analysis and machine learning models. Three ER+ and TNBC RNA seq datasets comprising 164 patients in-toto were selected for standard NGS hierarchical data processing and data analyses protocols. Enrichment pathway analysis and network analysis was done and finally top hub genes were identified. To come with a reliable classifier which could distinguish the distinct transcriptome patterns associated to ER+ and TNBC, ML models were built employing Naïve Bayes, SVM and kNN. 1730 common DEG's exhibiting significant logFC values with 0.05 p-value threshold were identified. A list of top ten hub genes were screened on the basis of maximal clique centrality (MCC) which included CDC20, CDK1, BUB1, AURKA, CDCA8, RRM2, TTK, CENPF, CEP55 and NDC80.These genes were found to be involved in crucial cell cycle pathways. k-Nearest Neighbor (kNN) model was observed to be best classifier with accuracy 84%, specificity 66% and sensitivity 95% to differentiate between ER+ and TNBC RNA-Seq transcriptomes. Our screened list of 10 hub genes can thus help unearth novel molecular signatures implicated in ER+ and TNBC onset, prognosis and design of novel protocols for breast cancer diagnostics and therapeutics. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most common cancer in women. Progression-free survival for hormone receptor-positive/human epidermal growth factor receptor-2-negative metastatic breast cancer treated with endocrine therapy in combination with cyclin4/6-dependent kinase is approximately 25 months. This case represents metastatic breast cancer treated with endocrine therapy, leading to long-term survival. Case presentation: A 40-year-old Syrian woman diagnosed with hormone receptor-negative breast cancer was treated surgically with adjuvant chemotherapy and radiotherapy. She developed local and nodal recurrences that were hormone receptor-positive, followed by a recurrence of malignant pleural effusion. She was initially treated with chemotherapy and then placed on endocrine therapy with a complete response from 2014 until now. The patient also suffered from adverse events of medications, such as heart failure and osteoporosis, which were treated appropriately. Conclusion: This case demonstrates a long-lasting complete response to metastatic breast cancer with malignant pleural effusion. This shows the validity of endocrine therapy in recurrent hormone receptor-positive breast cancer, especially in countries that cannot afford targeted therapies or genetic tests. It also highlights the necessity for a better understanding of the prognostic and predictive factors. [ABSTRACT FROM AUTHOR]

Enteric neurons are critical in maintaining organ homeostasis within the small intestine, and their dysregulation are implicated in gastrointestinal disorders and neurodegenerative diseases. Most in vitro models lack enteric innervation, limiting basic discovery and disease modeling research. Here, a high‐throughput 3D microphysiological system (MPS), or organ chip is presented that supports a primary epithelial monolayer interfacing directly with encapsulated primary enteric neurons. The device features twelve 3D MPSs per device and gravity‐driven flow via a laboratory rocker to induce biomimetic shear stress on the epithelium culture and provide continuous nutrient presentation. Intestinal and neural tissue exhibited expected morphologies. Neural gene upregulation in the epithelium suggests RNA contamination from proximal enteric neurons extending neurites toward the epithelial monolayer. With the enteric nervous system (ENS), barrier integrity significantly increased for both TEER and permeability assays, a 1.25‐fold greater resistance and 10% lower permeability as compared to epithelium cultured alone. The presence of the ENS resulted in a significant (1.4‐fold) reduction in epidermal growth factor (EGF). Additionally, several key epithelial genes are compared between duodenal tissue and epithelial monolayers with and without neurons present. Results demonstrated changes in cytokine gene expression and WNT pathways, highlighting innervation is essential to create more biomimetic and physiologically relevant in vitro models. [ABSTRACT FROM AUTHOR]

