A facile fluid pressure system reveals differential cellular response to interstitial pressure gradients and flow.

Interstitial fluid pressure gradients and interstitial flow have been shown to drive morphogenic processes that shape tissues and influence progression of diseases including cancer. The advent of porous media microfluidic approaches has enabled investigation of the cellular response to interstitial flow, but questions remain as to the critical biophysical and biochemical signals imparted by interstitial fluid pressure gradients and resulting flow on resident cells and extracellular matrix (ECM). Here, we introduce a low-cost method to maintain physiological interstitial fluid pressures that is built from commonly accessible laboratory equipment, including a laser pointer, camera, Arduino board, and a commercially available linear actuator. We demonstrate that when the system is connected to a microfluidic device containing a 3D porous hydrogel, physiologic pressure is maintained with sub-Pascal resolution and when basic feedback control is directed using an Arduino, constant pressure and pressure gradient can be maintained even as cells remodel and degrade the ECM hydrogel over time. Using this model, we characterized breast cancer cell growth and ECM changes to ECM fibril structure and porosity in response to constant interstitial fluid pressure or constant interstitial flow. We observe increased collagen fibril bundling and the formation of porous structures in the vicinity of cancer cells in response to constant interstitial fluid pressure as compared to constant interstitial flow. Collectively, these results further define interstitial fluid pressure as a driver of key pathogenic responses in cells, and the systems and methods developed here will allow for future mechanistic work investigating mechanotransduction of interstitial fluid pressures and flows.

Microphysiological model of PIK3CA-driven vascular malformations reveals a role of dysregulated Rac1 and mTORC1/2 in lesion formation.

Somatic activating mutations of PIK3CA are associated with development of vascular malformations (VMs). Here, we describe a microfluidic model of PIK3CA-driven VMs consisting of human umbilical vein endothelial cells expressing PIK3CA activating mutations embedded in three-dimensional hydrogels. We observed enlarged, irregular vessel phenotypes and the formation of cyst-like structures consistent with clinical signatures and not previously observed in cell culture models. Pathologic morphologies occurred concomitant with up-regulation of Rac1/p21-activated kinase (PAK), mitogen-activated protein kinase cascades (MEK/ERK), and mammalian target of rapamycin (mTORC1/2) signaling networks. We observed differential effects between alpelisib, a PIK3CA inhibitor, and rapamycin, an mTORC1 inhibitor, in mitigating matrix degradation and network topology. While both were effective in preventing vessel enlargement, rapamycin failed to reduce MEK/ERK and mTORC2 activity and resulted in hyperbranching, while inhibiting PAK, MEK1/2, and mTORC1/2 mitigates abnormal growth and vascular dilation. Collectively, these findings demonstrate an in vitro platform for VMs and establish a role of dysregulated Rac1/PAK and mTORC1/2 signaling in PIK3CA-driven VMs.

Spatiotemporal regulation of human IFN-ε and innate immunity in the female reproductive tract.

Although published studies have demonstrated that IFN-ε has a crucial role in regulating protective immunity in the mouse female reproductive tract, expression and regulation of IFN-ε in the human female reproductive tract (hFRT) have not been characterized to our knowledge. We obtained hFRT samples from a well-characterized cohort of women to enable us to comprehensively assess ex vivo IFN-ε expression in the hFRT at various stages of the menstrual cycle. We found that among the various types of IFNs, IFN-ε was uniquely, selectively, and constitutively expressed in the hFRT epithelium. It had distinct expression patterns in the surface and glandular epithelia of the upper hFRT compared with basal layers of the stratified squamous epithelia of the lower hFRT. There was cyclical variation of IFN-ε expression in the endometrial epithelium of the upper hFRT and not in the distal FRT, consistent with selective endometrial expression of the progesterone receptor and regulation of the IFNE promoter by progesterone. Because we showed IFN-ε stimulated important protective IFN-regulated genes in FRT epithelium, this characterization is a key element in understanding the mechanisms of hormonal control of mucosal immunity.

