Loss of ATRX promotes aggressive features of osteosarcoma with increased NF-κB signaling and integrin binding.

Osteosarcoma (OS) is a lethal disease with few known targeted therapies. Here, we show that decreased ATRX expression is associated with more aggressive tumor cell phenotypes, including increased growth, migration, invasion, and metastasis. These phenotypic changes correspond with activation of NF-κB signaling, extracellular matrix remodeling, increased integrin αvß3 expression, and ETS family transcription factor binding. Here, we characterize these changes in vitro, in vivo, and in a data set of human OS patients. This increased aggression substantially sensitizes ATRX-deficient OS cells to integrin signaling inhibition. Thus, ATRX plays an important tumor-suppression role in OS, and loss of function of this gene may underlie new therapeutic vulnerabilities. The relationship between ATRX expression and integrin binding, NF-κB activation, and ETS family transcription factor binding has not been described in previous studies and may impact the pathophysiology of other diseases with ATRX loss, including other cancers and the ATR-X α thalassemia intellectual disability syndrome.

Orthopedic and Surgical Management of the Patient With Duchenne Muscular Dystrophy.

Orthopedic care is an important aspect of the overall management of patients with Duchenne muscular dystrophy (DMD). In addition to progressive muscle weakness and loss of function, patients may develop joint contractures, scoliosis, and osteoporosis, causing fractures; all of these necessitate intervention by a multidisciplinary team including an orthopedic surgeon as well as rehabilitation specialists such as physio- and occupational therapists. The causes of these musculoskeletal complications are multifactorial and are related to primary effects on the muscles from the disease itself, secondary effects from weak muscles, and the related side effects of treatments, such as glucocorticoid use that affect bone strength. The musculoskeletal manifestations of DMD change over time as the disease progresses, and therefore, musculoskeletal management needs change throughout the life span of an individual with DMD. In this review, we target pediatricians, neurologists, orthopedic surgeons, rehabilitation physicians, anesthesiologists, and other individuals involved in the management of patients with DMD by providing specific recommendations to guide clinical practice related to orthopedic issues and surgical management in this setting.

Diagnosis of limb-girdle muscular dystrophy 2A by immunohistochemical techniques.

The Western blot technique is currently the standard detection method for suspected limb girdle muscular dystrophy (LGMD) 2A (calpainopathy). This is the first report in the English literature of the successful application of immunohistochemical techniques to support a diagnosis of LGMD 2A. This approach is straightforward and appears to be reasonably specific. We propose that immunohistochemical methods should be re-evaluated for the screening of undiagnosed patients with suspected LGMD 2A.

Abnormal vertebral segmentation and the notch signaling pathway in man.

Abnormal vertebral segmentation (AVS) in man is a relatively common congenital malformation but cannot be subjected to the scientific analysis that is applied in animal models. Nevertheless, some spectacular advances in the cell biology and molecular genetics of somitogenesis in animal models have proved to be directly relevant to human disease. Some advances in our understanding have come through DNA linkage analysis in families demonstrating a clustering of AVS cases, as well as adopting a candidate gene approach. Only rarely do AVS phenotypes follow clear Mendelian inheritance, but three genes-DLL3, MESP2, and LNFG-have now been identified for spondylocostal dysostosis (SCD). SCD is characterized by extensive hemivertebrae, trunkal shortening, and abnormally aligned ribs with points of fusion. In familial cases clearly following a Mendelian pattern, autosomal recessive inheritance is more common than autosomal dominant and the genes identified are functional within the Notch signaling pathway. Other genes within the pathway cause diverse phenotypes such as Alagille syndrome (AGS) and CADASIL, conditions that may have their origin in defective vasculogenesis. Here, we deal mainly with SCD and AGS, and present a new classification system for AVS phenotypes, for which, hitherto, the terminology has been inconsistent and confusing.

First successful lower-extremity transplantation: technique and functional result.

Composite tissue transplantation has emerged as a viable alternative to prosthetics and complex reconstructive surgery. Thus far it is reserved for cases which cannot be effectively reconstructed and where it offers some benefits over prostheses. It has been used in the upper extremity with encouraging results and, most recently, in the face. This report outlines what is believed to be the first such use in the lower extremity. A normal lower limb in a 3-month-old ischiopagus twin who was not going to survive was transplanted to the appropriate pelvic position, revascularized, and reinnervated in an otherwise healthy sister. The limb survived and, because of the immune compatibility, did not require immune suppressive therapy. The return of muscle function in the transplanted limb is encouraging. The transplanted limb appears to be fully sensate. In addition to reinnervation, the limb is now spontaneously under the cortical control of the recipient.