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Human RNAi therapy The ability to downregulate specific genes using systemically delivered short RNA molecules and the cellular mechanism known as RNA interference has been shown previously in mouse and non-human primate models. Davis et al . have now demonstrated for the first time in humans that a short interfering RNA (siRNA) molecule can be systemically delivered using nanoparticles to a solid tumour. The siRNA mediates directed cleavage of its target mRNA, thereby also reducing the protein level. This proof-of-principle study confirms the potential of this technology as a human therapeutic. It has previously been shown in mice and non-human primates that systemically delivered short RNA molecules can inhibit gene expression. Here it is shown that a short interfering RNA (siRNA) can be systemically delivered, using nanoparticles, to a solid tumour in humans. The siRNA mediates cleavage of its target mRNA, thereby also reducing levels of the encoded protein. This proof-of-principle study confirms the potential of this technology for treating human disease. Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients 1 , 2 . Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans 3 , and the potential use of RNAi for human therapy has been demonstrated by the finding that small interfering RNAs (siRNAs; approximately 21-base-pair double-stranded RNA) can elicit RNAi in mammalian cells without producing an interferon response 4 . We are at present conducting the first in-human phase I clinical trial involving the systemic administration of siRNA to patients with solid cancers using a targeted, nanoparticle delivery system. Here we provide evidence of inducing an RNAi mechanism of action in a human from the delivered siRNA. Tumour biopsies from melanoma patients obtained after treatment show the presence of intracellularly localized nanoparticles in amounts that correlate with dose levels of the nanoparticles administered (this is, to our knowledge, a first for systemically delivered nanoparticles of any kind). Furthermore, a reduction was found in both the specific messenger RNA (M2 subunit of ribonucleotide reductase ( RRM2 )) and the protein (RRM2) levels when compared to pre-dosing tissue. Most notably, we detect the presence of an mRNA fragment that demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the site predicted for an RNAi mechanism from a patient who received the highest dose of the nanoparticles. Together, these data demonstrate that siRNA administered systemically to a human can produce a specific gene inhibition (reduction in mRNA and protein) by an RNAi mechanism of action.

Histones in cancer Reports of altered epigenetic histone modifications in cancer cells have focused on individual gene promoters and so far none of these changes has been related to clinical outcome. Now aberrations of ‘global’ histone modification have been observed in prostate tumour patients. These do relate to clinical outcome, and suggest a useful means of prognosis. Aberrations in post-translational modifications of histones have been shown to occur in cancer cells but only at individual promoters 1 ; they have not been related to clinical outcome. Other than being targeted to promoters, modifications of histones, such as acetylation and methylation of lysine and arginine residues, also occur over large regions of chromatin including coding regions and non-promoter sequences, which are referred to as global histone modifications 2 . Here we show that changes in global levels of individual histone modifications are also associated with cancer and that these changes are predictive of clinical outcome. Through immunohistochemical staining of primary prostatectomy tissue samples, we determined the percentage of cells that stained for the histone acetylation and dimethylation of five residues in histones H3 and H4. Grouping of samples with similar patterns of modifications identified two disease subtypes with distinct risks of tumour recurrence in patients with low-grade prostate cancer. These histone modification patterns were predictors of outcome independently of tumour stage, preoperative prostate-specific antigen levels, and capsule invasion. Thus, widespread changes in specific histone modifications indicate previously undescribed molecular heterogeneity in prostate cancer and might underlie the broad range of clinical behaviour in cancer patients.

Carbon-fiber-reinforced polyetheretherketone implants offer several benefits over traditional metal implants. Their radiolucent property permits improved, artifact-free radiographic imaging. Their lower modulus of elasticity better matches that of bone. Their fatigue strength is greater than most metal implants. This article reviews the use of these implants in orthopedic surgery, including treatment of conditions involving the spine, trauma, tumor, and infection. [Carbon-fiber-reinforced polyetheretherketone implants offer several benefits over traditional metal implants. Their radiolucent property permits improved, artifact-free radiographic imaging. Their lower modulus of elasticity better matches that of bone. Their fatigue strength is greater than most metal implants. This article reviews the use of these implants in orthopedic surgery, including treatment of conditions involving the spine, trauma, tumor, and infection. [ Orthopedics. 2014; 37(12):825–830.]

