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American Journal of Reproductive... Dec 2018Oxidative stress (OS) plays a role in uterine tissue remodeling during pregnancy and parturition. While p38 MAPK is an OS-response kinase, a precise functional role is...
Oxidative stress (OS) plays a role in uterine tissue remodeling during pregnancy and parturition. While p38 MAPK is an OS-response kinase, a precise functional role is unknown. Therefore, we conducted a systematic review of literature on p38 MAPK expression, activation, and function in reproductive tissues throughout pregnancy and parturition, published between January 1980 and August 2017, using four electronic databases (Web of Science, PubMed, Medline, and CoCHRANE). We identified 418 reports; 108 were selected for full-text evaluation and 74 were included in final review. p38 MAPK was investigated using feto-maternal primary or immortalized cells, tissue explants, and animal models. Western blot was most commonly used to report phosphorylated (active) p38 MAPK. Human placenta (27), chorioamniotic membranes (14), myometrium (13), decidua (8), and cervix (1) were the studied tissues. p38 MAPK's functions were tissue and gestational age dependent. Isoform specificity was hardly reported. p38 MAPK activity was induced by ROS or proinflammatory cytokines to promote cell signaling linked to cell fate, primed uterus, ripened cervix, and proinflammatory cytokine/chemokine production. In 35 years, reports on p38 MAPK's role during pregnancy and parturition are scarce and current literature is insufficient to provide a comprehensive description of p38 MAPK's mechanistic role during pregnancy and parturition.
Topics: Animals; Disease Models, Animal; Female; Gene Expression Regulation; Genitalia, Female; Humans; Inflammation; Oxidative Stress; Parturition; Pregnancy; Reproduction; Signal Transduction; p38 Mitogen-Activated Protein Kinases
PubMed: 30178469
DOI: 10.1111/aji.13047 -
Cureus Nov 2019Intracranial metastatic melanoma is a major challenge for neuro-oncological teams. Historically, treatment has focused on surgical or radiosurgical treatment of... (Review)
Review
Intracranial metastatic melanoma is a major challenge for neuro-oncological teams. Historically, treatment has focused on surgical or radiosurgical treatment of appropriate lesions, mostly for palliative purposes. Immunotherapies and other targeted therapies (BRAF/mitogen-activated protein kinase kinase inhibitors (BRAFi/MEKi)) are mainstays of advanced melanoma therapy, yet the optimal timing and synergistic properties of concurrent combinations of these systemic therapies and stereotactic radiosurgery (SRS) are poorly understood. We performed a systematic review of the MEDLINE and Scopus databases focused on outcomes after therapy using SRS and either immunotherapies or targeted therapies in an effort to define the optimal timing. We defined concurrent therapy as SRS within three months of treatment with any systemic therapy. End points included local control, distant control, overall survival, and toxicities. We identified five retrospective cohort studies from the literature. These studies found that concurrent SRS plus immunotherapy or BRAFi/MEKi is well tolerated by most patients and generally improved local control, distant control, and overall survival. Importantly, no significant increases in toxicities were noted with concurrent therapy. Combining concurrent SRS with immunotherapy or BRAFi/MEKi may offer important advances for patients with intracranial metastatic melanoma. To address interstudy heterogeneity, we propose reporting two major time intervals defining "concurrent treatment": concurrent-SRS (≤4 weeks) and peri-SRS (≤3 months). Future large-scale, prospective trials considering truly concurrent SRS therapies with systemic therapies are desperately needed.
PubMed: 31886081
DOI: 10.7759/cureus.6147 -
Chinese Medical Journal Jul 2017Good's syndrome (GS) is a rare disease characterized by thymoma, hypogammaglobulinemia, low or absent B-cells, decreased T-cells, an inverted CD4+/CD8+ T-cell ratio and... (Review)
Review
BACKGROUND
Good's syndrome (GS) is a rare disease characterized by thymoma, hypogammaglobulinemia, low or absent B-cells, decreased T-cells, an inverted CD4+/CD8+ T-cell ratio and reduced T-cell mitogen proliferative responses. GS is difficult to diagnose preoperatively due to its rarity and lack of typical symptoms, the characteristics of Chinese GS patients are still lacking. This study aimed to systematically review all the clinical, laboratory, and immunologic findings of reported cases of Chinese patients with GS.