Background: Several urinary biomarkers have good diagnostic value for diabetic kidney disease (DKD); however, the predictive value is limited with the use of single biomarkers. We investigated the clinical value of Luminex liquid suspension chip detection of several urinary biomarkers simultaneously. Methods: The study included 737 patients: 585 with diabetes mellitus (DM) and 152 with DKD. Propensity score matching (PSM) of demographic and medical characteristics identified a subset of 78 patients (DM = 39, DKD = 39). Two Luminex liquid suspension chips were used to detect 11 urinary biomarkers according to their molecular weight and concentration. The biomarkers, including cystatin C (CysC), nephrin, epidermal growth factor (EGF), kidney injury molecule-1 (KIM-1), retinol-binding protein4 (RBP4), α1-microglobulin (α1-MG),β2-microglobulin (β2-MG), vitamin D binding protein (VDBP), tissue inhibitor of metalloproteinases-1 (TIMP-1), tumor necrosis factor receptor-1 (TNFR-1), and tumor necrosis factor receptor-2 (TNFR-2) were compared in the DM and DKD groups. The diagnostic values of single biomarkers and various biomarker combinations for early diagnosis of DKD were assessed using receiver operating characteristic (ROC) curve analysis. Results: Urinary levels of VDBP, RBP4, and KIM-1 were markedly higher in the DKD group than in the DM group (p < 0.05), whereas the TIMP-1, TNFR-1, TNFR-2, α1-MG, β2-MG, CysC, nephrin, and EGF levels were not significantly different between the groups. RBP4, KIM-1, TNFR-2, and VDBP reached p < 0.01 in univariate analysis and were entered into the final analysis. VDBP had the highest AUC (0.780, p < 0.01), followed by RBP4 (0.711, p < 0.01), KIM-1 (0.640, p = 0.044), and TNFR-2 (0.615, p = 0.081). However, a combination of these four urinary biomarkers had the highest AUC (0.812), with a sensitivity of 0.742 and a specificity of 0.760. Conclusions: The urinary levels of VDBP, RBP4, KIM-1, and TNFR-2 can be detected simultaneously using Luminex liquid suspension chip technology. The combination of these biomarkers, which reflect different mechanisms of kidney damage, had the highest diagnostic value for DKD. However, this finding should be explored further to understand the synergistic effects of these biomarkers. [ABSTRACT FROM AUTHOR]

Background: Xiaojin Pill (XJP) is a traditional Chinese medicine prescribed for treating benign prostatic hyperplasia (BPH). It has been proven to have multiple effects, such as regulating sex hormone levels, exhibiting anti-tumor, anti-inflammatory, analgesic, and anti-platelet aggregation properties, and improving immunity. However, the material basis of XJP's therapeutic effect on BPH and its metabolic process in vivo remains to be clarified. At the same time, many microorganisms that exist in the urogenital tract, including those related to BPH, can also affect the health of the host. Methods: Using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), the chemical components of XJP were identified. A BPH model was created through bilateral testicular ablation and injections of testosterone propionate. A comprehensive evaluation of XJP efficacy was conducted using pathological ELISA, TUNEL, and immunohistochemical techniques. In addition, UPLC-MS metabolomics and 16S rRNA sequencing revealed the serum metabolic profile and intestinal microbiota composition. We performed a Spearman correlation coefficient analysis to highlight the interactions between "intestinal microbiota-serum factors" and "intestinal microbiota-metabolites." Results: XJP contains 91 compounds that alleviate pathologies of BPH in rats, decreasing prostate weight, index, and serum levels of Dihydrotestosterone (DHT), Prostate-Specific Antigen (PSA), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) levels. It inhibits prostatic epithelial cell apoptosis and downregulates Bax, TGF-β1, and IGF-1 proteins in the caspase-3 pathway. Metabolomics studies have revealed 10 upregulated and 10 downregulated metabolites in treated rats, with 5-methylcytosine, uracil, and cytosine enriched in pyrimidine metabolism. L-arginine plays a pivotal role in metabolic pathways encompassing pyrimidine metabolism, arginine biosynthesis, and the mammalian target of rapamycin (mTOR) signaling pathway. 