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Clinical Advances in Hematology &... 2024
Topics: Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Receptor, trkA; Protein Kinase Inhibitors; Disease Management
PubMed: 38953727
DOI: No ID Found -
Clinical Advances in Hematology &... 2024
Topics: Humans; Thyroid Neoplasms; Lung Neoplasms; Oncogene Proteins, Fusion; Receptor, trkA
PubMed: 38953726
DOI: No ID Found -
Clinical Advances in Hematology &... 2024Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are implicated in various cancers, including those of the lung and thyroid. The prevalence of NTRK fusions is... (Review)
Review
Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are implicated in various cancers, including those of the lung and thyroid. The prevalence of NTRK fusions is 0.1 to 0.3% in non-small cell lung cancer (NSCLC) and as high as 26% in pediatric papillary thyroid carcinoma. Detection methods include immunohistochemistry, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, and next-generation sequencing. Management of NTRK fusion-positive lung cancer primarily involves targeted therapies, notably the tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib. Both agents demonstrate high response rates and durable disease control, particularly in metastatic adenocarcinoma of the lung. They are preferred as first-line treatments because of their efficacy over immunotherapy. Possible adverse events include dizziness, weight gain, neuropathy-like pain, and liver enzyme elevation. Larotrectinib and entrectinib also produce robust and durable responses in NTRK fusion-positive thyroid cancer that is refractory to radioactive iodine. Second-generation TRK inhibitors that have been designed to overcome acquired resistance are under investigation.
Topics: Humans; Protein Kinase Inhibitors; Thyroid Neoplasms; Lung Neoplasms; Indazoles; Pyrazoles; Oncogene Proteins, Fusion; Pyrimidines; Receptor, trkA; Benzamides; Treatment Outcome
PubMed: 38953725
DOI: No ID Found -
General Physiology and Biophysics Jul 2024Vitiligo is featured by manifestation of white maculae and primarily results from oxidative stress. Sphingosine kinase-1 (SPHK1) participates in oxidative stress. This...
Vitiligo is featured by manifestation of white maculae and primarily results from oxidative stress. Sphingosine kinase-1 (SPHK1) participates in oxidative stress. This paper was devised to explore the role of SPHK1 in vitiligo and to disclose the mechanism. PIG1 cell viability was appraised utilizing cell counting kit-8 assay while Western blot detected SPHK1 and four and a half LIM domains 2 (FHL2). The transduction efficacy of small interfering RNA (siRNA)-SPHK1, siRNA-FHL2 and pcDNA3.1 plasmid overexpressing FHL2 (Ov-FHL2) was checked using Western blot. Flow cytometry detected cell apoptotisis. Western blot detected mitochondrial cytochrome c (Mit-Cyt-c) and cytosolic cytochrome c (Cyto-Cyt-c). Dichloro-dihydro-fluorescein diacetate (DCFH-DA) detected reactive oxygen species (ROS) activity while oxidative stress markers were evaluated using corresponding assay kits. SPHK1 expression was discovered to be increased in hydrogen peroxide (H2O2)-challenged PIG1 cells and SPHK1 interference alleviated H2O2-challenged viability damage, apoptosis, oxidative stress and FHL2 expression in PIG1 cells. FHL2 depletion could suppress viability damage, apoptosis and oxidative stress in H2O2-challenged PIG1 cells. Rescue experiments demonstrated that the suppressive impacts of SPHK1 deficiency on PIG1 cell viability, apoptosis and oxidative stress induced by H2O2 were offset by FHL2 overexpression. Collectively, SPHK1 knockdown protected against vitiligo via the regulation of FHL2.
