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.

APPLIANCE OF CAD / CAM MODELING IN PROSTHETICS OF BONE DEFECTS OF FACIAL BONES.

OBJECTIVE: The aim: Improving the ability to restore the shape and function of the bones of the maxillofacial area through the use of their own techniques. PATIENTS AND METHODS: Materials and methods: Materials and methods: This research was carry out on the basis of the Department of Surgical Dentistry and Maxillofacial Surgery of Kharkov National Medical University in the Department of Head and Neck Surgery, Kharkov "Regional Clinical Hospital" (2018-2020 years). Examination and treatment of 26 patients, aged from 19 to 55 years, who needed reconstructive surgery to restore the anatomical shape, integrity and function of the maxilla or mandibular jaw. RESULTS: Results: All patients were treated according to the developed method (utility model patent № 145754 "Method of treating traumatic fractures of the maxillofacial area in adults using bone osteosynthesis 3D modeled titanium mini plates"), which consists in 3D modeling, based on previously performed computed tomography, and exploitation individually modeled titanium mini grids and titanium endoprostheses. The experience of this technique shown the advantage of the proposed method not only in the correction of traumatic defects, but also defects of the jaw bones that occur due to the removal of bulky neoplasms. CONCLUSION: Conclusions: Individual 3D simulated mini grids / plates and endoprostheses, according to the study provide maximum adaptation and restoration of anatomical shape, relief of jaws, their integrity and contour, provide prevention of pathological fractures by stabilizing residual bone tissue (titanium mini grids) serves as a carcass , provide prevention of prolapse (germination) of soft tissues in the area of postoperative bone defect (mini grid does not allow soft tissues to germinate in the area of postoperative bone defect on the outside), which improves functional and cosmetic results. Thus, our proposed method of osteosynthesis using 3D simulated titanium miniplates can be recommended for use in clinical practice.

Bioimpedance Spectroscopy: Basics and Applications.

In this review, we aim to introduce the reader to the technique of electrical impedance spectroscopy (EIS) with a focus on its biological, biomaterials, and medical applications. We explain the theoretical and experimental aspects of the EIS with the details essential for biological studies, i.e., interaction of metal electrodes with biological matter and liquids, strategies of measurement rate increasing, noise reduction in bio-EIS experiments, etc. We also give various examples of successful bio-EIS practical implementations in science and technology, from whole-body health monitoring and sensors for vision prosthetic care to single living cell examination platforms, virus disease research, biomolecules detection, and implementation of novel biomaterials. The present review can be used as a bio-EIS tutorial for students as well as a handbook for scientists and engineers because of the extensive references covering the contemporary research papers in the field.

Oncologic Outcomes of Surgery Versus SBRT for Non-Small-Cell Lung Carcinoma: A Systematic Review and Meta-analysis.

BACKGROUND: The optimal treatment of stage I non-small-cell lung carcinoma is subject to debate. The aim of this study was to compare overall survival and oncologic outcomes of lobar resection (LR), sublobar resection (SR), and stereotactic body radiotherapy (SBRT). METHODS: A systematic review and meta-analysis of oncologic outcomes of propensity matched comparative and noncomparative cohort studies was performed. Outcomes of interest were overall survival and disease-free survival. The inverse variance method and the random-effects method for meta-analysis were utilized to assess the pooled estimates. RESULTS: A total of 100 studies with patients treated for clinical stage I non-small-cell lung carcinoma were included. Long-term overall and disease-free survival after LR was superior over SBRT in all comparisons, and for most comparisons, SR was superior to SBRT. Noncomparative studies showed superior long-term overall and disease-free survival for both LR and SR over SBRT. Although the papers were heterogeneous and of low quality, results remained essentially the same throughout a large number of stratifications and sensitivity analyses. CONCLUSION: Results of this systematic review and meta-analysis showed that LR has superior outcomes compared to SBRT for cI non-small-cell lung carcinoma. New trials are underway evaluating long-term results of SBRT in potentially operable patients.

