BRAF and RET polymorphism association with thyroid cancer risk, a preliminary study from Khyber Pakhtunkhwa population.

BACKGROUND: Thyroid cancer, originating in the neck's thyroid gland, encompasses various types. Genetic mutations, particularly in BRAF and RET genes are crucial in its development. This study investigates the association between BRAF (rs113488022) and RET (rs77709286) polymorphisms and thyroid cancer risk in the Khyber Pakhtunkhwa (KP) population. METHODS: Blood samples from 100 thyroid cancer patients and 100 healthy controls were genotyped using ARMS-PCR followed by gel electrophoresis and statistical analysis. RESULTS: Analysis revealed a significant association between the minor allele T of BRAF (rs113488022) and thyroid cancer risk (P = 0.0001). Both genotypes of BRAF (rs113488022) showed significant associations with thyroid cancer risk (AT; P = 0.0012 and TT; P = 0.045). Conversely, the minor allele G of RET (rs77709286) exhibited a non-significant association with thyroid cancer risk (P = 0.2614), and neither genotype showed significant associations (CG; P = 0.317, GG; P = 0.651). Demographic and clinical parameters analysis using SPSS showed a non-significant association between BRAF and RET variants and age group (P = 0.878 and P = 0.536), gender (P = 0.587 and P = 0.21), tumor size (P = 0.796 and P = 0.765), or tumor localization (P = 0.689 and P = 0.727). CONCLUSION: In conclusion, this study emphasizes the significant association between BRAF polymorphism and thyroid cancer risk, while RET polymorphism showed a less pronounced impact. Further validation using larger and specific datasets is essential to establish conclusive results.

Non-coding RNAs and neuroinflammation: implications for neurological disorders.

Neuroinflammation is considered a balanced inflammatory response important in the intrinsic repair process after injury or infection. Under chronic states of disease, injury, or infection, persistent neuroinflammation results in a heightened presence of cytokines, chemokines, and reactive oxygen species that result in tissue damage. In the CNS, the surrounding microglia normally contain macrophages and other innate immune cells that perform active immune surveillance. The resulting cytokines produced by these macrophages affect the growth, development, and responsiveness of the microglia present in both white and gray matter regions of the CNS. Controlling the levels of these cytokines ultimately improves neurocognitive function and results in the repair of lesions associated with neurologic disease. MicroRNAs (miRNAs) are master regulators of the genome and subsequently control the activity of inflammatory responses crucial in sustaining a robust and acute immunological response towards an acute infection while dampening pathways that result in heightened levels of cytokines and chemokines associated with chronic neuroinflammation. Numerous reports have directly implicated miRNAs in controlling the abundance and activity of interleukins, TGF-B, NF-kB, and toll-like receptor-signaling intrinsically linked with the development of neurological disorders such as Parkinson's, ALS, epilepsy, Alzheimer's, and neuromuscular degeneration. This review is focused on discussing the role miRNAs play in regulating or initiating these chronic neurological states, many of which maintain the level and/or activity of neuron-specific secondary messengers. Dysregulated miRNAs present in the microglia, astrocytes, oligodendrocytes, and epididymal cells, contribute to an overall glial-specific inflammatory niche that impacts the activity of neuronal conductivity, signaling action potentials, neurotransmitter robustness, neuron-neuron specific communication, and neuron-muscular connections. Understanding which miRNAs regulate microglial activation is a crucial step forward in developing non-coding RNA-based therapeutics to treat and potentially correct the behavioral and cognitive deficits typically found in patients suffering from chronic neuroinflammation.

Significant association of BRCA1 (rs1799950), BRCA2 (rs144848) and TP53 (rs1042522) polymorphism with breast cancer risk in Pashtun population of Khyber Pakhtunkhwa, Pakistan.

