DNA Damage Activates TGF-ß Signaling via ATM-c-Cbl-Mediated Stabilization of the Type II Receptor TßRII.

Activation of both the DNA damage response (DDR) and transforming growth factor ß (TGF-ß) signaling induces growth arrest of most cell types. However, it is unclear whether the DDR activates TGF-ß signaling that in turn contributes to cell growth arrest. Here, we show that in response to DNA damage, ataxia telangiectasia mutated (ATM) stabilizes the TGF-ß type II receptor (TßRII) and thus enhancement of TGF-ß signaling. Mechanistically, ATM phosphorylates and stabilizes c-Cbl, which promotes TßRII neddylation and prevents its ubiquitination-dependent degradation. Consistently, DNA damage enhances the interaction among ATM, c-Cbl, and TßRII. The ATM-c-Cbl-TßRII axis plays a pivotal role in intestinal regeneration after X-ray-induced DNA damage in mouse models. Therefore, ATM not only mediates the canonical DDR pathway but also activates TGF-ß signaling by stabilizing TßRII. The double brake system ensures full cell-cycle arrest, allowing efficient DNA damage repair and avoiding passage of the damaged genome to the daughter cells.

Necesidad de políticas de salud pública en población adulta mayor: indicadores de envejecimiento en un Instituto de Seguridad Social en México / Need for public health policies in the elderly population: indicators of aging in a Social Security Institute in Mexico

Resumen Introducción: Un diagnóstico integral de población contempla dentro de sus componentes el análisis demográfico poblacional, que es indispensable en la formulación de las políticas públicas. La política de población tiene una naturaleza claramente transversal, pues todas las acciones en los ámbitos económico, social, político, cultural, geográfico, y obviamente, el demográfico, repercuten de una manera directa o indirecta en ella. Objetivos: Determinar la dinámica poblacional y el crecimiento global de la población adulta mayor (PAM) de 60 años y más. Materiales y métodos: Estudio transversal, retrospectivo. La información se obtuvo de los anuarios estadísticos institucionales del Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, México (de 1999-2015). Se analizaron varios indicadores demográficos de envejecimientoDE). Resultados: Se observó un incremento constante en puntos porcentuales en la proporción de PAM, el índice de envejecimiento, la razón de dependencia demográfica de la vejez, índice global de dependencia, índice dependencia de viejos e índice de estructura de la población activa (6, 19.2, 15.5, 8.5, 8.2 y 31.2%, respectivamente). El indicador global de ancianidad y el índice de masculinidad mostraron una disminución (0.6 y 3.1%, respectivamente). Conclusiones: Nuestros datos aportan evidencia que sugiere modificar y generar políticas públicas acordes a la PAM.

Abstract Introduction: An integral diagnosis of population contemplates within its components the population demographic analysis that is indispensable in the formulation of public policies. Population policy has a clearly transversal nature, since all actions in the economic, social, political, cultural, geographical, and obviously, demographic fields, have direct or indirect repercussions on it. Objectives: To determine the population dynamics and the global growth of the older adult population (OAP) of 60 years and more. Materials and methods: Cross-sectional, retrospective study. The information was obtained from the statistical yearbooks of the institute of security and social services of state workers, Mexico (1999-2015). Several demographic ageing indicators were analyzed. Results: There was a constant increase in percentage points in the proportion of OAP, index of ageing, demographic dependency ratio of old age, global index of dependence, index of dependence of old people, and index of the active population structure (6, 19.2, 15.5, 8.5, 8.2 and 31.2%, respectively). The indicator global index of dependence and masculinity showed a decrease (0.6 and 3.1%, respectively). Conclusions: Our data provide evidence that suggests modifying and generating public policies according to OAP.

Co-stimulatory function in primary germinal center responses: CD40 and B7 are required on distinct antigen-presenting cells.