Oncological Outcomes of Lobar Resection, Segmentectomy, and Wedge Resection for T1a Non-Small-Cell Lung Carcinoma: A Systematic Review and Meta-Analysis.

The optimal treatment of early-stage non-small-cell lung cancer (NSCLC) remains subject to debate. Lobar resection is considered the standard of care, but sublobar resections are a lung parenchymal-sparing treatment offering promising results. We conducted a systematic review and meta-analysis to compare oncological outcomes of lobar resections and parenchymal-sparing resections for T1a NSCLC. PubMed, EMBASE, Web of Knowledge Search, and the Cochrane Central Register of Controlled Trials were searched for studies reporting oncological outcomes following lobar or parenchymal-sparing resections. Two researchers independently identified studies and extracted data. Oncological outcomes were compared for each surgical modality using the Mantel-Haenszel method, and outcomes were pooled for each modality using the inverse variance method. A total of 11,195 studies were identified and 28 articles were included. For pT1a tumors, there was no difference in 5-year overall survival when lobar resection (n = 15,003) was compared to parenchymal-sparing resection (n = 1224), with a relative risk of 0.92 (95% confidence interval: 0.84-1.01). Five-year overall survival and disease-free survival after segmentectomy yielded equal survival compared to lobar resection in directly comparing studies and point estimates of noncomparative studies. In most comparisons, wedge resection showed comparable results to lobar resections and segmentectomy. Subanalysis of intentional parenchymal-sparing surgery showed favorable results. This study shows that parenchymal-sparing surgery yields equivocal survival compared to lobar surgery for stage T1a NSCLC. However, a drawback in implementing parenchymal-sparing resection for lobectomy-tolerable patients is the risk of nodal upstaging.

Protease Cargo in Circulating Exosomes of Breast Cancer and Ovarian Cancer Patients

Background: As is known, exosomes play an important role in promoting progression of cancers by increasing its invasive potential. The aim of this study was to evaluate the levels of tetraspanine-associated (ADAM-10) and tetraspanine-nonassociated proteases (20S proteasomes) in exosomes from culture medium, plasma exosomes of patients with breast tumors and plasma and ascites of ovarian tumor patients. Methods: MCF-7 and SVO-3 culture mediums and blood samples from healthy females (n = 30, HFs), patients with diffuse dyshormonal dysplasia of the breast (n=28, BBTPs), breast cancer patients (n=32, BCPs), borderline ovarian tumor patients (n=20, BOTPs) and blood and ascites samples ovarian cancer patients (n=35, OCPs) were included in the study. Exosomes from plasma, ascites and culture mediums were isolated and characterized in according to Extracellular Vesicles Society. The expression levels of 20S proteasome and ADAM-10 in exosomes were determined using flow cytometry and western blot analysis, correspondingly. Results: The subpopulation composition of the exosomes from MCF-7 culture medium and from blood plasma of HFs and breast diseases patients is similar, however CD9/CD24 subpopulation significantly increased at cell supernatant. The similar results was obtained for exosomes from SVO-3 medium and blood plasma and ascites of ovary tumor patients, but CD9/CD24 subpopulation significantly decreased at cells and illness samples, however CD63/CD24 exosomes increased significantly from cell supernatant. 20S proteasome level is significantly increased in exosomes from MCF-7 and SVO-3 culture medium, breast tumor patients and OCPs plasma in comparison to HUVEC culture medium and HFs plasma samples. At CD9-positive exosomes from BCPs plasma and MCF-7 was reveal a high expression of ADAM-10 and low expression is from BBDPs plasma and ovarian tumor patients plasma/ ascites samples. Exosomes from ascites OCP had high expression of ADAM-10 in the CD24-positive subpopulation. Conclusion: Breast and ovarian cancer development is connected with functioning of immune proteasome forms in plasma and ascites exosomes, while increased ADAM10 expression at CD9-positive exosome was associated with breast cancer and at CD24-positive subpopulation ­ with ovarian cancer. Obtained data confirm role of exosomal proteases in tumor progression.

The Enlarged Fibroid Uterus: Aberrant Arterial Supply via the Omental Artery.

