Impact of sarcopenia on treatment tolerance in United States veterans with diffuse large B-cell lymphoma treated with CHOP-based chemotherapy.

While sarcopenia has been associated with decreased overall survival in diffuse large B-cell (DLBCL) patients, the impact of sarcopenia on treatment tolerance has not been well-studied. We evaluated the association of sarcopenia with febrile neutropenia hospitalization, treatment-related mortality, and ability to complete standard number of cycles in a retrospective cohort of United States veterans diagnosed with DLBCL between 1998 and 2008 and treated with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab. Baseline body composition parameters were evaluated using computed tomography analysis. In total, 522 patients were included in the study, of whom 245 (47%) had baseline sarcopenia. After controlling for other variables, baseline sarcopenia was independently associated with increased risk of febrile neutropenia hospitalization (adjusted Odds Ratio (aOR) 1.64, 95% confidence interval (CI) 1.01-2.65) and inability to complete standard number of treatment cycles (aOR 1.49, 95% CI 1.02-2.16) compared with no baseline sarcopenia. There was a non-statistically significant trend toward higher treatment-related mortality in sarcopenic patients than non-sarcopenic patients (aOR 1.77, 95% CI 0.92-3.41). Sarcopenia is associated with increased risk of treatment intolerance and may be useful in guiding treatment planning and supportive care measures. Am. J. Hematol. 91:1002-1007, 2016. © 2016 Wiley Periodicals, Inc.

On the mechanism of palladium-catalyzed aromatic C-H oxidation.

The mechanism of Pd-catalyzed aromatic C-H oxidation chemistry continues to be vigorously discussed. Historically, Pd(II)/Pd(IV) catalysis cycles have been proposed. Herein, we present a detailed study of Pd(OAc)(2)-catalyzed aromatic C-H chlorination and propose dinuclear Pd(III) complexes as intermediates. We have identified a succinate-bridged dinuclear Pd(II) complex, which self-assembles during catalysis, as the catalyst resting state. In situ monitoring of catalysis has revealed that chlorination proceeds with turnover-limiting oxidation of a dinuclear resting state, and that acetate ions, liberated during the formation of the catalyst resting state, catalyze the bimetallic oxidation. Informed by reaction kinetics analysis, relevant dinuclear Pd(III) complexes have been prepared and observed to undergo selective C-Cl reductive elimination. Based on the combination of kinetic data obtained during catalysis and explicit structural information of relevant intermediates, we propose a Pd(II)(2)/Pd(III)(2) catalysis cycle for Pd(OAc)(2)-catalyzed aromatic C-H chlorination.

Weight change trends and overall survival in United States veterans with follicular lymphoma treated with chemotherapy.

Understanding weight change patterns in follicular lymphoma (FL) may be important for the assessment of prognosis as well as the long-term care of survivors. A retrospective cohort of United States veterans with a new diagnosis of FL between October 1, 1998 and September 30, 2010 was assembled. Weight changes were evaluated before, during, and after treatment in 896 FL patients who received cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab (CHOP ± R); cyclophosphamide, vincristine, and prednisone, with or without rituximab (CVP ± R); or rituximab monotherapy. Weight decreased an average of 1.4 kg during therapy, and >5% weight loss during this time period was associated with worse overall survival. Weight increased to an average of 1.4 kg above baseline by 24 months after treatment initiation, with 15% gaining greater than 10% of their baseline weight. Weight management strategies may be an important part of long-term survivorship planning.

Longitudinal Body Composition Changes in Diffuse Large B-cell Lymphoma Survivors: A Retrospective Cohort Study of United States Veterans.

BACKGROUND: Body composition parameters are associated with long-term health outcomes. We assessed longitudinal body composition changes in diffuse large B-cell lymphoma (DLBCL) survivors and identified clinical variables associated with the long-term development of sarcopenia and visceral obesity. METHODS: A retrospective cohort of United States veterans with DLBCL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab, was assembled. Muscle, subcutaneous fat, and visceral fat areas were measured with computed tomography analysis. Data were analyzed with repeated-measures analysis of variance and logistic regression. All statistical tests were two-sided. RESULTS: Three hundred forty-two patients were included. Muscle area initially decreased during treatment, then returned to baseline by 24 months after treatment. Subcutaneous fat area increased from baseline by 6.5% (95% confidence interval [CI] = 2.6% to 10.5%) during treatment and by 21.4% (95% CI = 15.7% to 27.2%) by 24 months after treatment. Visceral fat area increased from baseline by 4.5% (95% CI = -0.9% to 9.9%) during treatment and by 21.6% (95% CI = 14.8% to 28.4%) by 24 months after treatment. Variables associated with long-term development of sarcopenia included: baseline sarcopenia (adjusted odds ratio [aOR] = 17.21, 95% CI = 8.48 to 34.94), older than age 60 years (aOR = 2.93, 95% CI = 1.46 to 5.88), and weight loss greater than 5% during treatment (aOR = 2.40, 95% CI = 1.12 to 5.14). Variables associated with long-term visceral fat gain included: weight gain greater than 5% during treatment (aOR = 4.60, 95% CI = 2.42 to 8.74). CONCLUSIONS: DLBCL survivors undergo unfavorable long-term body composition changes. Patients at risk for the long-term development of sarcopenia or visceral obesity can be identified based on clinical risk factors and targeted for lifestyle interventions.

Structural characterization of the late competence protein ComFB from Bacillus subtilis.

Many bacteria take up DNA from their environment as part of the process of natural transformation. DNA uptake allows microorganisms to gain genetic diversity and can lead to the spread of antibiotic resistance or virulence genes within a microbial population. Development of genetic competence (Com) in Bacillus subtilis is a highly regulated process that culminates in expression of several late competence genes and formation of the DNA uptake apparatus. The late competence operon comF encodes a small protein of unknown function, ComFB. To gain insight into the function of ComFB, we determined its 3D structure via X-ray crystallography. ComFB is a dimer and each subunit consists of four α-helices connected by short loops and one extended ß-strand-like stretch. Each subunit contains one zinc-binding site formed by four cysteines, which are unusually spaced in the primary sequence. Using structure- and bioinformatics-guided substitutions we analyzed the inter-subunit interface of the ComFB dimer. Based on these analyses, we conclude that ComFB is an obligate dimer. We also characterized ComFB in vivo and found that this protein is produced in competent cells and is localized to the cytosol. Consistent with previous reports, we showed that deletion of ComFB does not affect DNA uptake function. Combining our results, we conclude that ComFB is unlikely to be a part of the DNA uptake machinery under tested conditions and instead may have a regulatory function.