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Technological advancements in electronics and micromachining now allow the development of discrete wireless brain implantable micro-devices. Applications of such devices include stimulation or sensing and could enable direct placement near regions of interest within the brain without the need for electrode leads or separate battery compartments that are at increased risk of breakage and infection. Clinical use of leadless brain implants is accompanied by novel risks, such as migration of the implant. Additionally, the encapsulation material of the implants plays an important role in mitigating unwanted tissue reactions. These risks have the potential to cause harm or reduce the service of life of the implant. In the present study, we have assessed post-implantation tissue reaction and migration of borosilicate glass-encapsulated micro-implants within the cortex of the brain. Twenty borosilicate glass-encapsulated devices (2 × 3.5 × 20 mm) were implanted into the parenchyma of 10 sheep for 6 months. Radiographs were taken directly post-surgery and at 3 and 6 months. Subsequently, sheep were euthanized, and GFAP and IBA-1 histological analysis was performed. The migration of the implants was tracked by reference to two stainless steel screws placed in the skull. We found no significant difference in fluoroscopy intensity of GFAP and a small difference in IBA-1 between implanted tissue and control. There was no glial scar formation found at the site of the implant’s track wall. Furthermore, we observed movement of up to 4.6 mm in a subset of implants in the first 3 months of implantation and no movement in any implant during the 3–6-month period of implantation. Subsequent histological analysis revealed no evidence of a migration track or tissue damage. We conclude that the implantation of this discrete micro-implant within the brain does not present additional risk due to migration.

Abstract Background Mammalian cells are flexible and can rapidly change shape when they contract, adhere, or migrate. The nucleus must be stiff enough to withstand cytoskeletal forces, but flexible enough to remodel as the cell changes shape. This is particularly important for cells migrating through confined spaces, where the nuclear shape must change in order to fit through a constriction. This occurs many times in the life cycle of a neutrophil, which must protect its chromatin from damage and disruption associated with migration. Here we characterized the effects of constricted migration in neutrophil-like cells. Results Total RNA sequencing identified that migration of neutrophil-like cells through 5- or 14-μm pores was associated with changes in the transcript levels of inflammation and chemotaxis-related genes when compared to unmigrated cells. Differentially expressed transcripts specific to migration with constriction were enriched for groups of genes associated with cytoskeletal remodeling. Hi-C was used to capture the genome organization in control and migrated cells. Limited switching was observed between the active (A) and inactive (B) compartments after migration. However, global depletion of short-range contacts was observed following migration with constriction compared to migration without constriction. Regions with disrupted contacts, TADs, and compartments were enriched for inactive chromatin. Conclusion Short-range genome organization is preferentially altered in inactive chromatin, possibly protecting transcriptionally active contacts from the disruptive effects of migration with constriction. This is consistent with current hypotheses implicating heterochromatin as the mechanoresponsive form of chromatin. Further investigation concerning the contribution of heterochromatin to stiffness, flexibility, and protection of nuclear function will be important for understanding cell migration in relation to human health and disease.

The liver possesses an extraordinary ability to regenerate after injury. Hepatocyte-driven liver regeneration is the default pathway in response to mild-to-moderate acute liver damage. When replication of mature hepatocytes is blocked, facultative hepatic progenitor cells (HPCs), also referred to as oval cells (OCs) in rodents, are activated. HPC/OCs have the ability to proliferate clonogenically and differentiate into several lineages including hepatocytes and bile ductal epithelia. This is a conserved liver injury response that has been studied in many species ranging from mammals (rat, mouse, and human) to fish. In addition, improper HPC/OC activation is closely associated with fibrotic responses, characterized by myofibroblast activation and extracellular matrix production, in many chronic liver diseases. Matrix remodeling and metalloprotease activities play an important role in the regulation of HPC/OC proliferation and fibrosis progression. Thus, understanding molecular mechanisms underlying HPC/OC activation has therapeutic implications for rational design of anti-fibrotic therapies. Keywords: Liver regeneration, Hepatic progenitor cells (HPCs), Oval cells (OCs), Liver injury, Hepatic fibrosis

Purpose. We sought to evaluate our experience using yttrium-90 (90Y) resin microsphere hepatic radioembolization as salvage therapy for liver-dominant metastatic colorectal cancer (mCRC). Methods. A retrospective review of consecutive patients with unresectable mCRC who were treated with 90Y after failing first and second line systemic chemotherapy. Demographics, treatment dose, biochemical and radiographic response, toxicities, and survival were examined. Results. Fifty-one patients underwent 90Y treatments of which 69% were male. All patients had previously undergone extensive chemotherapy, 31% had undergone previous liver-directed therapy and 24% had a prior liver resection. Using RECIST criteria, either stable disease or a partial response was seen in 77% of patients. Overall median survival from the time of first 90Y treatment was 10.2 months (95% CI = 7.5–13.0). The absence of extrahepatic disease at the time of treatment with 90Y was associated with an improved survival, median survival of 17.0 months (95% CI = 6.4–27.6), compared to those with extrahepatic disease at the time of treatment with 90Y, 6.7 months (95% CI = 2.7–10.6 Conclusion: 90Y therapy is a safe locoregional therapy that provides an important therapeutic option to patients who have failed first and second line chemotherapy and have adequate liver function and performance status.

