Increased fibrosis and impaired intratumoral accumulation of macromolecules in a murine model of pancreatic cancer co-administered with FGF-2

Pancreatic cancer is notorious for its poor prognosis. The histopathologic characteristic of pancreatic ductal adenocarcinoma (PDAC), which is the most common type of pancreatic cancer, is fibrosis within tumor tissue. Although fibrosis within tumor tissue is thought to impede drug therapy by interfering with the intratumoral accumulation of anti-tumor drugs, this hypothesis has yet to be proven directly in preclinical models. Here, we evaluated the effect of enhanced fibrosis on intratumoral accumulation of macromolecular drugs by increasing fibrosis in a murine tumor model of subcutaneously xenografted BxPC-3, a human PDAC cell line. When fibroblast growth factor-2 (FGF-2) was co-administered upon BxPC-3 inoculation, stromal fibrotic area was increased and was characterized by augmented murine collagen accumulation compared to inoculation of BxPC-3 alone, which correlated with increased monocyte/macrophage contents in the tumor tissues. We further discovered that the intratumoral accumulation of intravenously administrated fluorescein isothiocyanate-dextran of 2,000,000 Da (2 MDa) was significantly reduced in the FGF-2 co-administered tumors despite unaltered hyaluronan accumulation and pericyte coverage of the tumor neovasculature and increased lymphangiogenesis. Finally, we found that FGF-2 co-administered tumors are more refractory to macromolecular drug therapy using nab-paclitaxel (Abraxane). The model established and analyzed in this study, characterized by increased fibrotic component, provides a preclinical animal model suited to predict the intratumoral accumulation of macromolecular drugs and to evaluate the efficacy of drugs targeting the tumor stroma

Determination of stress state in deep subsea formation by combination of hydraulic fracturing in situ test and core analysis: A case study in the IODP Expedition 319

[1] In situ test of hydraulic fracturing (HF) provides the only way to observe in situ stress magnitudes directly. The maximum and minimum horizontal stresses, SHmax and Shmin, are determined from critical borehole pressures, i.e., the reopening pressure Pr and the shut-in pressure Ps, etc, observed during the test. However, there is inevitably a discrepancy between actual and measured values of the critical pressures, and this discrepancy is very significant for Pr. For effective measurement of Pr, it is necessary for the fracturing system to have a sufficiently small compliance. A diagnostic procedure to evaluate whether the compliance of the employed fracturing system is appropriate for SHmax determination from Pr was developed. Furthermore, a new method for stress measurement not restricted by the system compliance and Pr is herein proposed. In this method, the magnitudes and orientations of SHmax and Shmin are determined from (i) the cross-sectional shape of a core sample and (ii) Ps obtained by the HF test performed near the core depth. These ideas were applied for stress measurement in a central region of the Kumano fore-arc basin at a water depth of 2054?m using a 1.6?km riser hole drilled in the Integrated Ocean Drilling Program (IODP) Expedition 319. As a result, the stress decoupling through a boundary at 1285?m below seafloor was detected. The boundary separates new upper layers and old lower ones with an age gap of ~1.8?Ma, which is possibly the accretionary prism. The stress state in the lower layers is consistent with that observed in the outer edge of accretionary prism

Operational Review of the First Wireline In Situ Stress Test in Scientific Ocean Drilling

Scientific ocean drilling’s first in situ stress measurement was made at Site C0009A during Integrated Ocean Drilling Program (IODP) Expedition 319 as part of Nankai Trough Seismogenic Zone Experiment (NanTroSEIZE) Stage 2. The Modular Formation Dynamics Tester (MDT, Schlumberger)wireline logging tool was deployed in riser Hole C0009A to measure in situ formation pore pressure, formation permeability (often reported as mobility=permeability/viscosity), and the least principal stress (S3) at several isolated depths (Saffer et al., 2009; Expedition 319 Scientists, 2010). The importance of in situ stress measurements is not only for scientific interests in active tectonic drilling, but also for geomechanical and well bore stability analyses. Certain in situ tools were not previously available for scientific ocean drilling due to the borehole diameter and open hole limits of riserless drilling. The riser-capable drillship, D/V Chikyu,now in service for IODP expeditions, allows all of the techniques available to estimate the magnitudes and orientations of 3-D stresses to be used. These techniques include downhole density logging for vertical stress, breakout and caliper log analyses for maximum horizontal stress, core-based anelastic strain recovery (ASR, used in the NanTroSEIZE expeditions in 2007–2008), and leak-off test (Lin et al., 2008) and minifrac/hydraulic fracturing (NanTroSEIZE Expedition319 in 2009). In this report, the whole operational planning process related to in situ measurements is reviewed, and lessons learned from Expedition 319 are summarized for efficient planning and testing in the future

Robotic Renal Autotransplantation: A Feasibility Study in a Porcine Model

We investigated the feasibility of robotic renal autotransplantation (RAT) in a porcine model to reduce invasiveness of RAT. Five pigs underwent robotic RAT using the da Vinci® robotic system. A robotic left nephrectomy was performed in all cases. Robotic RAT was performed on the left side in all but one case. Four ports were used. In 3 cases, the kidney was taken out through the GelPort® and irrigated on ice with Ringer’s solution. In 2 cases, a complete intracorporeal robotic RAT was performed. An end-to-side anastomosis was performed between the renal vein and the external iliac vein and between the renal artery and the external iliac artery. Ureteroneocystostomy was also performed in 2 cases. All cases were performed robotically without open conversion. The median (IQR) console time was 3.1 (0.7) h, and the operative time was 3.8 (1.1) h. The estimated blood loss was 30 (0) ml. The warm ischemia time was 4.0 (0.2) min, and the cold ischemia time was 97 (17) min. Intracorporeal transarterial hypothermic renal perfusion was feasible in the 2 complete intracorporeal robotic RAT cases by using a perfusion catheter through a laparoscopic port. Robotic RAT has the potential to be a new minimally invasive substitute for conventional open surgery

A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10−8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10−4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10−11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS

Long-term temperature records following the M[subscript w] 7.9 Wenchuan (China) earthquake are consistent with low friction

Knowledge of the shear stress on a fault during slip is necessary for a physically-based understanding of earthquakes. Borehole temperature measurements inside the fault zone immediately after an earthquake can record the energy dissipated by this stress. In the first Wenchuan Earthquake Fault Zone Scientific Drilling Project hole (Sichuan province, China) we repeatedly measured temperature profiles from 1.3 to 5.3 yr after the 12 May 2008, M[subscript w] 7.9 Wenchuan earthquake. The previously identified candidate for the principal slip surface had only a small local temperature increase of at most 0.02°C with no obvious decay. The small amplitude of the temperature increase provides an upper bound for the frictional heat–generated coseismic slip, but is unlikely to be a frictionally generated signal. Two larger temperature anomalies are located above and within the fault zone. However, neither anomaly evolves as expected from a frictional transient. We conclude that the frictional heat from the Wenchuan earthquake remains elusive and the total heat generated at this location is much less than 29 MJ/m². Low friction during slip is consistent with the temperature data