Aberrant expression of epigenetic regulators of gene expression contributes to initiation and progression of cancer. During
recent years, considerable research efforts have focused on the role of ...histone acetyltransferases (HATs) and histone deacetylases
(HDACs) in cancer cells, and the identification of pharmacologic agents that modulate gene expression via inhibition of HDACs.
The following review highlights recent studies pertaining to HDAC expression in cancer cells, the plieotropic mechanisms by
which HDAC inhibitors (HDACi) mediate antitumor activity, and the potential clinical implications of HDAC inhibition as a
strategy for cancer therapy.
A new molecular subtype classification was recently proposed for SCLC. It is necessary to validate it in primary SCLC tumors by immunohistochemical (IHC) staining and define its clinical relevance.
...We used IHC to assess four subtype markers (ASCL1, NEUROD1, POU2F3, and YAP1) in 194 cores from 146 primary SCLC tumors. The profiles of tumor-associated CD3+ and CD8+ T-cells, MYC paralogs, SLFN11, and SYP were compared among different subtypes. Validation was performed using publicly available RNA sequencing data of SCLC.
ASCL1, NEUROD1, POU2F3, and YAP1 were the dominant molecular subtypes in 78.2%, 5.6%, 7%, and 2.8% of the tumors, respectively; 6.3% of the tumors were negative for all four subtype markers. Notably, three cases were uniquely positive for YAP1. Substantial intratumoral heterogeneity was observed, with 17.6% and 2.8% of the tumors being positive for two and three subtype markers, respectively. The non-ASCL1/NEUROD1 tumors had more CD8+ T-cells and manifested more frequently an “inflamed” immunophenotype. L-MYC and MYC were more often associated with ASCL1/NEUROD1 subtypes and non-ASCL1/NEUROD1 subtypes, respectively. SLFN11 expression was absent in 40% of the tumors, especially those negative for the four subtype markers. SYP was often expressed in the ASCL1 and NEUROD1 subtypes and was associated with less tumor-associated CD8+ T-cells and a “desert” immunophenotype.
We validated the new molecular subtype classification in primary SCLC tumors by IHC and identified several intriguing associations between subtypes and therapeutic markers. The new subtype classification may potentially assist treatment decisions in SCLC.
Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased ...sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy. Patients with histologically confirmed malignant mesothelioma were evaluated for inherited mutations in tumor suppressor genes. Survival was evaluated with respect to genotype and site of mesothelioma. Among 385 patients treated with platinum chemotherapy, median overall survival was significantly longer for patients with loss-of-function mutations in any of the targeted genes compared with patients with no such mutation (P = 0.0006). The effect of genotype was highly significant for patients with pleural mesothelioma (median survival 7.9 y versus 2.4 y, P = 0.0012), but not for patients with peritoneal mesothelioma (median survival 8.2 y versus 5.4 y, P = 0.47). Effect of patient genotype on overall survival, measured at 3 y, remained independently significant after adjusting for gender and age at diagnosis, two other known prognostic factors. Patients with pleural mesothelioma with inherited mutations in DNA repair and other tumor suppressor genes appear to particularly benefit from platinum chemotherapy compared with patients without inherited mutations. These patients may also benefit from other DNA repair targeted therapies such as poly-ADP ribose polymerase (PARP) inhibitors.
Long-term survival and antitumor immunity of adoptively transferred CD8+ T cells is dependent on their metabolic fitness, but approaches to isolate therapeutic T cells based on metabolic features are ...not well established. Here we utilized a lipophilic cationic dye tetramethylrhodamine methyl ester (TMRM) to identify and isolate metabolically robust T cells based on their mitochondrial membrane potential (ΔΨm). Comprehensive metabolomic and gene expression profiling demonstrated global features of improved metabolic fitness in low-ΔΨm-sorted CD8+ T cells. Transfer of these low-ΔΨm T cells was associated with superior long-term in vivo persistence and an enhanced capacity to eradicate established tumors compared with high-ΔΨm cells. Use of ΔΨm-based sorting to enrich for cells with superior metabolic features was observed in CD8+, CD4+ T cell subsets, and long-term hematopoietic stem cells. This metabolism-based approach to cell selection may be broadly applicable to therapies involving the transfer of HSC or lymphocytes for the treatment of viral-associated illnesses and cancer.
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•ΔΨm-based sorting segregates short-lived effector from memory T cell precursors•Low-ΔΨm CD8+ T cells demonstrate decreased oxidative stress•Low-ΔΨm T cells demonstrate superior antitumor activity•Low-ΔΨm marks self-renewing hematopoietic stem cells
Metabolic fitness is required for long-term function of T cells and HSC. Sukumar et al. describe a simple and clinically feasible method to isolate such metabolically robust cells, using a single parameter—mitochondrial membrane potential (ΔΨm)—for long-term survival, antitumor immunity, and hematopoietic reconstitution.
