In vitro test of external Qigong

BACKGROUND: Practitioners of the alternative medical practice 'external Qigong' generally claim the ability to emit or direct "healing energy" to treat patients. We investigated the ability of experienced Qigong practitioners to enhance the healthy growth of cultured human cells in a series of studies, each following a rigorously designed protocol with randomization, blinding and controls for variability. METHODS: Qigong practitioners directed healing intentionality toward normal brain cell cultures in a basic science laboratory. Qigong treatments were delivered for 20 minutes from a minimum distance of 10 centimeters. Cell proliferation was measured by a standard colony-forming efficiency (CFE) assay and a CFE ratio (CFE for treated samples/CFE for sham samples) was the dependent measure for each experiment. RESULTS: During a pilot study (8 experiments), a trend of increased cell proliferation in Qigong-treated samples (CFE Qigong/sham ratios > 1.0) was observed (P = 0.162). In a formal study (28 experiments), a similar trend was observed, with Qigong-treated samples showing on average more colony formation than sham samples (P = 0.036). In a replication study (60 experiments), no significant difference between Qigong-treated samples and sham samples was observed (P = 0.465). CONCLUSION: We observed an apparent increase in the proliferation of cultured cells following external Qigong treatment by practitioners under strictly controlled conditions, but we did not observe this effect in a replication study. These results suggest the need for more controlled and thorough investigation of external Qigong before scientific validation is claimed

Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme

Purpose : Loss of PTEN, which is common in glioblastoma multiforme (GBM), results in activation of the mammalian target of rapapmycin (mTOR), thereby increasing mRNA translation of a number of key proteins required for cell-cycle progression. CCI-779 is an inhibitor of mTOR. The primary objectives of this study were to determine the efficacy of CCI-779 in patients with recurrent GBM and to further assess the toxicity of the drug. Experimental Design : CCI-779 was administered weekly at a dose of 250 mg intravenously for patients on enzyme-inducing anti-epileptic drugs (EIAEDs). Patients not on EIAEDs were initially treated at 250 mg; however, the dose was reduced to 170 mg because of intolerable side effects. Treatment was continued until unacceptable toxicity, tumor progression, or patient withdrawal. The primary endpoint was 6-month progression-free survival. Results : Forty-three patients were enrolled; 29 were not on EIAEDs. The expected toxicity profile of increased lipids, lymphopenia, and stomatitis was seen. There were no grade IV hematological toxicities and no toxic deaths. One patient was progression free at 6 months. Of the patients assessable for response, there were 2 partial responses and 20 with stabilization of disease. The median time to progression was 9 weeks. Conclusions : CCI-779 was well tolerated at this dose schedule; however, there was no evidence of efficacy in patients with recurrent GBM. Despite initial disease stabilization in approximately 50% of patients, the durability of response was short. Because of the low toxicity profile, CCI-779 may merit exploration in combination with other modalities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45273/1/10637_2005_Article_1444.pd

Nuclear FABP7 immunoreactivity is preferentially expressed in infiltrative glioma and is associated with poor prognosis in EGFR-overexpressing glioblastoma

BACKGROUND: We previously identified brain type fatty acid-binding protein (FABP7) as a prognostic marker for patients with glioblastoma (GBM). Increased expression of FABP7 is associated with reduced survival. To investigate possible molecular mechanisms underlying this association, we compared the expression and subcellular localization of FABP7 in non-tumor brain tissues with different types of glioma, and examined the expression of FABP7 and epidermal growth factor receptor (EGFR) in GBM tumors. METHODS: Expression of FABP7 in non-tumor brain and glioma specimens was examined using immunohistochemistry, and its correlation to the clinical behavior of the tumors was analyzed. We also analyzed the association between FABP7 and EGFR expression in different sets of GBM specimens using published DNA microarray datasets and semi-quantitative immunohistochemistry. In vitro migration was examined using SF763 glioma cell line. RESULTS: FABP7 was present in a unique population of glia in normal human brain, and its expression was increased in a subset of reactive astrocytes. FABP7 immunoreactivity in grade I pilocytic astrocytoma was predominantly cytoplasmic, whereas nuclear FABP7 was detected in other types of infiltrative glioma. Nuclear, not cytoplasmic, FABP7 immunoreactivity was associated with EGFR overexpression in GBM (N = 61, p = 0.008). Expression of the FABP7 gene in GBM also correlated with the abundance of EGFR mRNA in our previous microarray analyses (N = 34, p = 0.016) and an independent public microarray dataset (N = 28, p = 0.03). Compared to those negative for both markers, nuclear FABP7-positive/EGFR-positive and nuclear FABP7-positive/EGFR-negative GBM tumors demonstrated shortest survival, whereas those only positive for EGFR had intermediate survival. EGFR activation increased nuclear FABP7 immunoreactivity in a glioma cell line in vitro, and inhibition of FABP7 expression suppressed EGF-induced glioma-cell migration. Our data suggested that in EGFR-positive GBM the presence of nuclear FABP7 immunoreactivity increases the risk of poor prognosis CONCLUSION: In this study, we identified a possible mechanism as the basis of the association between nuclear FABP7 and poor prognosis of GBM. FABP7 expression can be found in all grades of astrocytoma, but neoplastic cells with nuclear FABP7 were only seen in infiltrative types of tumors. Nuclear FABP7 may be induced by EGFR activation to promote migration of GBM tumor cells. Positive nuclear FABP7 and EGFR overexpression correlated with short survival in EGFR-positive GBM patients. Therefore, nuclear FABP7 immunoreactivity could be used to monitor the progression of EGFR-overexpressed GBM

