Citations

AbstractLung cancer is a leading cause of cancer deaths worldwide. Despite advances in chemotherapy, radiation therapy, and surgery, lung cancer continues to have a low 5‐year survival rate, highlighting a dire need for more effective means of prevention, diagnosis, prognosis, and treatment. Mouse models that recapitulate the clinical features of advanced human lung cancer are critical for testing novel therapeutic approaches. This unit describes a highly reproducible, easy‐to‐establish orthotopic murine model of lung cancer, provides methods for in vivo imaging and monitoring of tumor growth, and discusses the usefulness of this model for translational lung cancer research and the development of therapeutic strategies. Curr. Protoc. Pharmacol. 62:14.27.1‐14.27.17. © 2013 by John Wiley & Sons, Inc.

Arterial wall stiffness can be associated with various diseases. The stiffness of an artery can be assessed by measurement of the pulse wave velocity (PWV). PWV is directly related to the Youngs modulus by the well-known Moens–Korteweg equation. Usually, PWV is estimated using the foot-to-foot method. However, the foot of the pressure wave is not very clear due to reflected waves. Also, the pressure wave is normally at a low frequency, hence, the time resolution is low. PWV is an average indicator of artery stiffness between the two measuring points, therefore it is not easy to identify local stiffness. We propose producing a very short pulse wave in the arterial wall using ultrasound radiation force and measuring its propagation speed along the artery by laser. The temporal resolution of this method is in the range of microseconds, which allows PWV to be measured accurately over a few millimeters. Experiments were carried out on a silicone tube in gelatin. PWV was measured by two scanning methods: (1) fixed source and scanning detector, (2) scanning source and fixed detector. Results: PWV was measured at 2 mm/40 μs by both methods. The Doppler technique was also tested which is potentially suitable for clinical applications.

Vibro-acoustography is an imaging technique that maps the acoustic response of an object to a localized harmonic radiation force. This force is generated by two interfering continuous-wave ultrasound beams at slightly different frequencies f1 and f2. The system point-spread function (PSF) is related to the radiation force on a point-target. Imaging artifacts depend on the PSF sidelobes, which can be reduced by mismatching the sidelobes of each ultrasound beam. Here, we propose a beamforming approach based on an 8-element sector transducer with consecutive elements alternately driven at f1 and f2. The transducer generates two ultrasound beams skewed by 22.5° with respect to each other. The system PSF is analytically derived. The theory is validated by experiments using a small steel sphere (radius =0.2 mm) as a point-target. A laser vibrometer is used to measure the vibration of the sphere and evaluate the PSF of the system. Theoretically, the PSF sidelobes are under −15.8 dB in eight spots circularly distributed and separated by 22.5°, which agrees with the experimental results. Simulation shows that with 16 elements sidelobes are under −35.2 dB. In conclusion, sector transducers for vibro-acoustography may have lower sidelobes as the number of array elements is increased. [Work supported by Grant Nos. EB00535-01, EB2640, and IMG0100744.]

Vibro-acoustography is a technique that uses the radiation force of amplitude-modulated ultrasound to evaluate the dynamic response of an object at the modulation frequency. One potential application of this technique is to assess the reaction of the host tissue to the implant material by evaluating the mechanical properties of the tissue surrounding the implant. To do this, we use vibro-acoustography to measure the frequency response of the implant, and use this information to evaluate the mechanical parameters of the surrounding. Two theoretical models are developed to study the dynamic response of an implant in tissue. The first model is for an implant (1×25-mm steel beam) fully embedded in a viscoelastic medium (tissue). The second model is for a partially embedded implant with one part exposed to the open environment. The exposed end is rigidly connected to a base, and the other end is freely embedded in the viscoelastic medium. At the interface between the two media matching of boundary conditions is achieved to determine the force response. For both models eigenvalues and eigenfunctions are determined and transfer functions are evaluated. The first two natural frequencies compare well with available experimental and finite-element data.

