Response of pulmonary artery intimal sarcoma to surgery, radiotherapy and chemotherapy: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pulmonary artery intimal sarcoma is a rare disease with no characteristic symptoms. It is difficult to diagnose early and is frequently misdiagnosed as a pulmonary embolism.</p> <p>Case presentation</p> <p>Here we report a case of pulmonary artery intimal sarcoma in a 54-year-old woman presenting with complaints of shortness of breath on exertion. Echocardiography and a computed tomography scan showed that the right pulmonary artery trunk was blocked by a low-density mass. The patient was diagnosed with pulmonary artery intimal sarcoma by pathology and a complete mass resection was performed. After experiencing 10 months of disease-free survival, she was re-admitted because of the recurrence and metastasis of the tumor. Radiotherapy and chemotherapy were performed; however, only limited success was achieved. The patient died 15 months after the initial onset of symptoms.</p> <p>Conclusion</p> <p>Some patients with intimal sarcoma of the pulmonary artery can benefit from radiotherapy and chemotherapy as well as surgery.</p

Inference of population splits and mixtures from genome-wide allele frequency data

Many aspects of the historical relationships between populations in a species are reflected in genetic data. Inferring these relationships from genetic data, however, remains a challenging task. In this paper, we present a statistical model for inferring the patterns of population splits and mixtures in multiple populations. In this model, the sampled populations in a species are related to their common ancestor through a graph of ancestral populations. Using genome-wide allele frequency data and a Gaussian approximation to genetic drift, we infer the structure of this graph. We applied this method to a set of 55 human populations and a set of 82 dog breeds and wild canids. In both species, we show that a simple bifurcating tree does not fully describe the data; in contrast, we infer many migration events. While some of the migration events that we find have been detected previously, many have not. For example, in the human data we infer that Cambodians trace approximately 16% of their ancestry to a population ancestral to other extant East Asian populations. In the dog data, we infer that both the boxer and basenji trace a considerable fraction of their ancestry (9% and 25%, respectively) to wolves subsequent to domestication, and that East Asian toy breeds (the Shih Tzu and the Pekingese) result from admixture between modern toy breeds and "ancient" Asian breeds. Software implementing the model described here, called TreeMix, is available at http://treemix.googlecode.comComment: 28 pages, 6 figures in main text. Attached supplement is 22 pages, 15 figures. This is an updated version of the preprint available at http://precedings.nature.com/documents/6956/version/

Pre-mRNA Splicing Modulation by Antisense Oligonucleotides

Pre-mRNA splicing, a dynamic process of intron removal and exon joining, is governed by a combinatorial control exerted by overlapping cis-elements that are unique to each exon and its flanking intronic sequences. Splicing cis-elements are usually 4-to-8-nucleotide-long linear motifs that provide binding sites for specific proteins. Pre-mRNA splicing is also influenced by secondary and higher order RNA structures that affect accessibility of splicing cis-elements. Antisense oligonucleotides (ASOs) that block splicing cis-elements and/or affect RNA structure have been shown to modulate splicing in vivo. Therefore, ASO-based strategies have emerged as a powerful tool for therapeutic manipulation of splicing in pathological conditions. Here we describe an ASO-based approach to increase the production of the full-length SMN2 mRNA in spinal muscular atrophy patient cells

Neddylation inhibition upregulates PD‐L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149569/1/ijc32379_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149569/2/ijc32379-sup-0001-Supinfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149569/3/ijc32379.pd

Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis

<p>Abstract</p> <p>Background</p> <p>Toll-like receptors (TLRs) have garnered an extraordinary amount of interest in cancer research due to their role in tumor progression. By activating the production of several biological factors, TLRs induce type I interferons and other cytokines, which drive an inflammatory response and activate the adaptive immune system. The aim of this study was to investigate the expression and clinical relevance of TLR3, 4 and 9 in breast cancer.</p> <p>Methods</p> <p>The expression levels of TLR3, TLR4 and TLR9 were analyzed on tumors from 74 patients with breast cancer. The analysis was performed by immunohistochemistry.</p> <p>Results</p> <p>Samples of carcinomas with recurrence exhibited a significant increase in the mRNA levels of TLR3, TLR4 and TLR9. Tumors showed high expression of TLRs expression levels by cancer cells, especially TLR4 and 9. Nevertheless, a significant percentage of tumors also showed TLR4 expression by mononuclear inflammatory cells (21.6%) and TLR9 expression by fibroblast-like cells (57.5%). Tumors with high TLR3 expression by tumor cell or with high TLR4 expression by mononuclear inflammatory cells were significantly associated with higher probability of metastasis. However, tumours with high TLR9 expression by fibroblast-like cells were associated with low probability of metastasis.</p> <p>Conclusions</p> <p>The expression levels of TLR3, TLR4 and TLR9 have clinical interest as indicators of tumor aggressiveness in breast cancer. TLRs may represent therapeutic targets in breast cancer.</p

