Citations

Drug resistance is an obstacle in the therapy of acute lymphoblastic leukemia (ALL). Whether the physical properties such as the motility of the cells contribute to the survival of ALL cells after drug treatment has recently been of increasing interest, as they could potentially allow the metastasis of solid tumor cells and the migration of leukemia cells. We hypothesized that chemotherapeutic treatment may alter these physical cellular properties. To investigate the motility of chemotherapeutics-treated B-cell ALL (B-ALL) cells, patient-derived B-ALL cells were treated with chemotherapy for 7 days and left for 12 h without chemotherapeutic treatment. Two parameters of motility were studied, velocity and migration distance, using a time-lapse imaging system. The study revealed that compared to non-chemotherapeutically treated B-ALL cells, B-ALL cells that survived chemotherapy treatment after 7 days showed reduced motility. We had previously shown that Tysabri and P5G10, antibodies against the adhesion molecules integrins α4 and α6, respectively, may overcome drug resistance mediated through leukemia cell adhesion to bone marrow stromal cells. Therefore, we tested the effect of integrin α4 or α6 blockade on the motility of chemotherapeutics-treated ALL cells. Only integrin α4 blockade decreased the motility and velocity of two chemotherapeutics-treated ALL cell lines. Interestingly, integrin α6 blockade did not affect the velocity of chemoresistant ALL cells. This study explores the physical properties of the movements of chemoresistant B-ALL cells and highlights a potential link to integrins. Further studies to investigate the underlying mechanism are warranted.

The surface tension of biological fluids is an important parameter because the mechanical properties of fluids are closely linked with hematological diseases and other pathophysiologies. Capillary waves are associated with fluid mechanical properties. Here, we propose a method that utilizes the acoustic radiation force (ARF) to generate propagating waves and optical coherence tomography (OCT) to measure the wave motion. This ARF-OCT method is capable of evaluating the surface tension of fluids, water and porcine whole blood in this study, based on the dispersion relation of capillary waves. Two-dimensional Fourier transforms were used to decompose frequency components of wave motion images to obtain a k-space representation and estimate the wave phase velocity. The phase velocity of capillary waves was obtained from the experimental results and compared to theoretical calculations. The surface tensions of water and porcine whole blood were determined from the experimental results. We first report that capillary waves measured with OCT can be a new promising modality for measuring the surface tension of fluids. The proposed method could be used to differentiate actual pathologic fluids or blood from those taken from healthy subjects and as a biomarker in future biomedical applications.

e14507 Background: Regorafenib, an oral multikinase inhibitor of VEGFR2/3, PDGFRb, KIT, FGFR, RET, RAF and TIE2, is efficacious in refractory mCRC but its mechanism of action is unclear and predictive biomarkers are lacking. Methods: We assessed tumor and circulatory biomarkers in a phase 2 study of regorafenib in refractory mCRC patients. Regorafenib was administered orally at 160mg/d for 3 out of 4 weeks. Post cycle 2 response was assessed by RECIST 1.1. Subjects were scheduled for FDG PET-CT scans (pre + D15) and paired core needle tumor biopsies for IHC analysis (pre + D21) in cycle 1. Archival tumor mutations were evaluated using Sequenom MassARRAY OncoCarta Panel V1.0 assay. Results: 35 patients were treated; 49% received > 4 prior therapies and 43% had prior bevacizumab. Median PFS was 3.45 mths (95% CI: 3.40-3.49), ORR was 3% and disease control rate [DCR] (PR + SD at 8 wks) was 57%. Early PET responses (EORTC criteria) were seen in 49%, but did not predict for DCR (p=1.0). Fatigue, hand foot skin reaction (HFSR), voice change and diarrhea occurred in > 30% of subjects. Grade 3-5 toxicities occurred in 46%, the commonest being HFSR and rash (17% each). Median relative dose intensity was 92%; 43% required > 1 dose reduction, 60% required > 1 dose interruption. KRAS (29%), BRAF (9%), EGFR (9%), NRAS (6%) KIT (3%), PIK3CA (3%), PDGFRA (3%) and CDK (3%) mutations were detected in archival tumors. None predicted for ORR or DCR; PFS was identical in KRAS mutant vs wt patients (3.45 mths, p=0.39) and similar in BRAF mutant vs wt patients (3.48 vs 3.45 mths, p=0.10). The patient with the longest PFS (12.6 mths) had a BRAF mutation. Amongst the 10 paired tumor samples available, IHC markers upregulated in >50% cases were pMEK, pERK, pJun and pJNK, whilst those downregulated/ unchanged in >50% were pKIT, pVEGFR2, CD31 [vascular endothelial cells (ECs)] and podoplanin (lymphatic ECs). The greatest change was observed in podoplanin expression, corresponding to a 60% reduction in lymphatic vessel density. Conclusions: FDG-PET responses in cycle 1 did not predict for regorafenib clinical benefit in mCRC patients. Targeting lymphatic/vascular ECs in the tumor microenvironment may be a more significant antitumor mechanism of regorafenib than MAP kinase pathway inhibition. Clinical trial information: NCT01189903.