BACKGROUND: Single nucleotide polymorphism (SNPs) in BRCA1, BRCA2 and TP53 has been widely associated with breast cancer risk in different ethnicities with inconsistent results. There is no such study conducted so far in the Pashtun population of Khyber Pakhtunkhwa, Pakistan. Therefore, this study was conducted to check BRCA1 (rs1799950), BRCA2 (rs144848) and TP53 (rs1042522) polymorphism with breast cancer risk in Pashtun population of Khyber Pakhtunkhwa, Pakistan. METHODS: This study, consisting 140 breast cancer patients and 80 gender and age matched healthy controls were subjected to confirm BRCA1, BRCA2 and TP53 polymorphism. Clinicopathological data and blood samples were taken from all the participants. DNA was extracted and SNPs were confirmed using T-ARMS-PCR protocol. RESULTS: Our data indicated that BRCA1, BRCA2, and TP53 selected SNPs risk allele and risk allele containing genotypes displayed significant association (p < 0.05) with breast cancer risk in the Pashtun population of Khyber Pakhtunkhwa, Pakistan. CONCLUSION: All the three selected SNPs of BRCA1, BRCA2 and TP53 showed significant association with breast cancer risk in the Pashtun population of Khyber Pakhtunkhwa, Pakistan. However, more investigation will be required on large data sets to confirm the selected SNPs and other SNPs in the selected and other related genes with the risk of breast cancer.

The Effect of Locking Screws on Distal Component Fixation in Total Wrist Arthroplasty Using a Cadaver Model.

Purpose: The advent of total wrist arthroplasty has allowed for motion-sparing surgical treatment for wrist arthritis. The Integra Freedom Total Wrist Arthroplasty recently incorporated locking caps into its distal component fixation to minimize implant micromotion and improve osseous integration. The purpose of this study was to assess the kinematic effect of locking caps in a cadaveric model. Methods: The Integra Freedom was implanted in 4 matched-pair cadavers and tested with and without the use of the locking caps, with the testing order randomized. Each specimen was tested on a custom testing system in a position of 15° of radial deviation, neutral position, and 15° of ulnar deviation with 25 N, 50 N, 75 N, and 100 N of compressive force. The rotation of the capitate, trapezoid, and hamate at all positions was measured using a 3-dimensional digitizer. Results: Statistical analysis showed no difference in carpal rotation between the nonlocking cap and locking cap groups at all testing loads and wrist positions. The absolute motion of the distal row was minimal. However, of the total 216 loads/positions tested, only 4 (1.8%) showed a rotation of greater than 2° and only 34 (15.7%) showed a rotation of greater than 1°. Conclusions: This study shows that in a time zero cadaveric model, the initial osseous fixation of the distal component in the Integra Freedom is robust with or without locking caps. The addition of locking caps did not have a kinematic effect on distal carpal row fixation. However, further investigation into its clinical role is necessary. Clinical Relevance: At time zero, there is minimal carpal motion after implantation of the Integra Freedom Total Wrist with functional loading. The addition of locking caps did not lead to any decrease in carpal motion.

Reaction mechanisms for electrolytic manganese dioxide in rechargeable aqueous zinc-ion batteries.

This study reports the phase transformation behaviour associated with electrolytic manganese dioxide (EMD) utilized as the positive electrode active material for aqueous zinc-ion batteries. Electrochemical techniques, including galvanostatic charge-discharge and rotating ring-disk electrode measurements, and microstructural techniques, using X-ray powder diffraction, scanning electron microscopy, and transmission/scanning transmission electron microscopy, were utilized to characterize the positive electrode at different stages of discharge and charge of zinc-ion cells. The results indicate that, during discharge, a fraction of EMD undergoes a transformation to ZnMn2O4 (spinel-type) and Zn2+ is intercalated into the tunnels of the γ- and ε-MnO2 phases, forming ZnxMnO2 (tunnel-type). When a critical concentration of Mn3+ in the intercalated ZnxMnO2 species is reached, a disproportionation/dissolution reaction is triggered leading to the formation of soluble Mn2+ and hydroxide (OH-) ions; the latter precipitates as zinc hydroxide sulfate (ZHS, Zn4(OH)6(SO4)·5H2O) by combination with the ZnSO4/H2O electrolyte. During charge, Zn2+ is reversibly deintercalated from the intergrown tunneled phases (γ-/ε-ZnxMnO2), Mn2+ is redeposited as layered chalcophanite (ZnMn3O7·3H2O), and ZHS is decomposed by protons (H+) formed during the electrochemical deposition of chalcophanite.

A High-Throughput Small Molecule Screen Identifies Ouabain as Synergistic with miR-34a in Killing Lung Cancer Cells.

