39 research outputs found
Future therapeutic targets in rheumatoid arthritis?
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches
Spreading of complex regional pain syndrome: not a random process
Complex regional pain syndrome (CRPS) generally remains restricted to one limb but occasionally may spread to other limbs. Knowledge of the spreading pattern of CRPS may lead to hypotheses about underlying mechanisms but to date little is known about this process. The objective is to study patterns of spread of CRPS from a first to a second limb and the factors associated with this process. One hundred and eighty-five CRPS patients were retrospectively evaluated. Cox’s proportional hazards model was used to evaluate factors that influenced spread of CRPS symptoms. Eighty-nine patients exhibited CRPS in multiple limbs. In 72 patients spread from a first to a second limb occurred showing a contralateral pattern in 49%, ipsilateral pattern in 30% and diagonal pattern in 14%. A trauma preceded the onset in the second limb in 37, 44 and 91%, respectively. The hazard of spread of CRPS increased with the number of limbs affected. Compared to patients with CRPS in one limb, patients with CRPS in multiple limbs were on average 7 years younger and more often had movement disorders. In patients with CRPS in multiple limbs, spontaneous spread of symptoms generally follows a contralateral or ipsilateral pattern whereas diagonal spread is rare and generally preceded by a new trauma. Spread is associated with a younger age at onset and a more severely affected phenotype. We argue that processes in the spinal cord as well as supraspinal changes are responsible for spontaneous spread in CRPS
Suppression of Lung Adenocarcinoma Progression by Nkx2-1
Despite the high prevalence and poor outcome of patients with
metastatic lung cancer the mechanisms of tumour progression and
metastasis remain largely uncharacterized. Here we modelled
human lung adenocarcinoma, which frequently harbours activating
point mutations in KRAS and inactivation of the p53 pathway,
using conditional alleles in mice. Lentiviral-mediated somatic
activation of oncogenic Kras and deletion of p53 in the lung epithelial
cells of Kras[superscript LSL-G12D/+];p53[superscript flox/flox] mice initiates lung adenocarcinoma
development4. Although tumours are initiated synchronously
by defined genetic alterations, only a subset becomes malignant,
indicating that disease progression requires additional alterations.
Identification of the lentiviral integration sites allowed us to distinguish
metastatic from non-metastatic tumours and determine the
gene expression alterations that distinguish these tumour types.
Cross-species analysis identified the NK2-related homeobox transcription
factor Nkx2-1 (also called Ttf-1 or Titf1) as a candidate
suppressor of malignant progression. In this mouse model, Nkx2-1
negativity is pathognomonic of high-grade poorly differentiated
tumours. Gain- and loss-of-function experiments in cells derived
from metastatic and non-metastatic tumours demonstrated that
Nkx2-1 controls tumour differentiation and limitsmetastatic potential
in vivo. Interrogation of Nkx2-1-regulated genes, analysis of
tumours at defined developmental stages, and functional complementation
experiments indicate that Nkx2-1 constrains tumours in
part by repressing the embryonically restricted chromatin regulator
Hmga2. Whereas focal amplification of NKX2-1 in a fraction of
human lung adenocarcinomas has focused attention on its oncogenic
function, our data specifically link Nkx2-1 downregulation
to loss of differentiation, enhanced tumour seeding ability and
increased metastatic proclivity. Thus, the oncogenic and suppressive
functions ofNkx2-1 in the sametumourNational Institutes of Health (U.S.) (grant U01-CA84306 )National Institutes of Health (U.S.) (grant K99-CA151968)Howard Hughes Medical InstituteLudwig Center for Molecular OncologyNational Cancer Institute (U.S.) (Cancer Center Support (core) grant P30-CA14051