Expression (Exp) of FIP200 and Rb in breast cancer (BreastCA) metastasis (met) to the brain.

2011 ◽  
Vol 29 (27_suppl) ◽  
pp. 222-222
Author(s):  
N. Hashemi Sadraei ◽  
M. Burgett ◽  
M. S. Ahluwalia ◽  
R. Tipps ◽  
D. Khosla ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Dna Analysis ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Deletion Mutations ◽  
The Us ◽  
Her 2 ◽  
The Brain ◽  
Gene Alterations

222 Background: BreastCA is the 2nd leading cause of cancer deaths in women in the US. Although the outcome for BreastCA with brain met remains poor, there is significant variation in overall survival (OS). Yet, there are no markers or models to predict OS. FIP200 regulates several pathways. In the nucleus, it inhibits cell proliferation by promoting Rb-1 and p21, and in the cytoplasm it promotes cell survival by inhibiting Pyk2 and regulating autophagy. It has been reported that FIP200 gene is deleted or mutated in 20% of primary BreastCAs, and its Exp is correlated with Rb1 levels. FIP200 Exp, its cellular localization, and gene alterations have not been examined in brain met of any cancer. Methods: Brain met tissues of 21 BreastCA patients (pts) biopsied in our institution between 8/2000 and 3/2010 were obtained and Exp of FIP200 and Rb1 were analyzed. Biopsies were selected based on tissue adequacy and prior diagnosis (Dx) of invasive intra-ductal BreastCA. Immunohistochemistry (IHC) was used to evaluate the localization and Exp levels of FIP200 and Rb1 which in turn were tested as predictors of OS. Genetic alterations in FIP200 and Rb1 were examined after DNA extraction. Results: Median time from Dx to met was 23 (range 0-245) months (mos), and median OS from Dx was 43 (range 6-264) mos. Nuclear Exp of Rb1 in < 30% vs. ≥ 30% of cells were seen in 11 vs. 10 pts. Median OS was 39 (range 6-264) mos for Rb1 Exp < 30% and 47 (range 20-190) mo for Rb1 Exp ≥ 30%. Nuclear Exp of FIP200 in <20% vs. ≥ 20% of cells were seen in 13 vs. 8 pts. Median OS was 39 (range 6-264) mo for FIP200 nuclear Exp <20% and 45 (range 43-122) mo for FIP200 Exp ≥ 20%. DNA analysis of 11 pts for copy number variations and loss of heterozygocity (LOH) showed no deletion mutations in FIP200 or Rb1, loss of p53 in 4 of 11, ErbB2 (Her-2) amplification in 4 of 11, and no EGFR gene mutations. Conclusions: The nuclear Exp of Rb1 in brain met from invasive intra-ductal BreastCA may be linked OS. An expanded study is underway to define whether nuclear FIP200 in >20% of cells correlates with nuclear Rb and OS in BreastCA.

FIP200 and Rb1 expression in CNS metastasis from breast cancer (CNS met): Potential predictors of patient outcome.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2014-2014
Author(s):  
Nooshin Hashemi Sadraei ◽  
Ilya Ulasov ◽  
Monica Burgett ◽  
Amy S Nowacki ◽  
Richard Prayson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Survival ◽  
Cellular Localization ◽  
Dna Analysis ◽  
Metastatic Breast ◽  
Genetic Alterations ◽  
Negative Regulator ◽  
Array Analysis ◽  
Number Variation ◽  
Low Expression