T cell-dependent germinal center (GC) responses require coordinated interactions of T cells with two antigen-presenting cell (APC) populations, B cells and dendritic cells (DCs), in the presence of B7- and CD40-dependent co-stimulatory pathways. Contrary to the prevailing paradigm, we found unique cellular requirements for B7 and CD40 expression in primary GC responses to vaccine immunization with protein antigen and adjuvant: B7 was required on DCs but was not required on B cells, whereas CD40 was required on B cells but not on DCs in the generation of antigen-specific follicular helper T cells, antigen-specific GC B cells, and high-affinity class-switched antibody production. There was, in fact, no requirement for coexpression of B7 and CD40 on the same cell in these responses. Our findings support a substantially revised model for co-stimulatory function in the primary GC response, with crucial and distinct contributions of B7- and CD40-dependent pathways expressed by different APC populations and with important implications for understanding how to optimize vaccine responses or limit autoimmunity.

Clinico-biological significance of suppressor of cytokine signaling 1 expression in acute myeloid leukemia.

Suppressor of cytokine signaling 1 (SOCS1) protein, which encodes a member of signal transducers and activators of transcription-induced inhibitors, takes part in a negative regulation of cytokine signaling. The mechanism of SOCS1 in tumor carcinogenesis is complex and there have been no studies concerning the clinic-biologic implication of SOCS1 expression in acute myeloid leukemia (AML). Here, we first identified that higher bone marrow (BM) SOCS1 expression was closely associated with older age, FLT3-ITD, NPM1 and DNMT3A mutations, but negatively correlated with CEBPA mutation in patients with de novo AML. Compared to patients with lower SOCS1 expression, those with higher expression had lower complete remission rates and shorter overall survival. Further, higher expression of SOCS1 in the BM was an independent unfavorable prognostic factor irrespective of age, white blood cell, cytogenetics and gene mutations. Next, we generated zebrafish model overexpressing SOCS1 by spi1 promoter, which showed kidney marrow from adult SOCS1 zebrafish had increased myelopoiesis, myeloid progenitors and the kidney or spleen structure were effaced and distorted, mimicking leukemia phenotype. The SOCS1/FLT3-ITD double transgenic fish could further facilitate the leukemic process. The results indicate SOCS1 plays an important role in AML and its higher expression serves as a new biomarker to risk-stratify AML patients.

Protein disulfide isomerase a4 acts as a novel regulator of cancer growth through the procaspase pathway.

Protein disulfide isomerase a4 (PDIA4) is implicated in the growth and death of tumor cells; however, its molecular mechanism and therapeutic potential in cancer are unclear. Here, we found that PDIA4 expression was upregulated in a variety of tumor cell lines and human lung adenocarcinoma tissues. Knockdown and overexpression of PDIA4 in tumor cells showed that PDIA4 facilitated cell growth via the reduction of caspases 3 and 7 activity. Consistently, Lewis lung carcinoma cells overexpressing PDIA4 grew faster than did parental cells in tumor-bearing mice, as shown by a reduced survival rate, increased tumor size and metastasis, and decreased cell death and caspases 3 and 7 activity. PDIA4 knockdown resulted in opposite outcomes. Moreover, results obtained in mice with spontaneous hepatoma indicated that PDIA4 deficiency significantly reduced hepatic tumorigenesis and cyst formation and increased mouse survival, tumor death, and caspases 3 and 7 activity. Mechanistic studies illustrated that PDIA4 negatively regulated tumor cell death by inhibiting degradation and activation of procaspases 3 and 7 via their mutual interaction in a CGHC-dependent manner. Finally, we found that 1,2-dihydroxytrideca-5,7,9,11-tetrayne, a PDIA4 inhibitor, reduced tumor development via enhancement of caspase-mediated cell death in TSA tumor-bearing mice. These findings characterize PDIA4 as a negative regulator of cancer cell apoptosis and suggest that PDIA4 is a potential therapeutic target for cancer.

Vortex sound radiation in a flow duct with a dipole source and a flexible wall of finite length.

The noise attenuation of fan-ducted noise at low blade-passage frequency remains a challenge. The present study investigates the noise reduction mechanism of a tensioned membrane housing device that directly controls the sound radiation from the doublet which is enclosed in an infinitely long duct with a point vortex. The time dependent sound radiation mechanism and the vibro-acoustics coupling mechanism of the systems are studied by adopting the potential theory and matched asymptotic expansion technique. The silencing performance of such a passive approach depends on the amplitude and phase of the sound field created by the doublet and the acoustic pressure induced by the membrane oscillation in order to achieve sound cancellation. Results show that the response of membrane vibration is strongly associated with the flow field induced by the grazing uniform flow and also the fluid loading generated by the inviscid vortex. The geometrical property of the cavity and the mechanical properties of the flexible membranes play important roles in controlling the performance of the proposed device.

