bluuebunny/crossref_metadata_2025 huggingface dataset:
Singularities of the hypergeometric system associated with a monomial curve
Authors: Castro-Jiménez Francisco , Takayama Nobuki
Published: July 2005

We compute, using

D

\mathcal {D}

-module restrictions, the slopes of the irregular hypergeometric system associated with a monomial curve. We also study rational solutions and reducibility of such systems.
Irreducibility of equisingular families of curves
Authors: Keilen Thomas
Published: July 2005

In 1985 Joe Harris proved the long-standing claim of Severi that equisingular families of plane nodal curves are irreducible whenever they are nonempty. For families with more complicated singularities this is no longer true. Given a divisor

D
D

on a smooth projective surface

Σ
\Sigma

it thus makes sense to look for conditions which ensure that the family

V

|

D

|

i
r
r

(

S

1

,
…
,

S

r

)

V_{|D|}^{irr}\big (\mathcal {S}_1,\ldots ,\mathcal {S}_r\big )

of irreducible curves in the linear system

|

D

|

l

|D|_l

with precisely

r
r

singular points of types

S

1

,
…
,

S

r

\mathcal {S}_1,\ldots ,\mathcal {S}_r

is irreducible. Considering different surfaces, including general surfaces in

P

C

3

\mathbb P_{\mathbb C}^3

and products of curves, we produce a sufficient condition of the type
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="sigma-summation Underscript i equals 1 Overscript r Endscripts degree left-parenthesis upper X left-parenthesis script upper S Subscript i Baseline right-parenthesis right-parenthesis squared greater-than gamma dot left-parenthesis upper D minus upper K Subscript normal upper Sigma Baseline right-parenthesis squared comma">

∑

i
=
1

r

deg
⁡

(

X
(

S

i

)

)

2

>
γ
⋅
(
D
−

K
Σ

)
2

,

\begin{equation*} \sum \limits _{i=1}^r\deg \big (X(\mathcal {S}_i)\big )^2 > \gamma \cdot (D- K_\Sigma )^2, \end{equation*}

where

γ
\gamma

is some constant and

X
(

S

i

)

X(\mathcal {S}_i)

some zero-dimensional scheme associated to the singularity type. Our results carry the same asymptotics as the best known results in this direction in the plane case, even though the coefficient is worse. For most of the surfaces considered these are the only known results in that direction.
Combinatorics of rooted trees and Hopf algebras
Authors: Hoffman Michael
Published: July 2005

We begin by considering the graded vector space with a basis consisting of rooted trees, with grading given by the count of non-root vertices. We define two linear operators on this vector space, the growth and pruning operators, which respectively raise and lower grading; their commutator is the operator that multiplies a rooted tree by its number of vertices, and each operator naturally associates a multiplicity to each pair of rooted trees. By using symmetry groups of trees we define an inner product with respect to which the growth and pruning operators are adjoint, and obtain several results about the associated multiplicities.

Now the symmetric algebra on the vector space of rooted trees (after a degree shift) can be endowed with a coproduct to make a Hopf algebra; this was defined by Kreimer in connection with renormalization. We extend the growth and pruning operators, as well as the inner product mentioned above, to Kreimer’s Hopf algebra. On the other hand, the vector space of rooted trees itself can be given a noncommutative multiplication: with an appropriate coproduct, this leads to the Hopf algebra of Grossman and Larson. We show that the inner product on rooted trees leads to an isomorphism of the Grossman-Larson Hopf algebra with the graded dual of Kreimer’s Hopf algebra, correcting an earlier result of Panaite.
Zero entropy, non-integrable geodesic flows and a non-commutative rotation vector
Authors: Butler Leo
Published: July 2005

Let

g

\mathfrak g

be a

2
2

-step nilpotent Lie algebra; we say

g

\mathfrak g

is non-integrable if, for a generic pair of points

p
,

p
′

∈

g

∗

p,p’ \in \mathfrak g^*

, the isotropy algebras do not commute:

[

g

p

,

g

p
′

]
≠
0

[\mathfrak g_p,\mathfrak g_{p’}] \neq 0

. Theorem: If

G
G

is a simply-connected

2
2

-step nilpotent Lie group,

g

=

L
i
e

(
G
)

\mathfrak g ={\mathrm {Lie}}(G)

is non-integrable,

D
>
G

D > G

is a cocompact subgroup, and

g

{\mathbf g}

is a left-invariant Riemannian metric, then the geodesic flow of

g

{\mathbf g}

on

T
∗

(
D
∖
G
)

T^*(D \backslash G)

is neither Liouville nor non-commutatively integrable with

C
0

C^0

first integrals. The proof uses a generalization of the rotation vector pioneered by Benardete and Mitchell.
Self-intersection class for singularities and its application to fold maps
Authors: Ohmoto Toru , Saeki Osamu , Sakuma Kazuhiro
Published: July 2005

Let

f
:
M
→
N

f :M \to N

be a generic smooth map with corank one singularities between manifolds, and let

S
(
f
)

S(f)

be the singular point set of

f
f

. We define the self-intersection class

I
(
S
(
f
)
)
∈

H
∗

(
M
;

Z

)

I(S(f)) \in H^*(M; \mathbf {Z})

of

S
(
f
)

S(f)

using an incident class introduced by Rimányi but with twisted coefficients, and give a formula for

I
(
S
(
f
)
)

I(S(f))

in terms of characteristic classes of the manifolds. We then apply the formula to the existence problem of fold maps.
On the Iwasawa 𝜆-invariants of real abelian fields
Authors: Tsuji Takae
Published: July 2005