Retrorsine has been used extensively to inhibit proliferation of resident hepatocytes in various transplantation models. Here we report a successful alternative to currently unavailable retrorsine that can be used in cellular transplantation models. Based on structural and molecular similarities, we investigate the use of monocrotaline (MCT) in cell transplantation studies in rodents. In this study, MCT was given to rats intraperitoneally in two injections 2 weeks apart. Two weeks after the final injection, a partial hepatectomy followed by splenic hepatocyte transplantation was performed. The results indicate that MCT, at two doses of 30 mg/kg, highly enhances liver repopulation by donor hepatocytes following partial hepatectomy and produces 15.3 ± 4.9% liver repopulation within the first 6 weeks following transplantation. Additionally, we tested the effectiveness of MCT in a murine model. Using two injections of 50 mg/kg each, given 2 weeks apart, hepatocyte proliferation in the native liver was inhibited and subsequent oval cell transplants engrafted at 18 ± 21.3% after 16 weeks posttransplantation. In conclusion, MCT can be used as an effective selective pressure for donor hepatocytes in cell transplantation to the liver in rodents.

Bis-(pentafluorophenyl)boryl ferrocene, 1, was prepared via borylation of ferrocene with HB[(C.sub.6][F.sub.5]).sub.2] or via a transmetallation reaction involving FcHgCl and ClB[(C.sub.6] [F.sub.5]).sub.2] in 87-91% yield. The compound is characterized by a deep maroon colour. A significant intramolecular iron--boron interaction is manifested in the solution spectroscopic (Fe [vector] B charge transfer band at ~230 nm, [epsilon] = 1.33 x [10.sup.4]) and solid-state crystallographic data (Fe-B = 2.924 [Angstrom]) This interaction has an impact on the Lewis acidity of the boron center which, unlike the related compound B[(C.sub.6][F.sub.5]).sub.2], does not strongly bind Lewis bases such as acetone, THF, or acetonitrile. However, an adduct between the stronger base P[Me.sub.3] and 1 forms readily and this complex (2) was fully characterized. The electron withdrawing -B[(C.sub.6][F.sub.5]).sub.2] group causes 1 to be oxidized at +450 mV relative to ferrocene. Oxidation of 1 with [NO][B[F.sub.4]], AgOS[O.sub.2]C[F.sub.3], or Ag[C.sub.6][F.sub.5] leads to the zwitterionic ferrocenium borates 3-F, 3-OTf, and 3-[C.sub.6][F.sub.5], respectively. Each of these compounds was characterized spectroscopically and via X-ray crystallography. The properties of these compounds relative to 1 suggest that oxidation of the iron center significantly enhances the Lewis acidity of the boron center. Due to the [sigma]-donating ability of the borate substituents, zwitterions 3 are weaker oxidizing agents than unsubstituted ferrocenium salts. Key words: organoboranes, ferrocene derivatives, Lewis acids.

The diborylated ferrocene compound 1,1'-Fc[[B[([C.sub.6][F.sub.5]).sub.2]].sub.2] (2) was prepared via a transmetallation reaction involving 1,1'-Fc[(HgCl).sub.2] and two equivalents of ClB[([C.sub.6][F.sub.5]).sub.2]. Although this reaction is very clean spectroscopically, isolated yields of 2 were never greater than 40% owing to the high solubility of the compound in non-donor solvents. Compound 2 is similar in its properties to the related monoborylated complex FcB[([C.sub.6][F.sub.5]).sub.2] (1) reported previously, particularly the UV-vis spectrum, which exhibits an intense charge transfer absorption ([[lambda].sub.max] = 233 nm, [epsilon] = 1.64 x [10.sup.4]) assignable to an [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] transition. However, 2, is significantly more Lewis acidic than 1, reacting with weak donors such as acetonitrile at room temperature, and effecting methide abstraction from [Cp.sub.2]Zr[Me.sub.2] under mild conditions. Complex 2 also forms a bis(trimethylphosphine) adduct (3), which was structurally characterized via X-ray crystallography. Key words: organoboranes, ferrocene derivatives, multidentate Lewis acids.

Mature hepatocytes that were induced to proliferate in specially-formulated growth medium were found to exhibit the properties of bipotential hepatic stem cells. These hepatocytes required the presence of hepatocyte growth factor, epithelial growth factor, transforming growth factor alpha (TGF). The cells that developed in culture lost their ability to produce albumin and cytochrome P450IIB1 but were able to produce TGF-alpha and fibroblast growth factor. Cells from this culture that were transferred to matrigel developed the characteristics of mature hepatocytes.