Dermal fillers: pathophysiology, prevention and treatment of complications.

Dermal fillers are increasingly used for soft tissue augmentation of the face and hands. The widespread use of dermal fillers for rejuvenation has led to a rise in reports of associated complications. Although the majority of complications are mild and transient, serious and long-lasting complications have been observed. This article discusses the key complications including pigmentary changes, hypersensitivity reactions, infections, nodule formation, granulomatous reactions, vascular occlusion and migration of filler material. A thorough literature review was performed in addition to the combined extensive authors' (GP and FA) experience. Complications from fillers are increasingly being recognized and highlighted in the literature partly reflecting the growth in the market. This article provides a comprehensive overview of the filler complications with mechanisms of prevention and treatment per complication. A thorough understanding of the preventative and management strategies for the associated dermal filler complications will help the physician to prepare the patient well, and deal with complications that may arise effectively.

Expression of CALR mutants causes mpl-dependent thrombocytosis in zebrafish.

CALR mutations are identified in about 30% of JAK2/MPL-unmutated myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET) and primary myelofibrosis. Although the molecular pathogenesis of CALR mutations leading to MPNs has been studied using in vitro cell lines models, how mutant CALR may affect developmental hematopoiesis remains unknown. Here we took advantage of the zebrafish model to examine the effects of mutant CALR on early hematopoiesis and model human CALR-mutated MPNs. We identified three zebrafish genes orthologous to human CALR, referred to as calr, calr3a and calr3b. The expression of CALR-del52 and CALR-ins5 mutants caused an increase in the hematopoietic stem/progenitor cells followed by thrombocytosis without affecting normal angiogenesis. The expression of CALR mutants also perturbed early developmental hematopoiesis in zebrafish. Importantly, morpholino knockdown of mpl but not epor or csf3r could significantly attenuate the effects of mutant CALR. Furthermore, the expression of mutant CALR caused jak-stat signaling activation in zebrafish that could be blocked by JAK inhibitors (ruxolitinib and fedratinib). These findings showed that mutant CALR activates jak-stat signaling through an mpl-dependent mechanism to mediate pathogenic thrombopoiesis in zebrafish, and illustrated that the signaling machinery related to mutant CALR tumorigenesis are conserved between human and zebrafish.

T-cell development is regulated by the coordinated function of proximal and distal Lck promoters active at different developmental stages.

Expression of Lck, a T-cell lineage-specific tyrosine kinase critical for T-cell development and activation, can be mediated by either proximal or distal lck promoter. We generated BAC transgenic mice in which BAC lck promoter was deleted and bred these transgenes to an Lck knockout background. Lck-PROX mice, in which only the proximal promoter is functional, have maximal Lck protein and normal thymic development through CD4- CD8- double negative (DN) and CD4+ CD8+ double positive (DP) stages, but undetectable Lck later in development and reduced mature single positive thymocytes. In contrast, Lck-DIST mice, in which only distal promoter was functional, are deficient in Lck protein in DN and DP thymocytes and severely defective in early T-cell development, with a block at the DN3-DN4 beta checkpoint equivalent to complete Lck knockouts. The ability of the proximal lck promoter to support thymic development is independent of Fyn; while, in contrast, the distal lck promoter alone is completely unable to support development in the absence of Fyn. Notably, normal thymocyte development is restored by presence of both proximal and distal promoters, even when independently expressed on different lck genes. These results define distinct and complementary requirements for proximal and distal lck promoters during T-cell development.

Factors Determining Physical and Mental Quality of Life of Living Kidney Donors in Taiwan.