For a prime number

p
p

and a number field

k
k

, let

A
∞

A_\infty

denote the projective limit of the

p
p

-parts of the ideal class groups of the intermediate fields of the cyclotomic

Z

p

\mathbb {Z}_p

-extension over

k
k

. It is conjectured that

A
∞

A_\infty

is finite if

k
k

is totally real. When

p
p

is an odd prime and

k
k

is a real abelian field, we give a criterion for the conjecture, which is a generalization of results of Ichimura and Sumida. Furthermore, in a special case where

p
p

divides the degree of

k
k

, we also obtain a rather simple criterion.
A tracial quantum central limit theorem
Authors: Kuperberg Greg
Published: July 2005

We prove a central limit theorem for non-commutative random variables in a von Neumann algebra with a tracial state: Any non-commutative polynomial of averages of i.i.d. samples converges to a classical limit. The proof is based on a central limit theorem for ordered joint distributions together with a commutator estimate related to the Baker-Campbell-Hausdorff expansion. The result can be considered a generalization of Johansson’s theorem on the limiting distribution of the shape of a random word in a fixed alphabet as its length goes to infinity.
Moduli of suspension spectra
Authors: Klein John
Published: July 2005

For a

1
1

-connected spectrum

E
E

, we study the moduli space of suspension spectra which come equipped with a weak equivalence to

E
E

. We construct a spectral sequence converging to the homotopy of the moduli space in positive degrees. In the metastable range, we get a complete homotopical classification of the path components of the moduli space. Our main tool is Goodwillie’s calculus of homotopy functors.
The relationship between homological properties and representation theoretic realization of artin algebras
Authors: Iyama Osamu
Published: July 2005

We will study the relationship of quite different objects in the theory of artin algebras, namely Auslander-regular rings of global dimension two, torsion theories,

τ
\tau

-categories and almost abelian categories. We will apply our results to characterization problems of Auslander-Reiten quivers.
Discrete Morse functions from lexicographic orders
Authors: Babson Eric , Hersh Patricia
Published: July 2005

This paper shows how to construct a discrete Morse function with a relatively small number of critical cells for the order complex of any finite poset with

0
^

\hat {0}

and

1
^

\hat {1}

from any lexicographic order on its maximal chains. Specifically, if we attach facets according to the lexicographic order on maximal chains, then each facet contributes at most one new face which is critical, and at most one Betti number changes; facets which do not change the homotopy type also do not contribute any critical faces. Dimensions of critical faces as well as a description of which facet attachments change the homotopy type are provided in terms of interval systems associated to the facets. As one application, the Möbius function may be computed as the alternating sum of Morse numbers. The above construction enables us to prove that the poset

Π
n

/

S

λ

\Pi _n/S_{\lambda }

of partitions of a set

{

1

λ
1

,
…
,

k

λ
k

}

\{ 1^{\lambda _1 },\dots ,k^{\lambda _k }\}

with repetition is homotopy equivalent to a wedge of spheres of top dimension when

λ
\lambda

is a hook-shaped partition; it is likely that the proof may be extended to a larger class of

λ
\lambda

and perhaps to all

λ
\lambda

, despite a result of Ziegler (1986) which shows that

Π
n

/

S

λ

\Pi _n/S_{\lambda }

is not always Cohen-Macaulay.
The Dirichlet problem for harmonic maps from Riemannian polyhedra to spaces of upper bounded curvature
Authors: Fuglede Bent
Published: July 2005

This is a continuation of the Cambridge Tract “Harmonic maps between Riemannian polyhedra”, by J. Eells and the present author. The variational solution to the Dirichlet problem for harmonic maps with countinuous boundary data is shown to be continuous up to the boundary, and thereby uniquely determined. The domain space is a compact admissible Riemannian polyhedron with boundary, while the target can be, for example, a simply connected complete geodesic space of nonpositive Alexandrov curvature; alternatively, the target may have upper bounded curvature provided that the maps have a suitably small range. Essentially in the former setting it is further shown that a harmonic map pulls convex functions in the target back to subharmonic functions in the domain.
Stein’s method and Plancherel measure of the symmetric group
Authors: Fulman Jason
Published: July 2005

We initiate a Stein’s method approach to the study of the Plancherel measure of the symmetric group. A new proof of Kerov’s central limit theorem for character ratios of random representations of the symmetric group on transpositions is obtained; the proof gives an error term. The construction of an exchangeable pair needed for applying Stein’s method arises from the theory of harmonic functions on Bratelli diagrams. We also find the spectrum of the Markov chain on partitions underlying the construction of the exchangeable pair. This yields an intriguing method for studying the asymptotic decomposition of tensor powers of some representations of the symmetric group.
Finite time blow-up for a dyadic model of the Euler equations
Authors: Katz Nets , Pavlović Nataša
Published: July 2005

We introduce a dyadic model for the Euler equations and the Navier-Stokes equations with hyper-dissipation in three dimensions. For the dyadic Euler equations we prove finite time blow-up. In the context of the dyadic Navier-Stokes equations with hyper-dissipation we prove finite time blow-up in the case when the dissipation degree is sufficiently small.
Dynamical systems disjoint from any minimal system
Authors: Huang Wen , Ye Xiangdong
Published: July 2005

Furstenberg showed that if two topological systems

(
X
,
T
)

(X,T)

and

(
Y
,
S
)

(Y,S)

are disjoint, then one of them, say

(
Y
,
S
)

(Y,S)

, is minimal. When

(
Y
,
S
)

(Y,S)

is nontrivial, we prove that

(
X
,
T
)

(X,T)

must have dense recurrent points, and there are countably many maximal transitive subsystems of

(
X
,
T
)

(X,T)

such that their union is dense and each of them is disjoint from

(
Y
,
S
)

(Y,S)

. Showing that a weakly mixing system with dense periodic points is in

M

⊥

{\mathcal {M}}^{\perp }

, the collection of all systems disjoint from any minimal system, Furstenberg asked the question to characterize the systems in