MicroRNA-34 (miR-34) is one of the major families of tumor suppressor miRNAs often lost in cancers. Delivery of miR-34a mimics to affected tumors as a therapeutic strategy has been tried in pre-clinical studies and in a phase I clinical trial. One approach to increase efficacy and reduce toxicity is to rationally identify drug combinations with small molecules that synergize with miR-34a. In this study we performed a high-throughput screen of a large panel of small molecules with known biological activity and identified ouabain as a candidate small molecule that synergized with miR-34a in killing lung cancer cells. We elucidated autophagy activation as a key mechanism by which miR-34a and ouabain causes increased cytotoxicity in cells. We posit that this combinatorial approach could reduce the active dose of miR-34a needed in vivo to observe tumor shrinkage and potentiate the development of miR-34a combination therapies in the future.

Reliability of the Dorsal Tangential View in Assessment of Distal Radioulnar Joint Reduction in the Neutral, Pronated, and Supinated Positions in a Cadaver Model.

PURPOSE: Intraoperative assessment of distal radioulnar joint (DRUJ) alignment is often based on lateral radiographs whose interpretation is dependent upon positioning the forearm in neutral rotation. The dorsal tangential view (DTV) is a near-axial view of the dorsal wrist used in assessing dorsal screw penetration during radius fixation. The purpose of this study was to determine whether the DTV can also reliably assess DRUJ alignment in multiple forearm positions. METHODS: Four transhumeral cadaveric specimens were used to simulate an unstable DRUJ. The stabilizing soft tissue structures of the DRUJ were sectioned. Fluoroscopic DTV images were obtained with the DRUJ of each specimen held in 5 positions: dorsally dislocated, dorsally subluxated, reduced, volarly subluxated, and volarly dislocated. In each position, images were taken with the forearm in neutral rotation, full pronation, and full supination. Three observers independently assessed DRUJ position on DTV images. Intra- and interobserver reliability were assessed in each forearm position. RESULTS: Observers correctly identified DRUJ position as reduced, volarly malreduced, or dorsally malreduced on 94% of the DTV images (97%, 95%, and 92% in the neutral, supinated, and pronated forearm positions, respectively). Weighted kappa values for intraobserver reliability were 0.965, 0.964, and 0.965 for the 3 observers. The mean kappas for intraobserver reliability were 1.000, 0.967, and 0.930 with the forearm in neutral, supinated, and pronated positions, respectively. Weighted kappa values for interobserver reliability between paired observers were 0.948, 0.912, and 0.929. The mean kappa for interobserver reliability was 0.926, 0.931, and 0.930 for the forearm in neutral, supinated, and pronated positions, respectively. CONCLUSIONS: The DTV reliably demonstrated the position of the DRUJ independent of forearm rotation in a cadaveric model. CLINICAL RELEVANCE: Surgeons may consider the DTV as another tool for fluoroscopic verification of the DRUJ reduction in the operating room or clinic.

Human nuclear RNAi-defective 2 (NRDE2) is an essential RNA splicing factor.

The accurate inheritance of genetic material is a basic necessity in all domains of life and an unexpectedly large number of RNA processing factors are required for mitotic progression and genome stability. NRDE2 (nuclear RNAi defective-2) is an evolutionarily conserved protein originally discovered for its role in nuclear RNA interference (RNAi) and heritable gene silencing in Caenorhabditis elegans (C. elegans). The function of the human NRDE2 gene remains poorly understood. Here we show that human NRDE2 is an essential protein required for suppressing intron retention in a subset of pre-mRNAs containing short, GC-rich introns with relatively weak 5' and 3' splice sites. NRDE2 preferentially interacts with components of the U5 small nuclear ribonucleoprotein (snRNP), the exon junction complex, and the RNA exosome. Interestingly, NRDE2-depleted cells exhibit greatly increased levels of genomic instability and DNA damage, as well as defects in centrosome maturation and mitotic progression. We identify the essential centriolar satellite protein, CEP131, as a direct NRDE2-regulated target. NRDE2 specifically binds to and promotes the efficient splicing of CEP131 pre-mRNA, and depleting NRDE2 dramatically reduces CEP131 protein expression, contributing to impaired recruitment of critical centrosomal proteins (e.g., γ-tubulin and Aurora Kinase A) to the spindle poles during mitosis. Our work establishes a conserved role for human NRDE2 in RNA splicing, characterizes the severe genomic instability phenotypes observed upon loss of NRDE2, and highlights the direct regulation of CEP131 splicing as one of multiple mechanisms through which such phenotypes might be explained.

