From space to biomedicine: Enabling biomarker data science in the cloud.

NASA's Jet Propulsion Laboratory (JPL) is advancing research capabilities for data science with two of the National Cancer Institute's major research programs, the Early Detection Research Network (EDRN) and the Molecular and Cellular Characterization of Screen-Detected Lesions (MCL), by enabling data-driven discovery for cancer biomarker research. The research team pioneered a national data science ecosystem for cancer biomarker research to capture, process, manage, share, and analyze data across multiple research centers. By collaborating on software and data-driven methods developed for space and earth science research, the biomarker research community is heavily leveraging similar capabilities to support the data and computational demands to analyze research data. This includes linking diverse data from clinical phenotypes to imaging to genomics. The data science infrastructure captures and links data from over 1600 annotations of cancer biomarkers to terabytes of analysis results on the cloud in a biomarker data commons known as "LabCAS". As the data increases in size, it is critical that automated approaches be developed to "plug" laboratories and instruments into a data science infrastructure to systematically capture and analyze data directly. This includes the application of artificial intelligence and machine learning to automate annotation and scale science analysis.

On the redshift distribution and physical properties of ACT-selected DSFGs.

We present multi-wavelength detections of nine candidate gravitationally-lensed dusty star-forming galaxies (DSFGs) selected at 218GHz (1.4mm) from the ACT equatorial survey. Among the brightest ACT sources, these represent the subset of the total ACT sample lying in Herschel SPIRE fields, and all nine of the 218GHz detections were found to have bright Herschel counterparts. By fitting their spectral energy distributions (SEDs) with a modified blackbody model with power-law temperature distribution, we find the sample has a median redshift of z = 4.1 - 1.0 + 1.1 (68 per cent confidence interval), as expected for 218GHz selection, and an apparent total infrared luminosity of log 10 ( µ L IR / L ⊙ ) = 13.86 - 0.30 + 0.33 , which suggests that they are either strongly lensed sources or unresolved collections of unlensed DSFGs. The effective apparent diameter of the sample is µ d = 4.2 - 1.0 + 1.7 kpc , further evidence of strong lensing or multiplicity, since the typical diameter of dusty star-forming galaxies is 1.0-2.5 kpc. We emphasize that the effective apparent diameter derives from SED modelling without the assumption of optically thin dust (as opposed to image morphology). We find that the sources have substantial optical depth. ( τ = 4.2 - 1.9 + 3.7 ) to dust around the peak in the modified blackbody spectrum (λ obs ⩽ 500µm), a result that is robust to model choice.

The food retail environment and its use in a deprived, urban area of Scotland.

OBJECTIVES: This study sought to describe the food retail environment and its use in a deprived urban area in Scotland by mapping all food outlets and determining where residents do their main food shopping as well as investigating the availability of fresh fruit and vegetables (F&V) (as an indicator of healthy eating) and takeaway food. STUDY DESIGN: Cross-sectional study. METHODS: The food retail environment, the number, size and food availability of all food outlets, was mapped in Viewpark, a small community located to the east of Glasgow. Subsequently a validated questionnaire was used to determined food shopping usage and habits. RESULTS: There was high availability of common fresh fruit and vegetables (F&V) and very high availability of fast food outlets. Only 9% of the sample shopped solely at local food outlets within Viewpark whilst 91% shopped at a large supermarket outside Viewpark (n = 106). Walking was significantly negatively associated (B = -3.555, P = 0.008) with shopping outside the community. The majority of respondents (80%) reported buying F&V weekly and 57% purchased takeaways at least once a week - these individuals were employed, over 45 years old and had at least one child. CONCLUSIONS: The use of the local retail environment in a deprived community is influenced by car accessibility.

Expression of the Hypermethylated in Cancer gene (HIC-1) is associated with good outcome in human breast cancer.

