In this randomized multicenter study of 136 patients, 6 courses of CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) followed by rituximab (CHOP-R) were compared with rituximabsupplemented high-dose sequential chemotherapy with autografting (R-HDS) to assess the value of intensified chemotherapy as a first-line treatment for highrisk follicular lymphoma (FL) after the introduction of monoclonal antibodies. The analysis was intention to treat with event-free survival (EFS) as the primary endpoint. Complete remission (CR) was 62% with CHOP-R and 85% with R-HDS (P < .001). At a median follow-up (MFU) of 51 months, the 4-year EFS was 28% and 61%, respectively (P < .001), with no difference in overall survival (OS). Molecular remission (MR) was achieved in 44% of CHOP-R and 80% of R-HDS patients (P < .001), and was the strongest independent outcome predictor. Patients relapsing after CHOP-R underwent salvage R-HDS in 71% of cases. Salvage R-HDS had an 85% CR rate and a 68% 3-year EFS (MFU, 30 months). We conclude that (1) achieving MR is critical for effective disease control, regardless of which treatment is used; IntroductionIn the last 15 years, our approach to treatment of follicular lymphoma (FL) has evolved considerably, chiefly due to 3 major achievements. First, new agents, particularly rituximab, have improved overall outcome in patients with FL. 1,2 Second, a subset of patients with a rapid and progressive course has been recognized. [3][4][5] The International Prognostic Index (IPI), the age-adjusted IPI (aaIPI), and more recent FL-specific scores such as the Intergruppo Italiano Linfomi (IIL) score and Follicular Lymphoma International Prognostic Index (FLIPI) now allow simple and effective identification of these high-risk patients, whose management is currently far from satisfactory. 4,5 Finally, many phase 2 studies have demonstrated that the achievement of molecular remission (MR) as determined by polymerase chain reaction (PCR) is associated with a better outcome in the context of a wide array of different treatments. [6][7][8][9][10][11] In this rapidly evolving field, the place for intensified regimens with autologous stem cell transplantation (ASCT) is poorly defined. Most data arise from pre-rituximab studies. [12][13][14][15][16] ASCT improves overall survival (OS) in relapsed patients, 7,12 while data at diagnosis are less clear. The 3 phase 3 studies published so far The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 7, 2018. by guest www.bloodjournal.org From have been based on total body irradiation (TBI)-containing regimens, did not select patients according to validated prognostic scores, and did not include molecular analysis. [13][14][15] Two of these trials showed that intensive therapy ensures better progression-free survi...

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The marked improvement in metabolic profile, observed in severely obese patients with type 2 diabetes after a 7-d VLCD, was primarily due to the amelioration of β cell function, whereas no contribution of insulin sensitivity was shown. This trial was registered at www.clinicaltrials.gov as NCT01447524.

Phytoplasmas are obligate, phloem-restricted phytopathogens that are disseminated by phloem-sap-sucking insects. Phytoplasma infection severely impairs assimilate translocation in host plants and might be responsible for massive changes in phloem physiology. Methods to study phytoplasma- induced changes thus far provoked massive, native occlusion artifacts in sieve tubes. Hence, phytoplasma-phloem relationships were investigated here in intact Vicia faba host plants using a set of vital fluorescent probes and confocal laser-scanning microscopy. We focused on the effects of phytoplasma infection on phloem mass-flow performance and evaluated whether phytoplasmas induce sieve-plate occlusion. Apparently, phytoplasma infection brings about Ca(2+) influx into sieve tubes, leading to sieve-plate occlusion by callose deposition or protein plugging. In addition, Ca(2+) influx may confer cell wall thickening of conducting elements. In conclusion, phytoplasma effectors may cause gating of sieve-element Ca(2+) channels leading to sieve-tube occlusion with presumptive dramatic effects on phytoplasma spread and photoassimilate distribution.

