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International Journal of Molecular... Aug 2018Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumours, and its incidence is rising worldwide. Although survival can be improved by surgical... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumours, and its incidence is rising worldwide. Although survival can be improved by surgical resection when these tumours are detected at an early stage, this cancer is usually asymptomatic, and disease only becomes apparent after metastasis. Several risk factors are associated with this disease, the most relevant being chronic pancreatitis, diabetes, tobacco and alcohol intake, cadmium, arsenic and lead exposure, certain infectious diseases, and the mutational status of some genes associated to a familial component. PDAC incidence has increased in recent decades, and there are few alternatives for chemotherapeutic treatment. Endoplasmic reticulum (ER) stress factors such as GRP78/BiP (78 kDa glucose-regulated protein), ATF6α (activating transcription factor 6 isoform α), IRE1α (inositol-requiring enzyme 1 isoform α), and PERK (protein kinase RNA-like endoplasmic reticulum kinase) activate the transcription of several genes involved in both survival and apoptosis. Some of these factors aid in inducing a non-proliferative state in cancer called dormancy. Modulation of endoplasmic reticulum stress could induce dormancy of tumour cells, thus prolonging patient survival. In this systematic review, we have compiled relevant results concerning those endoplasmic reticulum stress factors involved in PDAC, and we have analysed the mechanism of dormancy associated to endoplasmic reticulum stress and its potential use as a chemotherapeutic target against PDAC.
Topics: Activating Transcription Factor 6; Animals; Antibodies; Carcinoma, Pancreatic Ductal; Communicable Diseases; Deoxycytidine; Diabetes Complications; Disease Models, Animal; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Endoribonucleases; Gene Expression Regulation; Heat-Shock Proteins; Humans; Pancreatic Neoplasms; Pancreatitis, Chronic; Protein Serine-Threonine Kinases; RNA, Small Interfering; Risk Factors; Sulfones; eIF-2 Kinase; Gemcitabine
PubMed: 30134550
DOI: 10.3390/ijms19092468 -
International Journal of Medical... 2021Although high-mobility group box 1 and heat-shock protein 70 are implicated in airway diseases and suggested as relevant diagnostic biomarkers, their control... (Meta-Analysis)
Meta-Analysis
Although high-mobility group box 1 and heat-shock protein 70 are implicated in airway diseases and suggested as relevant diagnostic biomarkers, their control concentrations in the airways have not yet been determined. This study aimed to evaluate concentration of healthy subjects for both these proteins in the upper and lower airways via meta-analysis. We searched MEDLINE, EMBASE, and Google Scholar for articles describing concentration of healthy subjects for these proteins. Data from healthy populations were combined using a random-effects model, and subgroup and sensitivity analyses were performed to determine between-study heterogeneity. We analyzed 22 studies involving 485 patients. Concentration of healthy subjects of high-mobility group box 1 and heat-shock protein 70 varied from "not detected" to 326.13 ng/mL and from 0.20 pg/mL to 9240.00 pg/mL, respectively, with the values showing significant heterogeneity. Subgroup analysis for high-mobility group box 1 revealed 13.63 ng/mL (95% CI 12.13-15.14), 100.31 ng/mL (95% CI -31.28-231.91), 9.54 ng/mL (95% CI 8.91-10.17), and 65.82 ng/mL (95% CI 55.51-76.14) for the lower airway, upper airway, pediatric populations, and adults, respectively, whereas that for heat-shock protein 70 revealed 20.58 pg/mL (95% CI 7.87-33.29) for the lower airway and 9240.00 ±11820 pg/mL for the upper airway. Although concentrations of healthy subjects of these proteins varied in the upper and lower airways, the levels of both these proteins were higher in the upper airway than in the lower airway, and these concentrations differed according to the age and sampling procedure. Our findings support the further evaluation of these proteins as biomarkers for airway-related diseases.
Topics: Biomarkers; HMGB1 Protein; HSP70 Heat-Shock Proteins; Healthy Volunteers; Humans; Reference Values; Respiratory Mucosa
PubMed: 33746593
DOI: 10.7150/ijms.53500 -
Medicine Jul 2022The SET-CAN/NUP214 fusion gene resulting from chromosomal del(9)(q34.11q34.13) or t(9;9) (q34;q34) has been found in T-cell acute lymphoblastic leukemia (T-ALL), B-cell...
BACKGROUND
The SET-CAN/NUP214 fusion gene resulting from chromosomal del(9)(q34.11q34.13) or t(9;9) (q34;q34) has been found in T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), acute myeloid leukemia (AML) and myeloid sarcoma (MS). Furthermore, the SET-CAN/NUP214 fusion gene has been found in the T-ALL cell line LOUCY and the AML line MEGAL. The common features of these cases are insensitivity to chemotherapy and poor prognosis. We reviewed the characteristics and prognostic significance of the SET-CAN/NUP214 fusion gene in hematological malignancies.
