An Immunogenetic Signature of Ongoing Antigen Interactions in Splenic Marginal Zone Lymphoma Expressing IGHV1-2*04 Receptors.

Purpose: Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation.

Experimental Design: We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM).

Results: ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV)1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P= 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene).

Conclusions: These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease.

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.

Ajustes razonables en la rehabilitación de polígonos de viviendas: aplicación al barrio Montserrat de Terrassa (Barcelona)

La introducción de ajustes razonables para facilitar la accesibilidad universal en los edificios de vivienda ha adquirido una gran relevancia desde la publicación de la Ley 8/2013 de 26 de Junio de rehabilitación, regeneración y renovación urbanas. La complejidad y coste de estos procesos no es fácil de conjugar con la atención a las necesidades funcionales y dimensionales que las personas con discapacidad y otros colectivos con limitaciones requieren. En este artículo se aborda este dilema y se aplica para el caso de la rehabilitación accesible de viviendas del Barrio Montserrat de Terrassa, Barcelona, representativo de tantos polígonos residenciales y obreros construidos en los años 50, 60 y 70 en España.

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.