BACKGROUND: Living-donor kidney transplantation has a positive influence on recipients' life expectancy and improves quality of life for patients with end-stage renal disease compared with dialysis patients. Evaluation of the physical and mental quality of life for donors can promote positive perceptions about donation and help potential donors in their decision-making process. The aim of this study was to explore the predictive factors of quality of life for living kidney donors. METHODS: A cross-sectional and descriptive design was used, and the study was conducted from January to July 2013. The donors were a convenience sample of 34 participants who had undergone kidney transplant surgery >1 year earlier. RESULTS: The results showed that kidney donors had a low to moderate physical and mental quality of life. Multiple regression analysis revealed that financial concerns and anxiety explained 27.8% of the total variance of quality of life in the physical component. Anxiety and paid work explained 61.4% of the total variance of quality of life in the mental component. CONCLUSIONS: After renal transplantation, living kidney donors experienced low to moderate quality of life. Because donors are family members (siblings, sons or daughters, spouses, or parents), monthly family income is a significant issue that influences both the decision to donate and quality of life after transplantation. Our findings suggest that pre-transplantation assessment must include social workers as part of the health care team to evaluate the impact of a donor's financial status on post-transplantation quality of life.

Genetic alterations and their clinical implications in older patients with acute myeloid leukemia.

A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.

Mesothelin-specific cell-based vaccine generates antigen-specific immunity and potent antitumor effects by combining with IL-12 immunomodulator.

Ovarian cancer is a gynecologic malignancy with a high mortality rate. In the present study, we developed a novel cell-based vaccine, Meso-VAX, to generate mesothelin antigen-specific immune responses and immunotherapy against ovarian cancer. Mesothelin, a secreted protein anchored at the cell membrane, has recently been identified as a potential new tumor antigen for ovarian cancer. In this study, mice vaccinated with Meso-VAX and adeno-associated virus (AAV)-IL-12 exhibited dramatic increases in the number of mesothelin-specific CD4(+) helper and CD8(+) cytotoxic T-cell precursors, higher titers of anti-mesothelin Abs and in vitro tumor killing activity, and all of these mice were tumor-free after 60 days of tumor challenge. In addition, a significant reduction in peritoneal tumors and longer survival were noted in the mice vaccinated with Meso-VAX combined with AAV-IL-12. CD4(+) helper and CD8(+) cytotoxic T lymphocytes were essential for the antitumor effect generated by Meso-VAX combined with AAV-IL-12. The post-vaccination sera of the mice vaccinated with Meso-VAX and AAV-IL-12 also showed mesothelin-specific complement-dependent cell-mediated cytotoxicity. Our results suggest that a Meso-VAX cell-based vaccine combined with AAV-IL-12 can generate antigen-specific immunological responses and antitumor effects on ovarian cancer.

Saggy skin as a presenting sign of angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare, aggressive form of peripheral T-cell lymphoma that has a variety of cutaneous manifestations. To our knowledge, saggy skin has not been documented as one of these manifestations. We report a case of a patient with angioimmunoblastic T-cell lymphoma presenting initially with pruritus and saggy skin, which later progressed into erythroderma despite chemotherapy; the disease eventually resolved with autologous stem cell transplant. Appreciating the cutaneous manifestations of AITL may allow for earlier diagnosis and treatment.

Molecular characterization of twenty polymorphic microsatellite markers in the polyploid fruit tree species Syzygium samarangense (Myrtaceae).

Syzygium samarangense (Blume) Merr. & Perry (wax apple) is an important commercial fruit tree in Southeast Asia. Here, microsatellite markers were developed to evaluate genetic diversity and distinguish cultivars in this species. In total, 161 microsatellite loci with sufficient flanking sequences to design primer sets were isolated from wax apple using a magnetic bead-enrichment method. Fifty-eight primer sets were designed based on the flanking sequences of each single sequence repeat (SSR) locus and were tested using 14 wax apple cultivars/lines. Twenty SSR loci were found to be polymorphic and transferable across the 14 wax apple cultivars/lines. The number of alleles and effective number of alleles detected per locus ranged from 4 to 12 and from 1.697 to 9.800, respectively. The expected heterozygosity ranged from 0.150 to 0.595 (mean = 0.414). Polymorphism information content values ranged from 0.502 to 0.866 (mean = 0.763). These new microsatellite loci will be of value for characterization of genetic diversity in wax apples and for the identification of cultivars.

TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution.

