Plasma Cells Are Obligate Effectors of Enhanced Myelopoiesis in Aging Bone Marrow.

Aging results in increased myelopoiesis, which is linked to the increased incidence of myeloid leukemias and production of myeloid-derived suppressor cells. Here, we examined the contribution of plasma cells (PCs) to age-related increases in myelopoiesis, as PCs exhibit immune regulatory function and sequester in bone marrow (BM). PC number was increased in old BM, and they exhibited high expression of genes encoding inflammatory cytokines and pathogen sensors. Antibody-mediated depletion of PCs from old mice reduced the number of myeloid-biased hematopoietic stem cells and mature myeloid cells to levels in young animals, but lymphopoiesis was not rejuvenated, indicating that redundant mechanisms inhibit that process. PCs also regulated the production of inflammatory factors from BM stromal cells, and disruption of the PC-stromal cell circuitry with inhibitors of the cytokines IL-1 and TNF-α attenuated myelopoiesis in old mice. Thus, the age-related increase in myelopoiesis is driven by an inflammatory network orchestrated by PCs.

The layered development of mouse B and T Cells.

Traditional models of lymphopoiesis present B and T cell development as a linear process that initiates in the fetus and continues after birth in the bone marrow and thymus, respectively. However, this view of lymphocyte development is not in accord with reports, dating back several decades, indicating that the types of lymphocytes generated before and after birth differ. In this regard, selected γδ T cells, and those that utilize the Vγ3 receptor in particular, and innate-like B-1 B cells preferentially arise during fetal blood cell development. This review synthesizes data from multiple laboratories, with an emphasis on our own work using mouse models, demonstrating that innate and conventional B and T cells emerge in hematopoietic stem cell independent and dependent waves of development that are differentially regulated. This layering of lymphocyte development has implications for understanding the composition of the adult immune system and may provide insights into the origin of various lymphocytic leukemias.

Distinct Genetic Networks Orchestrate the Emergence of Specific Waves of Fetal and Adult B-1 and B-2 Development.

B cell development is often depicted as a linear process initiating in the fetus and continuing postnatally. Using a PU.1 hypomorphic mouse model, we found that B-1 and B-2 lymphopoiesis occurred in distinct fetal and adult waves differentially dependent on the Sfpi1 14 kB upstream regulatory element. The initial wave of fetal B-1 development was absent in PU.1 hypomorphic mice, while subsequent fetal and adult waves emerged. In contrast, B-2 lymphopoiesis occurred in distinct fetal and adult waves. Whole-transcriptome profiling of fetal and adult B cell progenitors supported the existence of three waves of B-1 and two waves of B-2 development and revealed that the network of transcription factors governing B lineage specification and commitment was highly divergent between B-1 and B-2 progenitors. These findings support the view that the B-1 and B-2 lineages are distinct and provide a genetic basis for layering of immune system development.

Age-period-cohort analysis of lung cancer mortality inequalities in Southern Spain: missed opportunities for implementing equitable tobacco control policies.

BACKGROUND: Lung cancer mortality in European countries shows different epidemiological patterns according to sex and socioeconomic variables. Some countries show decreasing rates in both sexes, while others show a delayed profile, with increasing mortality in women, inconsistently influenced by socioeconomic status. Our aim was to evaluate the effect of age, period and birth cohort on lung cancer mortality inequalities in men and women in Andalusia, the southernmost region in Spain. METHODS: We used the Longitudinal Database of the Andalusian Population, which collects demographic and mortality data from the 2001 census cohort of more than 7.35 million Andalusians, followed up between 2002 and 2016. Mortality rates were calculated for men and women by educational level, and small-area deprivation. Poisson models were used to assess trends in socioeconomic inequalities in men and women. Finally, age-period-cohort (APC) models were used separately for each educational level and gender. RESULTS: There were 39,408 lung cancer deaths in men and 5,511 in women, yielding crude mortality rates of 78.1 and 11.4 × 105 person-years, respectively. In men higher mortality was found in less educated groups and inequalities increased during the study period: i.e. the rate ratio for primary studies compared to university studies increased from 1.30 (CI95:1.18-1.44) to 1.57 (CI95:1.43-1.73). For women, educational inequalities in favour of the less educated tended to decrease moderately. In APC analysis, a decreasing period effect in men and an increasing one in women were observed. Cohort effect differed significantly by educational level. In men, the lower the educational level, the earlier the peak effect was reached, with a 25-year difference between the least-educated and college-educated. Conversely, college-educated women reached the peak effect with a 12-year earlier cohort than the least-educated women. The decline of mortality followed the same pattern both in men and women, with the best-educated groups experiencing declining rates with earlier birth cohorts. CONCLUSIONS: Our study reveals that APC analysis by education helps to uncover changes in trends occurring in different socioeconomic and gender groups, which, combined with data on smoking prevalence, provide important clues for action. Despite its limitations, this approach to the study of lung cancer inequalities allows for the assessment of gaps in historical and current tobacco policies and the identification of population groups that need to be prioritised for public health interventions.