A new cancer gene, HIC-1 (Hypermethylated in Cancer) telomeric to p53 on chromosome 17p may be of clinical importance in sporadic breast cancer. Regional DNA hypermethylation of 17p13.3 resulting in suppression of gene expression has been shown to precede 17p structural changes in human carcinogenesis. In addition, loss of heterozygosity studies have suggested clinically significant involvement of a gene on 17p13.3 associated with poor prognosis in breast cancer. Using RT-PCR analysis, we demonstrate that the MCF7 (wild type p53) cell line expressed HIC-1 transcripts but the MDAMB231 (mutant p53) cell line did not, suggesting loss of HIC-1 expression and p53 malfunction may be synergistic events in sporadic breast cancer. HIC-1 expression was examined using RT-PCR on RNA extracted from 50 primary untreated, human breast cancers and was detected in only 7/50 (14%) cancers. All seven patients with HIC-1 expression were alive without disease recurrence after 8 years follow-up and 5/7 had detectable p53 wild type mRNA expression. This suggests that retained HIC-1 expression may offer a survival advantage. However the seven cancers had 17p13.3 loss of heterozygosity (LOH; four patients), a feature previously associated with poor prognosis, or were homozygous (three patients) suggesting there may be two genes at 17p13.3 involved in breast carcinogenesis. Using a demethylating drug 5-aza-2'-deoxycytidine (DeoxyC), HIC-1 expression was restored in the MDAMB231 cells, also suggesting restoration of HIC-1 function by reversing HIC-1 hypermethylation may offer a therapeutic avenue in breast cancer.

FEV(6) is an acceptable surrogate for FVC in the spirometric diagnosis of airway obstruction and restriction.

We analyzed the FEV(1)/FEV(6) and FEV(1)/FVC results of 502 consecutive patients in the spirometric diagnosis of airway obstruction. We also examined the agreement between FEV(6) and FVC in the spirometric diagnosis of restriction. Technically acceptable test results were obtained from 337 subjects (67%). The sensitivity of FEV(1)/FEV(6) for diagnosing airway obstruction as defined by FEV(1)/ FVC was 95.0%; the specificity was 97.4%. When interpretations differed, the measured values were all close to the lower limits of the reference ranges. When analysis included +/- 100-ml variability in FEV(1) and FEV(6), the sensitivity increased to 99.5% and the specificity to 100%. The reproducibility of FEV(6) was superior to that of FVC. These results suggest that FEV(6) is an accurate, reliable alternative to FVC for diagnosing airway obstruction and that FEV(6) is reasonably comparable to FVC for the spirometric diagnosis of restriction. FEV(6) is more reproducible and less physically demanding for patients.

Primary health care needs for travel medicine training in Britain.

BACKGROUND: In the UK, travel health advice is mainly provided by practice nurses and general practitioners (GPs). The need for their improved education in travel medicine has been highlighted through previous studies and by an increasing number of requests for training. METHODS: A questionnaire-based survey of 3900 GP practices was conducted to assess training requirements and to establish the demand for an academic course in travel medicine. 1430 (37%) questionnaires were completed. RESULTS: 93% of practices provided a pretravel advice service. 87% of GPs advised an average of 10 travelers per month and only 48% immunized travelers. 98% of nurses advised and immunized an average of 28 travelers a month. 21% of GPs and two-thirds of nurses had attended one or more training sessions in travel medicine. Over 90% of the sample (83% of GPs and 98% of nurses) expressed an interest in attending a formal training program in travel medicine. Eligibility for Post Graduate Education Awards (PGEA) was important for most GPs (88%). Nurses valued approval by the English National Board for Nursing (88%) and a system of Credit Accumulation & Transfer (CATS) (82%). Funding for a course would be met in full by 18% of respondents (mainly GPs) and a further 20% would contribute to fees. Most GPs and nurses have ready access to a range of information sources, e.g., a postgraduate medical centre (85%) and a medical library (91%). Computerized access to information was feasible as 93% had a computer and 54% had a modem attached. CONCLUSIONS: The discipline of travel medicine is becoming increasingly specialized. Future practitioners will need to enhance their skills to meet the demands of today's travelers. Our results show that general practice staff are keen to develop such skills. Specialist training courses need to be expanded to meet this demand.

Allelic imbalance at chromosome 17p13.3 (YNZ22) in breast cancer is independent of p53 mutation or p53 overexpression and is associated with poor prognosis at medium-term follow-up.