2014 Background: Patients with CNS met have a poor outcome with significant variation in overall survival. No marker to predict survival exists. Rb1 is a negative regulator of the cell cycle, and FiP200 is an upstream signaling node that is distributed between the nucleus and cytoplasm. Nuclear FIP200 inhibits cell proliferation by promoting expression of Rb1, whereas cytoplasmic FIP200 promotes cell survival through autophagy. Previously FIP200 deletion/mutation has been reported in 20% of primary invasive breast cancer [BR ca] patients. FIP200 cellular localization and genetic alterations have not been examined in CNS met. Methods: A retrospective analysis of BR ca and CNS met was performed based on tissue availability from 2 institutions. FIP200 and Rb1 expression and localization was evaluated by immunohistochemistry. Genetic alterations were evaluated by DNA array analysis. Results: 80 patients (42 BR ca and 38 CNS met) were identified. Overall CNS met samples had significantly higher levels of cytoplasmic FIP200 as compared to BR ca (52% vs 24% respectively, p=0.0002) and increased expression of FIP200 around areas of hypoxia/necrosis, consistent with increased autophagy. There was also a significant increase in expression of nuclear FIP200 and Rb1 in the CNS met compared to BR ca (p=0.0007 and p=0.0055 respectively). Median survival from development of CNS met was longer in the group with high levels of nuclear Rb1; 14 (3-27) vs 20 (12-33) months (low expression < 20% vs high ≥ 20%, p=0.1). The same finding was observed with FIP200, longer survival was observed with high nuclear expression; 16 (7-33) vs 19 (0.4-27) months (low expression <20% vs high ≥ 20%, p=0.2). Our DNA analysis for copy number variation and LOH in CNS met revealed no deletion in Rb1 or FIP200. Conclusions: The pattern of expression of Rb1 and FIP200 in CNS met is different from BR ca. Notably, cytoplasmic FIP200 which promotes cell survival is highly expressed in CNS mets vs BR ca. This suggests metastatic breast cancer cells utilize autophagy as a survival mechanism. In addition, there is a trend to better survival of those patients with CNS met who express high nuclear FIP200 and Rb1, both of which have anti-proliferative roles in the nucleus.

Moving past the vaccine/autism controversy - to examine potential vaccine neurological harms

2020 ◽  
pp. 1-15
Author(s):  
Peter R. Breggin
Keyword(s):  
Neurological Disorders ◽  
Developmental Disorder ◽  
Physical Symptoms ◽  
Psychosocial Disorders ◽  
The Us ◽  
Potential Vaccine ◽  
Research And Education ◽  
The Brain ◽  
New Vaccines

BACKGROUND: The vaccine/autism controversy has caused vast scientific and public confusion, and it has set back research and education into genuine vaccine-induced neurological disorders. The great strawman of autism has been so emphasized by the vaccine industry that it, and it alone, often appears in authoritative discussions of adverse effects of the MMR and other vaccines. By dismissing the chimerical vaccine/autism controversy, vaccine defenders often dismiss all genuinely neurological aftereffects of the MMR (measles, mumps, and rubella) and other vaccines, including well-documented events, such as relatively rare cases of encephalopathy and encephalitis. OBJECTIVE: This report explains that autism is not a physical or neurological disorder. It is not caused by injury or disease of the brain. It is a developmental disorder that has no physical origins and no physical symptoms. It is extremely unlikely that vaccines are causing autism; but it is extremely likely that they are causing more neurological damage than currently appreciated, some of it resulting in psychosocial disabilities that can be confused with autism and other psychosocial disorders. This confusion between a developmental, psychosocial disorder and a physical neurological disease has played into the hands of interest groups who want to deny that vaccines have any neurological and associated neuropsychiatric effects. METHODS: A review of the scientific literature, textbooks, and related media commentary is integrated with basic clinical knowledge. RESULTS: This report shows how scientific sources have used the vaccine/autism controversy to avoid dealing with genuine neurological risks associated with vaccines and summarizes evidence that vaccines, including the MMR, can cause serious neurological disorders. Manufacturers have been allowed by the US Food and Drug Administration (FDA) to gain vaccine approval without placebo-controlled clinical trials. CONCLUSIONS: The misleading vaccine autism controversy must be set aside in favor of examining actual neurological harms associated with vaccines, including building on existing research that has been ignored. Manufacturers of vaccines must be required to conduct placebo-controlled clinical studies for existing vaccines and for government approval of new vaccines. Many probable or confirmed neurological adverse events occur within a few days or weeks after immunization and could be detected if the trials were sufficiently large. Contrary to current opinion, large, long-term placebo-controlled trials of existing and new vaccines would be relatively easy and safe to conduct.