B-1 B cell development in the fetus and adult.

Models of hematopoiesis often depict lymphocyte production as a uniform process in which a homogenous population of hematopoietic stem cells (HSCs) generates progenitors from which all types of lymphocytes are derived. However, it is increasingly evident that these schemes are too simplistic and that the lymphoid potential of HSCs and precursors arising in the embryo, fetus, neonate, and adult is remarkably distinct. We review recent findings regarding the development of B lymphocytes, and the B-1 B cell lineage in particular, as a case in point. These studies show that B-1 and B-2 B cells involved in innate and adaptive immune responses, respectively, arise in staggered waves of development from distinct progenitors. We discuss the implications of this layered model of B cell development for understanding normal and dysregulated B lymphopoiesis.

Challenges for hospital management in supporting nurses to deliver humanized care.

Hospitals are paying increasing attention to the delivery of humanized care. The purpose of this study was to explore from the nursing perspective what hospital managers might do to facilitate this. A secondary analysis from a primary ethnographic study regarding dignity in nursing practice was conducted. Twenty interviews of internal medicine nurses from four hospitals were analyzed, and three main themes were identified: Management of nursing teams, Management of ethical values, and Management of the context. It is important for institutional values to be closely aligned with those of the nursing profession, and nurse managers play a key role in ensuring that the latter are applied in practice. The proposed actions offer a cost-effective framework through which nurses and managers may promote the delivery of humanized care.

Differential Expression of PU.1 and Key T Lineage Transcription Factors Distinguishes Fetal and Adult T Cell Development.

The PU.1 transcription factor plays a critical role in the regulation of T cell development, so a report that it is dispensable for fetal thymopoiesis is puzzling. To understand this paradox, we examined the requirement for PU.1, encoded by Spi1, during fetal, neonatal, and adult thymopoiesis in a PU.1 hypomorphic mouse generated by deletion of the Spi1 14-kb upstream regulatory element and by analysis of patterns of gene expression in fetal and adult T cell progenitors. Our data demonstrate that the initiation of thymopoiesis during early gestation is less dependent on PU.1 compared with T cell differentiation in adults and that fetal T cell progenitors express lower levels of Spi1 compared with their adult counterparts. We also show that expression of the core network of T lineage transcription factors regulated by PU.1 differs in fetal and adult T cell progenitors. In particular, PU.1-regulated genes that promote T cell differentiation are differentially expressed in fetal versus adult early T lineage progenitors. These results indicate that the transcriptional differences between the fetal and adult T cell developmental programs are driven in part by differential levels of PU.1 expression and that this likely underlies the differences in the properties of fetal and adult T cell progenitors.

Fetal B-cell lymphopoiesis and the emergence of B-1-cell potential.

Most B cells in peripheral lymphoid tissues are produced in adult bone marrow and are referred to as B-2 cells. A minor B-cell population, known as the B-1-cell population, that is mainly involved in innate immune responses has been identified in mice. In contrast to B-2 cells, B-1-cell progenitors are produced most efficiently during fetal life. This Review focuses on the emergence of B-1-cell potential during embryogenesis, summarizes recent advances in the delineation of a fetal B-1-cell-specified progenitor, and discusses the possibility that distinct fetal and adult B-cell developmental programmes might be operative in humans.

Murine B-1 B cell progenitors initiate B-acute lymphoblastic leukemia with features of high-risk disease.

B-1 and B-2 B cells derive from distinct progenitors that emerge in overlapping waves of development. The number of murine B-1 progenitors peaks during fetal development whereas B-2 B cell production predominates in adult bone marrow. Many genetic mutations that underlie B-acute lymphoblastic leukemia (B-ALL) occur in the fetus, at which time B-1 progenitor numbers are high. However, whether B-ALL can initiate in B-1 progenitors is unknown. In the present study, we report that BCR-ABL-transformed murine B-1 progenitors can be B-ALL cells of origin and demonstrate that they initiate disease more rapidly than do oncogene-expressing B-2 progenitors. We further demonstrate that B-1 progenitors exhibit relative resistance to apoptosis and undergo significant growth following oncogene expression, and we propose that these properties underlie the accelerated kinetics with which they initiate leukemia. These results provide a developmental perspective on the origin of B-ALL and indicate B cell lineage as a factor influencing disease progression.

