Increased Risk of Cervical Dysplasia in Long-Term Survivors of Allogeneic Stem Cell Transplantation—Implications for Screening and HPV Vaccination

AbstractAs more women survive allogeneic stem cell transplantation (SCT), the development of genital human papilloma virus (HPV)-related squamous intraepithelial lesions (SIL) warrants study. Thirty-five of 38 females followed prospectively long-term after SCT for hematological malignancies (median: 7 years posttransplant) were adults and had cervical cytology testing. Acute graft-versus-host-disease (aGVHD) occurred in 9 and chronic (cGVHD) in 34 patients. Six (17%) continued receiving systemic immunosuppressive therapy (IST) for cGVHD >3 years after SCT. Of 15 (43%) with abnormal cytology, 12 (34%) patients had HPV-related SIL (median time to SIL 51 months, range: 22-108) including high-grade SIL in 7 (20%). Patients requiring continued IST had the highest risk (odds ratio [OR] 4.6, 95% confidence interval [CI] 1.1-16.4; P = .019). This high incidence of SIL in long-term SCT survivors underscores the importance of gynecologic assessment after transplantation, especially in those requiring IST. This may portend an increased risk of genital or other HPV-related malignancies

Donor origin of circulating endothelial progenitors after allogeneic bone marrow transplantation

AbstractEndothelial cell precursors circulate in blood and express antigens found on hematopoietic stem cells, suggesting that such precursors might be subject to transplantation. To investigate, we obtained adherence-depleted peripheral blood mononuclear cells from 3 individuals who had received a sex-mismatched allogeneic bone marrow transplant (BMT) and cultured the cells on fibronectin-coated plates with endothelial growth factors. The phenotype of the spindle-shaped cells that emerged in culture was characterized by immunofluorescent staining, and the origin of the cells was determined using a polymerase chain reaction (PCR)-based assay for polymorphic short tandem repeats (STRs). The cells manifested a number of endothelial characteristics-such as von Wlllebrand factor, CD31, and Flk-1/KDR expression; Bandeiraea simplicifolia lectin 1 binding; and acetylated low-density lipoprotein uptake-but lacked expression of certain markers of activation or differentiation, including intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and the epitope for the anti-endothelial cell antibody P1H12. For each patient and at all time points studied (ranging from 5 to 52 months after transplantation), STR-PCR analysis showed that cultured cells and nucleated blood cells came exclusively from the bone marrow donor. These results demonstrate that circulating endothelial progenitors are both transplantable and capable of long-term repopulation of human allogeneic BMT recipients.Biol Blood Marrow Transplant 2000;6(3A):301-8

Comparing and contrasting the νμ→ντ\nu_{\mu} \to \nu_{\tau} and νμ→νs\nu_{\mu} \to \nu_s solutions to the atmospheric neutrino problem with SuperKamiokande data

The $\nu_{\mu} \to \nu_{\tau}$ and $\nu_{\mu} \to \nu_s$ solutions to the atmospheric neutrino problem are compared with SuperKamiokande data. The differences between these solutions due to matter effects in the Earth are calculated for the ratio of $\mu$-like to $e$-like events and for up-down flux asymmetries. These quantities are chosen because they are relatively insensitive to theoretical uncertainties in the overall neutrino flux normalisation and detection cross-sections and efficiencies. A $\chi^2$ analysis using these quantities is performed yielding $3\sigma$ ranges which are approximately given by $(0.725 - 1.0, 4 \times 10^{-4} - 2 \times 10^{-2} eV^2)$ and $(0.74 - 1.0, 1 \times 10^{-3} - 2 \times 10^{-2} eV^2)$ for $(\sin^2 2\theta,\Delta m^2)$ for the $\nu_{\mu} \to \nu_{\tau}$ and $\nu_{\mu} \to \nu_s$ solutions, respectively. Values of $\Delta m^2$ smaller than about $2 \times 10^{-3}$ eV$^2$ are disfavoured for the $\nu_{\mu} \to \nu_s$ solution, suggesting that future long baseline experiments should see a positive signal if this scenario is the correct one.Comment: revtex, 22 pages, 12 figure

Common \u3cem\u3eTDP1\u3c/em\u3e Polymorphisms in Relation to Survival Among Small Cell Lung Cancer Patients: A Multicenter Study from the International Lung Cancer Consortium

Background—DNA topoisomerase inhibitors are commonly used for treating small-cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common TDP1 single-nucleotide polymorphisms (SNP) are associated with overall survival among SCLC patients. Methods—Two TDP1 SNPs (rs942190 and rs2401863) were analyzed in 890 patients from 10 studies in the International Lung Cancer Consortium (ILCCO). The Kaplan–Meier method and Cox regression analyses were used to evaluate genotype associations with overall mortality at 36 months postdiagnosis, adjusting for age, sex, race, and tumor stage. Results—Patients homozygous for the minor allele (GG) of rs942190 had poorer survival compared with those carrying AA alleles, with a HR of 1.36 [95% confidence interval (CI): 1.08–1.72, P = 0.01), but no association with survival was observed for patients carrying the AG genotype (HR = 1.04, 95% CI, 0.84–1.29, P = 0.72). For rs2401863, patients homozygous for the minor allele (CC) tended to have better survival than patients carrying AA alleles (HR = 0.79; 95% CI, 0.61–1.02, P = 0.07). Results from the Genotype Tissue Expression (GTEx) Project, the Encyclopedia of DNA Elements (ENCODE), and the ePOSSUM web application support the potential function of rs942190. Conclusions—We found the rs942190 GG genotype to be associated with relatively poor survival among SCLC patients. Further investigation is needed to confirm the result and to determine whether this genotype may be a predictive marker for treatment efficacy of DNA topoisomerase inhibitors

Experiences of non-progressive and augmented labour among nulliparous women: a qualitative interview study in a Grounded Theory approach

<p>Abstract</p> <p>Background</p> <p>Non-progressive labour is the most common complication in nulliparas and is primarily treated by augmentation. Augmented labour is often terminated by instrumental delivery. Little qualitative research has addressed experiences of non-progressive and augmented deliveries. The aim of this study was to gain a deeper understanding of the experience of non-progressive and augmented labour among nulliparas and their experience of the care they received.</p> <p>Methods</p> <p>A qualitative study was conducted using individual interviews. Data was collected and analysed according to the Grounded Theory method. The participants were a purposive sample of ten women. The interviews were conducted 4–15 weeks after delivery.</p> <p>Results</p> <p>The women had contrasting experiences during the birth process. During labour there was a conflict between the expectation of having a natural delivery and actually having a medical delivery. The women experienced a feeling of separation between mind and body. Interacting with the midwife had a major influence on feelings of losing and regaining control. Reconciliation between the contrasting feelings during labour was achieved. The core category was named Dialectical Birth Process and comprised three categories: Balancing natural and medical delivery, Interacting, Losing and regaining control.</p> <p>Conclusion</p> <p>A dialectical process was identified in these women's experiences of non-progressive labour. The process is susceptible to interaction with the midwife; especially her support to the woman's feeling of being in control. Midwives should secure that the woman's recognition of the fact that the labour is non-progressive and augmentation is required is handled with respect for the dialectical process. Augmentation of labour should be managed as close to the course of natural labour and delivery as possible.</p

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment