Kinetic Study of the Esterase-like Activity of Albumin following Condensation by Macromolecular Crowding.

The ability of bovine serum albumin (BSA) to form condensates in crowded environments has been discovered only recently. Effects of this condensed state on the secondary structure of the protein have already been unraveled as some aging aspects, but the pseudo-enzymatic behavior of condensed BSA has never been reported yet. This article investigates the kinetic profile of para-nitrophenol acetate hydrolysis by BSA in its condensed state with poly(ethylene) glycol (PEG) as the crowding agent. Furthermore, the initial BSA concentration was varied between 0.25 and 1 mM which allowed us to modify the size distribution, the volume fraction, and the partition coefficient (varying from 136 to 180). Hence, the amount of BSA originally added was a simple way to modulate the size and density of the condensates. Compared with dilute BSA, the initial velocity (vi) with condensates was dramatically reduced. From the Michaelis-Menten fits, the extracted Michaelis constant Km and the maximum velocity Vmax decreased in control samples without condensates when the BSA concentration increased, which was attributed to BSA self-oligomerization. In samples containing condensates, the observed vi was interpreted as an effect of diluted BSA remaining in the supernatants and from the condensates. In supernatants, the crowding effect of PEG increased the kcat and catalytic efficiency. Last, Vmax was proportional to the volume fraction of the condensates, which could be controlled by varying its initial concentration. Hence, the major significance of this article is the control of the size and volume fraction of albumin condensates, along with their kinetic profile using liquid-liquid phase separation.

Bendamustine/Rituximab Plus Cytarabine/Rituximab, With or Without Acalabrutinib, for the Initial Treatment of Transplant-Eligible Mantle Cell Lymphoma Patients: Pooled Data From Two Pilot Studies.

INTRODUCTION: Mantle cell lymphoma (MCL) is a moderately aggressive lymphoma subtype, generally viewed as incurable. For younger, fit patients, the standard of care remains various high-dose cytarabine-based induction regimens followed by autologous hematopoietic cell transplant and 3 years of rituximab maintenance. Despite reasonably good outcomes, with median progression-free survival in the range of 7 to 9 years, most patients eventually relapse, indicating a need to improve the safety and tolerability of remission induction strategies. METHODS: Given the impressive activity of bendamustine/rituximab (BR) in older patients with MCL, we developed an induction regimen modeled after the Nordic Regimen but substituted BR in place of R-CHOP. In a second pilot study, we incorporated the second-generation Bruton tyrosine kinase inhibitor (BTKi), acalabrutinib, into the regimen. The primary endpoint of both studies was stem cell mobilization success rate. RESULTS: All patients successfully underwent stem cell harvest in both studies. CONCLUSION: The experience from our single institution pilot study suggested that sequential rather than alternating BR and cytarabine/rituximab (CR) was easier to administer from the standpoint of toxicities and subsequent dose modifications. Safety and efficacy data from the 2 pilot studies, FitMCL 1.0 and 2.0, were similar. The pilot studies provided preliminary safety data supporting the development of the NCTN trial EA4181, assessing three different induction regimens with or without acalabrutinib.

Initial and Consolidation Therapy for Younger Patients with Mantle Cell Lymphoma.

Mantle cell lymphoma is an incurable B-cell malignancy. Treatment of young fit patients is particularly challenging, because careful consideration should be made when building a long-term treatment strategy that would provide longer remissions and increase patients' quality of life. Most young fit patients achieve long remissions with a combination of immunochemotherapy containing rituximab and high-dose cytarabine, followed by high-dose chemotherapy and autologous stem-cell transplantation. The addition of maintenance therapy with rituximab following autologous stem-cell transplantation prolongs the time to relapse and increases overall survival. Despite an intensive approach, late relapses are common and are usually treated with novel agents.

Bispecific Antibodies for the Treatment of Acute Myeloid Leukemia.

PURPOSE OF REVIEW: Bispecific antibodies combine antigen recognition sites from two or more antibodies into a single construct allowing simultaneous binding to multiple targets. Bispecific antibodies exist which can redirect immune effector cells against acute myeloid leukemia (AML) targets. This review will highlight the progress to date and the challenges in developing bispecific antibodies for the treatment of AML. RECENT FINDINGS: Currently, a number of bispecific antibody formats including bispecific T cell engagers, dual affinity retargeting proteins, and tandem diabodies are in clinical development for AML. These antibodies target antigens present on AML blasts, including CD33, and the low affinity IL3 receptor, CD123. T cell redirecting bispecific antibodies in early phase clinical trials for AML include AG330, flotetuzumab, JNJ-63709178, and AMV564. Bispecific antibodies represent a promising immunotherapeutic approach for the treatment of cancer. The results of ongoing studies in AML will elucidate the potential for these agents in AML.