In this study we investigated telomere restriction fragment (TRF) length in a panel of mature B-cell lymphoproliferative disorders (MBCLDs) and correlated this parameter with histology and histopathogenesis in relation to the germinal center (GC). We assessed 123 MBCLD samples containing 80% or more tumor cells. TRF length was evaluated by Southern blot analysis using a chemiluminescence-based assay. GC status was assessed through screening for stable and ongoing somatic mutations within the immunoglobulin heavy-chain genes. Median TRF length was 6170 bp (range, 1896-11 200 bp) and did not correlate with patient age or sex. TRF length was greater in diffuse large cell lymphoma, Burkitt lymphoma, and follicular lymphoma (medians: 7789 bp, 9471 bp, and 7383 bp, respectively) than in mantle cell lymphoma and chronic lymphocytic leukemia (medians: 3582 bp and 4346 bp, respectively). GC-derived MBCLDs had the longest telomeres, whereas those arising from GC-inexperienced cells had the shortest (P < 10 ؊9 ). We conclude that (1) TRF length in MBCLD is highly heterogeneous; (2) GC-derived tumors have long telomeres, suggesting that minimal telomere erosion occurs during GC-derived lymphomagenesis; and (3)

Bois Noir is an emergent disease of grapevine that has been associated to a phytoplasma belonging to the XII-A stolbur group. In plants, phytoplasmas have been found mainly in phloem sieve elements, from where they spread moving through the pores of plates, accumulating especially in source leaves. To examine the expression of grapevine genes involved in sucrose transport and metabolism, phloem tissue, including sieve element/companion cell complexes and some parenchyma cells, was isolated from healthy and infected leaves by means of laser microdissection pressure catapulting (LMPC). Site-specific expression analysis dramatically increased sensitivity, allowing us to identify specific process components almost completely masked in whole-leaf analysis. Our findings showed decreased phloem loading through inhibition of sucrose transport and increased sucrose cleavage activity, which are metabolic changes strongly suggesting the establishment of a phytoplasma-induced switch from carbohydrate source to sink. The analysis focused at the infection site also showed a differential regulation and specificity of two pathogenesisrelated thaumatin-like genes (TL4 and TL5) of the PR-5 family.

Some evidences suggest that telomere restriction fragment length (TRF-L) is an effective indicator of histopathogenesis in B-cell tumors. As histopathogenesis is relevant for B-cell chronic lymphocytic leukemia (B-CLL) prognosis, TRF-L was assessed by Southern blot in 201 patients and compared to variable immunoglobulin heave chain gene mutational status (VH-MS) and to other known prognostic features. Overall survival (OS), time to first treatment (TTFT) and progressionfree survival (PFS) were evaluated. Our results indicate the following: (1) TRF-L is heterogeneous among B-CLL patients (median 6014 bp, range 1465-16 762); (2) TRF-L correlates to VH-MS (r 2 ¼ 0.1994, Po0.0001) with VH-mutated patients showing long and VH-unmutated short telomeres; however, 41% of VH-unmutated and 5% of VH-mutated patients did not show this correlation and were thus defined as 'discordant'; (3) TRF-L effectively predicts outcome in terms of TTFT, PFS and OS; (4) VH-unmutated discordant patients have a better clinical outcome than VH-unmutated concordant patients (OS Po0.01, PFS Po0.05) and similar to that of VH-mutated patients (OS, PFS P ¼ NS). Compared to VH-unmutated concordant patients, VHunmutated discordant patients showed no peculiarity in their immunoglobulin rearrangement nor in their flow cytometry or fluorescence in situ hybridization profile. In conclusion, TRF-L can be helpful to refine prognostication of B-CLL patients, particularly those with a VH-unmutated immunoglobulin sequence.

Grapevine can be severely affected by phytoplasmas, which are phytopathogenic Mollicutes invading the sieve elements of the host plant. The biochemical and molecular relationships between phytoplasmas and their hosts remain largely unexplored. Equally unknown is an interesting aspect of the pathogen–plant interaction called “recovery,” which is a spontaneous remission of symptoms in previously symptomatic plants. Recovered plants develop resistance mechanisms correlated with ultrastructural and biochemical changes in the sieve elements. Callose as well as sugars are involved in several plant defense processes and signaling. In the present work we have examined the possible involvement of callose, as well as callose synthase, sugar transporter, and cell wall invertase genes, during the infection and after “recovery” of grapevine from bois noir (BN). Ultrastructural investigation of leaf tissue showed that callose accumulated in the sieve elements of diseased grapevine; moreover, two genes encoding for callose synthase were up-regulated in the infected leaves. Regarding sucrose, expression analysis showed that sucrose transport and cleavage were severely affected by BN phytoplasma, which induced the establishment of a carbohydrate sink in the source leaf, and was analogous to other obligate biotrophs that acquire most of their nutrients from the host plant. Interestingly, whereas in recovered plants the transcript level of sucrose synthase was similar to healthy plants, sucrose transporters as well as cell wall invertase were expressed to a greater degree in recovered leaves than in healthy ones. Recovered plants seem to acquire structural and molecular changes leading to increases in sucrose transport ability and defense signaling.