METHODS
We searched for case reports and articles up to January 2017 using PubMed, China National Knowledge Infrastructure, Wangfang database and China Science and Technology Journal Database with the following words in combinations as key words: "thymoma," "hypogammaglobulinemia," and "Good's syndrome." The text words and MeSH terms were entered depending on the databases characteristics. The reference lists from retrieved articles were also screened for additional applicable studies. The authors were restricted to Chinese. There was no language restriction.
RESULTS
Forty-seven patients were reported in 27 studies. We found that GS has a nationwide distribution and that most cases (83%) have been described on the mainland of China. The initial clinical presentation is varied, ranging from symptoms related to the thymoma to infections resulting from immunodeficiency. Type AB (50%) is the most common histologic type of thymomas in Chinese GS patients according to the World Health Organization classification of thymomas. With respect to infection, sinopulmonary infection (74%) is the most common type, followed by skin infection (10%) and intestinal tract infection (10%). Diarrhea was presented in 36% of patients, and autoimmune manifestations were presented in 36% of patients.
CONCLUSIONS
GS is a rare association of thymoma and immunodeficiency with a poor prognosis. Astute clinical acumen and increased awareness of the clinical and immunological profile of GS are needed to increase early diagnosis, that would benefit improved therapeutic effects.
Topics: Agammaglobulinemia; Animals; China; Humans; Immunologic Deficiency Syndromes; Rare Diseases; Thymoma; Thymus Neoplasms
PubMed: 28639577
DOI: 10.4103/0366-6999.208234 -
Current Oncology (Toronto, Ont.) Oct 2022Breast cancer represents the most common type of cancer and is the leading cause of death due to cancer among women. Thus, the prevention and early diagnosis of breast... (Review)
Review
Breast cancer represents the most common type of cancer and is the leading cause of death due to cancer among women. Thus, the prevention and early diagnosis of breast cancer is of primary urgency, as well as the development of new treatments able to improve its prognosis. Nerve Growth Factor (NGF) is a neurotrophic factor involved in the regulation of neuronal functions through the binding of the Tropomyosin receptor kinase A (TrkA) and the Nerve Growth Factor receptor or Pan-Neurotrophin Receptor 75 (NGFR/p75NTR). In addition, its precursor (pro-NGF) can extert biological activity by forming a trimeric complex with NGFR/p75NTR and sortilin, or by binding to TrkA receptors with low affinity. Several examples of in vitro and in vivo evidence show that NGF is both synthesized and released by breast cancer cells, and has mitogen, antiapoptotic and angiogenic effects on these cells through the activation of different signaling cascades that involve TrkA and NGFR/p75NTR receptors. Conversely, pro-NGF signaling has been related to breast cancer invasion and metastasis. Other studies suggested that NGF and its receptors could represent a good diagnostic and prognostic tool, as well as promising therapeutic targets for breast cancer. In this paper, we comprehensively summarize and systematically review the current experimental evidence on this topic. INPLASY ID: INPLASY2022100017.
Topics: Female; Humans; Nerve Growth Factor; Receptor, trkA; Breast Neoplasms; Receptor, Nerve Growth Factor; Signal Transduction
PubMed: 36354700
DOI: 10.3390/curroncol29110640 -
Biomedicine & Pharmacotherapy =... Sep 2022Development and identification of molecular compounds capable of killing or inhibiting transformed cells promoting carcinogenesis without inducing toxic effects to the... (Review)
Review
Development and identification of molecular compounds capable of killing or inhibiting transformed cells promoting carcinogenesis without inducing toxic effects to the normal cells are of utmost significance. A systematic review was conducted in screening for important literature was extensively performed by searching the Web of Science, Ovid, BMC Springer, Elsevier, Embase, and MEDLINE databases for optimum selectivity. Google Scholar was also used to supplement information. Pharmacotherapeutic biomolecules active against colon cancer carcinogenesis in Musa acuminata and Musa balbisiana (bananas), Punica granatum L (pomegranate), Glycine max (Soybean), Brassica oleracea L var. italica Plenck (Broccoli), and Hibiscus rosa-sinesis and Hibiscus sabdariffa (hibiscus) were evaluated. Signaling pathways like phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), protein kinase B (AKT), and nuclear factor-kappa B (NFκB) correlate the mediation of COX-2 expression. Increased levels of COX-2 are correlated with the occurrence and progression of colon cancer. Natural antioxidants in herbal plants including polyphenols and carotenoids inhibit the oxidation of lipids, proteins, and nucleic acids and thereby preventing the initiation of oxidizing chain reactions. These bioactive compounds should be considered an important dietary supplement.
