MDX‐1097 induces antibody‐dependent cellular cytotoxicity against kappa multiple myeloma cells and its activity is augmented by lenalidomide

MDX‐1097 is an antibody specific for a unique B cell antigen called kappa myeloma antigen (KMA) that consists of cell membrane‐associated free kappa light chain (κFLC). KMA was detected on kappa human multiple myeloma cell lines (κHMCLs), on plasma cells (PCs) from kappa multiple myeloma (κMM) patients and on κPC dyscrasia tissue cryosections. In primary κMM samples, KMA was present on CD38+ cells that were CD138 and CD45 positive and/or negative. MDX‐1097 exhibited a higher affinity for KMA compared to κFLC and the latter did not abrogate binding to KMA. MDX‐1097‐mediated antibody‐dependent cellular cytotoxicity (ADCC) and in vitro exposure of target cells to the immunomodulatory drug lenalidomide resulted in increased KMA expression and ADCC. Also, in vitro exposure of peripheral blood mononuclear cells (PBMCs) to lenalidomide enhanced MDX‐1097‐mediated ADCC. PBMCs obtained from myeloma patients after lenalidomide therapy elicited significantly higher levels of MDX‐1097‐mediated ADCC than cells obtained prior to lenalidomide treatment. These data establish KMA as a relevant cell surface antigen on MM cells that can be targeted by MDX‐1097. The ADCC‐inducing capacity of MDX‐1097 and its potentiation by lenalidomide provide a powerful rationale for clinical evaluation of MDX‐1097 alone and in combination with lenalidomide.     

Posterior Surgical Treatment of Cervical Spondylotic Myelopathy: Review Article

Background

Cervical spondylosis is now recognised as the leading cause of myelopathy and spinal cord dysfunction worldwide. Chronic spinal cord compression results in chronic inflammation, cellular apoptosis, and microvacular insufficiency, which are thought to the biologic basis for cervical spondylotic myelopathy (CSM).

Questions/Purposes

Our purpose was to address the key principles of CSM, including natural history and presentation, pathogenesis, optimal surgical approach, results and complication rates of posterior surgical approaches for CSM so that the rationale for addressing CSM by a posterior approach can be fully understood.

Methods

We conducted a systematic search of PubMed/MEDLINE and the Cochrane Collaboration Library for literature published through February 2014 to identify articles that evaluated CSM and its management. Reasons for exclusion included patients with ossification of the posterior longitudinal ligament (OPLL), patients with degenerative disc disease without CSM, and patients with spine tumor, trauma and infection. Meeting abstracts/proceedings, white articles and editorials were additionally excluded.

Results

The search strategy yielded 1,292 articles, which was reduced to 52 articles, after our exclusion criteria were introduced. CSM is considered to be a surgical disorder due to its progressive nature. There is currently no consensus in the literature whether multilevel spondylotic compression is best treated via an anterior or posterior surgical approach.

Conclusion

Multilevel CSM may be safely and effectively treated using a posterior approach, either by laminoplasty or with a laminectomy and fusion technique.

Electronic supplementary material

The online version of this article (doi:10.1007/s11420-014-9425-5) contains supplementary material, which is available to authorized users.     

Relation of coronary atherosclerosis determined by electron beam computed tomography and plasma levels of n-terminal pro-brain natriuretic peptide in a multiethnic population-based sample (the Dallas Heart Study)

Elevated plasma levels of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP) are seen in the setting of cardiac ischemia and are associated with adverse outcomes in patients with coronary artery disease. The mechanisms leading to natriuretic peptide elevation in patients with coronary artery disease, including the contribution of coronary atherosclerosis itself, have not been fully elucidated. Measurement of NT-pro-BNP, electron beam computed tomography, and cardiac magnetic resonance imaging were performed in 2,445 subjects from the Dallas Heart Study who were free of heart failure and renal insufficiency. Electron beam computed tomography-determined coronary artery calcium scores were categorized as none (<10), mild (> or =10 to <100), moderate (> or =100 to <400), and severe (> or =400). NT-pro-BNP levels increased significantly across increasing coronary artery calcium score categories (p <0.0001 for trend). In multivariate models adjusted for age, gender, race, body mass index, hypertension, history of myocardial infarction, angina, angiotensin-converting enzyme inhibitor use, beta-blocker use, left ventricular (LV) ejection fraction, and LV mass, higher coronary artery calcium scores remained independently associated with higher log NT-pro-BNP levels (p = 0.03). This association persisted in similar models excluding patients with low LV ejection fractions, LV hypertrophy, angina pectoris, and a history of myocardial infarction. In conclusion, these findings support the hypothesis that coronary atherosclerosis may directly influence the activation of the cardiac neurohormonal system.     