Neuro-Optometric Treatment of Complications from a Cerebellar Astrocytoma

2020 ◽  
pp. 304-312
Keyword(s):  
Visual System ◽  
Common Site ◽  
Us Army ◽  
Cranial Nerve Palsies ◽  
Pilocytic Astrocytomas ◽  
The Us ◽  
Extent Of Damage ◽  
Functional Components ◽  
The Brain

Background: Insult to the brain, whether from trauma or other etiologies, can have a devastating effect on an individual. Symptoms can be many and varied, depending on the location and extent of damage. This presentation can be a challenge to the optometrist charged with treating the sequelae of this event as multiple functional components of the visual system can be affected. Case Report: This paper describes the diagnosis and subsequent ophthalmic management of an acquired brain injury in a 22 year old male on active duty in the US Army. After developing acute neurological symptoms, the patient was diagnosed with a pilocytic astrocytoma of the cerebellum. Emergent neurosurgery to treat the neoplasm resulted in iatrogenic cranial nerve palsies and a hemispheric syndrome. Over the next 18 months, he was managed by a series of providers, including a strabismus surgeon, until presenting to our clinic. Lenses, prism, and in-office and out-of-office neurooptometric rehabilitation therapy were utilized to improve his functioning and make progress towards his goals. Conclusions: Pilocytic astrocytomas are the most common primary brain tumors, and the vast majority are benign with excellent surgical prognosis. Although the most common site is the cerebellum, the visual pathway is also frequently affected. If the eye or visual system is affected, optometrists have the ability to drastically improve quality of life with neuro-optometric rehabilitation.

Metabolism of Oxalate in Humans: A Potential Role Kynurenine Aminotransferase/Glutamine Transaminase/Cysteine Conjugate Betalyase Plays in Hyperoxaluria

2019 ◽  
Vol 26 (26) ◽  
pp. 4944-4963 ◽  
Author(s):  
Qian Han ◽  
Cihan Yang ◽  
Jun Lu ◽  
Yinai Zhang ◽  
Jianyong Li
Keyword(s):  
Cellular Localization ◽  
Structural Characteristics ◽  
Gene Mutations ◽  
Primary Hyperoxaluria ◽  
Glycolate Oxidase ◽  
Kynurenine Aminotransferase ◽  
Underlying Mechanisms ◽  
Urinary Oxalate Excretion ◽  
Glyoxylate Aminotransferase ◽  
Oxalate Metabolism

Hyperoxaluria, excessive urinary oxalate excretion, is a significant health problem worldwide. Disrupted oxalate metabolism has been implicated in hyperoxaluria and accordingly, an enzymatic disturbance in oxalate biosynthesis can result in the primary hyperoxaluria. Alanine-glyoxylate aminotransferase-1 and glyoxylate reductase, the enzymes involving glyoxylate (precursor for oxalate) metabolism, have been related to primary hyperoxalurias. Some studies suggest that other enzymes such as glycolate oxidase and alanine-glyoxylate aminotransferase-2 might be associated with primary hyperoxaluria as well, but evidence of a definitive link is not strong between the clinical cases and gene mutations. There are still some idiopathic hyperoxalurias, which require a further study for the etiologies. Some aminotransferases, particularly kynurenine aminotransferases, can convert glyoxylate to glycine. Based on biochemical and structural characteristics, expression level, and subcellular localization of some aminotransferases, a number of them appear able to catalyze the transamination of glyoxylate to glycine more efficiently than alanine glyoxylate aminotransferase-1. The aim of this minireview is to explore other undermining causes of primary hyperoxaluria and stimulate research toward achieving a comprehensive understanding of underlying mechanisms leading to the disease. Herein, we reviewed all aminotransferases in the liver for their functions in glyoxylate metabolism. Particularly, kynurenine aminotransferase-I and III were carefully discussed regarding their biochemical and structural characteristics, cellular localization, and enzyme inhibition. Kynurenine aminotransferase-III is, so far, the most efficient putative mitochondrial enzyme to transaminate glyoxylate to glycine in mammalian livers, which might be an interesting enzyme to look for in hyperoxaluria etiology of primary hyperoxaluria and should be carefully investigated for its involvement in oxalate metabolism.

Bilateral Striatal Necrosis with Polyneuropathy with a Novel SLC25A19 (Mitochondrial Thiamine Pyrophosphate Carrier OMIMI*606521) Mutation: Treatable Thiamine Metabolic Disorder—A Report of Two Indian Cases

2019 ◽  
Vol 50 (05) ◽  
pp. 313-317 ◽  
Author(s):  
Vykuntaraju K. Gowda ◽  
Varunvenkat M. Srinivasan ◽  
Kapil Jehta ◽  
Maya D. Bhat
Keyword(s):  
Gene Mutations ◽  
Febrile Illness ◽  
Flaccid Paralysis ◽  
Thiamine Pyrophosphate ◽  
Homozygous Mutation ◽  
Missense Variation ◽  
Magnetic Resonance Imaging Mri ◽  
The Brain ◽  
Generation Sequencing ◽  
Striatal Necrosis