Uterine artery embolization is considered a first-line therapy for symptomatic fibroids and is occasionally required to mitigate operative risk prior to total abdominal hysterectomy or myomectomy. We present a pictorial review of parasitized omental artery supply to the enlarged fibroid uterus in three patients undergoing preoperative uterine artery embolization. A detailed understanding of variant uterine blood supplies is crucial when performing fibroid embolization. Although omental artery supply to the fibroid uterus is an unusual finding, aortography to include mesenteric arteries may be necessary when anomalous blood supply to the enlarged fibroid uterus is suspected.

Goal-directed program after sleeve gastrectomy improves weight loss.

BACKGROUND: The aim of our study is to determine if a goal-directed program improves weight loss after sleeve gastrectomy. METHODS: Our goal-directed program involves setting excess weight loss targets at fixed intervals after sleeve gastrectomy. We identified patients in 3 bariatric centers between April 2010 and July 2013 and compared the center that has a goal-directed weight loss program (goal-directed program) with the other 2 centers (standard program). RESULTS: A total of 211 patients were included, with 129 patients in the goal-directed weight loss program. The 2 groups were similar in terms of gender distribution, ethnicity distribution, age, and preoperative weight, preoperative body mass index, and surgical technique. The follow-up rates at 3, 6, 9, and 12 months for patients in the goal-directed program was 84.5%, 75.2%, 59.7%, and 82.2%, respectively, compared with 65.9%, 68.3%, 51.2%, and 68.3% for the standard program. The percentage total weight loss at 3, 6, 9, and 12 months was 17.1%, 23.3%, 26.8%, and 28.6%, respectively, for the goal-directed program, compared with 15.3%, 21.8%, 24.4%, and 25.4%, respectively, for the standard program. The mean excess weight loss at 3, 6, 9, and 12 months were 40%, 54%, 62%, and 67%, respectively, for the goal-directed program group, and 36%, 50%, 54%, and 55%, respectively, for the standard program, where statistical significance (P<.005) was achieved at 12 months. CONCLUSION: Our results suggest that a goal-directed protocol may improve weight loss outcomes after laparoscopic sleeve gastrectomy.

Is Elective Gastroscopy Prior to Bariatric Surgery in an Asian Cohort Worthwhile?

BACKGROUND: The preoperative use of gastroscopy for patients undergoing bariatric surgery remains controversial. We aim to evaluate the diagnostic yield of gastroscopy and the clinical significance in asymptomatic individuals undergoing bariatric surgery in Asia. METHODS: We retrospectively reviewed the medical records of all patients undergoing gastroscopy prior to bariatric surgery at the National University Hospital and Khoo Teck Puat Hospital, Singapore, between Jan 2006 and June 2013. Gastroscopy findings were classified into four groups: group 1 (normal study), group 2 (abnormal findings that do not modify surgical approach), group 3 (abnormal findings that modify surgical approach) and group 4 (absolute contraindications to immediate surgery). RESULTS: During the study period, 208 asymptomatic individuals were evaluated by gastroscopy prior to bariatric surgery. Gastroscopy was normal in 70 (33.6 %). Group 2 comprised 67 (32.2 %) patients with mild gastritis or oesophagitis. Group 3 included 69 (33.2 %) patients diagnosed with erosive gastritis or oesophagitis, peptic ulcer disease, hiatal hernia or mass lesions. There were 2 patients (1.0 %) in group 4. One patient had a gastro-oesophageal junction adenocarcinoma, and 1 had a gastrointestinal stroma tumour. In group 3, modification of surgical approach included concurrent hiatal hernia repair, institution of medical therapy with delay in surgery, further evaluation of mass lesions and change in choice of surgical procedures. CONCLUSIONS: Routine gastroscopy for asymptomatic bariatric patients has a high diagnostic yield. Given the high percentage of patients with clinically important lesions, our current experience supports the use of routine preoperative gastroscopy prior to bariatric surgery in Singapore.

The convenient preparation of stable aryl-coated zerovalent iron nanoparticles.