M

⊥

{\mathcal {M}}^{\perp }

. We show that a weakly mixing system with dense regular minimal points is in

M

⊥

{\mathcal {M}}^{\perp }

, and each system in

M

⊥

{\mathcal {M}}^{\perp }

has dense minimal points and it is weakly mixing if it is transitive. Transitive systems in

M

⊥

{\mathcal {M}}^{\perp }

and having no periodic points are constructed. Moreover, we show that there is a distal system in

M

⊥

{\mathcal {M}}^{\perp }

. Recently, Weiss showed that a system is weakly disjoint from all weakly mixing systems iff it is topologically ergodic. We construct an example which is weakly disjoint from all topologically ergodic systems and is not weakly mixing.
Harnack inequalities for non-local operators of variable order
Authors: Bass Richard , Kassmann Moritz
Published: July 2005

We consider harmonic functions with respect to the operator
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="script upper L u left-parenthesis x right-parenthesis equals integral left-bracket u left-parenthesis x plus h right-parenthesis minus u left-parenthesis x right-parenthesis minus 1 Subscript left-parenthesis StartAbsoluteValue h EndAbsoluteValue less-than-or-equal-to 1 right-parenthesis Baseline h dot nabla u left-parenthesis x right-parenthesis right-bracket n left-parenthesis x comma h right-parenthesis d h period">

L

u
(
x
)
=
∫
[
u
(
x
+
h
)
−
u
(
x
)
−

1

(

|

h

|

≤
1
)

h
⋅
∇
u
(
x
)
]
n
(
x
,
h
)

d
h
.

\mathcal {L} u(x)=\int [u(x+h)-u(x)-1_{(|h|\leq 1)} h\cdot \nabla u(x)] n(x,h) \, dh.

\]
Under suitable conditions on

n
(
x
,
h
)

n(x,h)

we establish a Harnack inequality for functions that are nonnegative and harmonic in a domain. The operator

L

\mathcal {L}

is allowed to be anisotropic and of variable order.
On the Cohen-Macaulay modules of graded subrings
Authors: Hanes Douglas
Published: July 2005

We give several characterizations for the linearity property for a maximal Cohen-Macaulay module over a local or graded ring, as well as proofs of existence in some new cases. In particular, we prove that the existence of such modules is preserved when taking Segre products, as well as when passing to Veronese subrings in low dimensions. The former result even yields new results on the existence of finitely generated maximal Cohen-Macaulay modules over non-Cohen-Macaulay rings.
A theta function identity and its implications
Authors: Liu Zhi-Guo
Published: July 2005

In this paper we prove a general theta function identity with four parameters by employing the complex variable theory of elliptic functions. This identity plays a central role for the cubic theta function identities. We use this identity to re-derive some important identities of Hirschhorn, Garvan and Borwein about cubic theta functions. We also prove some other cubic theta function identities. A new representation for

∏

n
=
1

∞

(
1
−

q
n

)

10

\prod _{n=1}^\infty (1-q^n)^{10}

is given. The proofs are self-contained and elementary.
The Aronsson-Euler equation for absolutely minimizing Lipschitz extensions with respect to Carnot-Carathéodory metrics
Authors: Bieske Thomas , Capogna Luca
Published: July 2005

We derive the Euler-Lagrange equation (also known in this setting as the Aronsson-Euler equation) for absolute minimizers of the

L

∞

L^{\infty }

variational problem
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="StartLayout Enlarged left-brace 1st Row inf StartAbsoluteValue EndAbsoluteValue nabla Subscript 0 Baseline u StartAbsoluteValue EndAbsoluteValue Subscript upper L Sub Superscript normal infinity Subscript left-parenthesis normal upper Omega right-parenthesis Baseline comma u equals g element-of upper L i p left-parenthesis partial-differential normal upper Omega right-parenthesis on partial-differential normal upper Omega comma EndLayout">

{

inf

|

|

∇
0

u

|

|

L

∞

(
Ω
)

,
u
=
g
∈
L
i
p
(
∂
Ω
)
 on 
∂
Ω
,

\begin {cases} \inf ||\nabla _0 u||_{L^{\infty }(\Omega )}, u=g\in Lip(\partial \Omega ) \text { on }\partial \Omega , \end {cases}

\]
where

Ω
⊂

G

\Omega \subset \mathbf {G}

is an open subset of a Carnot group,

∇
0

u

\nabla _0 u

denotes the horizontal gradient of

u
:
Ω
→

R

u:\Omega \to \mathbb {R}

, and the Lipschitz class is defined in relation to the Carnot-Carathéodory metric. In particular, we show that absolute minimizers are infinite harmonic in the viscosity sense. As a corollary we obtain the uniqueness of absolute minimizers in a large class of groups. This result extends previous work of Jensen and of Crandall, Evans and Gariepy. We also derive the Aronsson-Euler equation for more “regular" absolutely minimizing Lipschitz extensions corresponding to those Carnot-Carathéodory metrics which are associated to “free" systems of vector fields.
Knot theory for self-indexed graphs
Authors: Graña Matías , Turaev Vladimir
Published: July 2005

We introduce and study so-called self-indexed graphs. These are (oriented) finite graphs endowed with a map from the set of edges to the set of vertices. Such graphs naturally arise from classical knot and link diagrams. In fact, the graphs resulting from link diagrams have an additional structure, an integral flow. We call a self-indexed graph with integral flow a comte. The analogy with links allows us to define transformations of comtes generalizing the Reidemeister moves on link diagrams. We show that many invariants of links can be generalized to comtes, most notably the linking number, the Alexander polynomials, the link group, etc. We also discuss finite type invariants and quandle cocycle invariants of comtes.
On the complexity of the integral closure
Authors: Ulrich Bernd , Vasconcelos Wolmer
Published: July 2005