AbstractEvaluating mechanical properties of biological soft tissues and viscous mucus is challenging because of complicated dynamic behaviors. Soft condensed matter models have been successfully used to explain a number of dynamical behaviors. Here, we reported that optical coherence elastography (OCE) is capable of quantifying mechanical properties of soft condensed matters, micellar fluids. A 7.5 MHz focused transducer was utilized to generate acoustic radiation force exerted on the surface of soft condensed matters in order to produce Rayleigh waves. The waves were recorded by optical coherence tomography (OCT). The Kelvin‐Voigt model was adopted to evaluate shear modulus and loss modulus of soft condensed matters. The results reported that various concentrations of micellar fluids can provide reasonable ranges of elasticity from 65.71 to 428.78 Pa and viscosity from 0.035 to 0.283 Pa·s, which are close to ranges for actual biological samples, like mucus. OCE might be a promising tool to differentiate pathologic mucus samples from healthy cases as advanced applications in the future.

Wormlike micellar (WM) fluids exhibit a self-assembly property and viscoelastic behavior which make them a promising material for representing biological fluids, ultrasoft tissue phantoms and drug delivery carriers. Although WM biochemistry has been investigated, the mechanical properties have been rarely discussed because of the complexity of soft matter systems. Here, we demonstrate that optical coherence elastography (OCE) is capable of measuring Rayleigh wave of micellar fluids. Three solutions with concentrations of 100, 200, 300 and 400 mM, were considered in the study. Ultrasound excitation to produce Rayleigh waves was accomplished using 7.5 MHz burst excitation signals of length 4.0 ms repeated at a rate of 19 Hz. The optical coherence tomography (OCT) acquisition was set to 50 lateral positions and 4000 A-scans for each lateral position at a 76 kHz scan rate for total acquisition time of 52.6 ms. Ultrasound-based shear wave elastography, implemented on a Verasonics system, was used to obtain group and phase velocity of the shear wave in all micellar fluids as reference. Our research results demonstrated that Rayleigh wave in micellar fluids can be evaluated by OCE and mechanical properties like Young’s modulus can be assessed. A wide of concentration ranges of WM fluids would provide a more realistic model to mimic biological fluids and tissues.

Patients with chronic kidney disease (CKD) and renal transplant rejection are at high risk to develop advanced pathology including glomerular sclerosis and renal interstitial fibrosis. The elasticity of kidney tissues is associated with the disease progression and can be evaluated with ultrasound elastography. Understanding how tissue pathology changes the renal mechanical properties is crucial. Optical coherence elastography (OCE) might be a promising tool for evaluating renal tissues due to higher resolution. A phantom with 8% gelatin and 2% cellulose (50 mm) was fabricated to validate the ability of OCE to bulk materials and the results were confirmed by comparing the dataset obtained with an ultrasound-based Verasonics system as the ground truth. Excitation signals, composed with 4 cycles of a 400 Hz harmonic wave repeated at a rate of 38 Hz, were directly applied to the surface area with two directions and cortical regions of ex vivo porcine kidneys that had been cut open. Preliminary results showed that the velocity of surface wave on the cortical regions was near 1 m/s and corresponded with the result of shear waves from Verasonics system (1.2 m/s). Our study demonstrated that OCE has an ability to assess the mechanical properties of bulk materials and is a promising tool to evaluate mechanical properties of renal tissue with high resolution and sensitivity.

Significance The energy-producing organelle mitochondrion contains its own compact genome, which is separate from the nuclear genome. In nearly all mammals, this mitochondrial genome is inherited exclusively from the mother, and transmission of paternal mitochondria or mitochondrial DNA (mtDNA) has not been convincingly demonstrated in humans. In this paper, we have uncovered multiple instances of biparental inheritance of mtDNA spanning three unrelated multiple generation families, a result confirmed by independent sequencing across multiple unrelated laboratories with different methodologies. Surprisingly, this pattern of inheritance appears to be determined in an autosomal dominantlike manner. This paper profoundly alters a widespread belief about mitochondrial inheritance and potentially opens a novel field in mitochondrial medicine.