Topics: Oxidative Stress; Phosphotransferases (Alcohol Group Acceptor); Hydrogen Peroxide; LIM-Homeodomain Proteins; Humans; Melanocytes; Cell Survival; Apoptosis; Transcription Factors; Muscle Proteins; Cell Line
PubMed: 38953574
DOI: 10.4149/gpb_2024011 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Jun 2024Alzheimer's disease (AD) is a severe threat to human health and one of the three major causes of human death.Double-stranded RNA-dependent protein kinase (PKR) is an... (Review)
Review
Alzheimer's disease (AD) is a severe threat to human health and one of the three major causes of human death.Double-stranded RNA-dependent protein kinase (PKR) is an interferon-induced protein kinase involved in innate immunity.In the occurrence and development of AD,PKR is upregulated and continuously activated.On the one hand,the activation of PKR triggers an integrated stress response in brain cells.On the other hand,it indirectly upregulates the expression of β-site amyloid precursor protein cleaving enzyme 1 and facilitates the accumulation of amyloid-β protein (Aβ),which could activate PKR activator to further activate PKR,thus forming a sustained accumulation cycle of Aβ.In addition,PKR can promote Tau phosphorylation,thereby reducing microtubule stability in nerve cells.Inflammation in brain tissue,neurotoxicity resulted from Aβ accumulation,and disruption of microtubule stability led to the progression of AD and the declines of memory and cognitive function.Therefore,PKR is a key molecule in the development and progression of AD.Effective PKR detection can aid in the diagnosis and prediction of AD progression and provide opportunities for clinical treatment.The inhibitors targeting PKR are expected to control the activity of PKR,thereby controlling the progression of AD.Therefore,PKR could be a target for the development of therapeutic drugs for AD.
Topics: Alzheimer Disease; Humans; eIF-2 Kinase; Amyloid beta-Peptides; tau Proteins; Phosphorylation; Brain; Amyloid beta-Protein Precursor
PubMed: 38953267
DOI: 10.3881/j.issn.1000-503X.15792 -
Frontiers in Immunology 2024Chimeric antigen receptor T (CAR-T) cell therapies have achieved remarkable success in the treatment of hematological tumors. However, given the distinct features of...
BACKGROUND
Chimeric antigen receptor T (CAR-T) cell therapies have achieved remarkable success in the treatment of hematological tumors. However, given the distinct features of solid tumors, particularly heterogeneity, metabolic aggressiveness, and fewer immune cells in tumor microenvironment (TME), the practical utility of CAR-T cells for solid tumors remains as a challenging issue. Meanwhile, although anti-PD-1 monoclonal antibody (mAb) has shown clinical efficacy, most mAbs also show limited clinical benefits for solid tumors due mainly to the issues associated with the lack of immune cells in TME. Thus, the infiltration of targeted immunological active cells into TME could generate synergistic efficacy for mAbs.
METHODS
We present a combinational strategy for solid tumor treatment, which combines armored-T cells to express Fc-gamma receptor I (FcγRI) fragment on the surfaces for targeting various tumors with therapeutically useful mAbs. Choosing CD20 and HER-2 as the targets, we characterized the and efficacy and latent mechanism of the combination drug by using flow cytometry, ELISA and other methods.
RESULTS
The combination and preprocessing of armored T-cells with corresponding antibody of Rituximab and Pertuzumab exerted profound anti-tumor effects, which is demonstrated to be mediated by synergistically produced antibody-dependent cellular cytotoxicity (ADCC) effects. Meanwhile, mAb was able to carry armored-T cell by preprocessing for the infiltration to TME in cell derived xenograft (CDX) model.
CONCLUSIONS
This combination strategy showed a significant increase of safety profiles from the reduction of antibody doses. More importantly, the present strategy could be a versatile tool for a broad spectrum of cancer treatment, with a simple pairing of engineered T cells and a conventional antibody.
Topics: Receptors, IgG; Humans; Animals; Mice; Neoplasms; T-Lymphocytes; Tumor Microenvironment; Antibodies, Monoclonal; Cell Line, Tumor; Xenograft Model Antitumor Assays; Immunotherapy, Adoptive; Receptor, ErbB-2; Antineoplastic Agents, Immunological; Receptors, Chimeric Antigen; Female; Antigens, CD20
PubMed: 38953027
DOI: 10.3389/fimmu.2024.1400177 -
PeerJ 2024Ovarian cancer is an aggressive malignancy with high mortality known for its considerable metastatic potential. This study aimed to explore the expression and functional...