The computation of the integral closure of an affine ring has been the focus of several modern algorithms. We will treat here one related problem: the number of generators the integral closure of an affine ring may require. This number, and the degrees of the generators in the graded case, are major measures of cost of the computation. We prove several polynomial type bounds for various kinds of algebras, and establish in characteristic zero an exponential type bound for homogeneous algebras with a small singular locus.
Quantum cohomology of partial flag manifolds
Authors: Buch Anders
Published: July 2005

We give elementary geometric proofs of the structure theorems for the (small) quantum cohomology of partial flag varieties

SL
⁡
(
n
)

/

P

\operatorname {SL}(n)/P

, including the quantum Pieri and quantum Giambelli formulas and the presentation.
On the behavior of the algebraic transfer
Authors: Bruner Robert , Hà Lê , Hưng Nguyễn
Published: July 2005

Let
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="upper T r Subscript k Baseline colon double-struck upper F 2 circled-times Underscript upper G upper L Subscript k Baseline Endscripts upper P upper H Subscript i Baseline left-parenthesis upper B double-struck upper V Subscript k Baseline right-parenthesis right-arrow upper E x t Subscript script upper A Superscript k comma k plus i Baseline left-parenthesis double-struck upper F 2 comma double-struck upper F 2 right-parenthesis">

T

r
k

:

F

2

⊗

G

L
k

P

H
i

(
B

V

k

)
→
E
x

t

A

k
,
k
+
i

(

F

2

,

F

2

)

Tr_k:\mathbb {F}_2\underset {GL_k}{\otimes } PH_i(B\mathbb {V}_k)\to Ext_{\mathcal {A}}^{k,k+i}(\mathbb {F}_2, \mathbb {F}_2)

be the algebraic transfer, which is defined by W. Singer as an algebraic version of the geometrical transfer
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="t r Subscript k Baseline colon pi Subscript asterisk Superscript upper S Baseline left-parenthesis left-parenthesis upper B double-struck upper V Subscript k Baseline right-parenthesis Subscript plus Baseline right-parenthesis right-arrow pi Subscript asterisk Superscript upper S Baseline left-parenthesis upper S Superscript 0 Baseline right-parenthesis">

t

r
k

:

π
∗
S

(
(
B

V

k

)
+

)
→

π
∗
S

(

S
0

)

tr_k: \pi _*^S((B\mathbb {V} _k)_+) \to \pi _*^S(S^0)

. It has been shown that the algebraic transfer is highly nontrivial and, more precisely, that

T

r
k

Tr_k

is an isomorphism for

k
=
1
,
2
,
3

k=1, 2, 3

. However, Singer showed that

T

r
5

Tr_5

is not an epimorphism. In this paper, we prove that

T

r
4

Tr_4

does not detect the nonzero element

g
s

∈
E
x

t

A

4
,
12
⋅

2
s

(

F

2

,

F

2

)

g_s\in Ext_{\mathcal {A}}^{4,12\cdot 2^s}(\mathbb {F}_2, \mathbb {F}_2)

for every

s
≥
1

s\geq 1

. As a consequence, the localized

(
S

q
0

)

−
1

T

r
4

(Sq^0)^{-1}Tr_4

given by inverting the squaring operation

S

q
0

Sq^0

is not an epimorphism. This gives a negative answer to a prediction by Minami.
Analysis on products of fractals
Authors: Strichartz Robert
Published: July 2005

For a class of post–critically finite (p.c.f.) fractals, which includes the Sierpinski gasket (SG), there is a satisfactory theory of analysis due to Kigami, including energy, harmonic functions and Laplacians. In particular, the Laplacian coincides with the generator of a stochastic process constructed independently by probabilistic methods. The probabilistic method is also available for non–p.c.f. fractals such as the Sierpinski carpet. In this paper we show how to extend Kigami’s construction to products of p.c.f. fractals. Since the products are not themselves p.c.f., this gives the first glimpse of what the analytic theory could accomplish in the non–p.c.f. setting. There are some important differences that arise in this setting. It is no longer true that points have positive capacity, so functions of finite energy are not necessarily continuous. Also the boundary of the fractal is no longer finite, so boundary conditions need to be dealt with in a more involved manner. All in all, the theory resembles PDE theory while in the p.c.f. case it is much closer to ODE theory.
Finite dimensional representations of symplectic reflection algebras associated to wreath products
Authors: Etingof Pavel , Montarani Silvia
Published: July 2005

Using deformation theory of representations of algebras, we construct families of finite dimensional representations of symplectic reflection algebras associated to wreath products.
Empirical Strategies for Various Manifestations of Multilevel Data
Authors: Franzese Robert J.
Published: July 2005

Equivalent separate-subsample (two-step) and pooled-sample (one-step) strategies exist for any multilevel-modeling task, but their relative practicality and efficacy depend on dataset dimensions and properties and researchers' goals. Separate-subsample strategies have difficulties incorporating cross-subsample information, often crucial in time-series cross-section or panel contexts (subsamples small and/or cross-subsample information great) but less relevant in pools of independently random surveys (subsamples large; cross-sample information small). Separate-subsample estimation also complicates retrieval of macro-level-effect estimates, although they remain obtainable and may not be substantively central. Pooled-sample estimation, conversely, struggles with stochastic specifications that differ across levels (e.g., stochastic linear interactions in binary dependent-variable models). Moreover, pooled-sample estimation that models coefficient variation in a theoretically reduced manner rather than allowing each subsample coefficient vector to differ arbitrarily can suffer misspecification ills insofar as this reduced specification is lacking. Often, though, these ills are limited to inefficiencies and standard-error inaccuracies that familiar efficient (e.g., feasible generalized least squares) or consistent-standard-error estimation strategies can satisfactorily redress.
Institutional Context, Cognitive Resources and Party Attachments Across Democracies
Authors: Huber John D. , Kernell Georgia , Leoni Eduardo L.
Published: July 2005