Genetic regulation of thymocyte progenitor aging.

The number of T cell progenitors is significantly reduced in the involuted thymus, and the growth and developmental potential of the few cells that are present is severely attenuated. This review provides an overview of how aging affects T cell precursors before and following entry into the thymus and discusses the age-related genetic changes that may occur in them. Finally, interventions that rejuvenate thymopoiesis in the elderly by targeting T cell progenitors are discussed.

Fibroblast growth factor-7 partially reverses murine thymocyte progenitor aging by repression of Ink4a.

Involution of the thymus results in reduced production of naive T cells, and this in turn is thought to contribute to impaired immunity in the elderly. Early T-cell progenitors (ETPs), the most immature intrathymic T-cell precursors, harvested from the involuted thymus exhibit a diminished proliferative potential and increased rate of apoptosis and as a result their number is significantly reduced. In the present study, we show that these age-induced alterations result in part from increased expression of the Ink4a tumor-suppressor gene in ETPs. We also show that repression of Ink4a in aged ETPs results in their partial rejuvenation and that this can be accomplished by in vivo fibroblast growth factor 7 administration. These results define a genetic basis for thymocyte progenitor aging and demonstrate that the senescence-associated gene Ink4a can be pharmacologically repressed in ETPs to partially reverse the effects of aging.

Paediatric celiac patients carrying the HLA-DR7-DQ2 and HLA-DR3-DQ2 haplotypes display small clinical differences.

AIM: The aim of this study was to determine the relevance of HLA-DR7-DQ2 typing in a prospective cohort of paediatric coeliac disease patients from Southern Europe. METHODS: This cross-sectional study tested 249 paediatric patients with coeliac disease. HLA-DR3-DQ2 was typed in combination with HLA-DR7-DQ2 to screen for the HLA-DQ2 haplotype. The histological, analytical and clinical characteristics of the subjects were recorded. RESULTS: A total of 91 coeliac patients were diagnosed: 96.7% carried HLA-DQ2 and 4.4% carried HLA-DQ8. In percentage terms, 80.2% of patients carried HLA-DR3-DQ2 and 34.1% carried HLA-DR7-DQ2. We did not find significant differences between HLA-DR7-DQ2 and HLA-DR3-DQ2 paediatric patients with respect to histological damage and clinical characteristics, except for irritability and weight loss. These characteristics were more frequent in HLA-DQ2trans than in HLA-DQ2cis (22.2% vs. 0.0% [p = 0.035] and 55.6% vs. 21.4% [p = 0.017], respectively). Coeliac-specific autoantibody levels were higher in HLA-DQ2cis than one half of HLA-DQ2trans patients (105.5 vs. 19.2 U/mL, p = 0.014). CONCLUSION: Small clinical differences were found between paediatric coeliac patients carrying HLA-DR7-DQ2 and HLA-DR3-DQ2. For a correct screening of HLA-DQ2, at least in our geographical population, the HLA-DR7-DQ2 haplotype should be typed due to its frequency and clinical presentation.

Reduced production of B-1-specified common lymphoid progenitors results in diminished potential of adult marrow to generate B-1 cells.

B-1 B cells have been proposed to be preferentially generated from fetal progenitors, but this view is challenged by studies concluding that B-1 production is sustained throughout adult life. To address this controversy, we compared the efficiency with which hematopoietic stem cells (HSCs) and common lymphoid progenitors (CLPs) from neonates and adults generated B-1 cells in vivo and developed a clonal in vitro assay to quantify B-1 progenitor production from CLPs. Adult HSCs and CLPs generated fewer B-1 cells in vivo compared with their neonatal counterparts, a finding corroborated by the clonal studies that showed that the CLP compartment includes B-1- and B-2-specified subpopulations and that the former cells decrease in number after birth. Together, these data indicate that B-1 lymphopoiesis is not sustained at constant levels throughout life and define a heretofore unappreciated developmental heterogeneity within the CLP compartment.

Embryonic day 9 yolk sac and intra-embryonic hemogenic endothelium independently generate a B-1 and marginal zone progenitor lacking B-2 potential.