Topics: Carcinogenesis; Colonic Neoplasms; Cyclooxygenase 2; Hibiscus; Humans; Phosphatidylinositol 3-Kinases; Plants, Medicinal
PubMed: 35820316
DOI: 10.1016/j.biopha.2022.113383 -
Frontiers in Bioscience (Landmark... Jan 2022p38 MAPK (mitogen-activated protein kinases) family proteins (α, β, γ and δ) are key inflammatory kinases and play an important role in relaying and processing...
p38 MAPK (mitogen-activated protein kinases) family proteins (α, β, γ and δ) are key inflammatory kinases and play an important role in relaying and processing intrinsic and extrinsic signals in response to inflammation, stress, and oncogene to regulate cell growth, cell death and cell transformation. Recent studies in genetic mouse models revealed that p38α in epithelial cells mostly suppresses whereas in immune cells it promotes inflammation and inflammation-associated oncogenesis. On the contrary, p38γ and p38δ signaling in immune and epithelial cells is both pro-inflammatory and oncogenic. This review summarizes recent discoveries in this field, discusses possible associated mechanisms, and highlights potentials of systemically targeting isoform-specific p38 MAPKs. Understanding of p38 MAPK isoform-specific and cell/tissue- and perhaps stage-dependent effects and their integrated regulated activity in inflammation and in inflammation-associated oncogenesis is essential for effectively targeting this group of kinases for therapeutic intervention.
Topics: Animals; Carcinogenesis; Inflammation; Mice; Mitogen-Activated Protein Kinases; Protein Isoforms; p38 Mitogen-Activated Protein Kinases
PubMed: 35090336
DOI: 10.31083/j.fbl2701031 -
Current Genomics Nov 2018Involvement of life stress in Late-Onset Alzheimer's Disease (LOAD) has been evinced in longitudinal cohort epidemiological studies, and endocrinologic evidence suggests... (Review)
Review
Involvement of life stress in Late-Onset Alzheimer's Disease (LOAD) has been evinced in longitudinal cohort epidemiological studies, and endocrinologic evidence suggests involvements of catecholamine and corticosteroid systems in LOAD. Early Life Stress (ELS) rodent models have successfully demonstrated sequelae of maternal separation resulting in LOAD-analogous pathology, thereby supporting a role of insulin receptor signalling pertaining to GSK-3beta facilitated tau hyper-phosphorylation and amyloidogenic processing. Discussed are relevant ELS studies, and findings from three mitogen-activated protein kinase pathways (JNK/SAPK pathway, ERK pathway, p38/MAPK pathway) relevant for mediating environmental stresses. Further considered were the roles of autophagy impairment, neuroinflammation, and brain insulin resistance. For the meta-analytic evaluation, 224 candidate gene loci were extracted from reviews of animal studies of LOAD pathophysiological mechanisms, of which 60 had no positive results in human LOAD association studies. These loci were combined with 89 gene loci confirmed as LOAD risk genes in previous GWAS and WES. Of the 313 risk gene loci evaluated, there were 35 human reports on epigenomic modifications in terms of methylation or histone acetylation. 64 microRNA gene regulation mechanisms were published for the compiled loci. Genomic association studies support close relations of both noradrenergic and glucocorticoid systems with LOAD. For HPA involvement, a CRHR1 haplotype with MAPT was described, but further association of only HSD11B1 with LOAD found; however, association of FKBP1 and NC3R1 polymorphisms was documented in support of stress influence to LOAD. In the brain insulin system, IGF2R, INSR, INSRR, and plasticity regulator ARC, were associated with LOAD. Pertaining to compromised myelin stability in LOAD, relevant associations were found for BIN1, RELN, SORL1, SORCS1, CNP, MAG, and MOG. Regarding epigenetic modifications, both methylation variability and de-acetylation were reported for LOAD. The majority of up-to-date epigenomic findings include reported modifications in the well-known LOAD core pathology loci MAPT, BACE1, APP (with FOS, EGR1), PSEN1, PSEN2, and highlight a central role of BDNF. Pertaining to ELS, relevant loci are FKBP5, EGR1, GSK3B; critical roles of inflammation are indicated by CRP, TNFA, NFKB1 modifications; for cholesterol biosynthesis, DHCR24; for myelin stability BIN1, SORL1, CNP; pertaining to (epi)genetic mechanisms, hTERT, MBD2, DNMT1, MTHFR2. Findings on gene regulation were accumulated for BACE1, MAPK signalling, TLR4, BDNF, insulin signalling, with most reports for miR-132 and miR-27. Unclear in epigenomic studies remains the role of noradrenergic signalling, previously demonstrated by neuropathological findings of childhood nucleus caeruleus degeneration for LOAD tauopathy.