Abstract Background SLC25A19 gene mutations cause Amish congenital lethal microcephaly and bilateral striatal necrosis with polyneuropathy. We are reporting two cases of bilateral striatal necrosis with polyneuropathy due to SLC25A19 gene mutations. Methods A 36-month-old boy and a 5-year-old girl, unrelated, presented with recurrent episodes of flaccid paralysis and encephalopathy following nonspecific febrile illness. Examination showed dystonia and absent deep tendon reflexes. Results Nerve conduction studies showed an axonal polyneuropathy. Magnetic resonance imaging (MRI) of the brain in both cases showed signal changes in the basal ganglia. Next-generation sequencing revealed a novel homozygous missense variation c.910G>A (p.Glu304Lys) in the SLC25A19 gene in the boy and a homozygous mutation c.869T > A (p. Leu290Gln) in the SLC25A19 gene in the girl. Mutations were validated by Sanger sequencing, and carrier statuses of parents of both children were confirmed. Both children improved with thiamine supplementation. Conclusion If any child presents with recurrent encephalopathy with flaccid paralysis, dystonia, and neuropathy, a diagnosis of bilateral striatal necrosis with polyneuropathy due to SLC25A19 mutations should be considered and thiamine should be initiated.

scholarly journals Genomic Mosaicism Formed by Somatic Variation in the Aging and Diseased Brain

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1071
Author(s):  
Isabel Costantino ◽  
Juliet Nicodemus ◽  
Jerold Chun
Keyword(s):  
Dna Sequence ◽  
Technology Development ◽  
Copy Number Variations ◽  
Brain Cell ◽  
Brain Diseases ◽  
Multiple Forms ◽  
Somatic Variation ◽  
Dna Content Variation ◽  
Effects Of Aging ◽  
The Brain

Over the past 20 years, analyses of single brain cell genomes have revealed that the brain is composed of cells with myriad distinct genomes: the brain is a genomic mosaic, generated by a host of DNA sequence-altering processes that occur somatically and do not affect the germline. As such, these sequence changes are not heritable. Some processes appear to occur during neurogenesis, when cells are mitotic, whereas others may also function in post-mitotic cells. Here, we review multiple forms of DNA sequence alterations that have now been documented: aneuploidies and aneusomies, smaller copy number variations (CNVs), somatic repeat expansions, retrotransposons, genomic cDNAs (gencDNAs) associated with somatic gene recombination (SGR), and single nucleotide variations (SNVs). A catch-all term of DNA content variation (DCV) has also been used to describe the overall phenomenon, which can include multiple forms within a single cell’s genome. A requisite step in the analyses of genomic mosaicism is ongoing technology development, which is also discussed. Genomic mosaicism alters one of the most stable biological molecules, DNA, which may have many repercussions, ranging from normal functions including effects of aging, to creating dysfunction that occurs in neurodegenerative and other brain diseases, most of which show sporadic presentation, unlinked to causal, heritable genes.

scholarly journals The CRISPR/Cas9 Minipig—A Transgenic Minipig to Produce Specific Mutations in Designated Tissues

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3024
Author(s):  
Martin Fogtmann Berthelsen ◽  
Maria Riedel ◽  
Huiqiang Cai ◽  
Søren H. Skaarup ◽  
Aage K. O. Alstrup ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Yellow Fluorescent Protein ◽  
Somatic Cells ◽  
Genetic Alterations ◽  
Lung Epithelial Cells ◽  
Target Cells ◽  
Multiple Gene ◽  
Conditional Expression ◽  
Gene Alterations