Molecular and immunohistochemical studies of genetic events on chromosome 17p were prospectively compared with conventional clinical and pathological parameters and disease behaviour at a minimum of 72 months follow-up. In a series of 91 patients with primary operable breast cancer, 37 out of 91 (41%) patients had disease relapse and 23 out of 91 (25%) had died during the follow-up period. Allelic imbalance at the YNZ22 locus (17p13.3), demonstrated in 33 out of 63 (52%) informative patients, was significantly associated with disease recurrence (P < 0.01, 2 d.f. Cox analysis) and showed a trend towards impaired survival (P = 0.08, 2 d.f. Cox analysis) after a mean follow-up of 84 months for survivors. By contrast, p53 mutation (in 10 out of 60, 17% of cancers), p53 allelic imbalance (in 23 out of 56, 41% informative patients), p53 mRNA expression (in 47 out of 87, 54% patients), p53 mRNA overexpression (in 24 out of 87, 28%) or p53 protein expression (detected in 25/76, 32%) were not associated with disease behaviour. There was no significant association between allelic imbalance at YNZ22 and any abnormality of p53 DNA, RNA or protein. Allelic imbalance at 17p13.3 (YNZ22) serves as a marker of poor prognosis in breast cancer. As yet unidentified genes on 17p13.3, distinct from and telomeric to p53, are therefore likely to be of clinical importance in breast cancer.

Consortium study on 1280 breast carcinomas: allelic loss on chromosome 17 targets subregions associated with family history and clinical parameters.

The pattern of loss of heterozygosity (LOH) on chromosome 17 in human breast cancer is complicated and shows many different regions of loss. In an attempt to narrow down the relevant regions of LOH on chromosome 17, we have studied the deletion pattern and its association with clinical parameters in 1280 breast carcinoma-venous blood lymphocyte pairs. In total, 42 different chromosome 17 loci were investigated, and between 25 and 625 cases were analyzed at each locus. The frequency of LOH observed on the p arm was much higher than that observed on the q arm. The opposite effect was observed in 52 ovarian cancer cases investigated, with less LOH on 17p than on 17q. Patterns of loss consistent with interstitial and terminal deletions, as well as loss of either the p or q arm or monosomy 17 were observed. To determine whether loss at particular loci may be associated with biological features of breast tumors, clinical data including age of onset, family history of breast cancer, tumor histopathology, tumor size, estrogen receptor (ER) status, and occurrence of lymph node or distant metastases were collected for each case. Overall, large-sized, ER-negative, lymph node-positive ductal tumors showed the highest frequencies of LOH, with ER-negative and ductal tumors showing LOH for markers along the majority of the chromosome. Eight regions of chromosome 17 appear to be associated with human breast cancer, two on 17p and six on 17q. These regions were not necessarily in the areas exhibiting the highest frequencies of LOH but were defined by interstitial and terminal deletions in multiple independent cases. Seven of these regions showed statistically significant differences in LOH associated with clinical parameters. These data strongly suggest that loci on chromosome 17 may determine aspects of tumor presentation and disease behavior in human breast cancer and pinpoint candidate tumor suppressor gene loci.

Detailed mapping and loss of heterozygosity analysis suggests a suppressor locus involved in sporadic breast cancer within a distal region of chromosome band 17p13.3.

The chromosome region 17p13.3 is thought to encode a tumour suppressor gene involved in sporadic breast cancer and other malignancies. Physical ordering of markers has been carried out by a series of multicolour fluorescent in situ hybridisation (FISH) experiments, using isolated yeast artificial chromosomes (YACs) and cosmids. Eight polymorphic markers ordered within this new physical map and one external marker were used to investigate the pattern of loss of heterozygosity in a panel of 40 sporadic breast tumour patients. The data revealed a region of high loss (60%) within distal 17p13.3, defined by markers D17S926, D17S695 and D17S849 which mapped close together. A contig of YACs was constructed physically linking these three markers.

Gender reassignment surgery for male primary transsexuals.

This article describes certain innovations and aspects of surgical technique together with some surgical assessments of results in a series of 58 operations for gender reassignment undertaken by the author over the past 24 years. The salient new features described are: (i) to prevent the early and late vaginal contractures that commonly follow previously accepted methods of neo-vagina construction, the technique of dissecting a new vaginal canal has been improved, and an improved skin graft (double-layered) is added to the peno-scroto-perineal flaps used to line the vaginal canal--these split-skin grafts, superimposed upon a meshed thick dermal graft, do not contract nearly as much as solitary split-skin grafts; (ii) the vagina is suspended laterally by the testicular cords, threaded above the superior pubic rami; and (iii) repeated intermittent use of a vaginal vibrator is substituted for an indwelling vaginal mould, resulting in better compliance and a more pliable vagina.