PubMed: 30386171
DOI: 10.2174/1389202919666171229145156 -
International Journal of Molecular... Jun 2023Pituitary tumors (PT) are mostly benign, although occasionally they demonstrate aggressive behavior, invasion of surrounding tissues, rapid growth, resistance to... (Review)
Review
Pituitary tumors (PT) are mostly benign, although occasionally they demonstrate aggressive behavior, invasion of surrounding tissues, rapid growth, resistance to conventional treatments, and multiple recurrences. The pathogenesis of PT is still not fully understood, and the factors responsible for its invasiveness, aggressiveness, and potential for metastasis are unknown. RAF/MEK/ERK and mTOR signaling are significant pathways in the regulation of cell growth, proliferation, and survival, its importance in tumorigenesis has been highlighted. The aim of our review is to determine the role of the activation of PI3K/AKT/mTOR and RAF/MEK/ERK pathways in the pathogenesis of pituitary tumors. Additionally, we evaluate their potential in a new therapeutic approach to provide alternative therapies and improved outcomes for patients with aggressive pituitary tumors that do not respond to standard treatment. We perform a systematic literature search using the PubMed, Embase, and Scopus databases (search date was 2012-2023). Out of the 529 screened studies, 13 met the inclusion criteria, 7 related to the PI3K/AKT/mTOR pathway, and 7 to the RAF/MEK/ERK pathway (one study was used in both analyses). Understanding the specific factors involved in PT tumorigenesis provides opportunities for targeted therapies. We also review the possible new targeted therapies and the use of mTOR inhibitors and TKI in PT management. Although the RAF/MEK/ERK and PI3K/AKT/mTOR pathways play a pivotal role in the complex signaling network along with many interactions, further research is urgently needed to clarify the exact functions and the underlying mechanisms of these signaling pathways in the pathogenesis of pituitary adenomas and their role in its invasiveness and aggressive clinical outcome.