Exercise and weight loss interventions and miRNA expression in women with breast cancer.

PURPOSE: Obesity and weight gain are associated with comorbidities including a higher risk of tumor recurrence and cancer-related deaths among breast cancer (BC) survivors; however, the underlying mechanisms linking obesity and cancer are poorly understood. Given the lack of clinically validated BC biomarkers, obesity and weight-loss studies utilize serum biomarkers as the intermediary outcomes of tumor recurrence. Studies have indicated microRNAs (miRNA)s are reliable biomarkers for cancer. We hypothesized that miRNA expression correlates with obesity and weight loss amongst BC survivors. This would yield insight into the biological pathways by which this association occurs, enabling more precise development of therapeutics. PATIENTS AND METHODS: We correlated baseline body mass index (BMI) with serum miRNA expression in 121 BC survivors enrolled in the Hormones and Physical Exercise (HOPE) trial. We then analyzed expression of the 35 most abundant miRNAs from HOPE in a six-month randomized controlled weight-loss trial (Lifestyle, Exercise, and Nutrition; LEAN) in 100 BC survivors. Ingenuity pathway analysis (IPA) software was used to identify biological pathway targets of the BMI-associated and intervention-responsive miRNAs using predictive biomarkers. RESULTS: Pearson correlations in HOPE identified eight miRNAs associated with BMI, including miR-191-5p (r = - 0.22, p = 0.016) and miR-122-5p (r = 0.25, p = 0.0048). In the LEAN validation study, levels of miR-191-5p significantly increased during the six-month intervention (p = 0.082). Ingenuity Pathway Analysis identified "Estrogen-mediated S-phase entry" (HOPE p = 0.003; LEAN p < 0.001) and "Molecular mechanisms of cancer" (HOPE p = 0.02; LEAN p < 0.001) as the top canonical pathways that significantly correlated with BMI-associated and intervention-responsive miRNAs and contain obesity and cancer-relevant genes including the E2F family of transcription factors and CCND1, which have been implicated in sporadic BC. CONCLUSION: While the association between obesity and BC recurrence and mortality has been demonstrated in the literature, mechanisms underlying the link between weight gain and cancer are unclear. Using two independent clinical trials, we identified novel miRNAs associative to BMI and weight loss that contribute to the development of cancer. Predictive modeling of miRNA targets identified multiple canonical pathways associated with cancer, highlighting potential mechanisms explaining the link between BMI and increased cancer risk.

linc00673 (ERRLR01) is a prognostic indicator of overall survival in breast cancer.

LncRNAs are novel noncoding RNAs involved in the epigenetic regulation of gene expression by recruiting ribonucleoprotein complexes to specific genomic loci to initiate histone methylation and/or other chromatin modifications. LncRNAs themselves function as tumor suppressors or oncogenes, depending on the gene regulatory networks they govern. We identified lnc00673 (ERRLR01) as a marker of overall survival (OS) in breast cancer patients. Specifically, ERRLR01 levels were elevated in triple-negative breast cancer (TNBC) as compared with Luminal-A, Luminal-B, and HER2 breast cancer subtypes. ERRLR01 levels were also inversely correlated with breast cancer survival across all breast cancer patients. Upon stratification, OS in ERα- tumors correlated with negative overall survival, while in ERα+ tumors, ERRLR01 correlated with positive outcomes. This suggests ERRLR01 is modulated by hormone signaling in breast cancer. Gene-network analysis revealed ERRLR01 correlated with distinct pathways including "epithelial development" and "cellular differentiation." These data suggest ERRLR01 operates as an oncogene in TNBC, as well as a biomarker in breast cancer patients.

Prdm1 Regulates Thymic Epithelial Function To Prevent Autoimmunity.