The TP53 mutation is frequently detected in acute myeloid leukemia (AML) patients with complex karyotype (CK), but the stability of this mutation during the clinical course remains unclear. In this study, TP53 mutations were identified in 7% of 500 patients with de novo AML and 58.8% of patients with CK. TP53 mutations were closely associated with older age, lower white blood cell (WBC) and platelet counts, FAB M6 subtype, unfavorable-risk cytogenetics and CK, but negatively associated with NPM1 mutation, FLT3/ITD and DNMT3A mutation. Multivariate analysis demonstrated that TP53 mutation was an independent poor prognostic factor for overall survival and disease-free survival among the total cohort and the subgroup of patients with CK. A scoring system incorporating TP53 mutation and nine other prognostic factors, including age, WBC counts, cytogenetics and gene mutations, into survival analysis proved to be very useful to stratify AML patients. Sequential study of 420 samples showed that TP53 mutations were stable during AML evolution, whereas the mutation was acquired only in 1 of the 126 TP53 wild-type patients when therapy-related AML originated from different clone emerged. In conclusion, TP53 mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression.

Is surviving enough? Coping and impact on activities of daily living among melanoma patients with lymphoedema.

We assessed the impact of lymphoedema (defined as ≥ 10% limb volume change) on quality of life (QOL), ability to perform activities of daily living (ADLs) and coping in 277 melanoma patients. Limb volume was measured prospectively, pre-operatively and every 3-6 months for 18 months post-operatively using a perometer. Three questionnaires were administered to measure QOL, coping and impact on ADLs. Statistical analyses were conducted using longitudinal logistic regression models. At 18 months, the cumulative incidence of lymphoedema was 31% in patients with upper extremity nodal basin treatment and 40% in lower extremity nodal basin treatment patients. Patients with lower extremity lymphoedema reported lower QOL scores than those with upper extremity lymphoedema. Over 18 months, both groups with mild and moderate lymphoedema showed improvement in coping [odds ratio (OR): 6.67, 95% confidence interval (CI): 3.30-13.47] and performance of ADLs (OR: 7.46, CI: 3.38-16.47). Over the course of 18 months, men were found to have poorer coping scores than women (OR: 2.91, CI: 1.35-6.27). Lymphoedema was associated with improvement in coping over time (P = 0.08) and a higher reported interference with ADLs (OR: 2.53, CI: 1.29-4.97). Patient education about lymphoedema at the time of surgical consent may improve self-efficacy and coping ability. Effective management of lymphoedema may improve patient QOL and reduce interference with ADLs.

Regulation of T cell development by c-Cbl: essential role of Lck.

A canonical pre-TCR/TCR signaling pathway critical for thymic T cell development involves sequential phosphorylation and signaling through Lck, Zap70, Lat and Slp76. However, we and others have previously reported that genomic deletion of c-Cbl (Cbl) partially or completely reverses the defects in thymic development in mice deficient in Zap70, Slp76, Lat or Vav1, indicating the presence of alternative pathways normally suppressed by Cbl. To further elucidate pre-TCR/TCR signaling pathways involved in thymic development, we characterized the effect of Cbl inactivation on developmental and signaling defects in mice deficient in proximal signaling molecules Lck and Zap70. Inactivation of Cbl partially reversed defective T cell development in Zap70 (-/-) mice and reversed defects in phosphorylation of Erk, Plc-γ1, Vav1 and Akt, in TCR-stimulated Cbl (-/-) Zap70 (-/-) thymocytes. Recent reports identified an essential role of Lck in associating with CD4 and CD8 coreceptors and mediating the requirement for MHC restriction in TCR recognition. Since TCR recognition has been shown to be MHC-restricted in Cbl (-/-) mice, it was of interest to determine whether the requirement for Lck remained unmodified by Cbl deletion. Indeed, in contrast to the effect of Cbl inactivation in partially or fully bypassing requirements for other TCR signaling components, inactivation of Cbl did not reverse either defective T cell development or defective phosphorylation of TCR signaling molecules in Lck (-/-) mice. Thus, Lck, which plays a unique role in enforcing MHC restriction, is essential for thymic development in presence or absence of Cbl, ensuring MHC restriction of T cells derived from either pathway.