This paper develops and tests arguments about how national-level social and institutional factors shape the propensity of individuals to form attachments to political parties. Our tests employ a two-step estimation procedure that has attractive properties when there is a binary dependent variable in the first stage and when the number of second-level units is relatively small. We find that voters are most likely to form party attachments when group identities are salient and complimentary. We also find that institutions that assist voters in retrospectively evaluating parties—specifically, strong party discipline and few parties in government—increase partisanship. These institutions matter most for those individuals with the fewest cognitive resources, measured here by education.
Nontoxic membrane translocation peptide from protamine, low molecular weight protamine (LMWP), for enhanced intracellular protein delivery: in vitro and in vivo study
Authors: Park Yoon Jeong , Chang Li‐Chien , Liang Jun Feng , Moon Cheol , Chung Chong‐Pyoung , Yang Victor C.
Published: July 2005

Naturally derived, nontoxic peptides from protamine by the authors, termed low molecular weight protamines (LMWPs), possess high arginine content and carry significant sequence similarity to that of TAT, by far the most potent protein transduction domain peptide. Therefore, it was hypothesized that these LMWPs would also inherit the similar translocation activity across the cell membrane, which enables any impermeable species to be transduced into the cells. LMWPs were prepared by enzymatic digestion of protamine, examined their capability of transducing an impermeable protein toxin into the tumor cells by chemical conjugation, and determined cytotoxicity of transduced protein toxin (e.g., gelonin) against cancer cell lines and a tumor‐bearing mouse. In vitro results showed that LMWPs could indeed translocate themselves into several mammalian cell lines as efficiently as TAT, thereby transducing impermeable gelonin into the cells by chemical conjugation. In vivo studies further confirmed that LMWP could carry an impermeable gelonin across the tumor mass and subsequently inhibit the tumor growth. In conclusion, the presence of equivalent cell translocation potency, absence of toxicity of peptide itself, and the suitability for low‐cost production by simple enzymatic digestion could expand the range of clinical applications of LMWPs, including medical imaging and gene/protein therapies.
Prospective identification of cardiac progenitors by a novel single cell‐based cardiomyocyte induction
Authors: Yamashita Jun K. , Takano Makoto , Hiraoka‐Kanie Mina , Shimazu Chikashi , Peishi Yan , Yanagi Kentoku , Nakano Akiko , Inoue Emi , Kita Fumiyo , Nishikawa Shin‐Ichi
Published: July 2005

Dissection of cardiomyocyte differentiation process at the cellular level is indispensable in the research for cardiac development and regeneration. Previously, we have established an embryonic stem cell differentiation system that reproduces early vascular development from progenitor cells that express Flk1, a vascular endothelial growth factor receptor, by the combinatory application of 2‐dimensional culture and flowcytometry. Here we show that cardiomyocytes can be successfully induced from a single Flk1+ cell on 2‐dimensional culture, enabling the direct observation of differentiating cardiomyocytes and the prospective identification of cardiac progenitor potentials. Flk1+ cells could give rise to cardiomyocytes, as well as endothelial cells, from a single cell by the co‐culture on OP9 stroma cells in a fusion‐independent manner. Among the cell populations in intermediate stages from Flk1+ cells to cardiomyocytes, Flk1+/CXCR4+/vascular endothelial cadherin− cells were cardiac‐specific progenitors at the single cell level. Noggin, a bone morphogenetic protein inhibitor, abolished cardiomyocyte differentiation by inhibiting the cardiac progenitor induction. However, wnt inhibitors Dkk‐1 or Frizzled‐8/Fc chimeric protein augmented, but wnt3a inhibited, cardiomyocyte differentiation. In vitro reproduction of cardiomyocyte differentiation process should be a potent tool for the cellular and molecular elucidation of cardiac development, which would provide various targets for cardiac regeneration.
Immunotherapy in multiple myeloma – possibility or probability?
Authors: Harrison S. J. , Cook G.
Published: July 2005

In a small number of patients with multiple myeloma (MM), long‐term disease‐free survival has been achieved by harnessing the immune phenomenon, ‘graft‐versus‐tumour’ effect, induced by allogeneic haemopoietic stem cell transplantation. This has prompted many investigators to examine ways in which a patient's own immune system can be more effectively directed against their disease, with the ultimate aim of tumour eradication. In this review we assess the current understanding of immunobiology in MM, and how the different components of the immune system, such as dendritic cells, T cells and natural killer cells, may be harnessed using in‐vitro and in‐vivo priming techniques. We look at the clinical immunotherapy trials reported to date and whether, in light of the current information, immunotherapy for MM is an achievable goal.
Perinatal stroke – risk factors and management
Authors: Chalmers Elizabeth A.
Published: July 2005