Autoimmunity is largely prevented by medullary thymic epithelial cells (TECs) through their expression and presentation of tissue-specific Ags to developing thymocytes, resulting in deletion of self-reactive T cells and supporting regulatory T cell development. The transcription factor Prdm1 has been implicated in autoimmune diseases in humans through genome-wide association studies and in mice using cell type-specific deletion of Prdm1 in T and dendritic cells. In this article, we demonstrate that Prdm1 functions in TECs to prevent autoimmunity in mice. Prdm1 is expressed by a subset of mouse TECs, and conditional deletion of Prdm1 in either Keratin 14- or Foxn1-expressing cells in mice resulted in multisymptom autoimmune pathology. Notably, the development of Foxp3+ regulatory T cells occurs normally in the absence of Blimp1. Importantly, nude mice developed anti-nuclear Abs when transplanted with Prdm1 null TECs, but not wild-type TECs, indicating that Prdm1 functions in TECs to regulate autoantibody production. We show that Prdm1 acts independently of Aire, a crucial transcription factor implicated in medullary TEC function. Collectively, our data highlight a previously unrecognized role for Prdm1 in regulating thymic epithelial function.

Androgen receptor and miR-206 regulation in prostate cancer.

In the United States, prostate cancer is the second leading cause of cancer-related deaths among men with an approximately 220,000 patients diagnosed with the disease in 2015. Prostate cancer is a hormone-driven tumor, and a common therapy is androgen-deprivation therapy (ADT) that involves anti-androgen treatments and/or castration therapy. Understanding the molecular basis for androgen-independent tumors is crucial toward developing new therapies for these patients. Understanding how androgen receptor itself functions is an important step in elucidating this process. Androgen receptor (AR), NR3C4, is a nuclear hormone receptor and functions as a DNA-binding transcription factor that regulates the expression of protein-coding genes. Translocation of AR to improper gene promoter elements or DNA-binding sites can result in an alteration in gene expression and thus normal prostate function. Therefore, it is crucial to understand which AR-promoter interactions are drivers of disease, as compared to promiscuous or benign AR-binding interactions. While a large portion of our genome is considered a gene desert, it is now appreciated that these regions of the genome contain non-coding RNA genes such as microRNAs (miRNAs). These non-coding RNAs have enormous regulatory potential, as they post-transcriptionally regulate gene expression by binding to messenger RNAs (mRNAs) to promote degradation or intervention of translational processes. In this review, we focus specifically on the notion that mis-regulation of non-coding RNAs such as miRNAs by improper AR-DNA binding are an important component that promotes prostate cancer. We also highlight the role of miR-206 and the interaction of miR-206 and AR within this process, given this is a miRNA known to be regulated by hormones in both breast and prostate cancer.

The regulatory role of miRNAs on VDR in breast cancer.

Triple negative breast cancer (TNBC) has been associated with the lack of three hormone receptors; estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2). However, a host of other steroid hormone receptors such as vitamin D receptor (VDR) is present in TNBC, and the role of these hormone receptors in breast tumorigenesis is unclear. The levels of microRNAs (miRNAs) are also expressed differently than in normal mammary epithelial cells. miRNAs are regulatory RNAs involved in various cellular functions, mainly gene silencing. Here, we reviewed the literature surrounding miRNAs in breast cancer, and performed in silico analysis to determine whether there was a correlation between levels of VDR in relation to miRNAs important in breast cancer development and tumorigenesis. We identified three miRNAs of interest, specifically, miR-23, miR-124, and miR-125. Through this research we determined the possibility that these miRNAs play an important role in controlling VDR activity and by virtue the development of breast cancer.

Targeting noncoding RNAs in disease.

Many RNA species have been identified as important players in the development of chronic diseases, including cancer. Over the past decade, numerous studies have highlighted how regulatory RNAs such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) play crucial roles in the development of a disease state. It is clear that the aberrant expression of miRNAs promotes tumor initiation and progression, is linked with cardiac dysfunction, allows for the improper physiological response in maintaining glucose and insulin levels, and can prevent the appropriate integration of neuronal networks, resulting in neurodegenerative disorders. Because of this, there has been a major effort to therapeutically target these noncoding RNAs. In just the past 5 years, over 100 antisense oligonucleotide-based therapies have been tested in phase I clinical trials, a quarter of which have reached phase II/III. Most notable are fomivirsen and mipomersen, which have received FDA approval to treat cytomegalovirus retinitis and high blood cholesterol, respectively. The continued improvement of innovative RNA modifications and delivery entities, such as nanoparticles, will aid in the development of future RNA-based therapeutics for a broader range of chronic diseases. Here we summarize the latest promises and challenges of targeting noncoding RNAs in disease.