The majority of B lymphocytes in the adult mouse are generated in the bone marrow from hematopoietic stem cells (HSCs) that first appear in the aorta-gonado-mesonephros region of the fetus on embryonic day (E) 10.5-11. Comparatively less is known about B-cell development during embryogenesis. For example, which specific embryonic tissues participate in B lymphopoiesis and whether hematopoietic differentiation is skewed toward specific B-cell subsets in the embryo are unanswered questions, because the systemic circulation is initiated early during embryogenesis, resulting in an admixture of cells potentially originating from multiple sites. We demonstrate, using Ncx1(-/-) mice that lack systemic blood circulation, that the E9 yolk sac (YS) and the intra-embryonic para-aortic splanchnopleura (P-Sp) tissues independently give rise to AA4.1(+)CD19(+)B220(lo-neg) B progenitor cells that preferentially differentiate into innate type B-1 and marginal zone (MZ) B cells but not into B-2 cells upon transplantation. We have further demonstrated that these B-1 progenitor cells arise directly from YS and P-Sp hemogenic endothelium. These results document the initial wave of innate B lymphopoietic progenitor cells available for seeding the fetal liver at E11. The results of these studies expand our knowledge of hemogenic endothelial sites specifying distinct B-1 and MZ cell fates apart from B-2 cells and independent of an HSC origin during development.

Transient PU.1 low fetal progenitors generate lymphoid progeny that contribute to adult immunity.

Hematopoietic stem cells and multipotential progenitors emerge in multiple, overlapping waves of fetal development. Some of these populations seed the bone marrow and sustain adult B- and T-cell development long-term after birth. However, others are present transiently, but whether they are vestigial or generate B and T cells that contribute to the adult immune system is not well understood. We now report that transient fetal progenitors distinguished by expression of low levels of the PU.1 transcription factor generated activated and memory T and B cells that colonized and were maintained in secondary lymphoid tissues. These included the small and large intestines, where they may contribute to the maintenance of gut homeostasis through at least middle age. At least some of the activated/memory cells may have been the progeny of B-1 and marginal zone B cells, as transient PU.1low fetal progenitors efficiently generated those populations. Taken together, our data demonstrate the potential of B- and T-cell progeny of transient PU.1low fetal progenitors to make an early and long-term contribution to the adult immune system.

[Association between reproductive history, breast cancer subtype, and survival in premenopausal women]. / Asociación entre la historia reproductiva, el subtipo de cáncer de mama y la supervivencia de mujeres premenopáusicas.

BACKGROUND AND OBJECTIVE: Reproductive history influences breast cancer risk. We analysed its association with tumour subtype and survival in premenopausal women. PATIENTS AND METHODS: Retrospective, observational study of premenopausal women with stage I-III breast carcinoma in the last 20 years. Review of reproductive history, clinical data, and treatments in health records. RESULTS: In 661 premenopausal women (32.40% of 1377 total cases), median age was 47 years (19-53), menarche 12 (7-17), first delivery 28 (16-41) and number of deliveries 2 (0-9). One hundred and eleven (18.20%) were nulliparous. Three hundred and fifty-nine (58.80%) used natural lactation, with a median duration of 6 months. Anovulatory drugs were used by 271 (44.40%), with a median duration of 36 months. Associations were found between menarche <10 years and lower risk of luminal subtype (OR: 0.52, 95% CI: 0.28-0.94; P=.03), between menarche >11 years and lower risk of HER2 subtype (OR: 0.50, 95% CI: 0.26-0.97; P=.04) and between first birth >30 years and lower risk of triple negative subtype (OR: 0.40, 95% CI: 0.17-0.93; P=.03). The 20-year overall and disease-free survival probabilities were 0.80 (95% CI: 0.71-0.90) and 0.72 (95% CI: 0.64-0.79) respectively. Patients with ≥1 delivery had better overall survival than nulliparous patients (HR: 0.51, 95% CI: 0.27-0.96, P=.04). CONCLUSIONS: The findings suggest an association between age at menarche and age at first delivery and breast cancer subtype. Nulliparity is associated with worse survival.

Clinicopathological and Genomic Identification of Breast Cancers with No Impact on Mortality.

BACKGROUND: Implementing mammogram screening means that clinicians are seeing many breast cancers that will never develop metastases. The purpose of this study was to identify subgroups of breast cancer patients who did not present events related to long-term breast cancer mortality, taking into account diagnosis at breast screening, absence of palpability and axillary involvement, and genomic analysis with PAM50. PATIENTS AND METHODS: To identify them, a retrospective observational study was carried out selecting patients without any palpable tumor and without axillary involvement, and a genomic analysis was performed with PAM50. RESULTS: The probability of distant metastasis-free interval (DMFI) of 337 patients was 0.92 (95% CI, 0.90-0.93) at 20 years and 0.96 (95% CI, 0.92-1.00) in 95 patients (28%) with available PAM50 tests. In 22 (23.15%) luminal A tumors and in 9 (9.47%) luminal B tumors smaller than 1 cm, and in HER2 and basal type tumors, there were no metastatic events (20-year DMFI of 1.00). CONCLUSION: Patients with nonpalpable breast cancer found at screening with negative nodes are at very low risk. It is possible to identify subgroups without metastatic events by determining the intrinsic subtype and tumor size less than 1 cm. Therefore, de-escalation of treatment should be considered.

