295 research outputs found
The waiting time paradox: population based retrospective study of treatment delay and survival of women with endometrial cancer in Scotland
No abstract available
The role of RHAMM in cancer: Exposing novel therapeutic vulnerabilities
PUBLISHED 10 August 2022Receptor for hyaluronic acid-mediated motility (RHAMM) is a cell surface receptor for hyaluronic acid that is critical for cell migration and a cell cycle protein involved in microtubule assembly and stability. These functions of RHAMM are required for cellular stress responses and cell cycle progression but are also exploited by tumor cells for malignant progression and metastasis. RHAMM is often overexpressed in tumors and is an independent adverse prognostic factor for a number of cancers such as breast and prostate. Interestingly, pharmacological or genetic inhibition of RHAMM in vitro and in vivo ablates tumor invasiveness and metastatic spread, implicating RHAMM as a potential therapeutic target to restrict tumor growth and improve patient survival. However, RHAMM's pro-tumor activity is dependent on its subcellular distribution, which complicates the design of RHAMM-directed therapies. An alternative approach is to identify downstream signaling pathways that mediate RHAMM-promoted tumor aggressiveness. Herein, we discuss the pro-tumoral roles of RHAMM and elucidate the corresponding regulators and signaling pathways mediating RHAMM downstream events, with a specific focus on strategies to target the RHAMM signaling network in cancer cells.Josephine A. Hinneh, Joanna L. Gillis, Nicole L. Moore, Lisa M. Butler and Margaret M. Centener
DICER1 RNase IIIb domain mutations are infrequent in testicular germ cell tumours
Background: Testicular Germ Cell Tumours (TGCT) are the most frequently occurring malignancy in males from 15-45 years of age. They are derived from germ cells unable to undergo physiological maturation, although the genetic basis for this is poorly understood. A recent report showed that mutations in the RNase IIIb domain of DICER1, a micro-RNA (miRNA) processing enzyme, are common in non-epithelial ovarian cancers. DICER1 mutations were found in 60% of Sertoli-Leydig cell tumours, clustering in four codons encoding metal-binding sites. Additional analysis of 14 TGCT DNA samples identified one case that also contained a mutation at one of these sites. Findings. A number of previous studies have shown that DICER1 mutations are found in Q) within the RNase IIIb domain in one TGCT sample, which was predicted to disturb DICER1 function. Conclusion: Overall our findings suggest a mutation frequency in TGCTs of ∼1%. We conclude therefore that hot-spot mutations, frequently seen in Sertoli-Leydig cell tumours, are not common in TGCTs
Cripto: Expression, epigenetic regulation and potential diagnostic use in testicular germ cell tumors
Type II germ cell tumors arise after puberty from a germ cell that was incorrectly programmed during fetal life. Failure of testicular germ cells to properly differentiate can lead to the formation of germ cell neoplasia in situ of the testis; this precursor cell invariably gives rise to germ cell cancer after puberty. The Nodal co-receptor Cripto is expressed transiently during normal germ cell development and is ectopically expressed in non-seminomas that arise from germ cell neoplasia in situ, suggesting that its aberrant expression may underlie germ cell dysregulation and hence germ cell cancer. Here we investigated methylation of the Cripto promoter in mouse germ cells and human germ cell cancer and correlated this with the level of CRIPTO protein expression. We found hypomethylation of the CRIPTO promoter in undifferentiated fetal germ cells, embryonal carcinoma and seminomas, but hypermethylation in differentiated fetal germ cells