A comparison of procedures for analysing microsatellite (CA)-repeat polymorphisms.

Dinucleotide repeat sequences ('microsatellites') have been used as polymorphic genetic markers following amplification in the polymerase chain reaction (PCR). We have compared several methods of analysing the PCR products. The most reliable and unambiguous results were obtained when the PCR products were probed with a specific dinucleotide repeat oligonucleotide, so that only the microsatellite-containing products were detectable.

A human lymphoblastoid B line with an abnormally large MHC class II beta chain.

We have examined the MHC class II beta chains in lymphoblastoid cell lines from over 200 individuals and describe one line which possesses, in addition to normal beta chains, a species of beta chain of unusually high Mr and abnormal pI which appears to be a product of the DR locus. This abnormality in Mr, detected by SDS-gel electrophoresis, was apparent only in the presence of mercaptoethanol and was shown to be due to difference in polypeptide chain length rather than to extra glycosylation.

Indirect immunofluorescence labelling with complexes of phycoerythrin and monoclonal anti-phycoerythrin antibodies (PEAPE complexes).

We describe a method of immunofluorescence which is a lateral application of the principles of the APAAP immunohistochemical technique. Immune complexes of R-phycoerythrin and monoclonal anti-R-phycoerythrin (PEAPE complexes) were used in an indirect immunofluorescence technique to detect the binding to cells of monoclonal antibodies directed to IgM, HLA-DR and B cell activation and differentiation antigens. PEAPE complexes were linked to cell surface bound mAbs by unlabelled anti-mouse Ig antibodies to produce high levels of fluorescent staining. The sensitivity of this method of indirect immunofluorescence was enhanced by the sequential application of several cycles of anti-mouse Ig and PEAPE complexes.

A new set of monoclonal antibodies to human MHC class II alpha chains demonstrates that most alpha epitopes are inaccessible on the living cell surface.

When mice were immunized with a mixture of human MHC class II alpha and beta glycoprotein chains, the predominant antibody response was anti-alpha, and from a subsequent fusion experiment over 60 hybridomas showing anti-alpha activity were generated, compared with 11 anti-beta secretors. These findings contrast with the relative paucity of anti-alpha monoclonals described previously. Use of a miniaturized Western blot screening protocol was a critical factor in the present study since the anti-alpha monoclonals do not bind to the surface of living B cells and would therefore be missed in conventional screening assays. After glutaraldehyde fixation of target B lymphocytes or B-cell lines, the majority of anti-alpha monoclonals do react in a radio-immunobinding assay, although none binds as strongly as pan-reactive anti-beta chain antibodies. This suggests that the immunogenic epitopes of alpha chains are normally concealed by the three-dimensional folding of the alpha beta dimer. The anti-alpha monoclonals were all monomorphic but varied in the extent of their reactivity with alpha chains separated on one-dimensional and two-dimensional IEF gels. The most reactive antibodies identified up to seven distinct components among mature class II antigens from solubilized cell membranes.

The production and assessment of monoclonal antibodies to cortisol.

In an extensive series of experiments, Balb/C mice and Lou rats were immunised with 3-O-(carboxymethyl)oximinocortisol conjugated to bovine serum albumin. The spleen cells from selected animals were fused with cells from mouse or rat plasmacytoma lines. Out of many hundreds of hybridomas screened, more than seventy produced antibody that bound 125I-labeled cortisol. These cultures were investigated further for stability of antibody production, affinity for cortisol and cross-reactivity with other steroids. An unexpected but consistent finding was that immunised rats produced antibody which cross-reacted with 11-deoxycortisol to a level greater than 100% and this characteristic was reproduced by rat-rat hybridomas. Strategies designed to improve the chances of generating non-cross-reactive anti-cortisol monoclonal antibodies did not appear to be successful. Nevertheless, several monoclonals were identified with properties that suggest they may be useful for the development of sensitive and specific cortisol assays.

Serologically detectable H-Y ('male') antigen: Mr or myth?

The rejection by inbred female mice of skin from syngeneic males is provoked by the male-specific transplantation antigen H- Y. Here D. N. Crichton and C. M. Steel discuss conflicting claims surrounding the detection of H-Y antigen with polyclonal and monoclonal antibodies.