Experimental design for stable genetic manipulation in mammalian cell lines: lentivirus and alternatives

The use of third‐generation lentiviral vectors is now commonplace in most areas of basic biology. These systems provide a fast, efficient means for modulating gene expression, but experimental design needs to be carefully considered to minimize potential artefacts arising from off‐target effects and other confounding factors. This review offers a starting point for those new to lentiviral‐based vector systems, addressing the main issues involved with the use of lentiviral systems in vitro and outlines considerations which should be taken into account during experimental design. Factors such as selecting an appropriate system and controls, and practical titration of viral transduction are important considerations for experimental design. We also briefly describe some of the more recent advances in genome editing technology. TALENs and CRISPRs offer an alternative to lentivirus, providing endogenous gene editing with reduced off‐target effects often at the expense of efficiency.     

ZnO Nanoparticles Impose a Panmetabolic Toxic Effect Along with Strong Necrosis,Inducing Activation of the Envelope Stress Response in Salmonella enterica Serovar Enteritidis

In this study, we tested the antimicrobial activity of three metal nanoparticles (NPs), ZnO, MgO, and CaO NPs, against Salmonella enterica serovar Enteritidis in liquid medium and on solid surfaces. Out of the three tested metal NPs, ZnO NPs exhibited the most significant antimicrobial effect both in liquid medium and when embedded on solid surfaces. Therefore, we focused on revealing the mechanisms of surface-associated ZnO biocidal activity. Using the global proteome approach, we report that a great majority (79%) of the altered proteins in biofilms formed by Salmonella enterica serovar Enteritidis were downregulated, whereas a much smaller fraction (21%) of proteins were upregulated. Intriguingly, all downregulated proteins were enzymes involved in a wide range of the central metabolic pathways, including translation; amino acid biosynthetic pathways; nucleobase, nucleoside, and nucleotide biosynthetic processes; ATP synthesis-coupled proton transport; the pentose phosphate shunt; and carboxylic acid metabolic processes, indicating that ZnO NPs exert a panmetabolic toxic effect on this prokaryotic organism. In addition to their panmetabolic toxicity, ZnO NPs induced profound changes in cell envelope morphology, imposing additional necrotic effects and triggering the envelope stress response of Salmonella serovar Enteritidis. The envelope stress response effect activated periplasmic chaperones and proteases, transenvelope complexes, and regulators, thereby facilitating protection of this prokaryotic organism against ZnO NPs.     

Stenting an aortopulmonary conduit with peripheral cardiopulmonary bypass support

Although surgically created aortopulmonary (AP) shunts are uncommon in the adult congenital heart disease population, they are often used in patients with pulmonary atresia. For these patients, the shunt is a vital supply of pulmonary blood flow and thus obstruction of the shunt may lead to pulmonary hypoperfusion and hypoxia thereby increasing morbidity and mortality. This report describes a safe and effective method of stenting the conduit with the hemodynamic support of peripheral cardiopulmonary bypass (PCB). Prior to the procedure, a multimodality assessment of a stenosis in a kinked AP conduit using computed tomography, angiography, intravascular ultrasound (IVUS), and pressure wire assessment (PWA) was utilized. While PCB, IVUS, and PWA have all been used to great effect in various clinical scenarios, the combined use of these techniques has not been previously been described in the setting of intervention in adult congenital heart disease. © 2013 Wiley Periodicals, Inc.     

The Role of Procurement Biopsies in Acceptance Decisions for Kidneys Retrieved for Transplant

Background and objectives

There is a shortage of kidneys for transplant, and many patients on the deceased donor kidney transplant waiting list would likely benefit from kidneys that are currently being discarded. In the United States, the most common reason given for discarding kidneys retrieved for transplant is procurement biopsy results. This study aimed to compare biopsy results from discarded kidneys with discard attributed to biopsy findings, with biopsy results from comparable kidneys that were successfully transplanted.

Design, setting, participants, & measurements

In this retrospective, observational, case-control study, biopsy reports were examined from 83 kidneys discarded in 2010 due to biopsy findings (cases), 83 contralateral transplanted kidneys from the same donor (contralateral controls), and 83 deceased donors randomly matched to cases by donor risk profile (randomly matched controls). A second procurement biopsy was obtained in 64 of 332 kidneys (19.3%).

Results

The quality of biopsy reports was low, with amounts of tubular atrophy, interstitial inflammation, arteriolar hyalinosis, and acute tubular necrosis often not indicated; 69% were wedge biopsies and 94% used frozen tissue. The correlation between first and second procurement biopsies was poor; only 25% of the variability (R²) in glomerulosclerosis was explained by biopsies being from the same kidney. The percentages of glomerulosclerosis overlapped substantially between cases, contralateral controls, and randomly matched controls: 17.1%±15.3%, 9.0%±6.6%, and 5.0%±5.9%, respectively. Of all biopsy findings, only glomerulosclerosis>20% was independently correlated with discard (cases versus contralateral controls; odds ratio, 15.09; 95% confidence interval, 2.47 to 92.41; P=0.003), suggesting that only this biopsy result was used in acceptance decisions. One-year graft survival was 79.5% and 90.7% in contralateral and randomly matched controls, respectively, versus 91.6% among all deceased donor transplants in the Scientific Registry of Transplant Recipients.

Conclusions

Routine use of biopsies could lead to unnecessary kidney discards.