METHODS
This systematic literature search was conducted using the PubMed, Web of Science, Embase, and Cochrane Library databases. With the inclusion and exclusion criteria, we summarized all of the papers and performed a statistical analyses.
RESULTS
In general, the SET-CAN/NUP214 fusion gene is very rare in adult acute leukemia, more frequently found in T-ALL than in other types of leukemia, and more often in males. Flow cytometry data indicated that the markers CD34, CD33, CD13, and CD7 were common in SET-CAN/NUP214 positive acute leukemia, including ALL. Fluorescence in situ hybridization and arrays are important methods for detecting the fusion gene in newly diagnosed patients and can detect chromosomal del(9)(q34) will be detected. The chromosomal karyotype may be normal or complex, and, in terms of survival analysis, transplantation results in a better prognosis than chemotherapy alone.
CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS
The presence of SET-CAN/NUP214 fusion gene may be a Minimal Residual Disease of early recurrence, and it might be a poor indicator of outcome.
LIMITATIONS
The mechanism, clinical characteristics, therapy and prognosis of the SET-CAN/NUP214 fusion gene in hematological malignancies require further research.
Topics: Adult; DNA-Binding Proteins; Hematologic Neoplasms; Histone Chaperones; Humans; In Situ Hybridization, Fluorescence; Leukemia, Myeloid, Acute; Male; Nuclear Pore Complex Proteins; Oncogene Proteins, Fusion; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Transcription Factors
PubMed: 35905214
DOI: 10.1097/MD.0000000000029294 -
Croatian Medical Journal Apr 2019To propose potential mechanisms of action of electromagnetic fields (EMF) on astrocytes and microglia and to elucidate the role of heat shock proteins (HSP), adenosine...
AIM
To propose potential mechanisms of action of electromagnetic fields (EMF) on astrocytes and microglia and to elucidate the role of heat shock proteins (HSP), adenosine triphosphate (ATP), calcium ions (Ca2+), and hypoxia-inducible factor 1α (HIF1α) in neurorestoration following the application of EMF.
METHODS
We reviewed the existing studies within the public domain and cross-evaluated their results in order to conclude on the molecular mechanisms of microglia-astrocyte crosstalk at work during EMF treatment.
RESULTS
The existing studies suggest that EMF induces the increase of HSP70 expression and inhibition of HIF1α, thus decreasing inflammation and allowing the microglia-astrocyte crosstalk to initiate the formation of a glial scar within the central nervous system. Furthermore, by potentially up-regulating A2A and A3 adenosine receptors, EMF increases cAMP accumulation from astrocytes and reduces the expression of inflammatory cytokines TNF α and IL-8, thus initiating neurorestoration.
CONCLUSION
The microglia-astrocyte crosstalk during EMF treatment is crucial for the initiation of neurorestoration. Elucidating the exact mechanisms of EMF actions upon microglia and astrocytes, and its role in neurorestoration could be a key step in further research of the therapeutic potential of EMFs in various neurological disorders.
Topics: Adenosine Triphosphate; Animals; Astrocytes; Calcium; Cells, Cultured; Cytokines; Electromagnetic Fields; Heat-Shock Proteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Magnetic Field Therapy; Microglia; Neurodegenerative Diseases; Receptor Cross-Talk; Tumor Necrosis Factor-alpha
PubMed: 31044584
DOI: 10.3325/cmj.2019.60.127 -
Journal of Cancer Research and Clinical... Aug 2023Dysregulated expression of heat shock proteins (HSP) plays a fundamental role in tumor development and progression. Consequently, HSP90 may be an effective tumor target...
PURPOSE
Dysregulated expression of heat shock proteins (HSP) plays a fundamental role in tumor development and progression. Consequently, HSP90 may be an effective tumor target in oncology, including the treatment of gastrointestinal cancers.
METHODS
We carried out a systematic review of data extracted from clinicaltrials.gov and pubmed.gov, which included all studies available until January 1st, 2022. The published data was evaluated using primary and secondary endpoints, particularly with focus on overall survival, progression-free survival, and rate of stable disease.
RESULTS
Twenty trials used HSP90 inhibitors in GI cancers, ranging from phase I to III clinical trials. Most studies assessed HSP90 inhibitors as a second line treatment. Seventeen of the 20 studies were performed prior to 2015 and only few studies have results pending. Several studies were terminated prematurely, due to insufficient efficacy or toxicity. Thus far, the data suggests that HSP90 inhibitor NVP-AUY922 might improve outcome for colorectal cancer and gastrointestinal stromal tumors.
CONCLUSION
It currently remains unclear which subgroup of patients might benefit from HSP90 inhibitors and at what time point these inhibitors may be beneficial. There are only few new or ongoing studies initiated during the last decade.
