Genetically abnormal clones in histologically normal breast tissue.

Breast cancer is believed to develop as multiple genetic abnormalities accumulate, each conferring some growth advantage, but the timing and nature of the earliest steps in this progression are not yet elucidated. Proliferative breast lesions, associated with an increased risk of breast cancer although considered benign, recently were shown to contain clonal genetic abnormalities. Therefore, we hypothesized that clonal genetic abnormalities might be detectable before any phenotypic abnormalities are evident, ie, in histologically normal breast tissue. We examined DNA extracted from 95 normal-appearing breast ducts or terminal ductal-lobular units from 20 individuals at varying degrees of risk (those undergoing reduction mammoplasties, those with atypical hyperplastic proliferative lesions, and those already diagnosed with breast cancer). Using nine microsatellite markers, we sought evidence of genetic instability or of allelic imbalance (most likely representing loss of heterozygosity). We found genetically abnormal clones in 21/95 (22%) seemingly normal samples from 10/20 (50%) women from all three risk groups. In women under age 50, trends toward increased rates of abnormalities were noted with increased cancer risk. The abnormalities identified were more likely to be at sites of known or postulated tumor suppressor genes rather than at random or neutral loci. Our data indicate that genetic abnormalities potentially critical to breast tumorigenesis accumulate before pathological detection even of high-risk lesions and are detectable in tissue that is not only histologically benign but also completely normal.     

Extracting information on pneumonia in infants using natural language processing of radiology reports

Natural language processing (NLP) is critical for improvement of the healthcare process because it can encode clinical data in patient documents. Many clinical applications such as decision support require coded data to function appropriately. However, in order to be applicable for healthcare, performance must be adequate. A valuable automated application is the detection of infectious diseases, such as surveillance of pneumonia in newborns (e.g., neonates) because the disease produces significant rates of morbidity and mortality, and manual surveillance is challenging. Studies have demonstrated that automated surveillance using NLP is a useful adjunct to manual surveillance and an effective tool for infection control practitioners. This paper presents a study evaluating the feasibility of an NLP-based monitoring system to screen for healthcare-associated pneumonia in neonates. We estimated sensitivity, specificity, and positive predictive value by comparing results with clinicians' judgments. Sensitivity was 71% and specificity was 99%. Our results demonstrated that the automated method was feasible.     

Operant Conditioning of Heart Rate: Somatic Correlates

The relationships between heart rate (HR) and several parameters of somatic activity were evaluated in human subjects when shuck avoidance was made contingent on either increases or decreases in HR. In order to depict any influence of the contingency specific 10 HR, somatic activity was controlled to varying degrees by instructions and the use of non-contingent control groups. When increases in HR were reinforced, the contingency we found to influence somatic activity but an effect specific to HR was also observed. When decreases in HR were reinforced, there was no evidence that HR were influenced independently of somatic activity. The result are discussed with respect to several current issues.     

Molecular cloning and nucleotide sequence of the pestivirus bovine viral diarrhea virus

The RNA genome of the cytopathic NADL isolate of bovine viral diarrhea virus (BVDV) has been molecularly cloned and the nucleotide sequence determined. The cloned sequence was 12,573 nucleotides in length, corresponding to a molecular weight of 4.3 X 10(6), having a base composition of 32.2% A, 25.7% G, 22.1% U, and 20.0% C. However, the sequences at the 5' and 3' termini of the RNA have not been unequivocally established. A single major open reading frame extending the length of the molecule was found in the viral-sense (positive polarity) sequence. This open reading frame was capable of encoding 3988 amino acids, representing 449 kDa of protein.     

Genome scale comparison of Mycobacterium avium subsp. paratuberculosis with Mycobacterium avium subsp. avium reveals potential diagnostic sequences

The genetic similarity between Mycobacterium avium subsp. paratuberculosis and other mycobacterial species has confounded the development of M. avium subsp. paratuberculosis-specific diagnostic reagents. Random shotgun sequencing of the M. avium subsp. paratuberculosis genome in our laboratories has shown >98% sequence identity with Mycobacterium avium subsp. avium in some regions. However, an in silico comparison of the largest annotated M. avium subsp. paratuberculosis contigs, totaling 2,658,271 bp, with the unfinished M. avium subsp. avium genome has revealed 27 predicted M. avium subsp. paratuberculosis coding sequences that do not align with M. avium subsp. avium sequences. BLASTP analysis of the 27 predicted coding sequences (genes) shows that 24 do not match sequences in public sequence databases, such as GenBank. These novel sequences were examined by PCR amplification with genomic DNA from eight mycobacterial species and ten independent isolates of M. avium subsp. paratuberculosis. From these analyses, 21 genes were found to be present in all M. avium subsp. paratuberculosis isolates and absent from all other mycobacterial species tested. One region of the M. avium subsp. paratuberculosis genome contains a cluster of eight genes, arranged in tandem, that is absent in other mycobacterial species. This region spans 4.4 kb and is separated from other predicted coding regions by 1,408 bp upstream and 1,092 bp downstream. The gene upstream of this eight-gene cluster has strong similarity to mycobacteriophage integrase sequences. The GC content of this 4.4-kb region is 66%, which is similar to the rest of the genome, indicating that this region was not horizontally acquired recently. Southern hybridization analysis confirmed that this gene cluster is present only in M. avium subsp. paratuberculosis. Collectively, these studies suggest that a genomics approach will help in identifying novel M. avium subsp. paratuberculosis genes as candidate diagnostic sequences.     