and the differentiated types of non-seminomas. CRIPTO protein was strongly expressed in germ cell neoplasia in situ along with embryonal carcinoma, yolk sac tumor and seminomas. Further, cleaved CRIPTO was detected in media from seminoma and embryonal carcinoma cell lines, suggesting that cleaved CRIPTO may provide diagnostic indication of germ cell cancer. Accordingly, CRIPTO was detectable in serum from 6/15 patients with embryonal carcinoma, 5/15 patients with seminoma, 4/5 patients with germ cell neoplasia in situ cells only and in 1/15 control patients. These findings suggest that CRIPTO expression may be a useful serological marker for diagnostic and/or prognostic purposes during germ cell cancer management
Coamplification of DAD-R, SOX5, and EKI1 in human testicular seminomas, with specific overexpression of DAD-R, correlates with reduced levels of apoptosis and earlier clinical manifestation
Seminomas and nonseminomas represent the invasive stages of testicular
(TGCTs) of adolescents and adults. Although TGCTs are characterized by
extra copies of the short arm of chromosome 12, the genetic basis for gain
of 12p in the pathogenesis of this cancer is not yet understood. We have
demonstrated that gain of 12p is related to invasive growth and that
amplification of specific 12p sequences, i.e., 12p11.2-p12.1, correlates
with reduced apoptosis in the tumors. Here we show that three known genes
map within the newly determined shortest region of overlap of
amplification (SROA): DAD-R, SOX5, and EKI1. Whereas EKI1 maps close to
the telomeric region of the SROA, DAD-R is the first gene at the
centromeric region within the 12p amplicon. Although all three genes are
amplified to the same level within the SROA, expression of DAD-R is
significantly up-regulated in seminomas with the restricted 12p
amplification compared with seminomas without this amplicon. DAD-R is also
highly expressed in nonseminomas of various histologies and derived cell
lines, both lacking such amplification. This finding is of particular
interest because seminomas with the restricted 12p amplification and
nonseminomas are manifested clinically in the third decade of life and
show a low degree of apoptosis. In contrast, seminomas lacking a
restricted 12p amplification, showing significantly lower levels of DAD-R
with pronounced apoptosis, manifest clinically in the fourth decade of
life. A low level of DAD-R expression is also observed in normal
testicular parenchyma and in parenchyma containing the precursor cells of
this cancer, i.e., carcinoma in situ. Therefore, elevated DAD-R expression
in seminomas and nonseminomas correlates with invasive growth and a
reduced level of apoptosis associated with an earlier clinical
presentation. These data implicate DAD-R as a candidate gene responsible
in part for the pathological effects resulting from gain of 12p sequences
in TGCTs. In addition, our results also imply differences in expression
regulation of DAD-R between seminomas and nonseminomas
Restricted 12p amplification and RAS mutation in human germ cell tumors of the adult testis
Human testicular germ-cell tumors of young adults (TGCTs), both seminomas
and nonseminomas, are characterized by 12p overrepresentation, mostly as
isochromosomes, of which the biological and clinical significance is still
unclear. A limited number of TGCTs has been identified with an additional
high-level amplification of a restricted region of 12p including the K-RAS
proto-oncogene. Here we show that the incidence of these restricted 12p
amplifications is approximately 8% in primary TGCTs. Within a single cell
formation of i(12p) and restricted 12p amplification is mutually
exclusive. The borders of the amplicons cluster in short regions, and the
amplicon was never found in the adjacent carcinoma in situ cells.