Topics: HSP90 Heat-Shock Proteins; Gastrointestinal Neoplasms; Humans; Molecular Targeted Therapy; Isoxazoles; Resorcinols; Antineoplastic Agents; Clinical Trials as Topic
PubMed: 36966394
DOI: 10.1007/s00432-023-04689-z -
Biomolecules Jul 2021Alzheimer's disease (AD), a progressive neurodegenerative disease, affects approximately 50 million people worldwide, which warrants the search for reliable new... (Meta-Analysis)
Meta-Analysis
Alzheimer's disease (AD), a progressive neurodegenerative disease, affects approximately 50 million people worldwide, which warrants the search for reliable new biomarkers for early diagnosis of AD. Brain-derived exosomal (BDE) proteins, which are extracellular nanovesicles released by all cell lineages of the central nervous system, have been focused as biomarkers for diagnosis, screening, prognosis prediction, and monitoring in AD. This review focused on the possibility of BDE proteins as AD biomarkers. The articles published prior to 26 January 2021 were searched in PubMed, EMBASE, Web of Science, and Cochrane Library to identify all relevant studies that reported exosome biomarkers in blood samples of patients with AD. From 342 articles, 20 studies were selected for analysis. We conducted a meta-analysis of six BDE proteins and found that levels of amyloid-β42 (standardized mean difference (SMD) = 1.534, 95% confidence interval [CI]: 0.595-2.474), total-tau (SMD = 1.224, 95% CI: 0.534-1.915), tau phosphorylated at threonine 181 (SMD = 4.038, 95% CI: 2.312-5.764), and tau phosphorylated at serine 396 (SMD = 2.511, 95% CI: 0.795-4.227) were significantly different in patients with AD compared to those in control. Whereas, those of p-tyrosine-insulin receptor substrate-1 and heat shock protein 70 did not show significant differences. This review suggested that Aβ42, t-tau, p-T181-tau, and p-S396-tau could be effective in diagnosing AD as blood biomarkers, despite the limitation in the meta-analysis based on the availability of data. Therefore, certain BDE proteins could be used as effective biomarkers for AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Exosomes; HSP70 Heat-Shock Proteins; Humans; Insulin Receptor Substrate Proteins; Peptide Fragments; tau Proteins
PubMed: 34356604
DOI: 10.3390/biom11070980 -
Acta Obstetricia Et Gynecologica... Sep 2019Progestogens are widely used for the conservative treatment of endometrial hyperplasia and early endometrial cancer. Nevertheless, they do not achieve the regression in...
INTRODUCTION
Progestogens are widely used for the conservative treatment of endometrial hyperplasia and early endometrial cancer. Nevertheless, they do not achieve the regression in all cases. Although several immunohistochemical markers have been assessed to predict the response to treatment, their usefulness is still unclear. We aimed to analyze the usefulness of each immunohistochemical marker studied in predicting the response to progestogens in endometrial hyperplasia and early endometrial cancer.
MATERIAL AND METHODS
Electronic databases were searched for relevant articles from January 2000 to June 2018. All studies assessing the association of immunohistochemical markers with the outcome of the progestogen-based therapy in endometrial hyperplasia and early endometrial cancer were included. The expression of immunohistochemical markers in pretreatment phase and changes of expression during the follow-up were evaluated in relation to response to therapy and relapse.
RESULTS
Twenty-seven studies with 1360 women were included in the systematic review; 43 immunohistochemical markers were assessed. The most studied predictive markers in the pretreatment phase were progesterone and estrogen receptors, although with conflicting results; their isoforms, and in particular progesterone receptor B, appeared more promising. Further studies are needed to confirm the usefulness of mismatch repair proteins, Dusp6, GRP78 and PTEN combined with other molecules such as phospho-AKT or phospho-mTOR. In the follow-up phase, Nrf2 and survivin showed the stronger evidence; a role may also be played by Bcl2 and Ki67. Further studies are necessary for Fas, NCoR, AKR1C1, HE4, PAX2 and SPAG9.
CONCLUSIONS
Several immunohistochemical markers might be helpful in predicting the response to conservative treatment of endometrial hyperplasia and early endometrial cancer on pretreatment and follow-up specimens. Further studies are needed to confirm their usefulness and possibly integrate them in a predictive immunohistochemical panel.
Topics: Biomarkers, Tumor; Conservative Treatment; Endometrial Hyperplasia; Endometrial Neoplasms; Endoplasmic Reticulum Chaperone BiP; Female; Humans; Immunohistochemistry; Predictive Value of Tests; Progestins
PubMed: 30793281
DOI: 10.1111/aogs.13587 -
Pharmacology & Therapeutics Sep 2020Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its...
Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.
Topics: Cyclin-Dependent Kinases; Drug Resistance; E2F4 Transcription Factor; Holoenzymes; Humans; Lipid Droplets; Molecular Chaperones; Muscle Proteins; NF-kappa B; Neoplasms; Neurodegenerative Diseases; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteostasis; Tumor Suppressor Protein p53; Ubiquitin
PubMed: 32442437
DOI: 10.1016/j.pharmthera.2020.107579