16S rRNA sequencing revealed that XJP optimized the diversity and balance of intestinal flora in BPH rats by decreasing the Bacteroidetes/Firmicutes (B/F) ratio, enhancing the beneficial bacteria, such as Eggerthellaceae, Anaerovoracaceae, and Romboutsia, and suppressing the dysfunctional bacteria, such as Atopobiaceae, Prevotellaceae_NK3B31_group, Dorea, and Frisingicoccus. According to the Spearman correlation coefficient analysis, Lactobacillus was found to be most associated with serum factors, whereas Romboutsia showed the highest correlation with metabolites. This finding suggests that XJP modulates pyrimidine metabolism disorders in BPH rats, a regulation that aligns closely with Romboutsia, Prevotellaceae_NK3B31_group, Lactobacillus, Chujaibacter, and Enterorhabdus, thereby providing valuable biological insights. Conclusion: In summary, these findings indicate that XJP possesses a synergistic anti-BHP effect through its multi-component, multi-target, multi-gut microbiota, and multi-metabolic pathway properties. The effect involves the regulation of sex hormone levels, growth factors, and the anti-epithelial cell apoptosis process. The modulation of specific gut microbiota by the host and the involvement of multiple metabolic pathways are likely one of the significant mechanisms of XJP in treating BPH. Notably, pyrimidine metabolism and the intestinal microbial ecosystem are closely intertwined in this process. [ABSTRACT FROM AUTHOR]

This study investigates CD151, a protein linked to cancer progression, in non‐small cell lung cancer (NSCLC) patients without epidermal growth factor receptor (EGFR) mutations. These patients often have limited treatment options. The study used retrospective analysis to examine 157 adenocarcinoma biopsy specimens and 199 patient cases from The Cancer Genome Atlas, correlating CD151 expression with patient survival. Cellular studies revealed that CD151 interacts with EGFR, influencing epidermal growth factor (EGF)‐induced cell proliferation and the effectiveness of the EGFR inhibitor, erlotinib. A strong association was found between CD151 expression and EGFR mutation status. High CD151 expression in the absence of EGFR mutations is correlated with poorer survival outcomes. Biological assays showed that CD151 colocalizes and associates with EGFR, playing a crucial role in regulating EGF‐induced cell proliferation via the AKT and ERK1/2 pathways. Importantly, CD151 expression was found to influence the anti‐proliferative effects of the EGFR tyrosine kinase inhibitor, erlotinib. High CD151 expression, in the absence of EGFR mutations, was associated with poorer survival outcomes. It could serve as a potential prognostic marker and influence cellular responses to EGFR‐targeted treatments. This study highlights CD151 as a potential novel target for therapeutic intervention in NSCLC, especially in populations lacking EGFR mutations. [ABSTRACT FROM AUTHOR]

Introduction: Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) typically receive long-term trastuzumab treatment for several years. The aim of our study is to identify the incidence and characterize late-onset cardiotoxicity in patients with HER2-positive MBC receiving trastuzumab-based therapy. Methods: We retrospectively reviewed charts of HER2-positive MBC patients who received >1 year of trastuzumab-based therapy at the Massachusetts General Hospital Cancer Center over three-year period. The primary endpoint was development of trastuzumab-induced cardiotoxicity (TIC). Secondary endpoints included time to TIC development, incidence/duration of trastuzumab interruption due to TIC, incidence of permanent discontinuation of trastuzumab due to TIC, clinic visit, or hospitalization due to TIC. Results: Thirty-seven patients were included. Mean age was 56 years (range: 33–78 years, SD 9.5). Seven patients received prior doxorubicin and 14 patients received previous or concurrent breast irradiation. Mean duration of trastuzumab-based therapy was 57 months (range: 14–140 months, SD 39.3). Seven patients (18.9%) experienced TIC resulting in treatment interruption for two patients (28 and 78 days). The median time from starting trastuzumab therapy to TIC was 14 months (interquartile range: 11–29.5 months). The mean number of left ventricular ejection fraction (LVEF) assessment completed per year was 2.7 (range: 1.2–6.6, SD 1.1). Conclusion: Cardiotoxicity occurred in a minority of patients with HER2-positive MBC receiving trastuzumab-based therapy for more than one year. LVEF reductions to below the institutional lower limit of normal and therapy modifications were uncommon. [ABSTRACT FROM AUTHOR]