Stroke is an uncommon but increasingly recognised cause of mortality and long‐term neurological morbidity in children. A significant number of these events appear to be caused by thromboembolic disease and, as with other childhood thrombotic problems, the incidence of central nervous system events appears highest during the neonatal period. In contrast to peripheral arterial and venous thrombotic problems, it is likely that a proportion of cerebral thromboembolic events occur either in utero or perinatally and reflect different risk factors from those occurring in older infants and children. The pathophysiology of perinatal stroke is complex and in many cases is likely to be multifactorial. It is now recognised that risk factors may relate to both maternal and placental problems as well as fetal and neonatal disorders. Large prospective studies of perinatal stroke are currently lacking and efforts to define the relative contribution from each of these areas are at an early stage. The complex nature of these disorders requires collaboration between a number of different disciplines including obstetrics, fetal medicine, pathology, neonatology and neurology. Of particular interest to haematologists is the possible impact of prothrombotic abnormalities in the pathophysiology of these events and also the potential for the use of antithrombotic agents in both management and prevention.
Conventional second‐line salvage chemotherapy regimens are not warranted in patients with malignant lymphomas who have progressive disease after first‐line salvage therapy regimens
Authors: Ardeshna Kirit M. , Kakouros Nicholaos , Qian Wendi , Powell Michael G. , Saini Nishaat , D'Sa Shirley , Mackinnon Stephen , Hoskin Peter J. , Goldstone Anthony H. , Linch David C.
Published: July 2005

This study aimed to determine the outcome of patients with relapsed or refractory lymphoma who have an inadequate response to first‐line salvage therapy (1°ST) and who subsequently receive a second‐line salvage regimen (2°ST) with the intention of ultimately proceeding to high‐dose therapy. The outcome of 57 patients [Hodgkin's Lymphoma 17, histologically‐aggressive non‐Hodgkin's Lymphoma (NHL) 26, histologically‐indolent NHL 14] who received more than one modality of conventional‐dose salvage therapy was analysed. Sixteen patients had a partial response (PR) to 1°ST, but subsequently received 2°ST because the PR was judged to be inadequate (iPR) because of persisting disease bulk or marrow infiltration. Of these 16 patients, 10 (63%) continued to respond to 2°ST. Of the 15 patients who had stable disease following 1°ST, 5 (33%) responded to 2°ST. Only one of the 24 (4%) with progressive disease (PD) following 1°ST, responded to 2°ST. 25 of the 57 patients ultimately underwent stem cell transplantation. The 2‐year progression‐free survival (PFS) and the 3‐year overall survival (OS) for all patients was 24% and 31%, respectively. Long‐term survival was highly dependent on response to 1°ST (P = 0·0001); in patients with PD following 1°ST, the PFS and OS at 3 years was only 4%. This analysis indicates that patients with malignant lymphomas, who have PD on 1°ST, are not rescued by subsequent salvage regimens. They should either be treated palliatively or novel approaches should be explored.
Identification of APOBEC3B as a potential target for the graft‐versus‐lymphoma effect by SEREX in a patient with mantle cell lymphoma
Authors: Hishizawa Masakatsu , Imada Kazunori , Sakai Tomomi , Ueda Maki , Uchiyama Takashi
Published: July 2005

Recently, a graft‐versus‐lymphoma (GVL) effect has been shown in patients allografted for mantle cell lymphoma (MCL), but the antigenic targets of this response remain unclear. We screened an MCL cDNA expression library with sera at GVL response after allogeneic haematopoietic stem cell transplantation and isolated five genes including APOBEC3B. Antibody responses to APOBEC3B were correlated with clinical response. Furthermore, APOBEC3B‐specific T‐cell response was induced with one of the HLA‐A*0201 binding peptides. In addition, APOBEC3B mRNA appeared to be upregulated in some MCL. These findings warrant further investigation of APOBEC3B as a candidate gene eliciting an effective immune response against MCL.
Environmental risk factors for inhibitor development in children with haemophilia A: a case–control study
Authors: Santagostino Elena , Mancuso Maria Elisa , Rocino Angiola , Mancuso Giacomo , Mazzucconi Maria Gabriella , Tagliaferri Annarita , Messina Maria , Mannucci Pier Mannuccio
Published: July 2005

This case–control study investigated the interactions between genetic and environmental factors and inhibitor development in 108 children with haemophilia A exclusively treated with recombinant factor VIII (FVIII). Sixty patients with inhibitors were compared with 48 inhibitor‐free controls. Family history of inhibitors and null mutations in theFVIIIgene were more prevalent in cases than in controls (20% vs. 2%,P = 0·001 and 83% vs. 64%,P = 0·04, respectively). On the other hand, there was no difference between cases and controls for such putative risk factors of inhibitor development as amniocentesis/villocentesis, premature/caesarean birth, breast‐feeding, treatment during infections/vaccinations, surgical procedures and central nervous system bleeding. A trend was found for an increased risk of inhibitor development in children first treated at a young age (<11 months); however, this was not confirmed after adjusting for genetic factors. The implementation of prophylaxis was evaluated as a putative risk factor in a subgroup of 25 cases: seven who started prophylaxis prior to inhibitor development and 18 potentially eligible for prophylaxis because they were inhibitor‐free up to the age of 35 months (i.e. the upper limit of the age range at prophylaxis onset in cases and the median age at prophylaxis onset in controls). Patients who started prophylaxis had a lower inhibitor risk than those treated on demand (adjusted odds ratio 0·2, 95% confidence interval 0·06–0·9). The protective effect on inhibitor development shown by prophylaxis may represent an additional advantage prompting its use in haemophilic children.
Effects of imatinib and interferon on primitive chronic myeloid leukaemia progenitors
Authors: Angstreich Greg R. , Matsui William , Huff Carol Ann , Vala Milada S. , Barber James , Hawkins Anita L. , Griffin Constance A. , Douglas Smith B. , Jones Richard J.
Published: July 2005