Operando Nanobeam Diffraction to Follow the Decomposition of Individual Li2O2 Grains in a Nonaqueous Li-O2 Battery.

Intense interest in the Li-O2 battery system over the past 5 years has led to a much better understanding of the various chemical processes involved in the functioning of this battery system. However, detailed decomposition of the nanostructured Li2O2 product, held at least partially responsible for the limited reversibility and poor rate performance, is hard to measure operando under realistic electrochemical conditions. Here, we report operando nanobeam X-ray diffraction experiments that enable monitoring of the decomposition of individual Li2O2 grains in a working Li-O2 battery. Platelet-shaped crystallites with aspect ratios between 2.2 and 5.5 decompose preferentially via the more reactive (001) facets. The slow and concurrent decomposition of individual Li2O2 crystallites indicates that the Li2O2 decomposition rate limits the charge time of these Li-O2 batteries, highlighting the importance of using redox mediators in solution to charge Li-O2 batteries.

Distal Radius Hemiarthroplasty.

INTRODUCTION: Due to a higher risk for implant loosening, particularly of the distal component, patients with physically demanding lifestyles are infrequently considered for total wrist arthroplasty (TWA). A distal radius hemiarthroplasty may obviate the need for the strict restrictions recommended for patients treated by TWA, thus providing another surgical option for active patients with severe wrist arthritis, especially those with articular degeneration of the lunate facet of the radius, capitate head, or combination of both, who are not typically candidates for traditional motion-preserving procedures. MATERIALS AND METHODS: Eight fresh-frozen cadaver limbs (age range, 43-82 years) with no history of rheumatoid arthritis or upper extremity trauma were used. Radiodense markers were inserted in the radius and hand. Posteroanterior (PA) fluoroscopic images with the wrist in neutral, radial deviation, and ulnar deviation, and lateral images with the wrist in neutral, flexion, and extension were obtained for each specimen before implantation, after distal radius hemiarthroplasty, and after combined hemiarthroplasty and PRC. RESULTS: On the PA images, the capitate remained within 1.42 and 2.21 mm of its native radial-ulnar position following hemiarthroplasty and hemiarthroplasty with PRC, respectively. Lateral images showed the capitate remained within 1.06 mm of its native dorsal-volar position following hemiarthroplasty and within 4.69 mm following hemiarthroplasty with PRC. Following hemiarthroplasty, capitate alignment changed 2.33 and 2.59 mm compared with its native longitudinal alignment on PA and lateral films, respectively. These changes did not reach statistical significance. As expected, significant shortening in longitudinal alignment was seen on both PA and lateral films for hemiarthroplasty with PRC. CONCLUSION: A distal radius implant hemiarthroplasty with or without a PRC provides good static alignment of the wrist in a cadaver model and thus supports the concept as potential treatment alternatives for advanced wrist arthritis; however, combined hemiarthroplasty with a PRC has more clinical relevance because it avoids the risk of proximal carpal row instability and eliminates the commonly arthritic radioscaphoid joint.

Wrist Arthrodesis for Failed Total Wrist Arthroplasty.

PURPOSE: Treatment options for failed total wrist arthroplasty include implant revision, resection arthroplasty, and arthrodesis. Variable results associated with different techniques have been reported for arthrodesis and the procedure has substantial technical challenges, including restoration of wrist height, obtaining stable fixation, and achieving bony fusion. This study evaluates the radiographic results of a surgical technique for conversion of a failed arthroplasty to an arthrodesis. METHODS: A retrospective chart and radiograph review was performed in 20 wrists in 18 patients in whom conversion to an arthrodesis was performed using a contoured cancellous femoral head structural allograft and a wrist arthrodesis plate. Supplemental demineralized bone matrix combined with corticocancellous allograft chips was also used in 15 wrists. Median age at arthrodesis was 61 years (range, 45-78 years), and median follow-up was 34 months (range, 4-71 months). RESULTS: Nineteen of 20 wrists fused following the index procedure at a median of 4 months (range, 3-7 months). Proximal plate loosening occurred in 1 wrist but the joint still fused at 6 months; a successful osteotomy and revision of screw fixation was done 2 years later to correct the deformity and hardware irritation in this case. Complications were otherwise limited to 1 superficial infection that resolved with intravenous antibiotics. CONCLUSIONS: This technique for conversion of a failed total wrist arthroplasty to a wrist arthrodesis is safe, effective, and versatile. Wrist deformity is corrected, wrist height can be restored, stable fixation is obtained, and a high rate of fusion is achieved despite filling large defects using structural cancellous allograft. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity.

