Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing

Purpose: Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies.

Experimental Design: We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL.

Results: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02–4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05–4.55; P = 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08–5.2; P = 0.03).

Conclusions: We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively.

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications.

We performed an immunogenetic analysis of 345 IGHV-IGHD-IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; IGHV4-34, 12.8%; IGHV3-23, 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele (*)04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2(*)04 peaked at 31%. The IGHV1-2(*)04 rearrangements carried significantly longer complementarity-determining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2(*)04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97-99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2(*)04 allele.

The prognostic impact of clinical and molecular features in hairy cell leukaemia variant and splenic marginal zone lymphoma.

Hairy cell leukaemia variant (HCL-variant) and splenic marginal zone lymphoma (SMZL) are disorders with overlapping features. We investigated the prognostic impact in these disorders of clinical and molecular features including IGH VDJ rearrangements, IGHV gene usage and TP 53 mutations. Clinical and laboratory data were collected before therapy from 35 HCL-variant and 68 SMZL cases. End-points were the need for treatment and overall survival. 97% of HCL-variant and 77% of SMZL cases required treatment (P = 0·009). Survival at 5 years was significantly worse in HCL-variant [57% (95% confidence interval 38-73%)] compared with SMZL [84% (71-91%); Hazard Ratio 2·25 (1·20-4·25), P = 0·01]. In HCL-variant, adverse prognostic factors for survival were older age (P = 0·04), anaemia (P = 0·01) and TP 53 mutations (P = 0·02). In SMZL, splenomegaly, anaemia and IGHV genes with >98% homology to the germline predicted the need for treatment; older age, anaemia and IGHV unmutated genes (100% homology) predicted shorter survival. IGHV gene usage had no impact on clinical outcome in either disease. The combination of unfavourable factors allowed patients to be stratified into risk groups with significant differences in survival. Although HCL-variant and SMZL share some features, they have different outcomes, influenced by clinical and biological factors.

Financial Inclusion of The Small and Marginal Farmers by the Banking Sector in Kerala

Financial inclusion for inclusive growth is central to the developmental philosophy of most of the nations over the past decade. It has been a priority for policy makers and regulators in financial sector development for improving access and usage of financial services to achieve comprehensive financial inclusion. The initiatives taken towards financial inclusion can promote a more effective and efficient process to achieve significant improvements in financial inclusion are to establish and achieve shared and sustainable development and growth. Realising this, an increasing number of countries are committing to promote financial inclusion, encouraged by the growing body of country level experiences (World Bank, 2012). Financial inclusion basically means, broad based growth through participation as well as sharing the benefits from the growth process along with the under privileged and marginal segments of the economy. Evidence suggests that it has substantial benefits for equitable and sustainable growth. Inclusive growth ensures that while economy grows rapidly, all segments of society are involved in this growth process, ensuring equal opportunities, devoid of any regional or sectoral disparitiesIt is widely acknowledged that the objective ofinclusive growth is accomplished through the process of financial inclusion. Financial inclusion envisages bringing everyone, irrespective of financial status, into the banking fold for the individual progress and development and thereby achieving comprehensive growth with equity

Labor Scheduling Using NPV Estimates of the Marginal Benefit of Additional Labor Capacity

An extensive literature exists on the problems of daily (shift) and weekly (tour) labor scheduling. In representing requirements for employees in these problems, researchers have used formulations based either on the model of Dantzig (1954) or on the model of Keith (1979). We show that both formulations have weakness in environments where management knows, or can attempt to identify, how different levels of customer service affect profits. These weaknesses results in lower-than-necessary profits. This paper presents a New Formulation of the daily and weekly Labor Scheduling Problems (NFLSP) designed to overcome the limitations of earlier models. NFLSP incorporates information on how changing the number of employees working in each planning period affects profits. NFLP uses this information during the development of the schedule to identify the number of employees who, ideally, should be working in each period. In an extensive simulation of 1,152 service environments, NFLSP outperformed the formulations of Dantzig (1954) and Keith (1979) at a level of significance of 0.001. Assuming year-round operations and an hourly wage, including benefits, of $6.00, NFLSP's schedules were $96,046 (2.2%) and $24,648 (0.6%) more profitable, on average, than schedules developed using the formulations of Danzig (1954) and Keith (1979), respectively. Although the average percentage gain over Keith's model was fairly small, it could be much larger in some real cases with different parameters. In 73 and 100 percent of the cases we simulated NFLSP yielded a higher profit than the models of Keith (1979) and Danzig (1954), respectively.

Document Structures: Journeys, Marginal Material, Notes, Divisions, and Other Features

A journal of commercial voyages and domestic life on the Tigris River -- structure of the documents.