The Expanding Role of Extracellular Traps in Inflammation and Autoimmunity: The New Players in Casting Dark Webs.

The first description of a new form of neutrophil cell death distinct from that of apoptosis or necrosis was discovered in 2004 and coined neutrophil extracellular traps "(NETs)" or "NETosis". Different stimuli for NET formation, and pathways that drive neutrophils to commit to NETosis have been elucidated in the years that followed. Critical enzymes required for NET formation have been discovered and targeted therapeutically. NET formation is no longer restricted to neutrophils but has been discovered in other innate cells: macrophages/monocytes, mast Cells, basophils, dendritic cells, and eosinophils. Furthermore, extracellular DNA can also be extruded from both B and T cells. It has become clear that although this mechanism is thought to enhance host defense by ensnaring bacteria within large webs of DNA to increase bactericidal killing capacity, it is also injurious to innocent bystander tissue. Proteases and enzymes released from extracellular traps (ETs), injure epithelial and endothelial cells perpetuating inflammation. In the context of autoimmunity, ETs release over 70 well-known autoantigens. ETs are associated with pathology in multiple diseases: lung diseases, vasculitis, autoimmune kidney diseases, atherosclerosis, rheumatoid arthritis, cancer, and psoriasis. Defining these pathways that drive ET release will provide insight into mechanisms of pathological insult and provide potential therapeutic targets.

Multilayer microfluidic platform for the study of luminal, transmural, and interstitial flow.

Efficient delivery of oxygen and nutrients to tissues requires an intricate balance of blood, lymphatic, and interstitial fluid pressures (IFPs), and gradients in fluid pressure drive the flow of blood, lymph, and interstitial fluid through tissues. While specific fluid mechanical stimuli, such as wall shear stress, have been shown to modulate cellular signaling pathways along with gene and protein expression patterns, an understanding of the key signals imparted by flowing fluid and how these signals are integrated across multiple cells and cell types in native tissues is incomplete due to limitations with current assays. Here, we introduce a multi-layer microfluidic platform (MµLTI-Flow) that enables the culture of engineered blood and lymphatic microvessels and independent control of blood, lymphatic, and IFPs. Using optical microscopy methods to measure fluid velocity for applied input pressures, we demonstrate varying rates of interstitial fluid flow as a function of blood, lymphatic, and interstitial pressure, consistent with computational fluid dynamics (CFD) models. The resulting microfluidic and computational platforms will provide for analysis of key fluid mechanical parameters and cellular mechanisms that contribute to diseases in which fluid imbalances play a role in progression, including lymphedema and solid cancer.

Malignant Ascites in Ovarian Cancer: Cellular, Acellular, and Biophysical Determinants of Molecular Characteristics and Therapy Response.

Ascites refers to the abnormal accumulation of fluid in the peritoneum resulting from an underlying pathology, such as metastatic cancer. Among all cancers, advanced-stage epithelial ovarian cancer is most frequently associated with the production of malignant ascites and is the leading cause of death from gynecologic malignancies. Despite decades of evidence showing that the accumulation of peritoneal fluid portends the poorest outcomes for cancer patients, the role of malignant ascites in promoting metastasis and therapy resistance remains poorly understood. This review summarizes the current understanding of malignant ascites, with a focus on ovarian cancer. The first section provides an overview of heterogeneity in ovarian cancer and the pathophysiology of malignant ascites. Next, analytical methods used to characterize the cellular and acellular components of malignant ascites, as well the role of these components in modulating cell biology, are discussed. The review then provides a perspective on the pressures and forces that tumors are subjected to in the presence of malignant ascites and the impact of physical stress on therapy resistance. Treatment options for malignant ascites, including surgical, pharmacological and photochemical interventions are then discussed to highlight challenges and opportunities at the interface of drug discovery, device development and physical sciences in oncology.