Ontogeny of the transition from killer to caregiver in dwarf hamsters (Phodopus campbelli) with biparental care

Biparental Phodopus campbelli and uniparental P. sungorus juvenile litters (2 males, 2 females) both consumed amniotic fluid and placenta during the birth of younger siblings. Three days later, P. campbelli juveniles were most responsive to a displaced younger sibling. Thus, P. campbelli are responsive to pups as juvenile alloparents and as new parents; however, at intervening ages, infanticidal attack (bite) was seen. At 5, 7, 9, 11, or 13 weeks of age, male and female P. campbelli were given a 5-min test with an unrelated, 3-day-old, anesthetized pup. Females attacked more often than males, yet pup-retrieval rates did not differ. Female aggression increased with age and was replaced by retrieval behavior 3 days after parturition. Male attack ceased after a birth, but parental behavior did not increase, remaining below the rate for new fathers tested with their own awake pup. Over repeated testing, behavior in one test did not predict behavior in another. Transitions from caregiving alloparent to infanticidal adult and back to parental care were clear in females, but less discrete with this stimulus paradigm in these highly paternal males.     

Bone metastases from thyroid carcinoma: a histopathologic study with clinical correlates

CONTEXT: Only limited information exists on the pathologic aspects of thyroid carcinomas with bone metastases, most large studies having concentrated mainly on their clinical features. OBJECTIVE: To study in detail the morphologic features of thyroid carcinomas with skeletal metastases. DESIGN: Seventy-nine cases of thyroid carcinoma with bone metastases treated at Memorial Sloan-Kettering Cancer Center, New York, NY, between 1964 and 1998 were investigated, with emphasis on the pathology of the primary and/or metastatic tumors and comparison of the morphologic features of the tumors at both the sites, wherever possible. The tumors were also compared for various clinical parameters. RESULTS: The cohort consisted of 22 papillary, 17 follicular, 16 insular, 10 anaplastic, 9 Hürthle cell, and 5 medullary carcinomas. Of these cases, 68% had poorly differentiated or undifferentiated features in the primary and/or metastatic tumors. The metastatic tumors were better differentiated than the primary in one third of the cases (6 of 18). Only one case showed a less differentiated metastasis. The overall 5- and 10-year survival probabilities after the bone metastases were 29% and 13%, respectively (Kaplan-Meier method). Although both the tumor type and differentiation seemed to affect survivals after bone metastasis (P =.007 and.012, respectively) (log-rank test), this was primarily due to the much worse prognosis in the cases of anaplastic and medullary carcinoma. Cases of Hürthle cell carcinoma showed the longest median survival. There was no significant difference in survival among patients up to or older than 45 years at the time of metastases (P =.31). CONCLUSIONS: Most thyroid carcinomas with bone metastases are of papillary type, and most have poorly differentiated or undifferentiated features. The influence of the microscopic tumor type and tumor differentiation on survival after bone metastasis primarily appears to be due to the much worse prognosis among anaplastic and medullary carcinomas. Age at diagnosis of bone metastases does not influence survivals.     

Multiomics uncovers developing immunological lineages in human

The development of the human immune system during embryonic and fetal life has historically been difficult to research due to limited access to human tissue. Experimental animal models have been widely used to study development but cellular and molecular programmes may not be conserved across species. The advent of multiomic single-cell technologies and an increase in human developmental tissue biobank resources have facilitated single-cell multiomic studies focused on human immune development. A critical question in the near future is "How do we best reconcile scientific findings across multiple omic modalities, developmental time, and organismic space?" In this review, we discuss the application of single-cell multiomic technologies to unravel the major cellular lineages in the prenatal human immune system. We also identify key areas where the combined power of multiomics technologies can be leveraged to address specific immunological gaps in our current knowledge and explore new research horizons in human development.