Characterization of Epstein-Barr Virus miRNAome in Nasopharyngeal Carcinoma by Deep Sequencing

Virus-encoded microRNAs (miRNAs) have been shown to regulate a variety of biological processes involved in viral infection and viral-associated pathogenesis. Epstein-Barr virus (EBV) is a herpesvirus implicated in nasopharyngeal carcinoma (NPC) and other human malignancies. EBV-encoded miRNAs were among the first group of viral miRNAs identified. To understand the roles of EBV miRNAs in the pathogenesis of NPC, we utilized deep sequencing technology to characterize the EBV miRNA transcriptome in clinical NPC tissues. We obtained more than 110,000 sequence reads in NPC samples and identified 44 EBV BART miRNAs, including four new mature miRNAs derived from previously identified BART miRNA precursor hairpins. Further analysis revealed extensive sequence variations (isomiRs) of EBV miRNAs, including terminal isomiRs at both the 5′ and 3′ ends and nucleotide variants. Analysis of EBV genomic sequences indicated that the majority of EBV miRNA nucleotide variants resulted from post-transcriptional modifications. Read counts of individual EBV miRNA in NPC tissue spanned from a few reads to approximately 18,000 reads, confirming the wide expression range of EBV miRNAs. Several EBV miRNAs were expressed at levels similar to highly abundant human miRNAs. Sequence analysis revealed that most of the highly abundant EBV miRNAs share their seed sequences (nucleotides 2–7) with human miRNAs, suggesting that seed sequence content may be an important factor underlying the differential accumulation of BART miRNAs. Interestingly, many of these human miRNAs have been found to be dysregulated in human malignancies, including NPC. These observations not only provide a potential linkage between EBV miRNAs and human malignancy but also suggest a highly coordinated mechanism through which EBV miRNAs may mimic or compete with human miRNAs to affect cellular functions

Nonsense Mediated Decay Resistant Mutations Are a Source of Expressed Mutant Proteins in Colon Cancer Cell Lines with Microsatellite Instability

BACKGROUND: Frameshift mutations in microsatellite instability high (MSI-High) colorectal cancers are a potential source of targetable neo-antigens. Many nonsense transcripts are subject to rapid degradation due to nonsense-mediated decay (NMD), but nonsense transcripts with a cMS in the last exon or near the last exon-exon junction have intrinsic resistance to nonsense-mediated decay (NMD). NMD-resistant transcripts are therefore a likely source of expressed mutant proteins in MSI-High tumours. METHODS: Using antibodies to the conserved N-termini of predicted mutant proteins, we analysed MSI-High colorectal cancer cell lines for examples of naturally expressed mutant proteins arising from frameshift mutations in coding microsatellites (cMS) by immunoprecipitation and Western Blot experiments. Detected mutant protein bands from NMD-resistant transcripts were further validated by gene-specific short-interfering RNA (siRNA) knockdown. A genome-wide search was performed to identify cMS-containing genes likely to generate NMD-resistant transcripts that could encode for antigenic expressed mutant proteins in MSI-High colon cancers. These genes were screened for cMS mutations in the MSI-High colon cancer cell lines. RESULTS: Mutant protein bands of expected molecular weight were detected in mutated MSI-High cell lines for NMD-resistant transcripts (CREBBP, EP300, TTK), but not NMD-sensitive transcripts (BAX, CASP5, MSH3). Expression of the mutant CREBBP and EP300 proteins was confirmed by siRNA knockdown. Five cMS-bearing genes identified from the genome-wide search and without existing mutation data (SFRS12IP1, MED8, ASXL1, FBXL3 and RGS12) were found to be mutated in at least 5 of 11 (45%) of the MSI-High cell lines tested. CONCLUSION: NMD-resistant transcripts can give rise to expressed mutant proteins in MSI-High colon cancer cells. If commonly expressed in primary MSI-High colon cancers, MSI-derived mutant proteins could be useful as cancer specific immunological targets in a vaccine targeting MSI-High colonic tumours

