IntroductionNormal pressure hydrocephalus (NPH) has conventionally been treated by placement of a ventriculoperitoneal shunt. However, it can also be treated with a less invasive technique, an endoscopic third ventriculostomy (ETV). Unfortunately, there is a lack of evidence on the characteristics of NPH patients who are most likely to benefit from ETV. This study seeks to identify if patients at risk of dementia with NPH should be candidates for an ETV. MethodologyThirty-six NPH patients who underwent ETV at two institutions between July 2007 and December 2014 were pre-surgically assessed for various risk factors. At the time of ETV, a cortical biopsy was obtained and assessed for plaques consistent with dementia. Post-procedure, patients were followed and assessed for symptoms such as gait improvement, headache, memory problems, incontinence, and dementia. ETV success was defined as an improvement in gait. ResultsThe mean age of patients with successful ETVs was 65.8 ± 6.0 versus 74.5 ± 7.0 for failed ETVs. Sixty-seven percent of patients with negative biopsies showed gait improvement by the final follow-up appointment as compared to only 33% of patients with positive biopsies (p>0.05). Younger age was correlated with successful ETV (p=.003). Memory disturbance (p<0.05) and incontinence (p<0.05) after surgery were both associated with a lack of gait improvement at the final follow-up. ConclusionBiopsy was not a significant predictor of ETV success; however, there was a correlation between younger age and ETV success. Additional studies are required to determine if there is a relationship between cortical biopsy findings and ETV success.
Background: Previously we found that survivin is expressed on the surface of cancer cells in vitro, and is targetable using certain survivin-specific antibodies. The survivin gene is alternatively spliced into two alternative isoforms, ΔEX3 and 2B, which diverge structurally from the canonical isoform in their C-termini but retain a conserved BIR (Baculovirus IAP Repeat) domain. Methods: In order to characterize plasma membrane survivin (PM-SVN), tagged proteins representing canonical survivin (isoform 1), Δex3 and 2B were transiently expressed in multiple cancer cell line backgrounds. Relative surface expression was measured by flow cytometry staining of intact cells. Mutant constructs were used to determine the structural requirements for translocation. Imaging flow cytometry (Imagestream) was used to visualize survivin isoform localization, and to detect co-localization on the cell surface. Secreted exosomes were examined for expression of survivin isoforms. Results: Isoforms 1, Δex3 and 2B could be detected on the surface of HEK293T embryonic kidney, HeLa cervical adenocarcinoma, U87 glioblastoma, and A1207 glioblastoma cells. PM-SVN expression was variable, however Δex3 showed robust membrane expression across all cell lines. Deletion of a predicted transmembrane sequence in Δex3's unique C-terminus did not impair its translocation, and deletion of the first 10 amino acids, thought to be required for dimerization, disrupted surface expression only in HEK293T cells. Imaging flow cytometry analysis of cells revealed polar localization of PM-SVN, with specific punctate areas seen in 13-20% of cells. Staining with antibodies targeting both isoform 1 and Δex3 showed co-immunofluorescence in cell membrane puncta, indicating the formation of heterodimers. Stressing cells by heat shock increased the proportion of PM-SVN in 293T and A1207 cells; in 293T, this was accompanied by enrichment of survivin protein in secreted exosomes. Conclusions: In addition to canonical survivin, isoforms Δex3 and 2B are displayed on the surface of cancer cells, and can be secreted as exosomal cargo. Membrane translocation may be stress-induced and appears to require the conserved BIR domain. PM-SVN shows a polar distribution on the cell membrane, and isoforms 1 and Δex3 heterodimerize within these puncta. Citation Format: Sheila Figel, Meaghan Birkemeier, Sanam Dharma, Emma Steinmetz, Michael Ciesielski, Robert Fenstermaker. Canonical and noncanonical survivin isoforms translocate to the plasma membrane and are secreted in exosomes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2939.
Background: BIRC5/survivin is highly expressed in cancer cells and represents a promising therapeutic target. In order to complete a comprehensive survey of its splice variants, we applied a direct RT-PCR approach as well as next generation sequencing (NGS) to tumor cell cDNAs. We have identified 10 novel splice junctions and three novel splice variants of survivin. Methods: Survivin transcripts were amplified from A1207 (glioblastoma) HeLa (cervical adenocarcinoma) and U87 (glioblastoma) cDNAs. For manual identification of splice forms, individual products were subcloned into TOPO vector and sequenced. For NGS analysis, RT-PCR products used to generate libraries which were subjected to sequencing, after which resulting reads were mapped against the human reference genome and assembled by Trinity. Results: Survivin RT-PCR products from A1207 cDNA were isolated and selected for TOPO cloning/sequencing. Of seventeen clones, the canonical isoform was represented by 4, and known variants including Δex3, 2B and 3B were represented by 5. Two novel sequences were identified: 1) 2B/Δex3, which contains a 68 bp shuffled exon 4/3 segment between exons 3 and 4 plus the 2B insert, and 2) 4B, in which exon 4 is extended by 27 bp at its 5' end. Both of these transcripts are predicted to encode full-length proteins: 2B/Δex3 contains the 23 aa 2B insert plus Δex3's unique C-terminus; 4B contains a novel 9 aa motif embedded in survivin's C-terminal alpha helix. RT-PCR products from A1207, HeLa and U87 templates subjected to NGS yielded five full-length BIRC5 contigs, including the canonical isoform, Δex3, 2B, 3B, and the predicted variant 2B/3B. To identify novel splice junctions, sequences were searched excluding canonical exon boundaries. The resulting 151 reads represented 10 novel exon junctions, among which the greatest proportion consisted of exon 1 and 3 (71 reads, 47%), or an extension of exon 2B by 32 bp at its 3' end (35 reads, 23%). Two variants contained the extended version of exon 4 seen in isoform 4B. A primer annealing within exon 4B's unique 27 bp was subsequently used for RT-PCR to validate the expression of the full-length isoform in HeLa, U87, A1207 and HEK293T cells. Conclusions: We have identified multiple novel splice variants of survivin, including Δex3/2B, 4B, and Δex3/4B. Proteins encoded by these transcripts potentially have pro- or anti-oncogenic functions, and further studies are needed to delineate their role in survivin biologies. Citation Format: Sheila Figel, Meaghan Birkemeier, Jesse Luce, Prashant Singh, Jianmin Wang, Cheryl Frank, Sanam Dharma, Emma Steinmetz, Michael Ciesielski, Robert Fenstermaker. Identification of novel BIRC5/survivin splice variants in cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5873.
Main Outcome Measure(s): During each session, the current amplitude, ankle weight and repetitions were recorded. The average of two consecutive sessions was used to represent that data of every week. Repeated measure analysis of variances (ANOVA) was used to analyze data from weeks 1, 4, 8, 12 and 16. Results: Lifted weight significantly (P< 0.0001) increased over the 16 week training period for the right (19.6AE6.5 lbs.) and the left (20AE6.1 lbs.) legs. Amplitude of the current did not change significantly over the course of 16 week period. The amplitude of the current was significantly greater in the third and fourth sets compared to the first and second sets. Amplitude of the current was significantly lower in the left leg compared to the right leg in weeks 1, 4, 8, 12 and 16 of the training. The total number of repetitions was not different across the 16 weeks. Conclusions: Despite a progressive increase in weights, the amplitude of the current required to perform leg extension did not change over the 16 weeks of RT. A shin weight on average of 20 lbs. or less than 26 lbs. appears to be a safe strategy to perform dynamic leg extension in chronic individuals with SCI. There is a clear discrepancy in the amplitude of the current between the right and left legs; which requires further studies.
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