Imatinib has impressive activity against chronic myeloid leukaemia (CML), but does not appear to completely eradicate the disease. Although responses to interferon‐alpha (IFN) are slower and less dramatic than those to imatinib, they can be durable even after discontinuation of the drug. Unlike imatinib, the specific mechanisms responsible for IFN's clinical activity in CML are unknown. We found that IFN induced a G1 cell cycle arrest, as well as terminal differentiation, of the CML cell line KT‐1 and CML CD34+ cells from clinical specimens. Myeloid growth factors augmented the antileukaemic activity of IFN, and neutralising antibodies directed against myeloid growth factors inhibited IFN's antileukaemic activity. We next directly compared the effects of imatinib and IFN against differentiated and primitive CML progenitors from newly‐diagnosed patients. Although less active against CML granulocyte‐macrophage colony forming units than imatinib, IFN was significantly more toxic to primitive CML progenitors responsible for the maintenance of long‐term cultures. Imatinib and IFN appear to have divergent effects on CML progenitors at different stages of maturation, with imatinib more active against differentiated CML progenitors and IFN more active against primitive CML progenitors. The different target cells for these agents may explain the disparities in the kinetics and durability of their clinical responses. At least part of the clinical effect of IFN in CML appears to result from its ability to differentiate primitive CML progenitors.
Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graft‐versus‐host disease after allogeneic transplantation
Authors: Pérez‐Simón José A. , Díez‐Campelo María , Martino Rodrigo , Brunet Salut , Urbano Álvaro , Caballero María D. , de León Ángel , Valcárcel David , Carreras Enric , Del Cañizo María C. , López‐Fidalgo Jesús , Sierra Jordi , San Miguel Jesús F.
Published: July 2005

The graft‐versus‐host disease (GVHD) characteristics of 150 consecutive patients undergoing reduced intensity conditioning allogeneic (allo‐RIC) transplants and 88 patients undergoing myeloablative conditioning regimen were analysed. All patients received the same GVHD prophylaxis and peripheral blood stem cells from a human leucocyte antigen identical sibling. The cumulative incidence of acute GVHD (aGVHD) was 67% and 44% in the myeloablative and allo‐RIC regimen groups, respectively (P < 0·001), and was 39% vs. 29%, respectively (P = 0·043), for grades 2–4 aGVHD. Only conditioning type (myeloablative versus allo‐RIC) significantly influenced the incidence of aGVHD in multivariate analysis: Hazard ratio (HR) = 2·16 [95% confidence interval (CI): 1·52–3·07], P < 0·0001. The cumulative incidence of chronic GVHD (cGVHD) was 63% and 71% among myeloablative and allo‐RIC patients respectively (P = 0·084). This trend was because of the higher incidence of limited cGVHD, but not extensive cGVHD among allo‐RIC recipients [HR = 3·3 (95% CI: 1·42–8·08), P = 0·0017]. Moreover, among patients who developed cGVHD, the cumulative incidence of limited cGVHD was significantly lower in the myeloablative group than in the allo‐RIC group (7% vs. 25%, P = 0·007). Duration of immunosuppression was shorter among allo‐RIC patients (35·5% vs. 68·8% required systemic immunosuppression 36 months after transplant, P = 0·028). Although prospective controlled trials are required to further evaluate the effect of the conditioning regimen on GVHD, our results suggest that RIC modifies the incidence and characteristics of both acute and cGVHD after allogeneic transplantation, and decreases the immunosuppression requirements in long‐term follow up when compared with myeloablative conditioning.
Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft‐versus‐host disease
Authors: Couriel D. R. , Saliba R. , Escalón M. P. , Hsu Y. , Ghosh S. , Ippoliti C. , Hicks K. , Donato M. , Giralt S. , Khouri I. F. , Hosing C. , de Lima M. J. , Andersson B. , Neumann J. , Champlin R.
Published: July 2005

Chronic graft‐versus‐host disease (cGVHD) remains a major cause of morbidity and mortality in haematopoietic transplant recipients. Sirolimus is a macrocyclic triene antibiotic with immunosuppressive, antifungal and antitumour properties, that has activity in the prevention and treatment of acute GVHD. We conducted a phase II trial of sirolimus combined with tacrolimus and methylprednisolone in patients with steroid‐resistant cGVHD. Thirty‐five patients who developed GVHD after day 100 post‐transplant were studied. Six patients had a complete response and 16 a partial response with an overall response rate of 63%. Major adverse events related to the combination of tacrolimus and sirolimus were hyperlipidaemia, renal dysfunction and cytopenias. Four patients had thrombotic microangiopathy (TMA) and 27 (77%) had infectious complications. The median survival for the whole group was 15 months. A significantly better outcome was observed in patients with a platelet count ≥100 × 109/l, as well as in those with true chronic manifestations of GVHD compared to those with acute GVHD beyond day 100. Controlled trials comparing this approach with alternative strategies to determine which can best achieve the goal of GVHD‐free survival are warranted.
Clonal granulocytes in polycythaemia vera and essential thrombocythaemia have shortened telomeres
Authors: Ferraris Anna Maria , Pujic Natalija , Mangerini Rosa , Rapezzi Davide , Gallamini Andrea , Racchi Omar , Casciaro Salvatore , Gaetani Gian Franco
Published: July 2005

The purpose of this study was to evaluate telomere length in peripheral blood granulocytes and mononuclear cells collected from 22 women with polycythaemia vera (PV) and essential thrombocythaemia (ET). PV and ET are chronic myeloproliferative diseases whose heterogeneity of stem cell origin and clonal development has been established through analysis of X‐chromosome inactivation patterns. The results from clonality assay and determination of telomere length show that only clonal granulocytes have shortened telomeres.
Serological identification of adult T‐cell leukaemia‐associated antigens
Authors: Hishizawa Masakatsu , Imada Kazunori , Sakai Tomomi , Ueda Maki , Hori Toshiyuki , Uchiyama Takashi
Published: July 2005