Data on the influence of cold isostatic pre-compaction on mechanical properties of polycrystalline nickel sintered using Spark Plasma Sintering.

Data regarding bulk polycrystalline nickel samples obtained by powder metallurgy using Spark Plasma Sintering (SPS) are presented, with a special emphasis on the influence of a cold isostatic pre-compaction on the resulting morphologies and subsequent mechanical properties. Three types of initial powders are used, nanometric powders, micrometric powders and a mixture of the formers. For each type of powder, the SPS cycle has been optimized for the powders without pre-compaction and the same cycle has been used to also sinter pre-compacted powders.

Inotuzumab ozogamicin in B-cell acute lymphoblastic leukemias and non-Hodgkin's lymphomas.

INTRODUCTION: The expression profile of the CD22 antigen and its role in B-cell function make it an important target in B-cell leukemias and lymphomas. Inotuzumab ozogamicin (IO), a humanized monoclonal antibody targeting CD22, is one of the most promising monoclonal antibodies for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). AREAS COVERED: This article reviews the current literature of IO in adult leukemias and lymphomas. EXPERT OPINION: Single-agent IO has demonstrated activity in patients with relapsed B-cell ALL and non-Hodgkin lymphoma (NHL). It has also demonstrated favorable early results when combined with chemotherapy in older patients with ALL. There is potential for IO to be combined with other targeted therapies under development for these diseases; data are still early and further studies of IO are warranted. While the pivotal randomized study of IO for relapsed NHL versus physician's choice did not show a statistically significant advantage in response rate, the results of the pivotal study in ALL are not yet available.

Diverticulitis in the young is not more aggressive than in the elderly, but it tends to recur more often: systematic review and meta-analysis.

BACKGROUND AND AIM: For years, the natural course of diverticulitis in the young has been debatable in terms of its severity and recurrence rate, and no consensus has been reached regarding its treatment and timing of surgery. Thus, the study aims to evaluate by meta-analysis the natural course of acute diverticulitis in the young. METHODS: Data were obtained from electronic databases and manual search of studies comparing the course of diverticulitis in young versus elderly patients. The age cut-off was selected to be 40-50 years, and only studies using computed tomography as the sole modality for diagnosis were included. Primary outcomes were surgery during hospitalization and disease recurrence. Relative risks (RRs) with 95% confidence intervals (CIs) are reported. RESULTS: One thousand eighty publications were found, 12 of which were included. The total number of patients was 4982. Most young patients were males (RR 1.70, 95% CI 1.31-2.21), without tendency toward a more complicated disease at admission (RR 0.95, 95% CI 0.46-1.97). While there was no significant difference in the rate of surgery during hospitalization (RR 0.69, 95% CI 0.46-1.06), young patients underwent more elective surgeries (RR 2.39, 95% CI 1.82-3.15). No mortality was recorded among young patients. The disease recurrence rate was significantly higher than that of elderly patients (RR 1.70, 95% CI 1.31-2.21); however, no study specified the mean follow-up period for each group. CONCLUSIONS: The course of diverticulitis in the young is not more severe than that in elderly patients; however, the disease tends to recur more often. Therefore, while choosing a therapeutic regimen, factors other than age should also be considered.

The proliferation index of specific bone marrow cell compartments from myelodysplastic syndromes is associated with the diagnostic and patient outcome.

Myelodysplastic syndromes (MDS) are clonal stem cell disorders which frequently show a hypercellular dysplastic bone marrow (BM) associated with inefficient hematopoiesis and peripheral cytopenias due to increased apoptosis and maturation blockades. Currently, little is known about the role of cell proliferation in compensating for the BM failure syndrome and in determining patient outcome. Here, we analyzed the proliferation index (PI) of different compartments of BM hematopoietic cells in 106 MDS patients compared to both normal/reactive BM (n = 94) and acute myeloid leukemia (AML; n = 30 cases) using multiparameter flow cytometry. Our results show abnormally increased overall BM proliferation profiles in MDS which significantly differ between early/low-risk and advanced/high-risk cases. Early/low-risk patients showed increased proliferation of non-lymphoid CD34(+) precursors, maturing neutrophils and nucleated red blood cells (NRBC), while the PI of these compartments of BM precursors progressively fell below normal values towards AML levels in advanced/high-risk MDS. Decreased proliferation of non-lymphoid CD34(+) and NRBC precursors was significantly associated with adverse disease features, shorter overall survival (OS) and transformation to AML, both in the whole series and when low- and high-risk MDS patients were separately considered, the PI of NRBC emerging as the most powerful independent predictor for OS and progression to AML. In conclusion, assessment of the PI of NRBC, and potentially also of other compartments of BM precursors (e.g.: myeloid CD34(+) HPC), could significantly contribute to a better management of MDS.