BACKGROUND
Ovarian cancer is an aggressive malignancy with high mortality known for its considerable metastatic potential. This study aimed to explore the expression and functional role of Unc-51 like autophagy activating kinase 2 (ULK2) in the progression of ovarian cancer.
METHODS
ULK2 expression patterns in ovarian cancer tissues as well as benign tumor control samples obtained from our institution were evaluated using immunohistochemistry. Cell counting kit 8 and Transwell assays were applied to assess the effects of ULK2 overexpression on cell proliferation, migration and invasion, respectively. RNA sequencing was performed to explore potential mechanisms of action of ULK2 beyond its classical autophagy modulation.
RESULTS
Our experiments showed significant downregulation of ULK2 in ovarian cancer tissues. Importantly, low expression of ULK2 was markedly correlated with decreased overall survival. functional studies further demonstrated that overexpression of ULK2 significantly suppressed tumor cell proliferation, migration, and invasion. RNA sequencing analysis revealed a potential regulatory role of ULK2 in the insulin signaling pathway through upregulation of insulin-like growth factor binding protein-3 (IGFBP3) in ovarian cancer cells.
CONCLUSIONS
In summary, the collective data indicated that ULK2 acted as a tumor suppressor in ovarian cancer by upregulating the expression of IGFBP3. Our study underscores the potential utility of ULK2 as a valuable prognostic marker for ovarian cancer.
Topics: Humans; Female; Cell Movement; Ovarian Neoplasms; Cell Line, Tumor; Neoplasm Invasiveness; Cell Proliferation; Insulin-Like Growth Factor Binding Protein 3; Autophagy-Related Protein-1 Homolog; Gene Expression Regulation, Neoplastic; Up-Regulation; Signal Transduction; Protein Serine-Threonine Kinases
PubMed: 38952983
DOI: 10.7717/peerj.17628 -
PeerJ 2024Mitochondrial creatine kinase (MtCK) plays a pivotal role in cellular energy metabolism, exhibiting enhanced expression in various tumors, including colorectal cancer...
BACKGROUND
Mitochondrial creatine kinase (MtCK) plays a pivotal role in cellular energy metabolism, exhibiting enhanced expression in various tumors, including colorectal cancer (CRC). Creatine kinase mitochondrial 2 (CKMT2) is a subtype of MtCK; however, its clinical significance, biological functions, and underlying molecular mechanisms in CRC remain elusive.
METHODS
We employed immunohistochemical staining to discern the expression of CKMT2 in CRC and adjacent nontumor tissues of patients. The correlation between CKMT2 levels and clinical pathological factors was assessed. Additionally, we evaluated the association between CKMT2 and the prognosis of CRC patients using Kaplan-Meier survival curves and Cox regression analysis. Meanwhile, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression levels of in different CRC cell lines. Finally, we explored the biological functions and potential molecular mechanisms of CKMT2 in CRC cells through various techniques, including qRT-PCR, cell culture, cell transfection, western blot, Transwell chamber assays, flow cytometry, and co-immunoprecipitation.
RESULTS
We found that CKMT2 was significantly overexpressed in CRC tissues compared with adjacent nontumor tissues. The expression of CKMT2 is correlated with pathological types, tumor size, distant metastasis, and survival in CRC patients. Importantly, CKMT2 emerged as an independent prognostic factor through Cox regression analysis. Experimental downregulation of expression in CRC cell lines inhibited the migration and promoted apoptosis of these cells. Furthermore, we identified a novel role for CKMT2 in promoting aerobic glycolysis in CRC cells through interaction with lactate dehydrogenase B (LDHB).
CONCLUSION
In this study, we found the elevated expression of CKMT2 in CRC, and it was a robust prognostic indicator in CRC patients. CKMT2 regulates glucose metabolism amplifying the Warburg effect through interaction with LDHB, which promotes the growth and progression of CRC. These insights unveil a novel regulatory mechanism by which CKMT2 influences CRC and provide promising targets for future CRC therapeutic interventions.