Abstract Objective The incidence of thoracic injuries resulting from cardiopulmonary resuscitation (CPR) is not well characterized. We describe a case in which a CPR-associated atrial rupture was ...identified with ultrasound and successfully managed in the intensive care unit with a bedside thoracotomy and atrial repair. We then describe a systematic review with pooled data analysis of CPR-associated cardiovascular, pulmonary, pleural, and thoracic wall injuries. Data sources PubMed, Scopus, EMBASE, and Web of Science were searched to identify relevant published studies. Unpublished studies were identified by searching the Australian and New Zealand Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform, Cochrane Library, ClinicalTrials.gov, Current Controlled Trials, and Google. Study selection Inclusion criteria for the pooled analysis were any clinical or autopsy study in which (a) patients underwent cardiopulmonary resuscitation, (b) chest compressions were administered either manually or with the assistance of active compression–decompression devices, and (c) autopsy or dedicated imaging assessments were conducted to identify complications. Exclusion criteria for the pooled analysis were pre-clinical studies, case reports and abstracts. Data extraction Nine-hundred twenty-eight potentially relevant references were identified. Twenty-seven references met inclusion criteria. Data synthesis A systematic review of the literature is provided with pooled data analysis. Conclusions The incidence of reported CPR-associated cardiovascular and thoracic wall injuries varies widely. CPR with active compression–decompression devices has a higher reported incidence of cardiopulmonary injuries. Bedside ultrasound may be a useful adjunct to assess and risk-stratify patients to identify serious or life-threatening CPR-associated injuries.
Tumours progress despite being infiltrated by tumour-specific effector T cells. Tumours contain areas of cellular necrosis, which are associated with poor survival in a variety of cancers. Here, we ...show that necrosis releases intracellular potassium ions into the extracellular fluid of mouse and human tumours, causing profound suppression of T cell effector function. Elevation of the extracellular potassium concentration (K
) impairs T cell receptor (TCR)-driven Akt-mTOR phosphorylation and effector programmes. Potassium-mediated suppression of Akt-mTOR signalling and T cell function is dependent upon the activity of the serine/threonine phosphatase PP2A. Although the suppressive effect mediated by elevated K
is independent of changes in plasma membrane potential (V
), it requires an increase in intracellular potassium (K
). Accordingly, augmenting potassium efflux in tumour-specific T cells by overexpressing the potassium channel K
1.3 lowers K
and improves effector functions in vitro and in vivo and enhances tumour clearance and survival in melanoma-bearing mice. These results uncover an ionic checkpoint that blocks T cell function in tumours and identify potential new strategies for cancer immunotherapy.
Telomerase is an enzyme specialized in maintaining telomere lengths in highly proliferative cells. Loss-of-function mutations cause critical telomere shortening and are associated with the bone ...marrow failure syndromes dyskeratosis congenita and aplastic anemia and with idiopathic pulmonary fibrosis. Here, we sought to determine the spectrum of clinical manifestations associated with telomerase loss-of-function mutations.
Sixty-nine individuals from five unrelated families with a variety of hematologic, hepatic, and autoimmune disorders were screened for telomerase complex gene mutations; leukocyte telomere length was measured by flow fluorescence in situ hybridization in mutation carriers and some non-carriers; the effects of the identified mutations on telomerase activity were determined; and genetic and clinical data were correlated. In six generations of a large family, a loss-of-function mutation in the telomerase enzyme gene TERT associated with severe telomere shortening and a range of hematologic manifestations, from macrocytosis to acute myeloid leukemia, with severe liver diseases marked by fibrosis and inflammation, and one case of idiopathic pulmonary fibrosis but not with autoimmune disorders. Additionally, we identified four unrelated families in which loss-of-function TERC or TERT gene mutations tracked with marrow failure, pulmonary fibrosis, and a spectrum of liver disorders.
These results indicate that heterozygous telomerase loss-of-function mutations associate with but are not determinant of a large spectrum of hematologic and liver abnormalities, with the latter sometimes occurring in the absence of marrow failure. Our findings, along with the link between pulmonary fibrosis and telomerase mutations, also suggest a common pathogenic mechanism for fibrotic diseases in which defective telomere repair plays important role.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Limited information is available regarding mechanisms by which miRNAs contribute to pulmonary carcinogenesis. The present study was undertaken to examine expression and function of miRNAs induced by ...cigarette smoke condensate (CSC) in normal human respiratory epithelia and lung cancer cells.