Seminomas with the restricted 12p amplification virtually lacked apoptosis
and the tumor cells showed prolonged in vitro survival like seminoma cells
with a mutated RAS gene. However, no differences in proliferation index
between these different groups of seminomas were found. Although patients
with a seminoma containing a homogeneous restricted 12p amplification
presented at a significantly younger age than those lacking it, the
presence of a restricted 12p amplification/RAS mutation did not predict
the stage of the disease at clinical presentation and the treatment
response of primary seminomas. In 55 primary and metastatic tumors from 44
different patients who failed cisplatinum-based chemotherapy, the
restricted 12p amplification and RAS mutations had the same incidence a
Parity nonconservation in deuteron photoreactions
We calculate the asymmetries in parity nonconserving deuteron
photodisintegration due to circularly polarized photons gamma+d to n+p with the
photon laboratory energy ranging from the threshold up to 10 MeV and the
radiative capture of thermal polarized neutrons by protons n+p to gamma+d. We
use the leading order electromagnetic Hamiltonian neglecting the smaller
nuclear exchange currents. Comparative calculations are done by using the
Reid93 and Argonne v18 potentials for the strong interaction and the DDH and
FCDH "best" values for the weak couplings in a weak one-meson exchange
potential. A weak NDelta transition potential is used to incorporate also the
Delta(1232)-isobar excitation in the coupled-channels formalism.Comment: 14 pages, 13 figures (18 eps files), LaTeX2
Stem cell factor receptor (c-KIT) codon 816 mutations predict development of bilateral testicular germ-cell tumors
Testicular germ-cell tumors (TGCTs) of adolescents and adults originate
from intratubular germ cell neoplasia (ITGCN), which is composed of the
malignant counterparts of embryonal germ cells. ITGCN cells are
characterized, among others, by the presence of stem cell factor receptor
c-KIT. Once established, ITGCN will always progress to invasiveness.
Approximately 2.5-5% of patients with a TGCT will develop bilateral
disease and require complete castration, resulting in infertility, a need
for lifelong androgen replacement, and psychological stress. To date, the
only way to predict a contralateral tumor is surgical biopsy of the
contralateral testis to demonstrate ITGCN. We did a retrospective study of
224 unilateral and 61 proven bilateral TGCTs (from 46 patients, in three
independently collected series in Europe) for the presence of activating
c-KIT codon 816 mutations. A c-KIT codon 816 mutation was found in three
unilateral TGCT (1.3%), and in 57 bilateral TGCTs (93%; P < 0.0001). In
the two wild-type bilateral tumors for which ITGCN was available, the
preinvasive cells contained the mutation. The mutations were somatic in
origin and identical in both tumors. We conclude that somatic activating
codon 816 c-KIT mutations are associated with development of bilateral
TGCT. Detection of c-KIT codon 816 mutations in unilateral TGCT identifies
patients at risk for bilateral disease. These patients may undergo
tailored treatment to prevent the development of bilateral disease, with
retention of testicular hormonal function
POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors
Human germ cell tumors (GCTs) may have variable histology and clinical
behavior, depending on factors such as sex of the patient, age at clinical
diagnosis, and anatomical site of the tumor. Some types of GCT, i.e., the
seminomas/germinomas/dysgerminomas and embryonal carcinomas (the stem cell
component of nonseminomas), have pluripotent potential, which is
demonstrated by their capacity to differentiate into somatic and/or
extraembryonic elements. Although embryonal carcinoma cells are
intrinsically pluripotent, seminoma/germinoma/dysgerminoma cells, as well
as their precursor carcinoma in situ/gonadoblastoma cells, have the
phenotype of early germ cells that can be activated to pluripotency. The
other types of GCT (teratomas and yolk sac tumors of infants and newborn,
dermoid cyst of the ovary, and spermatocytic seminoma of elderly) are
composed of (fully) differentiated tissues and lack the appearance of
undifferentiated and pluripotent stem cells. OCT3/4, a transcription
factor also known as OTF3 and POU5F1, is involved in regulation of
pluripotency during normal development and is detectable in embryonic stem
and germ cells. We analyzed the presence of POU5F1 in GCT and other tumor
types using immunohistochemistry. The protein was consistently detected in
carcinoma in situ/gonadoblasto
Fertility, Living Arrangements, Care and Mobility
There are four main interconnecting themes around which the contributions in this book are based. This introductory chapter aims to establish the broad context for the chapters that follow by discussing each of the themes. It does so by setting these themes within the overarching demographic challenge of the twenty-first century – demographic ageing. Each chapter is introduced in the context of the specific theme to which it primarily relates and there is a summary of the data sets used by the contributors to illustrate the wide range of cross-sectional and longitudinal data analysed
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