Topics: Humans; Colorectal Neoplasms; Warburg Effect, Oncologic; Male; Female; Cell Line, Tumor; Prognosis; Creatine Kinase, Mitochondrial Form; Disease Progression; L-Lactate Dehydrogenase; Middle Aged; Cell Proliferation; Apoptosis; Gene Expression Regulation, Neoplastic
PubMed: 38952967
DOI: 10.7717/peerj.17672 -
Oncoimmunology 2024The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal... (Randomized Controlled Trial)
Randomized Controlled Trial
The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC) might benefit from potentially immunogenic, short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade (ICB). Three of 38 patients assigned to this experimental treatment had metastases from -mutant MSS-CRC, in general a poor-prognostic subgroup explored here. The ≥70-year-old females presented with ascending colon adenocarcinomas with intermediate tumor mutational burden (6.2-11.8 mutations per megabase). All experienced early disappearance of the primary tumor followed by complete response of all overt metastatic disease, resulting in progression-free survival as long as 20-35 months. However, they encountered recurrence at previously unaffected sites and ultimately sanctuary organs, or as intrahepatic tumor evolution reflected in the terminal loss of initially induced T-cell clonality in liver metastases. Yet, the remarkable first-line responses to short-course oxaliplatin-based chemotherapy alternating with ICB may offer a novel therapeutic option to a particularly hard-to-treat MSS-CRC subgroup.
Topics: Humans; Oxaliplatin; Female; Proto-Oncogene Proteins B-raf; Colorectal Neoplasms; Immune Checkpoint Inhibitors; Aged; Antineoplastic Combined Chemotherapy Protocols; Mutation; Microsatellite Instability; Treatment Outcome; Aged, 80 and over
PubMed: 38952672
DOI: 10.1080/2162402X.2024.2372886 -
Iranian Journal of Medical Sciences Jun 2024Despite its rarity, pulmonary capillary hemangiomatosis (PCH) presents a significant diagnostic challenge. Due to its similarity to other pulmonary vascular diseases,...
Despite its rarity, pulmonary capillary hemangiomatosis (PCH) presents a significant diagnostic challenge. Due to its similarity to other pulmonary vascular diseases, such as pulmonary veno-occlusive disease, it is characterized by abnormal pulmonary capillary proliferation, which is a rare cause of primary pulmonary hypertension. This case was the first reported instance of PCH in Shahid Rajaee Heart Hospital in Tehran, Iran, in 2023, which was confirmed by genetic testing. It highlighted the importance of considering PCH among the differential diagnoses for pulmonary hypertension, even in adolescent patients. The 13-year-old patient's main complaints were progressive exertional dyspnea and chest pain. He had no previous medical history and had not taken any pharmaceutical or herbal medications. Critical clinical findings included a heart murmur, an electrocardiogram revealing right ventricular hypertrophy, and echocardiogram evidence of pulmonary hypertension. The main diagnosis was PCH, as shown by CT findings of pulmonary artery dilatation and diffuse nodular ground glass opacities. Genetic tests indicated pathogenic EIF2AK4 mutations and suspicion of PCH. Therapeutic intervention included vasodilator therapy, which exacerbated the patient's condition. This case emphasized the importance of maintaining a high index of suspicion for rare causes of pulmonary hypertension, such as PCH. The outcome was to prepare the patient for lung transplantation. To differentiate PCH from other pulmonary vascular diseases, a combination of clinical presentation, radiologic studies, genetic analysis, and response to treatment is required to determine appropriate management, particularly lung transplantation.
Topics: Humans; Adolescent; Male; Hemangioma, Capillary; Hypertension, Pulmonary; Lung Neoplasms; Protein Serine-Threonine Kinases
PubMed: 38952636
DOI: 10.30476/ijms.2024.101215.3385