Metastasis in breast cancer is the first cause of death in patients. The epidermal growth factor (EGF) increases cancer cells' invasion, and migration. Melatonin's inhibitory effects on various types of cancer were confirmed. This study aimed to investigate whether melatonin could apply its impact through the EGF-related pathways or not. First, MDA-MB-231 and MCF7 cells were cultured, and then melatonin effects on cell viability were determined by MTT assay. Transwell invasion assay was applied to identify the invasiveness of these breast cancer cell lines under treatment of EGF and melatonin. Real-time RT-PCR then investigated the expression of MMP9 and MMP2 in determined groups. Cell proliferation was also assayed under EGF and melatonin treatment using Ki67 assessment by flow cytometry. The rate of invasion and migration of EGF-treated cells increased in both groups, in which melatonin caused increased invasion by EGF just in MCF7 cells. MMP9 and MMP2 expression increased significantly in both cell lines under EGF treatment, and melatonin increased these genes' expression in both cell lines (p<0.05). EGF increased the MMP9 and MMP2 gene expression, and melatonin increased EGF-induced expression (p<0.05). The EGF reduced the expression of the Ki67 protein in the MCF7 cell line, which was negatively affected by melatonin and EGF. In contrast, along with melatonin, EGF did not affect the proliferation of the MDA-MB-231 cell line. The results of this study show that melatonin in the presence of EGF does not show the anti-cancer properties previously described for this substance. [ABSTRACT FROM AUTHOR]

Background: Esophageal organoids from a variety of pathologies including cancer are grown in Advanced Dulbecco's Modified Eagle Medium-Nutrient Mixture F12 (hereafter ADF). However, the currently available ADF-based formulations are suboptimal for normal human esophageal organoids, limiting the ability to compare normal esophageal organoids with those representing a given disease state. Methods: We have utilized immortalized normal human esophageal epithelial cell (keratinocyte) lines EPC1 and EPC2 and endoscopic normal esophageal biopsies to generate three-dimensional (3D) organoids. To optimize the ADF-based medium, we evaluated the requirement of exogenous epidermal growth factor (EGF) and inhibition of transforming growth factor-(TGF)-β receptor-mediated signaling, both key regulators of the proliferation of human esophageal keratinocytes. We have modeled human esophageal epithelial pathology by stimulating esophageal 3D organoids with interleukin (IL)-13, an inflammatory cytokine, or UAB30, a novel pharmacological activator of retinoic acid signaling. Results: The formation of normal human esophageal 3D organoids was limited by excessive EGF and intrinsic TGFβ-receptor-mediated signaling. Optimized HOME0 improved normal human esophageal organoid formation. In the HOME0-grown organoids, IL-13 and UAB30 induced epithelial changes reminiscent of basal cell hyperplasia, a common histopathologic feature in broad esophageal disease conditions including eosinophilic esophagitis. Conclusions: HOME0 allows modeling of the homeostatic differentiation gradient and perturbation of the human esophageal epithelium while permitting a comparison of organoids from mice and other organs grown in ADF-based media. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor-2 (HER2)-positive breast cancer metastasis remains the primary cause of mortality among women globally. Targeted therapies have revolutionized treatment efficacy, with Trastuzumab (Trast), a monoclonal antibody, targeting HER2-positive advanced breast cancer. The tumor-homing peptide iRGD enhances the intratumoral accumulation and penetration of therapeutic agents. Liposomes serve as versatile nanocarriers for both hydrophilic and hydrophobic drugs. Gefitinib (GFB) is a potential anticancer drug against HER2-positive breast cancer, while Lycorine hydrochloride (LCH) is a natural compound with anticancer and anti-inflammatory properties. This study developed TPGS-COOH-coated liposomes co-loaded with GFB and LCH, prepared by the solvent injection method, and surface-functionalized with Trast and iRGD. The dual surface-decorated liposomes (DSDLs) were characterized for their particle size (PS), polydispersity index (PDI), zeta potential (ZP), surface chemistry, surface morphology, and their crystallinity during in-vitro drug release, drug encapsulation, and in-vitro cell line studies on SK-BR-3 and MDA-MB-231 breast cancer cells. The half-maximum inhibitory concentration (IC-50) values of single decorated liposomes (SDLs), iRGD-LP, and Trast-LP, as well as DSDLs (iRGD-Trast-LP) on SK-BR-3 cells, were 6.10 ± 0.42, 4.98 ± 0.36, and 4.34 ± 0.32 μg/mL, respectively. Moreover, the IC-50 values of SDLs and DSDLs on MDA-MB-231 cells were 15.12 ± 0.68, 13.09 ± 0.59, and 11.08 ± 0.48 μg/mL, respectively. Cellular uptake studies using confocal laser scanning microscopy (CLSM) showed that iRGD and Trast functionalization significantly enhanced cellular uptake in both cell lines. The wound-healing assay demonstrated a significant reduction in SDL and DSDL-treated MDA-MB-231 cell migration compared to the control. Additionally, the blood compatibility study showed minimal hemolysis (less than 5% RBC lysis), indicating good biocompatibility and biosafety. Overall, these findings suggest that TPGS-COOH-coated, GFB and LCH co-loaded, dual-ligand (iRGD and Trast) functionalized, multifunctional liposomes could be a promising therapeutic strategy for treating HER2-positive metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Summary: Oral tolerance promotes the suppression of immune responses to innocuous antigen and is primarily mediated by regulatory T cell (Tregs). The development of oral tolerance begins in early life during a "window of tolerance," which occurs around weaning and is mediated by components in breastmilk. Herein, we review the factors dictating this window and how Tregs are uniquely educated in early life. In early life, the translocation of luminal antigen for Treg induction is primarily dictated by goblet cell‐associated antigen passages (GAPs). GAPs in the colon are negatively regulated by maternally‐derived epidermal growth factor and the microbiota, restricting GAP formation to the "periweaning" period (postnatal day 11–21 in mice, 4–6 months in humans). The induction of solid food also promotes the diversification of the bacteria such that bacterially‐derived metabolites known to promote Tregs—short‐chain fatty acids, tryptophan metabolites, and bile acids—peak during the periweaning phase. Further, breastmilk immunoglobulins—IgA and IgG—regulate both microbial diversity and the interaction of microbes with the epithelium, further controlling which antigens are presented to T cells. Overall, these elements work in conjunction to induce a long‐lived population of Tregs, around weaning, that are crucial for maintaining homeostasis in adults. [ABSTRACT FROM AUTHOR]

The present experiment was conducted during January, 2018 to March, 2019 in the laboratory, Dept. of Veterinary Physiology, College of Veterinary Science, Assam Agricultural University, Khanapara, Guwahati, Assam (781022), India to investigate the effect of epidermal growth factor on in vitro maturation, fertilization and early embryonic development of cattle oocytes. A total of 318 nos. cattle ovaries were collected from slaughter houses for one year and 1089 nos. culturable oocytes were collected. 381 out of 1089 nos. culturable oocytes were subjected to EGF supplemented serum and serum free basic maturation media. The mean percentage of in-vitro maturation of cattle oocytes based on polar body extrusion was found to be significantly higher in EGF supplemented serum free basic maturation media (70.00±14.49) than the serum basic maturation media without EGF (54.17±7.19) respectively. But the mean percentages of in vitro maturation of cattle oocytes based on the cumulus expansion and polar body extrusion were found to be significantly higher in EGF supplemented serum free basic maturation media (77.59±5.48 and 70.00±14.49) than the value recorded in serum free basic maturation media without EGF (64.20±3.77 and 45.95±8.19). The mean cleavage percentages recorded at 4 cell, 8 cell, 16 cell and morula stages of embryos in EGF supplemented serum free culture media were found to be significantly higher than the value recorded in serum culture media without EGF. From the present experiment, it can be inferred that addition of EGF in serum free basic maturation media had little beneficial effect than serum basic maturation media. [ABSTRACT FROM AUTHOR]