The Somatic Genomic Landscape of Glioblastoma

We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

A clinical perspective on the 2016 WHO brain tumor classification and routine molecular diagnostics

The 2007 World Health Organization (WHO) classification of brain tumors did not use molecular abnormalities as diagnostic criteria. Studies have shown that genotyping allows a better prognostic classification of diffuse glioma with improved treatment selection. This has resulted in a major revision of the WHO classification, which is now for adult diffuse glioma centered around isocitrate dehydrogenase (IDH) and 1p/19q diagnostics. This revised classification is reviewed with a focus on adult brain tumors, and includes a recommendation of genes of which routine testing is clinically useful. Apart from assessment of IDH mutational status including sequencing of R132H-immunohistochemistry negative cases and testing for 1p/19q, several other markers can be considered for routine testing, including assessment of copy number alterations of chromosome 7 and 10 and of TERT promoter, BRAF, and H3F3A mutations. For “glioblastoma, IDH mutated” the term “astrocytoma grade IV” could be considered. It should be considered to treat IDH wild-type grades II and III diffuse glioma with polysomy of chromosome 7 and loss of 10q as glioblastoma. New developments must be more quickly translated into further revised diagnostic categories. Quality control and rapid integration of molecular findings into the final diagnosis and the communication of the final diagnosis to clinicians require systematic attention

Nuclear FABP7 immunoreactivity is preferentially expressed in infiltrative glioma and is associated with poor prognosis in EGFR-overexpressing glioblastoma.

BackgroundWe previously identified brain type fatty acid-binding protein (FABP7) as a prognostic marker for patients with glioblastoma (GBM). Increased expression of FABP7 is associated with reduced survival. To investigate possible molecular mechanisms underlying this association, we compared the expression and subcellular localization of FABP7 in non-tumor brain tissues with different types of glioma, and examined the expression of FABP7 and epidermal growth factor receptor (EGFR) in GBM tumors.MethodsExpression of FABP7 in non-tumor brain and glioma specimens was examined using immunohistochemistry, and its correlation to the clinical behavior of the tumors was analyzed. We also analyzed the association between FABP7 and EGFR expression in different sets of GBM specimens using published DNA microarray datasets and semi-quantitative immunohistochemistry. In vitro migration was examined using SF763 glioma cell line.ResultsFABP7 was present in a unique population of glia in normal human brain, and its expression was increased in a subset of reactive astrocytes. FABP7 immunoreactivity in grade I pilocytic astrocytoma was predominantly cytoplasmic, whereas nuclear FABP7 was detected in other types of infiltrative glioma. Nuclear, not cytoplasmic, FABP7 immunoreactivity was associated with EGFR overexpression in GBM (N = 61, p = 0.008). Expression of the FABP7 gene in GBM also correlated with the abundance of EGFR mRNA in our previous microarray analyses (N = 34, p = 0.016) and an independent public microarray dataset (N = 28, p = 0.03). Compared to those negative for both markers, nuclear FABP7-positive/EGFR-positive and nuclear FABP7-positive/EGFR-negative GBM tumors demonstrated shortest survival, whereas those only positive for EGFR had intermediate survival. EGFR activation increased nuclear FABP7 immunoreactivity in a glioma cell line in vitro, and inhibition of FABP7 expression suppressed EGF-induced glioma-cell migration. Our data suggested that in EGFR-positive GBM the presence of nuclear FABP7 immunoreactivity increases the risk of poor prognosisConclusionIn this study, we identified a possible mechanism as the basis of the association between nuclear FABP7 and poor prognosis of GBM. FABP7 expression can be found in all grades of astrocytoma, but neoplastic cells with nuclear FABP7 were only seen in infiltrative types of tumors. Nuclear FABP7 may be induced by EGFR activation to promote migration of GBM tumor cells. Positive nuclear FABP7 and EGFR overexpression correlated with short survival in EGFR-positive GBM patients. Therefore, nuclear FABP7 immunoreactivity could be used to monitor the progression of EGFR-overexpressed GBM

In vitro test of external Qigong

Abstract Background Practitioners of the alternative medical practice 'external Qigong' generally claim the ability to emit or direct "healing energy" to treat patients. We investigated the ability of experienced Qigong practitioners to enhance the healthy growth of cultured human cells in a series of studies, each following a rigorously designed protocol with randomization, blinding and controls for variability. Methods Qigong practitioners directed healing intentionality toward normal brain cell cultures in a basic science laboratory. Qigong treatments were delivered for 20 minutes from a minimum distance of 10 centimeters. Cell proliferation was measured by a standard colony-forming efficiency (CFE) assay and a CFE ratio (CFE for treated samples/CFE for sham samples) was the dependent measure for each experiment. Results During a pilot study (8 experiments), a trend of increased cell proliferation in Qigong-treated samples (CFE Qigong/sham ratios > 1.0) was observed (P = 0.162). In a formal study (28 experiments), a similar trend was observed, with Qigong-treated samples showing on average more colony formation than sham samples (P = 0.036). In a replication study (60 experiments), no significant difference between Qigong-treated samples and sham samples was observed (P = 0.465). Conclusion We observed an apparent increase in the proliferation of cultured cells following external Qigong treatment by practitioners under strictly controlled conditions, but we did not observe this effect in a replication study. These results suggest the need for more controlled and thorough investigation of external Qigong before scientific validation is claimed.</p