Lamivudine or adefovir dipivoxil alone or combined with immunoglobulin for preventing hepatitis B recurrence after liver transplantation.

BACKGROUND: Recurrence of hepatitis B virus (HBV) infection in the liver graft is a grave complication following liver transplantation for HBV cirrhosis. Hepatitis B immunoglobulin (HBIg) seems effective in increasing survival after liver transplantation. HBIg and anti-viral drugs are given alone or in combination for its prevention. OBJECTIVES: To assess the benefits and harms of different regimens for preventing HBV reactivation following liver transplantation. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until February 2010. We attempted to identify further trials by reviewing the reference lists and contacting the principal authors of identified trials. SELECTION CRITERIA: Randomised clinical trials addressing benefits and harms of lamivudine or adefovir dipivoxil alone or in combination with hepatitis B immunoglobulins (HBIg) for preventing recurrent HBV infection in patients who are liver transplanted due to HBV infection with or without hepatocellular carcinoma. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the trials for risk of bias and extracted data. We contacted study authors whenever information was lacking. We collected information on adverse events. The primary outcomes were all-cause mortality and reappearance of hepatitis B surface antigen in serum after liver transplantation. Relative risks were calculated from individual trials. MAIN RESULTS: Four trials, recruiting 136 participants, were included. Two trials compared lamivudine alone versus HBIg alone. Randomisation was performed one week after transplantation in one of the trials and after six months after transplantation in another; from transplantation until randomisation, HBIg alone was given to all patients in the two trials. A third trial compared combination treatment with lamivudine and HBIg versus lamivudine alone after one month of combination treatment, and a fourth trial compared the combination of lamivudine and HBIg versus a combination of lamivudine and adefovir dipivoxil after at least 12-month of lamivudine and HBIg combination treatment. Statistically significant differences were not detected in any of the comparisons and outcomes. All trials were open-labelled, and none of the trials were adequately powered to show a difference in HBV recurrence. No meta-analyses were performed since the identified trials assessed different comparisons. AUTHORS' CONCLUSIONS: This review could not derive clear evidence from randomised clinical trials for the treatment of patients with chronic HBV following liver transplantation for preventing recurrence of HBV infection. Large randomised clinical trials comparing long-term combination treatment to each of the monotherapy alone, including the newer antiviral drugs, are needed.

Takotsubo cardiomyopathy and QT interval prolongation: who are the patients at risk for torsades de pointes?

OBJECTIVES: QT interval prolongation is prevalent among patients with Takotsubo cardiomyopathy (TC), whereas torsades de pointes (TdP) has rarely been reported in these patients. We studied all peer-reviewed reports on TC-associated QT interval prolongation and all peer-reviewed reports on TC-associated TdP to characterize the clinical circumstances leading to TdP in patients with TC. METHODS: The literature search yielded 14 reports on TC-associated TdP and 26 reports on TC-associated QT interval prolongation. Overall, 15 patients with TC-associated TdP and 86 patients with TC-associated QT interval prolongation were reported. We systematically reviewed each report and recorded the risk factors for TdP as well as the clinical circumstances of TC. RESULTS: The prevalence of the male sex was higher among patients with TC-associated TdP relative to patients with TC-associated QT interval prolongation (26.7% vs 5.8%; P = .01). There was a trend in the mean maximal corrected QT interval being longer among patients with TC-associated TdP relative to patients with TC-associated QT interval prolongation (679.9 +/- 230.6 vs 555.9 +/- 63.8 milliseconds; P = .06). There were no differences between patients with TC-associated TdP and patients with TC-associated QT interval prolongation in mean age, maximal troponin levels, and lowest ejection fraction. Overall, 12 (80.0%) patients with TC-associated TdP had risk factors for TdP other than the female sex and systolic dysfunction, including suspicion of congenital long QT syndrome, bradycardia, hypokalemia, recent conversion from atrial fibrillation to sinus rhythm, and using QT prolonging agents. CONCLUSIONS: Men with TC-associated QT interval prolongation are at risk for TdP. Most patients with TC-associated TdP have risk factors for TdP other than the female sex and systolic dysfunction.