Background Acetabular fractures are quite challenging injuries for the orthopedic surgeon because of their low incidence and their deep and complex anatomy. The objective of this study was to evaluate surgeon-independent parameters that might influence radiographic outcome and early complication rates of high-energy acetabular fractures treated by open reduction and internal fixation via the Kocher-Langenbeck approach, the golden standard for posterior access. Methods One hundred sixty-seven consecutive patients (111 males and 56 females) with a mean age of 41.8 years and a mean follow-up period of 10 months were surgically treated by one experienced surgeon at a level I trauma center within 10 years. To quantify the radiographic outcome, the Matta, Brooker, and Epstein grades were used. Posttraumatic arthritis and avascular necrosis of the femoral head (defined as Helfet grades 3 or 4 and Ficat/Arlet stages 3 or 4, respectively) were evaluated. Furthermore, subgroup analyses according to fracture type, age, and gender were performed for each outcome measure and complication (infection, hemorrhagic shock, revision surgery, nerve damage, and need of a total hip arthroplasty). Results 65 A1, 34 A2, 51 B1, and 17 B2 fractures were identified according to the AO/ASIF classification. Of all patients, reduction was rated anatomic in 63.5%, imperfect in 22.2%, and poor in 14.4%. Degenerative changes were observed in 49.7%; 37.9% were affected by heterotopic ossification, 21.6% by posttraumatic arthritis, and 5.4% by avascular necrosis of the femoral head. Fifteen percent were diagnosed with a nerve damage, and 4.8% sustained an infection. Total hip arthroplasty was performed in 10.2%. Revision surgery due to secondary loss of reduction, seroma/hematoma, and wound infection was indicated in 6.0%. Conclusions Fracture type, age, and gender are prognostic factors for the surgical outcome after ORIF of high-energy acetabular fractures.

We describe a novel strategy (random forest clustering) for tumor profiling based on tissue microarray data. Random forest clustering is attractive for tissue microarray and other immunohistochemistry data since it handles highly skewed tumor marker expressions well and weighs the contribution of each marker according to its relatedness with other tumor markers. This is the first tumor class discovery analysis of renal cell carcinoma patients based on protein expression profiles. The tissue array data contained at least three tumor samples from each of 366 renal cell carcinoma patients. The eight tumor markers explore tumor proliferation, cell cycle abnormalities, cell mobility, and the hypoxia pathway. Since the procedure is unsupervised, no clinicopathological data or traditional classifications are used a priori. To explore whether the tissue microarray data can be used to identify fundamental subtypes of renal cell carcinoma patients, we first carried out random forest clustering of all 366 patients. By analyzing the tumor markers simultaneously, the procedure automatically detected classes that correspond to clear- vs non-clear cell tumors (demonstration of proof-of-principle). The resulting molecular grouping provides better prediction of survival (logrank P=0.000090) than this classical pathological grouping (logrank P=0.023). We then sought to extend the class discovery by searching for finer subclasses of clear cell patients. The procedure automatically discovered: (a) two classes corresponding to low- and high-grade patients (demonstration of proof-of-principle); (b) a subgroup of long-surviving clear cell patients with a distinct molecular profile and (c) two novel tumor subclasses in low-grade clear cell patients that could not be explained by any clinicopathological variables (demonstration of discovery).

Epidermal growth factor receptor (EGFR) overexpression occurs in nearly 50% of cases of glioblastoma (GBM), but its clinical and biological implications are not well understood. We have used Affymetrix high-density oligonucleotide arrays to demonstrate that EGFR-overexpressing GBMs (EGFR+) have a distinct global gene transcriptional profile. We show that the expression of 90 genes can distinguish EGFR+ from EGFR nonexpressing (EGFR−) GBMs, including a number of genes known to act as growth/survival factors for GBMs. We have also uncovered two additional novel molecular subtypes of GBMs, one of which is characterized by coordinate upregulation of contiguous genes on chromosome 12q13–15 and expression of both astrocytic and oligodendroglial genes. These results define distinct molecular subtypes of GBMs that may be important in disease stratification, and in the discovery and assessment of GBM treatment strategies.