Adult T‐cell leukaemia (ATL) is a peripheral T‐cell neoplasm caused by human T‐cell leukaemia virus type I (HTLV‐I). Several clinical observations suggest that some tumour‐associated antigens in ATL may be recognised by the immune system. In this study, we performed the serological screening of an expression library to identify ATL‐associated antigens by using materials from a unique ATL patient with long‐term stable disease. Among five distinct genes isolated, serine/arginine protein kinase 1 (SRPK1), which has been reported to have a restricted normal tissue distribution, was found to be overexpressed in most acute type ATL samples, but not in chronic type ATL or in normal peripheral blood mononuclear cells by real‐time reverse transcription polymerase chain reaction. Interestingly, the overexpression of SRPK1 in aggressive types of ATL was more exclusively observed at the protein level than at the mRNA level. Autologous antibody to SRPK1 was confirmed in the ATL patient using Western blot analysis with plasma, but not detected in asymptomatic HTLV‐I carriers or in healthy volunteers. These results indicate that SRPK1 may be useful for the development of therapeutic and diagnostic methods for patients with ATL.
AML1B transcriptional repressor function is impaired by the Flt3‐internal tandem duplication
Authors: Takahashi Shinichiro , Harigae Hideo , Kameoka Junichi , Sasaki Takeshi , Kaku Mitsuo
Published: July 2005

Fms‐like tyrosine kinase 3 (Flt3) is a type III receptor tyrosine kinase. The internal tandem duplication (ITD) of the juxtamembrane region of this receptor is the most prevalent mutation in acute myeloid leukaemia (AML). The silencing mediator of retinoic and thyroid hormone receptors (SMRT) co‐repressor recruits histone deacetylases (HDAC) and mediates transcriptional repression by interacting with various transcription factors. We recently reported that Flt3‐ITD interferes with the transcriptional and biological action of promyelocytic leukaemia zinc finger transcriptional repressor by dissociating it from SMRT. In this study, we aimed to clarify whether the repressional activity of other well‐known oncoproteins, such as AML1/Runx1 (AML1), is also affected by Flt3‐ITD. We verified that the repression activity of AML1B, the isoform of AML1, is dependent on HDAC activity by using HDAC inbitor trichostatin A in GAL4 reporter assays. Mammalian two‐hybrid assays demonstrated that this protein interacts with SMRT. Furthermore, this AML1B–SMRT interaction was disrupted by the overexpression of Flt3‐ITD, leading to the reduction of AML1B repression activity. Additionally, we showed AML1B repression target, p21 WAF1/CIP1, was aberrantly expressed in Flt3‐ITD stably expressed BaF3 cells. Taken together, Flt3‐ITD disrupts transcriptional repressor functions resulting in aberrant gene regulation in leukaemic cells.
Health‐related quality of life in children with sickle cell disease: child and parent perception
Authors: Panepinto Julie A. , O'Mahar Kerry M. , DeBaun Michael R. , Loberiza Fausto R. , Scott J. P.
Published: July 2005

Health‐related quality of life (HRQL) is an outcome that may be used to measure the impact of sickle cell disease on the child and their family but has not been routinely assessed in this disease. The objective of this study was to describe the HRQL of children with sickle cell disease as reported by the parent and the child, to compare the relationship between the two, and to determine the association of parent, child and disease characteristics on HRQL. Ninety‐five parents completed the Child Health Questionnaire (CHQ)‐Parent Form28 and 53 children completed the CHQ‐Child Form87. Compared with the child report, parents reported worse HRQL in the overall perception of health, physical functioning, behaviour and self esteem domains of HRQL (P < 0·005). Parent and child reports of HRQL correlated strongly in assessment of the impact of bodily pain (r = 0·58) on HRQL and moderately in physical functioning (r = 0·44), behaviour (r = 0·45), general health (r = 0·44), self esteem (r = 0·40) and changes in health (r = 0·33) domains. Disease status, neurobehavioral co‐morbidities, and parent education were associated with the HRQL of the child. Both the parent and child perspectives are needed to fully understand the impact of sickle cell disease on the HRQL of the child and effect of this disease on the family.
Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension
Authors: Machado Roberto F. , Martyr Sabrina , Kato Gregory J. , Barst Robyn J. , Anthi Anastasia , Robinson Michael R. , Hunter Lori , Coles Wynona , Nichols James , Hunter Christian , Sachdev Vandana , Castro Oswaldo , Gladwin Mark T.
Published: July 2005

Pulmonary hypertension is a frequent complication of sickle cell disease that is associated with haemolysis, impaired nitric oxide bioavailability and high mortality. We sought to evaluate the safety and efficacy of selective pulmonary vasodilators and antiproliferative agents in this at‐risk population. After optimising sickle cell disease therapy to stabilise haemoglobin and fetal haemoglobin levels, we evaluated the safety and efficacy of sildenafil in 12 patients with sickle cell disease and pulmonary hypertension. Sildenafil therapy (mean duration 6 ± 1 months) decreased the estimated pulmonary artery systolic pressure [50 ± 4 to 41 ± 3 mmHg; difference 9 mmHg, 95% confidence interval (CI): 0·3–17, P = 0·043] and increased the 6‐min walk distance (384 ± 30 to 462 ± 28 m; difference 78 m, 95% CI: 40–117, P = 0·0012). Transient headaches occurred in two patients and transient eye‐lid oedema in four patients. No episodes of priapism occurred in the three men in the study; two of them were on chronic exchange transfusions and one had erectile dysfunction. In conclusion: (1) sickle cell disease patients with anaemia and pulmonary hypertension have significant exercise limitation; (2) the 6‐min walk distance may be a valid endpoint in this population; (3) therapy with sildenafil appears safe and improves pulmonary hypertension and exercise capacity. Additional phase I studies in males with sickle cell disease followed by phase II/III placebo controlled trials evaluating the safety and efficacy of sildenafil therapy in sickle cell disease patients with pulmonary hypertension are warranted.