Micro-array and quantitative RT-PCR (qRT-PCR) techniques were used to assess miRNA and host gene expression in cultured cells, and surgical specimens. Software-guided analysis, RNA cross-link immunoprecipitation (CLIP), 3' UTR luciferase reporter assays, qRT-PCR, focused super-arrays and western blot techniques were used to identify and confirm targets of miR-31. Chromatin immunoprecipitation (ChIP) techniques were used to evaluate histone marks and transcription factors within the LOC554202 promoter. Cell count and xenograft experiments were used to assess effects of miR-31 on proliferation and tumorigenicity of lung cancer cells.
CSC significantly increased miR-31 expression and activated LOC554202 in normal respiratory epithelia and lung cancer cells; miR-31 and LOC554202 expression persisted following discontinuation of CSC exposure. miR-31 and LOC554202 expression levels were significantly elevated in lung cancer specimens relative to adjacent normal lung tissues. CLIP and reporter assays demonstrated direct interaction of miR-31 with Dickkopf-1 (Dkk-1) and DACT-3. Over-expression of miR-31 markedly diminished Dkk-1 and DACT3 expression levels in normal respiratory epithelia and lung cancer cells. Knock-down of miR-31 increased Dkk-1 and DACT3 levels, and abrogated CSC-mediated decreases in Dkk-1 and DACT-3 expression. Furthermore, over-expression of miR-31 diminished SFRP1, SFRP4, and WIF-1, and increased Wnt-5a expression. CSC increased H3K4Me3, H3K9/14Ac and C/EBP-β levels within the LOC554202 promoter. Knock-down of C/EBP-β abrogated CSC-mediated activation of LOC554202. Over-expression of miR-31 significantly enhanced proliferation and tumorigenicity of lung cancer cells; knock-down of miR-31 inhibited growth of these cells.
Cigarette smoke induces expression of miR-31 targeting several antagonists of cancer stem cell signaling in normal respiratory epithelia and lung cancer cells. miR-31 functions as an oncomir during human pulmonary carcinogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Whole-cell cancer vaccines are a promising strategy for treating cancer, but the characteristics of a favorable immune response are not fully understood. New insights could enable development of ...better vaccines, discovery of new antigens, and identification of biomarkers of efficacy. Using glyco-antigen microarrays, we demonstrate that GVAX Pancreas (a granulocyte macrophage colony-stimulating factor-modified whole-cell tumor vaccine) induces large immunoglobulin G and immunoglobulin M responses to many antigens, including tumor-associated carbohydrates, blood group antigens, α-Gal, and bovine fetuin. Antibody responses to α-Gal, a glycan found in fetal bovine serum (FBS) used to produce the vaccine, correlated inversely with overall survival and appear to compete with productive responses to the vaccine. H1299 lysate vaccine, produced with FBS, also induced responses to α-Gal and fetuin but not K562-GM, which is produced in serum-free medium. Our results provide new potential biomarkers to evaluate productive/unproductive immune responses and suggest that removal/reduction of FBS could improve the efficacy of whole-cell vaccines.
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•Antibody responses to a whole-cell vaccine were profiled with a glycan microarray•Large IgG and IgM responses to FBS antigens and tumor antigens were observed•Responses to non-human antigens correlated inversely with patient survival•Responses to non-human antigens out-compete productive response to the vaccine
Glycan microarrays were used to profile anti-carbohydrate antibody responses induced by whole-cell vaccines. Large IgG and IgM responses were detected, and certain responses correlated with survival. The results provide new indicators of vaccine efficacy and provide simple strategies to improve whole-cell vaccines.
Because of an improved understanding of lung cancer biology and improvement in systemic treatment, an oligometastatic state in which metastatic disease is present at a limited number of anatomic ...sites is being increasingly recognized. An oligoprogressive state, which is a similar but distinct entity, refers to disease progression at a limited number of anatomic sites, with continued response or stable disease at other sites of disease. Such an oligoprogressive state is best described in patients with NSCLC treated with molecular targeted therapy. Possible explanations for development of the oligoprogressive state include the presence of underlying clonal heterogeneity and extrinsic selection pressure due to the use of targeted therapy. Traditionally, local ablative therapy (LAT) has been limited to symptom palliation in patients with advanced NSCLC, but the presence of oligometastatic or oligoprogressive disease provides a unique opportunity to evaluate the role of LAT such as surgery, radiation therapy, radiofrequency ablation, or cryoablation. There is increasing evidence to support the clinical benefit of LAT in patients with NSCLC with limited metastatic disease and in selected individuals in whom resistance to targeted therapies develops. In the latter instance, adequate treatment of drug-resistant clones by LAT could potentially help in avoiding switching systemic therapy prematurely. This review focuses on the biology of oligometastatic and oligoprogressive NSCLC and describes the role of LAT in the treatment of these conditions.
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