Myoelectric control of robotic lower limb prostheses: a review of electromyography interfaces, control paradigms, challenges and future directions.

Objective.Advanced robotic lower limb prostheses are mainly controlled autonomously. Although the existing control can assist cyclic movements during locomotion of amputee users, the function of these modern devices is still limited due to the lack of neuromuscular control (i.e. control based on human efferent neural signals from the central nervous system to peripheral muscles for movement production). Neuromuscular control signals can be recorded from muscles, called electromyographic (EMG) or myoelectric signals. In fact, using EMG signals for robotic lower limb prostheses control has been an emerging research topic in the field for the past decade to address novel prosthesis functionality and adaptability to different environments and task contexts. The objective of this paper is to review robotic lower limb Prosthesis control via EMG signals recorded from residual muscles in individuals with lower limb amputations.Approach.We performed a literature review on surgical techniques for enhanced EMG interfaces, EMG sensors, decoding algorithms, and control paradigms for robotic lower limb prostheses.Main results.This review highlights the promise of EMG control for enabling new functionalities in robotic lower limb prostheses, as well as the existing challenges, knowledge gaps, and opportunities on this research topic from human motor control and clinical practice perspectives.Significance.This review may guide the future collaborations among researchers in neuromechanics, neural engineering, assistive technologies, and amputee clinics in order to build and translate true bionic lower limbs to individuals with lower limb amputations for improved motor function.

An objective methodology capturing online commodity marketing and other harms.

Increasingly life is lived online, yet little is known about the actual nature and extent of online content that people view due to the difficulty of recording real time exposure. This includes people's exposure to harmful commodity marketing. This study aimed to develop a methodology to assess the nature and extent of exposure to, and engagement with, unhealthy commodity marketing and other public health harms online, particularly children's exposure. A convenience sample of 16 young adult participants (aged 21-29) recorded their device usage for 2 days using Zoom software. Data were coded and analysed to assess the nature and extent of marketing for alcohol, gambling, junk food and smoking products. Four focus groups were conducted with participants to explore their data collection and coding experiences, and results assessed using thematic analysis. The study found that, with some modifications, this method was feasible for gathering real-time objective data from the online world that can be analysed for a range of public health harms, including marketing of unhealthy commodities. Larger studies are recommended to build global evidence for public health action in the online world.

Structural integrity with functional plasticity: what type I IFN receptor polymorphisms reveal.

The type I IFNs activate an array of signaling pathways, which are initiated after IFNs bind their cognate receptors, IFNα/ß receptor (IFNAR)1 and IFNAR2. These signals contribute to many aspects of human health including defense against pathogens, cancer immunosurveillance, and regulation of inflammation. How these cytokines interact with their receptors influences the quality of these signals. As such, the integrity of receptor structure is pivotal to maintaining human health and the response to immune stimuli. This review brings together genome wide association studies and clinical reports describing the association of nonsynonymous IFNAR1 and IFNAR2 polymorphisms with clinical disease, including altered susceptibility to viral and bacterial pathogens, autoimmune diseases, cancer, and adverse reactions to live-attenuated vaccines. We describe the amino acid substitutions or truncations induced by these polymorphisms and, using the knowledge of IFNAR conformational changes, IFNAR-IFN interfaces and overall structure-function relationship of the signaling complexes, we hypothesize the effect of these polymorphisms on receptor structure. That these predicted changes to IFNAR structure are associated with clinical manifestations of human disease, highlights the importance of IFNAR structural integrity to maintaining functional quality of these receptor-mediated responses. Type I IFNs are pivotal to innate immune responses and ultimately, to human health. Understanding the consequences of altered structure on the actions of these clinically significant cell receptors provides important information on the roles of IFNARs in health and disease.

Trauma-targeted delivery of tranexamic acid improves hemostasis and survival in rat liver hemorrhage model.