Autoreactive B cells have critical roles in a large diversity of autoimmune diseases, but the molecular pathways that control these cells remain poorly understood. We performed an in vivo functional screen of a lymphocyte-expressed microRNA library and identified miR-148a as a potent regulator of B cell tolerance. Elevated miR-148a expression impaired B cell tolerance by promoting the survival of immature B cells after engagement of the B cell antigen receptor by suppressing the expression of the autoimmune suppressor Gadd45α, the tumor suppressor PTEN and the pro-apoptotic protein Bim. Furthermore, increased expression of miR-148a, which occurs frequently in patients with lupus and lupus-prone mice, facilitated the development of lethal autoimmune disease in a mouse model of lupus. Our studies demonstrate a function for miR-148a as a regulator of B cell tolerance and autoimmunity.

The tumor-suppressive and potential therapeutic functions of miR-34a in epithelial carcinomas.

INTRODUCTION: Many RNA species have been identified as important players in the development of chronic diseases including cancer. Certain classes of regulatory RNAs such as microRNAs (miRNAs) have been investigated in such detail that bona fide tumor suppressive and oncogenic miRNAs have been identified. Because of this, there has been a major effort to therapeutically target these small RNAs. One in particular, a liposomal formulation of miR-34a (MRX34), has entered Phase I trials. AREAS COVERED: This review aims to summarize miRNA biology, its regulation within normal versus disease states and how it can be targeted therapeutically, with a particular emphasis on miR-34a. Understanding the complexity of a single miRNA will aid in the development of future RNA-based therapeutics for a broader range of chronic diseases. EXPERT OPINION: The potential of miRNAs to be developed into anti-cancer therapeutics has become an increasingly important area of research. miR-34a is a tumor suppressive miRNA across many tumor types through its ability to inhibit cellular proliferation, invasion and tumor sphere formation. miR-34a also shows promise within certain in vivo solid tumor models. Finally, as miR-34a moves into clinical trials it will be important to determine if it can further sensitize tumors to certain chemotherapeutic agents.

miR-34a Silences c-SRC to Attenuate Tumor Growth in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype with no clinically proven biologically targeted treatment options. The molecular heterogeneity of TNBC and lack of high frequency driver mutations other than TP53 have hindered the development of new and effective therapies that significantly improve patient outcomes. miRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are becoming promising therapeutic agents. We performed miRNA-profiling studies in different TNBC subtypes to identify miRNAs that significantly contribute to disease progression. We found that miR-34a was lost in TNBC, specifically within mesenchymal and mesenchymal stem cell-like subtypes, whereas expression of miR-34a targets was significantly enriched. Furthermore, restoration of miR-34a in cell lines representing these subtypes inhibited proliferation and invasion, activated senescence, and promoted sensitivity to dasatinib by targeting the proto-oncogene c-SRC. Notably, SRC depletion in TNBC cell lines phenocopied the effects of miR-34a reintroduction, whereas SRC overexpression rescued the antitumorigenic properties mediated by miR-34a. miR-34a levels also increased when cells were treated with c-SRC inhibitors, suggesting a negative feedback exists between miR-34a and c-SRC. Moreover, miR-34a administration significantly delayed tumor growth of subcutaneously and orthotopically implanted tumors in nude mice, and was accompanied by c-SRC downregulation. Finally, we found that miR-34a and SRC levels were inversely correlated in human tumor specimens. Together, our results demonstrate that miR-34a exerts potent antitumorigenic effects in vitro and in vivo and suggests that miR-34a replacement therapy, which is currently being tested in human clinical trials, represents a promising therapeutic strategy for TNBC.