Paolo Pani

A growth-constrained environment drives tumor progression in vivo

We recently have shown that selective growth of transplanted normal hepatocytes can be achieved in a setting of cell cycle block of endogenous parenchymal cells. Thus, massive proliferation of donor-derived normal hepatocytes was observed in the liver of rats previously given retrorsine (RS), a naturally occurring alkaloid that blocks proliferation of resident liver cells. In the present study, the fate of nodular hepatocytes transplanted into RS-treated or normal syngeneic recipients was followed. The dipeptidyl peptidase type IV-deficient (DPPIV−) rat model for hepatocyte transplantation was used to distinguish donor-derived cells from recipient cells. Hepatocyte nodules were chemically induced in Fischer 344, DPPIV+ rats; livers were then perfused and larger (>5 mm) nodules were separated from surrounding tissue. Cells isolated from either tissue were then injected into normal or RS-treated DPPIV− recipients. One month after transplantation, grossly visible nodules (2–3 mm) were seen in RS-treated recipients transplanted with nodular cells. They grew rapidly, occupying 80–90% of the host liver at 2 months, and progressed to hepatocellular carcinoma within 4 months. By contrast, no liver nodules developed within 6 months when nodular hepatocytes were injected into the liver of recipients not exposed to RS, although small clusters of donor-derived cells were present in these animals. Taken together, these results directly point to a fundamental role played by the host environment in modulating the growth and the progression rate of altered cells during carcinogenesis. In particular, they indicate that conditions associated with growth constraint of the host tissue can drive tumor progression in vivo.

Long-Term, Near-Total Liver Replacement by Transplantation of Isolated Hepatocytes in Rats Treated with Retrorsine

Genetically marked hepatocytes from dipeptidyl peptidase (DPP) IV+ Fischer 344 rats were transplanted into the liver of DPPIV- mutant Fischer 344 rats after a combined treatment with retrorsine, a pyrrolizidine alkaloid that blocks the hepatocyte cell cycle, and two-thirds partial hepatectomy. In female rats, clusters of proliferated DPPIV+ hepatocytes containing 20 to 50 cells/cluster, mostly derived from single transplanted cells, were evident at 2 weeks, increasing in size to hundreds of cells per cluster at 1 month and 1000 to several thousand cells per cluster at 2 months, representing 40 to 60% of total hepatocyte mass. This level of hepatocyte replacement remained constant for up to 1 year, the duration of experiments conducted. In male rats, liver replacement occurred more rapidly and was more extensive, with transplanted hepatocytes representing 10 to 15% of hepatocyte mass at 2 weeks, 40 to 50% at 1 month, 90 to 95% at 2 months, 98% at 4 months, and 99% at 9 months. Transplanted hepatocytes were integrated into the parenchymal plates, exhibited unique hepatic biochemical functions, and fully reconstituted a normal hepatic lobular structure. The extensive proliferation of transplanted cells in this setting of persistent inhibition of resident hepatocytes represents a new general model to study basic aspects of liver repopulation with potential applications in chronic liver disease and ex vivo gene therapy.

Testing general relativity with present and future astrophysical observations

One century after its formulation, Einsteins general relativity (GR) has made remarkable predictions and turned out to be compatible with all experimental tests. Most of these tests probe the theory in the weak-field regime, and there are theoretical and experimental reasons to believe that GR should be modified when gravitational fields are strong and spacetime curvature is large. The best astrophysical laboratories to probe strong-field gravity are black holes and neutron stars, whether isolated or in binary systems. We review the motivations to consider extensions of GR. We present a (necessarily incomplete) catalog of modified theories of gravity for which strong-field predictions have been computed and contrasted to Einsteins theory, and we summarize our current understanding of the structure and dynamics of compact objects in these theories. We discuss current bounds on modified gravity from binary pulsar and cosmological observations, and we highlight the potential of future gravitational wave measurements to inform us on the behavior of gravity in the strong-field regime.

Massive liver replacement by transplanted hepatocytes in the absence of exogenous growth stimuli in rats treated with retrorsine

A strategy for hepatocyte transplantation was recently developed whereby massive replacement of the recipient liver is achieved after a combined treatment with retrorsine, a pyrrolizidine alkaloid, and partial hepatectomy. We now investigated whether liver repopulation could occur in this animal model in the absence of any exogenous growth stimuli (eg, partial hepatectomy) for the transplanted cells. Dipeptidyl-peptidase type IV-deficient (DPPIV-) rats were used as recipients. Rats were given two injections of retrorsine (30 mg/kg each, 2 weeks apart), followed by transplantation of 2 x 10(6) hepatocytes isolated from a normal, syngeneic, DPPIV+ donor. At 2 weeks after transplantation, clusters of DPPIV+ hepatocytes occupied 3.3 +/- 0.9% of host liver, increasing to 38.2 +/- 6.3% at 2 months, and to 65.9 +/- 8.8% at 5 months. By 1 year, >95% of the original hepatocytes were replaced by donor-derived cells. Serum parameters related both to hepatocyte function and integrity (including glucose, bilirubin, total proteins, cholinesterase, alanine aminotransferase, and alkaline phosphatase) were in the normal range in retrorsine-treated and repopulated animals. These results provide further insights toward developing strategies for effective liver repopulation by transplanted hepatocytes with reduced toxicity for the host and potential clinical applicability.

Is the gravitational-wave ringdown a probe of the event horizon?