BACKGROUND: Trauma-associated hemorrhage and coagulopathy remain leading causes of mortality. Such coagulopathy often leads to a hyperfibrinolytic phenotype where hemostatic clots become unstable because of upregulated tissue plasminogen activator (tPA) activity. Tranexamic acid (TXA), a synthetic inhibitor of tPA, has emerged as a promising drug to mitigate fibrinolysis. TXA is US Food and Drug Administration-approved for treating heavy menstrual and postpartum bleeding, and has shown promise in trauma treatment. However, emerging reports also implicate TXA for off-target systemic coagulopathy, thromboembolic complications, and neuropathy. OBJECTIVE: We hypothesized that targeted delivery of TXA to traumatic injury site can enable its clot-stabilizing action site-selectively, to improve hemostasis and survival while avoiding off-target effects. To test this, we used liposomes as a model delivery vehicle, decorated their surface with a fibrinogen-mimetic peptide for anchorage to active platelets within trauma-associated clots, and encapsulated TXA within them. METHODS: The TXA-loaded trauma-targeted nanovesicles (T-tNVs) were evaluated in vitro in rat blood, and then in vivo in a liver trauma model in rats. TXA-loaded control (untargeted) nanovesicles (TNVs), free TXA, or saline were studied as comparison groups. RESULTS: Our studies show that in vitro, the T-tNVs could resist lysis in tPA-spiked rat blood. In vivo, T-tNVs maintained systemic safety, significantly reduced blood loss and improved survival in the rat liver hemorrhage model. Postmortem evaluation of excised tissue from euthanized rats confirmed systemic safety and trauma-targeted activity of the T-tNVs. CONCLUSION: Overall, the studies establish the potential of targeted TXA delivery for safe injury site-selective enhancement and stabilization of hemostatic clots to improve survival in trauma.

A comparison of the fascia iliaca block to the lumbar plexus block in providing analgesia following arthroscopic hip surgery: A randomized controlled clinical trial.

STUDY OBJECTIVE: This randomized controlled single blinded clinical trial compared the fascia iliaca block (FIB) and the lumbar plexus block (LPB) in patients with moderate to severe pain following hip arthroscopic surgery. DESIGN: Single blinded randomized trial. SETTING: Postoperative recovery area, postoperative days 0 and 1. PATIENTS: Fifty patients undergoing hip arthroscopy were approached in the Post Anesthesia Care Unit (PACU) if they had moderate to severe pain (defined as > or equal 4/10 on the numeric rating scale). Twenty-five patients were allocated to the FIB and twenty-five patients to the LPB. INTERVENTIONS: Fascia iliaca block or lumbar plexus block. MEASUREMENTS: A blinded observer recorded pain scores just prior to the block, 15 min following the block (primary endpoint), and then every 15 min for 2 h (or until the patient was discharged). Total PACU time and opioid use were recorded. Pain scores and analgesic use on postoperative day (POD) 0, and POD 1 were recorded. At 24 h post block the Quality of Recovery 9 questionnaire was administered. RESULTS: The mean pre-block pain scores were comparable between the two groups (P = 0.689). There was no difference in mean post block pain scores between the two groups at 15 min (P = 0.054). In the PACU patients who underwent a LPB consumed less opioids compared to FIB patients (P = 0.02), however no differences were noted between the two groups in PACU length of stay, or POD 0 or 1 opioid use. CONCLUSION: A fascia iliaca block is not inferior to a lumbar plexus block in reducing PACU pain scores in patients with moderate to severe pain following hip arthroscopic surgery and is a viable option to help manage postoperative pain following hip arthroscopic surgery.

Dairy Consumption and Risk of Testicular Cancer: A Systematic Review.