A novel approach for the in situ synthesis of zerovalent aryl-coated iron nanoparticles (NPs) based on diazonium salt chemistry is proposed. Surface-modified zerovalent iron NPs (ZVI NPs) were prepared by simple chemical reduction of iron(III) chloride aqueous solution followed by in situ modification using water soluble arenediazonium tosylate. The resulting NPs, with average iron core diameter of 21 nm, were coated with a 10 nm thick organic layer to provide long-term protection in air for the highly reactive zerovalent iron core up to 180 °C. The surface-modified iron NPs possess a high grafting density of the aryl group on the NPs surface of 1.23 mmol/g. FTIR spectroscopy, XRD, HRTEM, TGA/DTA, and elemental analysis were performed in order to characterize the resulting material.

A novel method for KIR-ligand typing by pyrosequencing to predict NK cell alloreactivity.

Studies have shown that KIR-ligand mismatching to predict NK cell alloreactivity may result in less relapse and better survival in patients with AML. KIR-ligands are distinguished by single nucleotide polymorphisms (SNPs) from HLA-B and HLA-C sequences. We hypothesized that pyrosequencing to determine KIR-ligand status by direct sequencing of the ligand epitope can be done as an alternative to high-resolution HLA-typing. Pyrosequencing is rapid and would be particularly useful in analysis of retrospective cohorts where high-resolution HLA-typing is unavailable or too expensive. To validate this assay, RNA and DNA from 70 clinical samples were tested for KIR-ligand by pyrosequencing. Primer binding to invariant regions without known SNPs was critical for KIR-ligand assignment by pyrosequencing to be in full concordance with high-resolution HLA-typing. Pyrosequencing is sensitive, specific, high-throughput, inexpensive, and can rapidly screen KIR-ligand status to evaluate potential alloreactive NK cell or transplant donors.

Mixture analysis of longitudinal binary data.

The dependence of longitudinal binary outcomes on covariates and the covariation observed between them is often modelled by (multivariate) logistic and probit models, respectively, assuming specified association structure or random effects. Alternatively, latent class models may be used that capture the covariation by assuming heterogeneity of the observational units regarding their reaction tendencies while postulating independence within classes. In the presence of a few categorical covariates, the multi-group method of latent class analysis allows one to relate the class sizes and the class-specific response probabilities to these covariates. Wheeze data from the Harvard Six-Cities study on respiratory health are a typical example for such a situation: at four occasions, the wheeze status of 537 children was examined, 187 among them exposed to maternal smoking and 350 not exposed. Thus, there is a single binary covariate (maternal smoking versus no maternal smoking) making easily applicable the multi-group method of latent class analysis. Based on a series of unrestricted and restricted models having up to three classes for the exposed and not-exposed subgroup each, no statistically significant effect of maternal smoking on children's wheeze status could be substantiated. Moreover, it was not possible to show statistically significant difference at all between the two distributions of wheeze patterns collected from exposed and not-exposed children.

Array-based comparative genomic hybridization analysis reveals recurrent chromosomal alterations and prognostic parameters in primary cutaneous large B-cell lymphoma.

PURPOSE: To evaluate the clinical relevance of genomic aberrations in primary cutaneous large B-cell lymphoma (PCLBCL). PATIENTS AND METHODS: Skin biopsy samples of 31 patients with a PCLBCL classified as either primary cutaneous follicle center lymphoma (PCFCL; n = 19) or PCLBCL, leg type (n = 12), according to the WHO-European Organisation for Research and Treatment of Cancer (EORTC) classification, were investigated using array-based comparative genomic hybridization, fluorescence in situ hybridization (FISH), and examination of promoter hypermethylation. RESULTS: The most recurrent alterations in PCFCL were high-level DNA amplifications at 2p16.1 (63%) and deletion of chromosome 14q32.33 (68%). FISH analysis confirmed c-REL amplification in patients with gains at 2p16.1. In PCLBCL, leg type, most prominent aberrations were a high-level DNA amplification of 18q21.31-q21.33 (67%), including the BCL-2 and MALT1 genes as confirmed by FISH, and deletions of a small region within 9p21.3 containing the CDKN2A, CDKN2B, and NSG-x genes. Homozygous deletion of 9p21.3 was detected in five of 12 patients with PCLBCL, leg type, but in zero of 19 patients with PCFCL. Complete methylation of the promoter region of the CDKN2A gene was demonstrated in one PCLBCL, leg type, patient with hemizygous deletion, in one patient without deletion, but in zero of 19 patients with PCFCL. Seven of seven PCLBCL, leg type, patients with deletion of 9p21.3 and/or complete methylation of CDKN2A died as a result of their lymphoma. CONCLUSION: Our results demonstrate prominent differences in chromosomal alterations between PCFCL and PCLBCL, leg type, that support their classification as separate entities within the WHO-EORTC scheme. Inactivation of CDKN2A by either deletion or methylation of its promoter could be an important prognostic parameter for the group of PCLBCL, leg type.