Efficacy of praziquantel and artemisinin derivatives for the treatment and prevention of human schistosomiasis: a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Praziquantel has been used as first-line drug for chemotherapy of schistosomiasis since 1984. Besides praziquantel, artemether and artesunate have also been used for the control of this infectious disease since late 1990s. In this article, we conducted a systematic review and meta-analysis to evaluate the antischistosomal efficacy of different medication strategies including monotherapy or combination therapies of these drugs.</p> <p>Results</p> <p>A number of 52 trials from 38 articles published in peer-reviewed journals before July 2011 were selected for analysis after searching the following literature databases: the Cochrane Library, PubMed/Medline, ISI Web of Science, Chinese Biomedicine Literature Database, and China National Knowledge Infrastructure. Our meta-analyses showed that a dosage of 30-60 mg/kg praziquantel compared with placebo produced a protection rate of about 76% (95% CI: 67%-83%) for treating human schistosomiasis, which varied from 70% to 76% with no significant differences among the subspecies <it>S. haematobium</it>, <it>S. japonicum </it>or <it>S. mansoni</it>. Protection rates were higher when praziquantel doses were elevated, as concluded from the nRCTs results: the protection rate of praziquantel at 40 mg/kg was 52% (95% CI: 49%-55%), and it increased to 91% (95% CI: 88%-92%) when the dosages were elevated to 60/80/100 mg/kg divided two or more doses. Multiple doses of artemether or artesunate over 1- or 2-week intervals resulted in protection rates of 65% to 97% for preventing schistosomiasis, and increased doses and shorter medication intervals improved their efficacies. Praziquantel and artemisinin derivatives (artemether or artesunate) in combination resulted in a higher protection rate of 84% (95% CI: 64%-91%) than praziquantel monotherapy for treatment. praziquantel and artesunate in combination had a great protection rate of 96% (95% CI: 78%-99%) for preventing schistosomes infection.</p> <p>Conclusions</p> <p>According to the results, praziquantel remains effective in schistosomiasis treatment, and multiple doses would improve its efficacy; meanwhile, praziquantel is also a good drug for preventing acute schistosomiasis morbidity. It's better to use multiple doses of artemether or artesunate with 1- or 2-week intervals for prevention against schistosome infection. Praziquantel and artemether or artesunate in combination perform better in treatment than praziquantel monotherapy, and they are especially suitable for treating the patients with repeated exposure to infected water.</p

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7. ISS-N1 is a complex regulatory element encompassing overlapping negative motifs and sequestering a cryptic splice site. More than 40 protein factors have been implicated in the regulation of SMN exon 7 splicing. There is evidence to support that multiple exons of SMN are alternatively spliced during oxidative stress, which is associated with a growing number of pathological conditions. Here, we provide the most up to date account of the mechanism of splicing regulation of the SMN genes

Gene Expression Analysis of Forskolin Treated Basilar Papillae Identifies MicroRNA181a as a Mediator of Proliferation

Auditory hair cells spontaneously regenerate following injury in birds but not mammals. A better understanding of the molecular events underlying hair cell regeneration in birds may allow for identification and eventually manipulation of relevant pathways in mammals to stimulate regeneration and restore hearing in deaf patients.Gene expression was profiled in forskolin treated (i.e., proliferating) and quiescent control auditory epithelia of post-hatch chicks using an Affymetrix whole-genome chicken array after 24 (n = 6), 48 (n = 6), and 72 (n = 12) hours in culture. In the forskolin-treated epithelia there was significant (p<0.05; >two-fold change) upregulation of many genes thought to be relevant to cell cycle control and inner ear development. Gene set enrichment analysis was performed on the data and identified myriad microRNAs that are likely to be upregulated in the regenerating tissue, including microRNA181a (miR181a), which is known to mediate proliferation in other systems. Functional experiments showed that miR181a overexpression is sufficient to stimulate proliferation within the basilar papilla, as assayed by BrdU incorporation. Further, some of the newly produced cells express the early hair cell marker myosin VI, suggesting that miR181a transfection can result in the production of new hair cells.These studies have identified a single microRNA, miR181a, that can cause proliferation in the chicken auditory epithelium with production of new hair cells