Dairy consumption has been studied extensively in terms of its relationship with testicular cancer (TC), yet this relationship remains unclear. In this systematic review, we aimed to answer whether TC development is associated with (a) high amounts of dairy product consumption, (b) the type of dairy product consumed, (c) increasing levels of dairy product consumption, and (d) dairy consumption during certain periods during the lifecourse. Following a systematic review of the literature, eight studies (all case-control studies) were included in our review. The included studies varied in terms of the dairy product(s) investigated (milk, cheese, cream, butter, and yoghurt) as well as the type of exposure to dairy consumption (e.g., high vs. low exposure, dose-response, and timing during lifecourse). We found that there was no strong evidence that high levels of dairy consumption are associated with risk of TC, conflicting evidence of a dose-response relationship, inconsistent evidence on whether certain types of dairy are more strongly associated with TC than others, and conflicting evidence that exposure during certain life-course periods affects TC risk more than other periods. There is no consistent evidence to support the premise that dairy product consumption is associated with the risk of TC development.

Physical activity and risk of testicular cancer: a systematic review.

BACKGROUND: Physical activity has been implicated as a risk factor in the development of testicular cancer (TC), but the relationship remains controversial. This systematic review pooled available evidence regarding this association. METHODS: Using Boolean search terms and following PRISMA guidelines, we examined the risk of TC across three categories of exposure: intensity (i.e. comparison of risk between those previously exposed to high, moderate and low levels of physical activity); dose-response (i.e. whether risk of TC increases or decreases with increasing exposure to physical activity); and the role of timing of physical activity (i.e. during early childhood or adolescence). RESULTS: Thirteen studies (11 case-control studies, 2 cohort studies) were included in the review. While some studies have reported a strong protective effect of high levels of physical activity on risk of TC, others have reported either no relationship or a weak direct association; and while a dose-response relationship has been identified across several studies, this relationship has been observed in both directions. Similarly conflicting results exist in terms of individual types of activity and the lifecourse timing of the physical activity. Reasons for this inconsistency may include the absence of any association, heterogeneous assessment of physical activity, misclassification bias and difference in sample sizes. CONCLUSIONS: On balance, there is presently no strong evidence of an association between physical activity and risk of subsequent TC. This review highlights key areas for future investigation that may clarify any association between physical activity and risk of testicular cancer.

Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes.

Lung cancer is emerging as a paradigm for disease molecular subtyping, facilitating targeted therapy based on driving somatic alterations. Here we perform transcriptome analysis of 153 samples representing lung adenocarcinomas, squamous cell carcinomas, large cell lung cancer, adenoid cystic carcinomas and cell lines. By integrating our data with The Cancer Genome Atlas and published sources, we analyse 753 lung cancer samples for gene fusions and other transcriptomic alterations. We show that higher numbers of gene fusions is an independent prognostic factor for poor survival in lung cancer. Our analysis confirms the recently reported CD74-NRG1 fusion and suggests that NRG1, NF1 and Hippo pathway fusions may play important roles in tumours without known driver mutations. In addition, we observe exon-skipping events in c-MET, which are attributable to splice site mutations. These classes of genetic aberrations may play a significant role in the genesis of lung cancers lacking known driver mutations.

Integrative bioinformatics links HNF1B with clear cell carcinoma and tumor-associated thrombosis.

Clear cell carcinoma (CCC) is a histologically distinct carcinoma subtype that arises in several organ systems and is marked by cytoplasmic clearing, attributed to abundant intracellular glycogen. Previously, transcription factor hepatocyte nuclear factor 1-beta (HNF1B) was identified as a biomarker of ovarian CCC. Here, we set out to explore more broadly the relation between HNF1B and carcinomas with clear cell histology. HNF1B expression, evaluated by immunohistochemistry, was significantly associated with clear cell histology across diverse gynecologic and renal carcinomas (P<0.001), as was hypomethylation of the HNF1B promoter (P<0.001). From microarray analysis, an empirically-derived HNF1B signature was significantly enriched for computationally-predicted targets (with HNF1 binding sites) (P<0.03), as well as genes associated with glycogen metabolism, including glucose-6-phophatase, and strikingly the blood clotting cascade, including fibrinogen, prothrombin and factor XIII. Enrichment of the clotting cascade was also evident in microarray data from ovarian CCC versus other histotypes (P<0.01), and HNF1B-associated prothrombin expression was verified by immunohistochemistry (P = 0.015). Finally, among gynecologic carcinomas with cytoplasmic clearing, HNF1B immunostaining was linked to a 3.0-fold increased risk of clinically-significant venous thrombosis (P = 0.043), and with a 2.3-fold increased risk (P = 0.011) in a combined gynecologic and renal carcinoma cohort. Our results define HNF1B as a broad marker of clear cell phenotype, and support a mechanistic link to glycogen accumulation and thrombosis, possibly reflecting (for gynecologic CCC) derivation from secretory endometrium. Our findings also implicate a novel mechanism of tumor-associated thrombosis (a major cause of cancer mortality), based on the direct production of clotting factors by cancer cells.