Distinct nuclear gene expression profiles in cells with mtDNA depletion and homoplasmic A3243G mutation.

The pathobiochemical pathways determining the wide variability in phenotypic expression of mitochondrial DNA (mtDNA) mutations are not well understood. Most pathogenic mtDNA mutations induce a general defect in mitochondrial respiration and thereby ATP synthesis. Yet phenotypic expression of the different mtDNA mutations shows large variations that are difficult to reconcile with ATP depletion as sole pathogenic factor, implying that additional mechanisms contribute to the phenotype. Here, we use DNA microarrays to identify changes in nuclear gene expression resulting from the presence of the A3243G diabetogenic mutation and from a depletion of mtDNA (rho0 cells). We find that cells respond mildly to these mitochondrial states with both general and specific changes in nuclear gene expression. This observation indicates that cells can sense the status of mtDNA. A number of genes show divergence in expression in rho0 cells compared to cells with the A3243G mutation, such as genes involved in oxidative phosphorylation. As a common response in A3243G and rho0 cells, mRNA levels for extracellular matrix genes are up-regulated, while the mRNA levels of genes involved in ubiquitin-mediated protein degradation and in ribosomal protein synthesis is down-regulated. This reduced expression is reflected at the level of cytosolic protein synthesis in both A3243G and rho0 cells. Our finding that mitochondrial dysfunction caused by different mutations affects nuclear gene expression in partially distinct ways suggests that multiple pathways link mitochondrial function to nuclear gene expression and contribute to the development of the different phenotypes in mitochondrial disease.

Cancer-associated mutations in chromatin remodeler hSNF5 promote chromosomal instability by compromising the mitotic checkpoint.

The hSNF5 subunit of human SWI/SNF ATP-dependent chromatin remodeling complexes is a tumor suppressor that is inactivated in malignant rhabdoid tumors (MRTs). Here, we report that loss of hSNF5 function in MRT-derived cells leads to polyploidization and chromosomal instability. Re-expression of hSNF5 restored the coupling between cell cycle progression and ploidy checkpoints. In contrast, cancer-associated hSNF5 mutants harboring specific single amino acid substitutions exacerbated poly- and aneuploidization, due to abrogated chromosome segregation. We found that hSNF5 activates the mitotic checkpoint through the p16INK4a-cyclinD/CDK4-pRb-E2F pathway. These results establish that poly- and aneuploidy of tumor cells can result from mutations in a chromatin remodeler.

Complex biallelic IGH rearrangements in IgM-expressing Z-138 cell line: Involvement of downstream immunoglobulin class switch recombination.

Chromosomal translocations involving the immunoglobulin (Ig) receptor loci usually disrupt and silence these loci. On the basis of observations in follicular lymphoma (FL) with downstream Ig heavy chain (IGH) class switch recombination (CSR), we hypothesized that downstream CSR-mediated chromosomal translocations would leave the V(D)J-Cmu transcription unit intact, thereby still allowing IgM expression from the IGH allele involved in the translocation. To test this hypothesis, we analyzed biallelic IGH translocations in the IgM-expressing cell line Z-138 by interphase FISH, DNA fiber-FISH, long-distance vectorette PCR, and DNA sequencing. One IGH allele was involved in a t(11;14), showing a break in the JH region that juxtaposed the Emu enhancer and the 3' Calpha enhancers to the cyclin D1 gene. The other IGH allele contained a t(8;14) breakpoint involving the 3' end of a Sgamma region, whereas the reciprocal breakpoint at 8q24 was approximately 40 kb centromeric of MYC. Molecular analysis showed that this IGH allele harbored a normal V(D)J-Cmu complex, which is responsible for IgM expression. These data show that chromosomal breakpoints such as the t(8;14) can occur in downstream IGH constant regions and do not necessarily interfere with Ig expression.