Background We investigated whether disease location influences survival in patients with peripheral arterial disease. Methods and Results Patients (n=12 731; mean age, 67.5±12.7 years; 57.4% male) who underwent outpatient noninvasive lower extremity arterial evaluation were followed up for 5.9±3.1 years for all‐cause mortality. Peripheral arterial disease (n=8930) was defined as a resting or postexercise ankle‐brachial index ( ABI ) ≤0.90, and normal ABI (n=3 801) was defined as a resting and postexercise ABI of 1.00 to 1.30. Presence or absence of disease at the proximal location or distal location was determined on the basis of D oppler signals in leg arteries; 42% had no PD or DD , 45% had proximal (14% postexercise PD only), 30% had distal disease, 17% had both proximal and distal disease, 28% had proximal only and 14% had distal only. We performed multivariable logistic regression to identify factors associated with disease location, and C ox proportional hazard regression to assess the respective effects of proximal or distal disease on survival. Older age, male sex, diabetes, heart failure, and critical limb ischemia were associated with distal disease, whereas female sex, smoking, hypertension, dyslipidemia, coronary heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, and critical limb ischemia were associated with proximal disease. Over a mean follow‐up of 5.9±3.1 years, 3039 patients (23.9%) died. After adjustment for potential confounders, the hazard ratios ( HR s) of death associated with PD only and DD only were 1.3 (1.3 to 1.4) and 1.5 (1.4 to 1.6), respectively. After additional adjustment for resting ABI , there was no significant association between proximal disease and death, whereas the association of distal disease with death remained significant ( HR , 1.2; 95% CI , 1.1 to 1.3). Conclusions In patients with peripheral arterial disease, proximal and distal disease locations were associated with distinctive risk factor and comorbidity profiles. Distal disease was associated with worse survival even after adjustment for risk factors, comorbidities, and resting ABI .

Purpose There is consensus that patients with light chain (AL) amyloidosis with hypercalcemia, renal failure, anemia, and lytic bone lesions attributable to clonal expansion of plasma cells (CRAB criteria) also have multiple myeloma (MM). The aim of this study was to examine the spectrum of immunoglobulin AL amyloidosis with and without MM, with a goal of defining the optimal bone marrow plasma cell (BMPC) number to qualify as AL amyloidosis with MM. Patients and Methods We identified 1,255 patients with AL amyloidosis seen within 90 days of diagnosis between January 1, 2000, and December 31, 2010. We defined a population of patients with coexisting MM on the basis of the existence of CRAB criteria (AL-CRAB). Receiver operating characteristic analysis determined the optimal BMPC cut point to predict for 1-year mortality in patients with AL amyloidosis without CRAB to produce two additional groups: AL only (≤ 10% BMPCs) and AL plasma cell MM (AL-PCMM; > 10% BMPCs). Results Among the 1,255 patients, 100 (8%) had AL-CRAB, 476 (38%) had AL-PCMM, and 679 (54%) had AL only. Their respective median overall survival rates were 10.6, 16.2, and 46 months (P < .001). Because the outcomes of AL-CRAB and AL-PCMM were similar, they were pooled for univariate and multivariate analyses. On multivariate analysis, pooled AL-CRAB and AL-PCMM retained negative prognostic value independent of age, Mayo Clinic AL amyloidosis stage, prior autologous stem-cell transplantation, and difference between the involved and uninvolved free light chain. Conclusion Patients with AL amyloidosis who have more than 10% BMPCs have a poor prognosis, similar to that of patients with AL-CRAB, and should therefore be considered together as AL amyloidosis with MM.

Abstract Smoldering multiple myeloma (SMM) bridges the gap between monoclonal gammopathy of undetermined significance (a mostly premalignant disorder) and active multiple myeloma (MM). Until recently, no interventional study in patients with SMM showed improved overall survival (OS) with therapy as compared with observation. A report from the PETHEMA-GEM (Programa Español de Tratamientos en Hematologica) group described both fewer myeloma-related events and better OS among patients with high-risk SMM who were treated with lenalidomide and dexamethasone. This unique study prompted us to review current knowledge about SMM and address the following questions: (1) Are there patients currently defined as SMM who should be treated routinely? (2) Should the definitions of SMM and MM be reconsidered? (3) Has the time come when not treating is more dangerous than treating? (4) Could unintended medical harm result from overzealous intervention? Our conclusion is that those patients with the highest-risk SMM (extreme bone marrow plasmacytosis, extremely abnormal serum immunoglobulin free light chain ratio, and multiple bone lesions detected only by modern imaging) should be reclassified as active MM so that they can receive MM-appropriate therapy and the paradigm of careful observation for patients with SMM can be preserved.

Lipid droplets (LDs) are lipid storage organelles that in hepatocytes may be catabolized by autophagy for use as an energy source, but the membrane-trafficking machinery regulating such a process is poorly characterized. We hypothesized that the large GTPase Dynamin 2 (Dyn2), well known for its involvement in membrane deformation and cellular protein trafficking, could orchestrate autophagy-mediated LD breakdown. Accordingly, depletion or pharmacologic inhibition of Dyn2 led to a substantial accumulation of LDs in hepatocytes. Strikingly, the targeted disruption of Dyn2 induced a dramatic four- to fivefold increase in the size of autolysosomes. Chronic or acute Dyn2 inhibition combined with nutrient deprivation stimulated the excessive tubulation of these autolysosomal compartments. Importantly, Dyn2 associated with these tubules along their length, and the tubules vesiculated and fragmented in the presence of functional Dyn2. These findings provide new evidence for the participation of the autolysosome in LD metabolism and demonstrate a novel role for dynamin in the function and maturation of an autophagic compartment.