It is commonly believed that the ringdown signal from a binary coalescence provides a conclusive proof for the formation of an event horizon after the merger. This expectation is based on the assumption that the ringdown waveform at intermediate times is dominated by the quasinormal modes of the final object. We point out that this assumption should be taken with great care, and that very compact objects with a light ring will display a similar ringdown stage, even when their quasinormal-mode spectrum is completely different from that of a black hole. In other words, universal ringdown waveforms indicate the presence of light rings, rather than of horizons. Only precision observations of the late-time ringdown signal, where the differences in the quasinormal-mode spectrum eventually show up, can be used to rule out exotic alternatives to black holes and to test quantum effects at the horizon scale.

Cholesterol content in tumor tissues is inversely associated with high-density lipoprotein cholesterol in serum in patients with gastrointestinal cancer

Background. The authors have previously demonstrated in different experimental models that sustained processes of cellular growth are characterized by alterations of cholesterol metabolism not only in the proliferating tissues but also in the plasma compartment.

Massive spin-2 fields on black hole spacetimes: Instability of the Schwarzschild and Kerr solutions and bounds on the graviton mass

Massive bosonic fields of arbitrary spin are predicted by general extensions of the standard model. It has been recently shown that there exists a family of bimetric theories of gravity—including massive gravity—which are free of Boulware-Deser ghosts at the nonlinear level. This opens up the possibility to describe consistently the dynamics of massive spin-2 particles in a gravitational field. Within this context, we develop the study of massive spin-2 fluctuations—including massive gravitons—around Schwarzschild and slowly rotating Kerr black holes. Our work has two important outcomes. First, we show that the Schwarzschild geometry is linearly unstable for small tensor masses, against a spherically symmetric mode. Second, we provide solid evidence that the Kerr geometry is also generically unstable, both against the spherical mode and against long-lived superradiant modes. In the absence of nonlinear effects, the observation of spinning black holes bounds the graviton mass μ to be μ≲5×10-23  eV.

Phase transitions between Reissner-Nordstrom and dilatonic black holes in 4D AdS spacetime

We study Einstein-Maxwell-dilaton gravity models in four-dimensional antide Sitter (AdS) spacetime which admit the Reissner-Nordstrom (RN) black hole solution. We show that below a critical temperature the AdS-RN solution becomes unstable against scalar perturbations and the gravitational system undergoes a phase transition. We show using numerical calculations that the new phase is a charged dilatonic black hole. Using the AdS/CFT correspondence we discuss the phase transition in the dual field theory both for non-vanishing temperatures and in the extremal limit. The extremal solution has a Lifshitz scaling symmetry. We discuss the optical conductivity in the new dual phase and find interesting behavior at low frequencies where it shows a “Drude peak”. The resistivity varies with temperature in a non-monotonic way and displays a minimum at low temperatures which is reminiscent of the celebrated Kondo effect.

Liver regeneration in response to partial hepatectomy in rats treated with retrorsine: a kinetic study.

BACKGROUND/AIM We have designed an experimental model in which transplantation of normal hepatocytes into rats previously treated with retrorsine (a naturally-occurring pyrrolizidine alkaloid) results in near-complete replacement of the recipient liver by donor-derived cells. Two/thirds partial hepatectomy was found to be essential for this process to occur. To probe this finding, in the present study we describe the kinetics of liver regeneration in response to partial hepatectomy in rats given retrorsine. METHODS Six-weeks-old male Fisher 344 rats received retrorsine (2 injections of 30 mg/kg each, i.p., 2 weeks apart), or the vehicle. Four weeks after the last injection, partial hepatectomy was performed and rats were killed at 1, 2, 3, 6, and 15 days thereafter. RESULTS At time zero, i.e. prior to partial hepatectomy, liver weight and total liver DNA content were significantly lower in retrorsine-treated animals compared to controls (DNA content: 19.2+/-1.7 vs. 25.7+/-1.1 mg/liver). Diffuse megalocytosis (enlarged hepatocytes) was present in the group exposed to retrorsine. By day 3 post-partial hepatectomy liver DNA content in control animals had more than doubled compared to day 1 values (20.2+/-1.5 vs. 8.8+/-1.2), while very little increase was seen in retrorsine-treated rats at the same time points (7.6+/-0.4 vs. 6.1+/-0.2). At 2 weeks after partial hepatectomy, total DNA content returned close to normal levels in the control group (26.9+/-1.0 mg/liver); however, the value was still very low in animals receiving retrorsine (9.1+/-0.7). Data on BrdU labeling were consistent with this pattern and indicated that DNA synthesis following partial hepatectomy was largely inhibited in the retrorsine group. Similarly, no mitotic response was observed in hepatocytes following partial hepatectomy in animals exposed to retrorsine. CONCLUSIONS These results clearly indicate that retrorsine exerts a strong and persistent cell cycle block on hepatocyte proliferation. Further, these results are in agreement with the hypothesis that selective proliferation of transplanted hepatocytes in retrorsine-treated animals is dependent, at least in part, on the persistent cell cycle block imposed by the alkaloid on endogenous parenchymal cells.

Black-hole bombs and photon-mass bounds.

Generic extensions of the standard model predict the existence of ultralight bosonic degrees of freedom. Several ongoing experiments are aimed at detecting these particles or constraining their mass range. Here we show that massive vector fields around rotating black holes can give rise to a strong superradiant instability, which extracts angular momentum from the hole. The observation of supermassive spinning black holes imposes limits on this mechanism. We show that current supermassive black-hole spin estimates provide the tightest upper limits on the mass of the photon (m(v) is < or approximately equal to 4×10(-20) eV according to our most conservative estimate), and that spin measurements for the largest known supermassive black holes could further lower this bound to m(v) < or approximately equal to 10(-22) eV. Our analysis relies on a novel framework to study perturbations of rotating Kerr black holes in the slow-rotation regime, that we developed up to second order in rotation, and that can be extended to other spacetime metrics and other theories.