Positioning of cervical carcinoma and Burkitt lymphoma translocation breakpoints with respect to the human papillomavirus integration cluster in FRA8C at 8q24.13.

Molecular cytogenetic analysis frequently shows human papillomavirus (HPV) integration near translocation breakpoints in cervical cancer cells. We have recently described a cluster of HPV18 integrations in the distal end of the common fragile site FRA8C at 8q24 in primary cervical carcinoma samples. Chromosome band 8q24 contains the MYC gene (alias c-MYC), FRA8C, and FRA8D. The MYC gene is frequently deregulated--usually by translocation or amplification--in various tumor types. In the present study, we performed a molecular cytogenetic analysis of HPV18 integration patterns and the 8q24 translocation in a primary cervical carcinoma and in HeLa cells using combined binary ratio-fluorescence in situ hybridization. Our aim was to determine how the chromosomal breaks involved in these events relate physically to the MYC gene; whether they map to the FRA8C site, the FRA8D site, or both; and how they correlate with the occurrence of DNA flexibility domains. The 8q24 translocation breakpoints mapped between stretches of integrated HPV18 sequences in the distal end of FRA8C. This region contained DNA helix flexibility clusters, several of which mapped in the vicinity of HPV integration sites and translocation breakpoints in cervical carcinomas. DNA helix flexibility clusters were also found near known MYC translocation breakpoints in Burkitt lymphomas (BL), but most BL breakpoints mapped clearly outside FRA8C. Our data revealed that FRA8C is involved in HPV integration and chromosomal translocations in cervical carcinoma; however, this fragile site is not involved in classical MYC translocations in most BLs. In the context of the familial nature of cervical cancer, FRA8C may be considered a candidate susceptibility region for cervical carcinoma.

Array comparative genomic hybridization with cyanin cis-platinum-labeled DNAs.

Fluorescent cis-platinum compounds that react with the N7 atom of guanine are useful for labeling nucleic acids influorescence hybridization applications. Here we report that cyanin (CyN) cis-platinum labeling of DNA samples for array comparative genomic hybridizations (arrayCGH) can be achieved reproducibly and reliably. We demonstrate that degrees of labeling of approximately 1% of all nucleotides in test and reference DNA samples with CyN3- and CyN5-cis-platinum produces arrayCGH signal-to-background ratios ranging from 30 to 40. The arrayCGH results achieved during analyses of mouse and human tumor samples were comparable to those achieved using enzymatic labeling. Thus, we conclude that Cy-cis-platinum labeling is an alternative to enzymatic labeling for arrayCGH.

A novel t(6;14)(q25-q27;q32) in acute myelocytic leukemia involves the BCL11B gene.

Cytogenetic studies in a patient with acute myelocytic leukemia (AML) revealed as the sole karyotypic alteration a half-cryptic rearrangement, identified with 48-color combined binary ratio-labeled fluorescence in situ hybridization (pq-COBRA-FISH) as a reciprocal t(6;14)(q?;q?). The breakpoints were later assigned on the basis of G-banding to t(6;14)(q25-q26;q32). FISH experiments using genomic probes showed that the breakpoint on 14q32.2 was within bacterial artificial chromosome RP11-782I5 and revealed BCL11B as the only candidate gene in the region. BCL11B is a homolog to BCL11A (2p13), a highly conserved gene implicated in mouse and human leukemias. To our knowledge, this is the first report implicating BCL11B in hematological malignancies. Because of lack of material, the translocation partner remains unknown.