The study evaluated the incidence of and complications associated with the use of an intramedullary nail vs open reduction and internal fixation (ORIF) with a sliding compression hip screw and plate in treating intertrochanteric fractures. The authors hypothesized that the biomechanically stronger and less invasive intramedullary nail would have superior results and fewer complications compared with ORIF. Patients followed for up to 1 year postoperatively were identified from the 5% nationwide sample of Medicare administrative claims data (1998–2007) using the corresponding The study evaluated the incidence of and complications associated with the use of an intramedullary nail vs open reduction and internal fixation (ORIF) with a sliding compression hip screw and plate in treating intertrochanteric fractures. The authors hypothesized that the biomechanically stronger and less invasive intramedullary nail would have superior results and fewer complications compared with ORIF. Patients followed for up to 1 year postoperatively were identified from the 5% nationwide sample of Medicare administrative claims data (1998–2007) using the corresponding International Classification of Diseases, 9th revision, Clinical Modification , codes 820.21 and 820.31. There were 9157 patients treated with intramedullary nails and 27,687 treated with compression screw and plate fixation. Intertrochanteric hip fractures treated with an intramedullary nail during this period increased from 3.3% to 63.1% compared with ORIF. Patients treated with an intramedullary nail had a higher adjusted risk of pulmonary embolism at 90 days ( P =.003) and a higher risk of mortality at 1 year ( P <.001) compared with those treated with ORIF. Patients who underwent intramedullary nailing during 2006 to 2007 had a lower adjusted risk of conversion to total hip replacement at 1 year ( P =.037) compared with those who had ORIF. Over the decade of the study, intramedullary nail usage increased 59.8% compared with ORIF. Increased use of intramedullary nails compared with ORIF has not shown improved outcomes or decreased complications in patients with intertrochanteric hip fractures. The increased use of intramedullary nails for intertrochanteric hip fractures appears to be multifactorial, including the less invasive nature of the surgery and increased experience with the closed surgical technique. [ Orthopedics. 2 015; 38(9):e799–e805.]

Thyroid transcription factor-1 (TTF-1) is a DNA-binding protein that is mainly expressed in thyroid and lung tissue, but has also been found in gynecologic tissue. Recent studies have suggested that TTF-1 has tumor suppressor function in lung adenocarcinoma models. In the current study, we examined whether expression of TTF-1 in benign endometrium and endometrial hyperplasia might impact on the risk of developing endometrial cancer. Formalin-fixed paraffin-embedded endometrial tissues obtained from 535 cases were used to construct an endometrial tissue microarray. One hundred fifty of 207 patients had multiple serial endometrial specimens including 46 patients who progressed to endometrial cancer. The tissue microarray included a range of histopathologies including benign endometrium (n=231), simple hyperplasia (n=105), complex hyperplasia (n=36), simple atypical hyperplasia (n=10), complex atypical hyperplasia (n=44), and endometrial carcinoma (n=109). Expression of TTF-1 by immunohistochemistry in benign endometrium and endometrial hyperplasia was correlated with progression to cancer and clinical features known to be associated with increased risk of developing endometrial cancer. Carcinoma specimens showed a significantly greater expression of TTF-1 compared with benign endometrium and non-atypical hyperplasia (P=0.0007 and P=0.05). Presence of TTF-1 expression in benign endometrium was associated with a significantly decreased risk of cancer development (P=0.003, hazards ratio=0.104, 95% CI: 0.024–0.455). TTF-1 expression in hyperplasia did not significantly correlate with progression to cancer. The data from our study show that TTF-1 expression in normal endometrium is associated with a reduced risk of endometrial cancer development. This observation suggests that TTF-1 might function as a tumor suppressor in endometrial tissue. TTF-1 expression in normal endometrium could potentially provide clinically useful information as a biomarker for the risk of endometrial cancer.