Valoração econômica do Parque Nacional da Lagoa do Peixe, RS

O objetivo deste trabalho foi valorar economicamente o Parque Nacional da Lagoa do Peixe (PNLP). O PNLP visa a preservar amostras de ecossistemas litorâneos, típicos da restinga costeira, dos quais dependem centenas de aves migratórias. A técnica empregada foi o Método de Valoração Contingente, o qual admite que a variação na disponibilidade do recurso altera o bem-estar das pessoas e, portanto, é possível identificar as disposições a pagar (DAP) dos indivíduos em relação a estas alterações. Para alcançar objetivo deste estudo, foram entrevistados 130 pessoas representando a população municípios que abrangem o Parque - Mostardas, São José do Norte e Tavares. Destas, 94% se mostraram dispostas a pagar pela preservação/conservação das amenidades ambientais no PNLP. Além disso, pôde-se constatar, por meio dos coeficientes estimados em modelos econométricos, que as DAP’s mantêm uma relação positiva com as variáveis renda e grau de escolaridade. A DAP média estimada foi de R$ 7,94 e isto levou a um valor econômico de R$ 54.770,12, no agregado, o que representa uma aproximação do valor anual de uso do PNLP. Essa estimativa pode indicar em quanto os usuários valorizam o ativo ambiental em questão.

Geoquímica dos filões máficos de Lagoa (Maciço de Morais, Trás-os-Montes, NE Portugal)

No Maciço de Morais, os gnaisses de Lagoa são intruídos por filões máficos, de idade precâmbrica-câmbrica, que cortam um "fabric" metamórfico precoce naqueles gnaisses. Os filões máficos de Lagoa têm características geoquímicas de toleítos continentais e testemunham processos ACF. A actividade magmática em que esses filões se inserem reflecte ascenção astenosférica subsequente ao sobre-espessamento crustal precâmbrico, correspondendo a uma manifestação precoce do regime tectónico/magmático que irá caracterizar, durante o Paleozóico inferior, o ciclo varisco ibérico.

Lagoa mirim: caracterização da pesca artesanal e composição da captura

Os ambientes aquáticos continentais da metade sul do RS são caracterizados por uma ampla planície costeira, onde destaca-se a Lagoa Mirim, com uma área total binacional (Brasil e Uruguai) de 3.750 Km². Nesta região, a pesca é uma importante atividade sócio-econômica, porém, a economia da região baseia-se no cultivo do arroz e na criação de gado. A proposta deste trabalho foi realizar um diagnóstico preliminar desta atividade na L. Mirim. A metodologia foi baseada na aplicação de formulários aos pescadores artesanais (perfil sócio-econômico e características da pesca) e na identificação das espécies que compunham a captura proveniente do desembarque pesqueiro no entorno da L. Mirim (Jaguarão, Santa Isabel e Santa Vitória do PalmarPorto e Curral Alto). Os dados de captura total de pescado foram provenientes de fontes independentes e complementares. O estudo sugere um perfil do pescador artesanal composto por 71% de indivíduos de sexo masculino, entre 20 e 65 anos de idade que costumam ficar de uma semana a quinze dias embarcados. A maioria (71%) dos pescadores artesanais entrevistados possui somente ensino fundamental e seus familiares geralmente estão envolvidos na atividade pesqueira. Foram identificados 28 locais de pesca e as principais espécies capturadas pela pesca artesanal foram: traíra Hoplias malabaricus, jundiá Rhandia aff. quelen, pintado Pimelodus maculatus, peixerei Odontesthes spp, viola-cascuda Loricariichthys anus e tambico Oligosarcus spp. A traíra foi a espécie mais representativa em peso (> 40%). Estas espécies apresentaram flutuações na composição das capturas ao longo do ano; os menores valores foram registrados entre julho e setembro (meses frios), exceto para o peixe-rei. A análise dos dados também aponta uma variação interanual dos valores totais de pescado e alguns fatores que podem estar associados à diminuição da captura são os prolongados períodos de seca na região, o uso da água na orizicultura e a falta de fiscalização da atividade pesqueira. Estudos baseados em estimativas de pescarias e conhecimento sobre a biologia das espécies capturadas podem fornecer subsídios para o correto manejo dos recursos pesqueiros, para tanto, são necessárias pesquisas que investiguem aspectos do uso sustentado das espécies de importância econômica na região e os possíveis efeitos da atividade pesqueira sobre a estrutura e a biodiversidade do ecossistema. Assim, para garantir a sustentabilidade da Lagoa Mirim, faz-se necessário envolver os pescadores artesanais e suas estratégias de pesca, em função de seus conhecimentos ecológicos, nas pesquisas que integram a elaboração das políticas públicas.

Análise dos efeitos da legislação urbanística na formação e crescimento do Bairro de Lagoa Nova: planos diretores de 1974, 1984 e 1994

To Analyze the Managing Plans of Natal in the decades of 1970, 1980 and 1990, identifying elements that had contributed for the growth of the Lagoa Nova quarter, capital one of the Rio Grande do Norte state. Ahead of the sped up growth of the urban centers, many times is not given to analyze which law had taken care of to its objective, and which the imperfections that had appeared during the application of these laws. To make the comparisons in you square them chosen at there distantinct times made possible to analyze the form as the ground of Lagoa Nova absorbed the proposals laws.Therefore toanalyze influences it of the Managing Plans, to make comparatives analyses between the urbanistics condicion, made possible to understand that the fabric urban of the quarter of Lagoa Nova is a true granary of information that it makes possible to the dedicated ones to the urban studies, a true field of analysis