Topics: Humans; MAP Kinase Signaling System; Proto-Oncogene Proteins c-akt; Pituitary Neoplasms; Phosphatidylinositol 3-Kinases; TOR Serine-Threonine Kinases; Mitogen-Activated Protein Kinase Kinases; Carcinogenesis
PubMed: 37446128
DOI: 10.3390/ijms241310952 -
Diagnostics (Basel, Switzerland) Mar 2023Thyroid cancer represents the prominent endocrine cancer in children. Papillary thyroid cancer (PTC) constitutes its most frequent (>90%) pediatric histological type.... (Review)
Review
Thyroid cancer represents the prominent endocrine cancer in children. Papillary thyroid cancer (PTC) constitutes its most frequent (>90%) pediatric histological type. Mutations energizing the mitogen-activated-protein kinase (MAPK) pathway are definitely related to PTC. Its most common genetic alteration is in proto-oncogene B-Raf (BRAF). Mutated BRAF is proposed as a prognostic tool in adult PTC. We conducted a systematic review and meta-analysis evaluating the association of mutated BRAF gene and prognostic clinicopathological characteristics of PTC in children/adolescents. Systematic search for relevant studies included PubMed, MEDLINE, Scopus, clinicaltrials.gov and Cochrane Library. Pooled estimates of odds ratios for categorical data and mean difference for continuous outcomes were calculated using random/fixed-effect meta-analytic models. BRAFV600E mutation presents a pooled pediatric/adolescent prevalence of 33.12%. Distant metastasis is significantly associated with mutated BRAF gene (OR = 0.32, 95% CI = 0.16-0.61, = 0.001). Tumor size (MD = -0.24, 95% CI = -0.62-0.135, = 0.21), multifocality (OR = 1.13, 95% CI = 0.65-2.34, = 0.74), vascular invasion (OR = 1.17, 95% CI = 0.67-2.05, = 0.57), lymph node metastasis (OR = 0.92, 95% CI = 0.63-1.33, = 0.66), extra-thyroid extension (OR = 0.78, 95% CI = 0.53-1.13, = 0.19) and tumor recurrence (OR = 1.66, 95% CI = 0.68-4.21, = 0.376) presented no association or risk with BRAF mutation among pediatric/adolescent PTC. Mutated BRAF gene in children and adolescents is less common than in adults. Mutation in BRAF relates significantly to distant metastasis among children/adolescents with PTC.
PubMed: 36980495
DOI: 10.3390/diagnostics13061187 -
Gynecologic Oncology Apr 2023The RAS/RAF/MEK/ERK (MAPK) pathway plays a role in ovarian carcinogenesis. Low-grade serous ovarian carcinoma (LGSOC) frequently harbors activating MAPK mutations. MAPK... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The RAS/RAF/MEK/ERK (MAPK) pathway plays a role in ovarian carcinogenesis. Low-grade serous ovarian carcinoma (LGSOC) frequently harbors activating MAPK mutations. MAPK inhibitors have been used in small subsets of ovarian carcinoma (OC) patients to control tumor growth. Therefore, we performed a meta-analysis to evaluate the effectiveness of MAPK inhibitors in OC patients. We aimed to determine the clinical benefit rate (CBR), the subgroup of MAPK inhibitors with the best CBR and overall response rate (ORR), and the most common adverse events.
METHODS
We conducted a search in PubMed, Embase via Ovid, the Cochrane library and clinicaltrials.gov on studies evaluating the efficacy of single MAPK pathway inhibition with MAPK pathway inhibitors in OC patients. Our primary outcome included the CBR, defined by the proportion of patients with stable disease (SD), complete (CR) and partial response (PR). Secondary outcomes included the ORR (including PR and CR) and grade 3 and 4 adverse events. Meta-analysis was performed using a random-effects model.
RESULTS
We included nine studies with a total of 319 OC patients, for which we determined a pooled CBR of 63% (95%-CI 39-84%, I = 92%). Combined treatment with Raf- and MEK inhibitors in in BRAF mutated LGSOC (n = 6) had the greatest efficacy with a CBR of 100% and ORR of 83%. MEK inhibitors had the best efficacy as a single agent. Subgroup analysis by tumor histology demonstrated a significantly higher CBR and ORR in patients with LGSOC, with a pooled CBR and ORR of 87% (95%-CI 81-92%, I = 0%) and 27% (95%-CI 10-48%, I = 77%) respectively. Adverse events of grade 3 or higher were reported frequently: 123 in 167 patients.
CONCLUSIONS
MEK inhibitors are the most promising single agents in (LGS)OC. However, dual MAPK pathway inhibition should be considered in patients with a BRAF mutation, or non-mutated OC with depleted treatment options due indications of higher efficacy and tolerable toxicity profiles.
Topics: Humans; Female; Proto-Oncogene Proteins B-raf; MAP Kinase Signaling System; Signal Transduction; Ovarian Neoplasms; Protein Kinase Inhibitors; Carcinoma, Ovarian Epithelial; Mutation; Mitogen-Activated Protein Kinase Kinases
PubMed: 36841040
DOI: 10.1016/j.ygyno.2023.01.038