CDX2 is an amplified lineage-survival oncogene in colorectal cancer.

The mutational activation of oncogenes drives cancer development and progression. Classic oncogenes, such as MYC and RAS, are active across many different cancer types. In contrast, "lineage-survival" oncogenes represent a distinct and emerging class typically comprising transcriptional regulators of a specific cell lineage that, when deregulated, support the proliferation and survival of cancers derived from that lineage. Here, in a large collection of colorectal cancer cell lines and tumors, we identify recurrent amplification of chromosome 13, an alteration highly restricted to colorectal-derived cancers. A minimal region of amplification on 13q12.2 pinpoints caudal type homeobox transcription factor 2 (CDX2), a regulator of normal intestinal lineage development and differentiation, as a target of the amplification. In contrast to its described role as a colorectal tumor suppressor, CDX2 when amplified is required for the proliferation and survival of colorectal cancer cells. Further, transcriptional profiling, binding-site analysis, and functional studies link CDX2 to Wnt/ß-catenin signaling, itself a key oncogenic pathway in colorectal cancer. These data characterize CDX2 as a lineage-survival oncogene deregulated in colorectal cancer. Our findings challenge a prevailing view that CDX2 is a tumor suppressor in colorectal cancer and uncover an additional piece in the multistep model of colorectal tumorigenesis.

Intraluminal erosion of laparoscopic gastric band tubing into duodenum with recurrent port-site infections.

BACKGROUND: Intraluminal erosion of a laparoscopic gastric band into the stomach has been reported as a complication of laparoscopic adjustable gastric banding. To our knowledge, however, intraluminal erosion of the band tubing into the duodenum has not been described. PATIENT AND METHODS: We report a 46-year-old man in whom a laparoscopic adjustable gastric band tubing eroded into the duodenal lumen, causing recurrent port-site infections. This complication was diagnosed on upper endoscopy and also, in retrospect, on an upper gastrointestinal barium study and computed tomography. RESULTS: The patient underwent surgical removal of the band and tubing, with a primary duodenal repair, and made a complete recovery without complications. CONCLUSION: Erosion of laparoscopic band tubing into the duodenum should be included in the differential diagnosis for recurrent port-site infections after laparoscopic adjustable gastric banding. Radiographic or endoscopic visualization of the intraluminal portion of the tubing may be required for confirmation. Definitive treatment of this complication entails surgical removal of the tubing from the duodenum.

Spermatogenesis in testis xenografts grafted from pre-pubertal Holstein bulls is re-established by stem cell or early spermatogonia.

