Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 19, 2023

Abstract The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism transmembrane transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, other specific molecules activate JAK-STAT signaling drive a series physiological pathological processes, including proliferation, metabolism, immune response, inflammation, malignancy. Dysregulated related genetic mutations are strongly associated activation cancer progression. Insights into structures functions have led development approval diverse drugs for clinical treatment diseases. Currently, been developed mainly target commonly divided three subtypes: cytokine or receptor antibodies, JAK inhibitors, STAT inhibitors. And novel agents also continue be tested in preclinical studies. effectiveness safety each kind drug warrant further scientific trials before put being applications. Here, we review current understanding fundamental composition function pathway. We discuss advancements JAK-STAT–related pathogenic mechanisms; targeted therapies various diseases, especially disorders, cancers; newly inhibitors; challenges directions field.

Language: Английский

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Hydrogen‐Bonded Organic Framework Nanoscintillators for X‐Ray‐Induced Photodynamic Therapy in Hepatocellular Carcinoma

Advanced Materials, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Abstract X‐ray induced photodynamic therapy (X‐PDT) leverages penetrating to generate singlet oxygen ( 1 O 2 ) for treating deep‐seated tumors. However, conventional X‐PDT typically relies on heavy metal inorganic scintillators and organic photosensitizers produce , which presents challenges related toxicity energy conversion efficiency. In this study, highly biocompatible phosphorescent nanoscintillators based hydrogen‐bonded frameworks (HOF) are designed engineered, termed BPT‐HOF@PEG, enhance in hepatocellular carcinoma (HCC) treatment. BPT‐HOF@PEG functions simultaneously as both scintillator photosensitizer, effectively absorbing transferring abundant . Both vitro vivo investigations demonstrate that internalized efficiently produces significant quantities of upon irradiation. Additionally, exposure directly inflicts DNA damage, the synergistic effects these mechanisms result pronounced cell death substantial tumor growth inhibition, with a inhibition rate up 90.4% assessments. RNA sequencing analyses reveal induces apoptosis Hepa1‐6 cells while inhibiting proliferation, culminating death. Therefore, work highlights considerable potential efficient HOF nanoscintillators‐based promising therapeutic approach HCC, providing effective alternative negligible patients unresectable

Language: Английский

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Characterization of HER2‐low breast cancer in young women with germline BRCA1/2 pathogenetic variants: Results of a large international retrospective cohort study

Cancer, Journal Year: 2024, Volume and Issue: 130(16), P. 2746 - 2762

Published: May 16, 2024

Abstract Background Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)‐low‐expressing BC has recently emerged as a novel therapeutic target not been characterized this rare patient subset. Methods Women newly diagnosed early‐stage HER2‐negative (HER2‐0 and HER2‐low) PVs from 78 health care centers worldwide were retrospectively included. Chi‐square test Student t ‐test used to describe variable distribution between HER2‐0 HER2‐low. Associations HER2‐low status assessed logistic regression. Kaplan–Meier method Cox regression analysis assess disease‐free survival (DFS) overall survival. Statistical significance was considered for p ≤ .05. Results Of 3547 included patients, 32.3% had BC, representing 46.3% of hormone receptor–positive 21.3% triple‐negative (TN) tumors. vs. more grade 1/2 ( < .001), node‐positive = .003). BRCA2 than BRCA1 .001). versus showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76–0.97) the population favorable (HR, 0.78; 0.64–0.95) 0.65; 0.46–0.93) TN subgroup. Luminal A–like tumors .014) luminal A‐like .019) worst DFS. Conclusions In young patients PVs, disease less frequent expected frequently linked luminal‐like disease. modestly improved prognosis.

Language: Английский

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Case report: Near-complete response to neratinib-based treatment in HR-positive HER2-amplified metastatic breast cancer refractory to trastuzumab deruxtecan

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 14

Published: Jan. 21, 2025

Breast cancer (BC) is the leading cause of cancer-related mortality among women. The backbone first-line treatment in HR+/HER2+ BC dual anti-HER2 blockade combined with taxane chemotherapy. Although this regimen exhibits high rates response and disease control both HR+ HR− cohorts, some patients could have intrinsic or develop acquired resistance to trastuzumab and/or pertuzumab. Here, we achieved a near-complete HER2 -amplified overexpressing metastatic twice through molecular tumor board (MTB) discussions: initially, deruxtecan (T-DXd) when IHC was positive, and, then, neratinib plus fulvestrant paclitaxel negative. Our case presents GATA3 NOTCH2 mutations, MCL1 CKS1B amplifications, as well ERBB3/KRAS overexpression ER signaling potential new mechanisms T-DXd. Furthermore, demonstrated that triplet combination induce remarkable T-DXd–refractory setting, which be explored future clinical trials HER2-activated (by RNA protein overexpression, amplification, mutation) patients. also highlights importance MTBs dynamically reactively manage course on per-patient basis.