Formation of B-1 B cells from neonatal B-1 transitional cells exhibits NF-κB redundancy.

The stages of development leading up to the formation of mature B-1 cells have not been identified. As a result, there is no basis for understanding why various genetic defects, and those in the classical or alternative NF-κB pathways in particular, differentially affect the B-1 and B-2 B cell lineages. In this article, we demonstrate that B-1 B cells are generated from transitional cell intermediates that emerge in a distinct neonatal wave of development that is sustained for ~2 wk after birth and then declines as B-2 transitional cells predominate. We further show that, in contrast to the dependence of B-2 transitional cells on the alternative pathway, the survival of neonatal B-1 transitional cells and their maturation into B-1 B cells occurs as long as either alternative or classical NF-κB signaling is intact. On the basis of these results, we have generated a model of B-1 development that allows the defects in B-1 and B-2 cell production observed in various NF-κB-deficient strains of mice to be placed into a coherent cellular context.

Follow-up of long-term survivors of breast cancer in primary care versus specialist attention.

BACKGROUND: Hospitals have traditionally been the place where the follow-up of breast cancer patients occurs in Spain. OBJECTIVE: To describe the evolution of long-term survivors of breast cancer according to type of follow-up received (in primary or specialist/hospital care), measuring impact of care type on health, cost, health-related quality of life (HRQL) and satisfaction results. METHOD: Retrospective study of cohorts with disease-free patients followed up for at least 5 years in Oncology. Using personal questionnaires, the type and cost of the follow-up, events, HRQL and satisfaction were analysed. RESULTS: Ninety-eight women were surveyed, 60 in primary and 38 in specialist care. There were no differences between groups in diagnosis of metastasis or new primary tumours. The number of annual visits per patient was 0.98 (0.48) in primary and 1.11 (0.38) in specialist care (P = 0.19). In primary, 44.6% were programmed and 55.4% on demand; in specialist, 94.6% were programmed and 5.4% on demand (P = 0.0001). The costs of follow-up in primary care were lower--€112.86 (77.54) versus €184.61 (85.87) per patient and year (P = 0.0001). No differences were reported in HRQL. Preference for specialist care was expressed by 80%, versus 10% for primary, with 10% indifferent. Patients showed greater satisfaction with specialist care in all questionnaire dimensions. CONCLUSIONS: Compliance with follow-up protocol was high in both groups. In specialist care nearly all the visits were programmed and in primary almost half were on demand. In our locality, primary is more cost-effective than specialist care, but patients express greater satisfaction with specialist follow-up and hence prefer it.

[Profile of women with breast disease wich does self-exploration. Which are the factors associated with this practice?]. / Mujer con patología mamaria.

BACKGROUND/AIMS: In recent decades the fight against breast cancer has focused primarily on the treatment and secondary prevention (early detection mainly). In the case of breast self-examination, althought it has not been prove to reduce mortality, it is important in cases detected by women themselves (it is estimated 90% of total), mainly in the interval cancers. OBJECTIVES: To identify within women with breast cancer, how many do self-examination and identify associated factors. Describe the clinical and pathological features of cancers in women who do perform self-examination. METHODOLOGY: In women diagnosed with breast cancer during 2007 in a hospital in the province of Cadiz, Spain, is reconstructed in retrospect the story related the cancer process: symptoms, psychosocial factors that determine the contact with the health system, preventive practices (self-examination, mammography screening). A description of the pathological tumor: presenting symptom, tumor size, node negative, grade of differentiation. RESULTS: We studied 149 women with breast cancer, from whom 52% did self-exploration. Women who performed self-examination were younger (54.78 years) against the women who did not (65.63 years), married (66.2%), active workers and have a higher educational level. The assessment of the first symptoms in these women as "important" is positively correlated with those women who practice self-examination. For other preventive practices, women who does self-examination are also the most actives in early detection programs (74.4% against 29.5% which didn't do self-examination). For the pathologic characteristics of tumor in women who did self-examination: the tumor size was 2.5 cm, 50.7/are well differentiated, and 59.1% of cases the nodes are negative. CONCLUSIONS: Women who does self-examination are younger, have higher educational level, are married, are active workers and are often involved in other preventive practices. On them, the tumors diagnosed have a smaller size, are diagnosed at earlier stages and usually present better degree of differentiation.