The generation of large transgenic animals is impeded by complex cloning, long maturation and gastrulation times. An introduction of multiple gene alterations increases the complexity. We have cloned a transgenic Cas9 minipig to introduce multiple mutations by CRISPR in somatic cells. Transgenic Cas9 pigs were generated by somatic cell nuclear transfer and were backcrossed to Göttingen Minipigs for two generations. Cas9 expression was controlled by FlpO-mediated recombination and was visualized by translation from red to yellow fluorescent protein. In vitro analyses in primary fibroblasts, keratinocytes and lung epithelial cells confirmed the genetic alterations executed by the viral delivery of single guide RNAs (sgRNA) to the target cells. Moreover, multiple gene alterations could be introduced simultaneously in a cell by viral delivery of sgRNAs. Cells with loss of TP53, PTEN and gain-of-function mutation in KRASG12D showed increased proliferation, confirming a transformation of the primary cells. An in vivo activation of Cas9 expression could be induced by viral delivery to the skin. Overall, we have generated a minipig with conditional expression of Cas9, where multiple gene alterations can be introduced to somatic cells by viral delivery of sgRNA. The development of a transgenic Cas9 minipig facilitates the creation of complex pre-clinical models for cancer research.

scholarly journals A Modified Method to Isolate Circulating Tumor Cells and Identify by a Panel of Gene Mutations in Lung Cancer

2021 ◽  
Vol 20 ◽  
pp. 153303382199527
Author(s):  
Helin Wang ◽  
Jieqing Wu ◽  
Qi Zhang ◽  
Jianqing Hao ◽  
Ying Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Detection Rate ◽  
Target Genes ◽  
White Blood Cells ◽  
Gene Mutations ◽  
Copy Number Variations ◽  
Immunomagnetic Beads ◽  
Membrane Rupture

The CellSearch system is the only FDA approved and successful used detection technology for circulating tumor cells(CTCs). However, the process for identification of CTCs by CellSearch appear to damage the cells, which may adversely affects subsequent molecular biology assays. We aimed to explore and establish a membrane-preserving method for immunofluorescence identification of CTCs that keeping the isolated cells intact. 98 patients with lung cancer were enrolled, and the efficacy of clinical detection of CTCs was examined. Based on the CellSearch principle, we optimized an anti-EpCAM antibody and improved cell membrane rupture. A 5 ml peripheral blood sample was used to enrich CTCs with EpCAM immunomagnetic beads. Fluorescence signals were amplified with secondary antibodies against anti-EpCAM antibody attached on immunomagnetic beads. After identifying CTCs, single CTCs were isolated by micromanipulation. To confirm CTCs, genomic DNA was extracted and amplified at the single cell level to sequence 72 target genes of lung cancer and analyze the mutation copy number variations (CNVs) and gene mutations. A goat anti-mouse polyclonal antibody conjugated with Dylight 488 was selected to stain tumor cells. We identified CTCs based on EpCAM+ and CD45+ cells to exclude white blood cells. In the 98 lung cancer patients, the detection rate of CTCs (≥1 CTC) per 5 ml blood was 87.76%, the number of detections was 1–36, and the median was 2. By sequencing 72 lung cancer-associated genes, we found a high level of CNVs and gene mutations characteristic of tumor cells. We established a new CTCs staining scheme that significantly improves the detection rate and allows further analysis of CTCs characteristics at the genetic level.

scholarly journals Molecular progression in unusual recurrent non-pediatric intracranial clear cell meningioma

2017 ◽  
Vol 24 (3) ◽  
pp. 244
Author(s):  
B. Domingo-Arrué ◽  
R. Gil-Benso ◽  
J. Megías ◽  
L. Navarro ◽  
T. San-Miguel ◽  
...  
Keyword(s):  
Clear Cell ◽  
Primary Tumour ◽  
Antigen Expression ◽  
Genetic Alterations ◽  
Clear Cell Meningioma ◽  
Initial Surgery ◽  
Homozygous Deletions ◽  
The Brain ◽  
Dependent Probe

We report a case of a recurrent clear cell meningioma (ccm) in the frontal lobe of the brain of a 67-year-old man. The patient developed three recurrences: at 3, 10, and 12 years after his initial surgery. Histopathology observations revealed a grade 2 ccm with positivity for vimentin and epithelial membrane antigen. Expression of E-cadherin was positive only in the primary tumour and in the first available recurrence. Fluorescence in situ hybridization analyses demonstrated 1p and 14q deletions within the last recurrence. Multiplex ligation-dependent probe amplification studies revealed a heterozygous partial NF2 gene deletion, which progressed to total loss in the last recurrence. The last recurrence showed homozygous deletions in CDKN2A and CDKN2B. The RASSF1 gene was hypermethylated during tumour evolution.In this report, we show the genetic alterations of a primary ccm and its recurrences to elucidate their relationships with the changes involved in the progression of this rare neoplasm.

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