Language: Английский

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Genomic Characterization and Prognostic Significance of Human Epidermal Growth Factor Receptor 2–Low, Hormone Receptor–Positive, Early Breast Cancers From the BIG 1-98 and SOFT Clinical Trials

JCO Precision Oncology, Journal Year: 2025, Volume and Issue: 9

Published: Jan. 1, 2025

PURPOSE To investigate whether hormone receptor–positive, human epidermal growth factor receptor 2–low (HR+HER2-low) versus HR+HER2-zero early breast cancers have distinct genomic and clinical characteristics. METHODS This study included HR+, HER2-negative from patients enrolled in the phase III, randomized BIG 1-98 SOFT trials that had undergone tumor sequencing. Tumors were classified HR+HER2-low if they a centrally reviewed HER2 immunohistochemistry (IHC) score of 1+ or 2+ with negative situ hybridization an IHC 0. RESULTS A total 1,795 tumors evaluable for this (BIG n = 520, 1,275). The frequency HER2-low was 37% 21% postmenopausal premenopausal cohorts, respectively. There no significant differences clinicopathologic variables between HER2-zero groups which consistent across both trials. difference risk distant recurrence (5-year % recurrence-free 94.0% v 92.8%, P .61, 1-98; 89.4% 92.7%, .31, SOFT, respectively). Somatic profiles similar exception MAP3K1 mutations more frequent 19% 5%, 11% 6%). Both ERBB2 copy number gene expression abundance significantly higher compared tumors; however, absolute small. Correlation values modest ( r 0.17). CONCLUSION In two large IHC, our findings do not support cancer as biologic entity among HR+HER2- cancers. Absolute median levels are small unclear relevance.

Language: Английский

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Impact of Prosigna test on adjuvant treatment decision in lymph node-negative early breast cancer—a prospective national multicentre study (EMIT-1)

ESMO Open, Journal Year: 2024, Volume and Issue: 9(6), P. 103475 - 103475

Published: June 1, 2024

•Forty-five percent of patients assigned to CT by routine classification were de-escalated no the Prosigna test.•The test identified lower-risk with molecular higher risk who offered escalated systemic treatment.•Incorporating in diagnostic work-up significantly reduced treatment discrepancies between hospitals.•The correlations Ki67 and ROR score among within different treatment/risk groups poor. BackgroundEMIT-1 is a national, observational, single-arm trial designed assess value Prosigna, Prediction Analysis Microarray using 50 gene classifier (PAM50)/Risk Recurrence (ROR), as tool, examining its impact on adjuvant decisions, clinical outcomes, side-effects cost-effectiveness. Here we present decisions.Patients methodsPatients hormone receptor-positive, human epidermal growth factor receptor 2-negative pT1-pT2 lymph node-negative early breast cancer (EBC) included. The standard histopathology assessments carried out. Clinicians' decisions recorded before (pre-Prosigna) after (post-Prosigna) results disclosed.ResultsOf 2217 included, 2178 had conclusive results. pre-Prosigna were: (NT) 27% patients, endocrine alone (ET) 38% chemotherapy (CT) followed ET (CT + ET) 35%. Post-Prosigna 25% NT, 51% 24% ET, respectively. Adjuvant changed 28% including 21% change use. Among pre-Prosigna, 45% post-Prosigna. Of 12% 8% NT; those 18% ET/CT ET. was more frequently recommended for aged ≤50 years. In subgroup pT1c-pT2 G2 intermediate (0.5-1.5× local laboratory median score), decision varied widely across hospitals (3%-51%). Post-Prosigna, variability use markedly (8%-24%). correlation this poor (r = 0.25-0.39). increased increasing histological grade, but ranges wide (for G1 0-79, 0-90, G3 16-94).ConclusionThe result all EBC groups, decreased categorized hospitals. EMIT-1 decisions. Patients disclosed. 16-94).

Language: Английский

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Hormone receptor-positive early breast cancer in young women: A comprehensive review

Cancer Treatment Reviews, Journal Year: 2024, Volume and Issue: 129, P. 102804 - 102804

Published: July 14, 2024

Language: Английский

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Frequency of somatic and germline variants of predisposition genes in young Chinese women with breast cancer

Breast Cancer Research and Treatment, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 5, 2025

Language: Английский

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Clinical-genomic characteristics of homologous recombination deficiency (HRD) in breast cancer: application model for practice

European journal of medical research, Journal Year: 2025, Volume and Issue: 30(1)

Published: April 7, 2025

Homologous recombination deficiency (HRD) affects breast cancer patients. Treatment guided by multigene testing may be particularly beneficial in HRD patients using platinum-based drugs and poly ADP-ribose polymerase inhibitor (PARPi). However, the optimal method for remains undetermined guidelines or consensus economic disparities limit availability of genetic testing. Prioritizing clinical-genomic characteristics is critical efficient utilization healthcare resources improved treatment accuracy. A total 93 who underwent were included study. According to machine learning model called genomic scar (GS) was defined as a score (GSS) ≥ 50 with deleterious mutation BRCA. Multivariate logistic regression analysis employed identify clinical-pathological factors potentially associated HRD. Suitable variables selected construct predictive model, model's efficacy evaluated area under receiver operating characteristic (ROC) curve. Internal validation performed bootstrap resampling (500 replicates). Patients harboring pathogenic BRCA exhibited higher GSS (99.85 vs 36.90). not detected 41.75% patients, 34.95% had but no mutations. risk human epidermal factor growth receptor 2 (HER2) low positive significantly lower compared HER2 negative (OR: 0.390, 95% CI: 0.159-0.959, P = 0.040). High Ki- 67 index strongly 28.434, 3.283-246.293, 0.002). Significant variations observed based on estrogen (ER) progesterone (PR) status, histological grade, molecular types. The ROC curve (AUC) combined prediction combining status 0.749, accuracy further validated replicates), resulting an AUC 0.730, indicating high status. did fully reflect are more likely exhibit results when undergoing ER, PR, HER- index, typing, grading have strong influence

Language: Английский

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Risk factors for early recurrence in patients with hormone receptor-positive, HER2-negative breast cancer: a retrospective cohort study in Japan (WJOG15721B)

Breast Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: April 10, 2025

Language: Английский

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