Xenografting of testis explants into recipient mice has resulted in successful restoration of spermatogenesis in several species. Most studies have utilized neonatal donor tissue, although a few have used prepubertal testes. In Holstein bulls, prepubertal development of the testis occurs between 16 and 32 weeks of age. The purpose of the present study was to determine the optimal age during prepubertal development of Holstein bulls for testis grafting. Explants of testis tissue from Holstein bulls between 12 and 32 weeks of age (2 bulls/age; 6 ages) were subcutaneously grafted into castrated or intact immunocompromised mice (n=8/age), then recovered after 75 and 173 days (n=4 mice/grafting period) and evaluated histologically for spermatogenic progression. Seminiferous tubules were assigned a score based on the most advanced type of germ cell present within the tubule and the average for all tubules scored (n=25) within an explant was calculated. Scores for all explants per mouse (n=6) were averaged to give a single spermatogenic progression score per mouse. No difference in spermatogenic progression of grafts between intact and castrated recipients was observed. Spermatocytes were observed in testis grafts from bulls of all ages 75 days post-grafting. At 173 days, the spermatogenic progression score for explants derived from 20 weeks bulls was greater than all ages except 12 weeks donors (p<0.05), with 8% of tubules containing spermatids. Donor material from bulls older than 20 weeks had lesser spermatogenic progression scores largely attributed to the greater number of atrophic tubules in grafts from older donors. Grafts from 28 and 32 weeks donors showed signs of degeneration by 75 days post-grafting, with 30 and 55% atrophic tubules, respectively, and lesser spermatogenic efficiency scores. By 173 days post-grafting, 72% of tubules in explants from 32 weeks donors were atrophic. The results of the present study suggest that the early stages of prepubertal development are optimal for testis grafting while advanced spermatogenesis in the donor tissue prior to grafting had a negative effect on graft development. Spermatogenesis within the grafts apparently needs to be re-established by spermatogonial stem cells or early spermatogonia.

Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis.

Prostate cancer is clinically heterogeneous, ranging from indolent to lethal disease. Expression profiling previously defined three subtypes of prostate cancer, one (subtype-1) linked to clinically favorable behavior, and the others (subtypes-2 and -3) linked with a more aggressive form of the disease. To explore disease heterogeneity at the genomic level, we carried out array-based comparative genomic hybridization (array CGH) on 64 prostate tumor specimens, including 55 primary tumors and 9 pelvic lymph node metastases. Unsupervised cluster analysis of DNA copy number alterations (CNA) identified recurrent aberrations, including a 6q15-deletion group associated with subtype-1 gene expression patterns and decreased tumor recurrence. Supervised analysis further disclosed distinct patterns of CNA among gene-expression subtypes, where subtype-1 tumors exhibited characteristic deletions at 5q21 and 6q15, and subtype-2 cases harbored deletions at 8p21 (NKX3-1) and 21q22 (resulting in TMPRSS2-ERG fusion). Lymph node metastases, predominantly subtype-3, displayed overall higher frequencies of CNA, and in particular gains at 8q24 (MYC) and 16p13, and loss at 10q23 (PTEN) and 16q23. Our findings reveal that prostate cancers develop via a limited number of alternative preferred genetic pathways. The resultant molecular genetic subtypes provide a new framework for investigating prostate cancer biology and explain in part the clinical heterogeneity of the disease.

The efficacy of topical silicone gel elastomers in the treatment of hypertrophic scars, keloid scars, and post-laser exfoliation erythema.

BACKGROUND: Dermatix is a Food and Drug Administration (FDA)-registered substantial equivalent to silicone gel sheeting for the prevention and management of hypertrophic scars and keloids. METHODS: A 90-day prospective study evaluated the efficacy of Dermatix, silicone gel sheeting, and a combination of these treatments in improving scars for 30 patients. Each patient had a bilateral scar that served as an untreated control. The outcome measures included profilometry analysis of scar topography before and after punch biopsies of the control and treated scars, symptoms associated with the scars, and patient evaluations of the ease of treatment. RESULTS: The results showed better resolution and improvement of scars with Dermatix treatment or the combined use of Dermatix and silicone gel sheeting than with silicone gel sheeting alone. Wound erythema was reduced, and collagen architectural reorientation was demonstrated histologically. Patients rated Dermatix as easier to use than silicone gel sheeting. Both Dermatix and silicone gel sheeting reduced symptoms of itching, irritation, and skin maceration. CONCLUSION: The results of this study indicate that Dermatix is a useful treatment for the management of abnormal scarring.