ABL kinases regulate the stabilization of HIF-1α and MYC through CPSF1.

The hypoxia-inducible factor 1-α (HIF-1α) enables cells to adapt and respond to hypoxia (Hx), and the activity of this transcription factor is regulated by several oncogenic signals and cellular stressors. While the pathways controlling normoxic degradation of HIF-1α are well understood, the mechanisms supporting the sustained stabilization and activity of HIF-1α under Hx are less clear. We report that ABL kinase activity protects HIF-1α from proteasomal degradation during Hx. Using a fluorescence-activated cell sorting (FACS)-based CRISPR/Cas9 screen, we identified HIF-1α as a substrate of the cleavage and polyadenylation specificity factor-1 (CPSF1), an E3-ligase which targets HIF-1α for degradation in the presence of an ABL kinase inhibitor in Hx. We show that ABL kinases phosphorylate and interact with CUL4A, a cullin ring ligase adaptor, and compete with CPSF1 for CUL4A binding, leading to increased HIF-1α protein levels. Further, we identified the MYC proto-oncogene protein as a second CPSF1 substrate and show that active ABL kinase protects MYC from CPSF1-mediated degradation. These studies uncover a role for CPSF1 in cancer pathobiology as an E3-ligase antagonizing the expression of the oncogenic transcription factors, HIF-1α and MYC.

Cooperative regulation of coupled oncoprotein synthesis and stability in triple-negative breast cancer by EGFR and CDK12/13.

Evidence has long suggested that epidermal growth factor receptor (EGFR) may play a prominent role in triple-negative breast cancer (TNBC) pathogenesis, but clinical trials of EGFR inhibitors have yielded disappointing results. Using a candidate drug screen, we identified that inhibition of cyclin-dependent kinases 12 and 13 (CDK12/13) dramatically sensitizes diverse models of TNBC to EGFR blockade. This combination therapy drives cell death through the 4E-BP1-dependent suppression of the translation and translation-linked turnover of driver oncoproteins, including MYC. A genome-wide CRISPR/Cas9 screen identified the CCR4-NOT complex as a major determinant of sensitivity to the combination therapy whose loss renders 4E-BP1 unresponsive to drug-induced dephosphorylation, thereby rescuing MYC translational suppression and promoting MYC stability. The central roles of CCR4-NOT and 4E-BP1 in response to the combination therapy were further underscored by the observation of CNOT1 loss and rescue of 4E-BP1 phosphorylation in TNBC cells that naturally evolved therapy resistance. Thus, pharmacological inhibition of CDK12/13 reveals a long-proposed EGFR dependence in TNBC that functions through the cooperative regulation of translation-coupled oncoprotein stability.

Osteopontin/secreted phosphoprotein-1 harnesses glial-, immune-, and neuronal cell ligand-receptor interactions to sense and regulate acute and chronic neuroinflammation.

Osteopontin (OPN) also known by its official gene designation secreted phosphoprotein-1 (SPP1) is a fascinating, multifunctional protein expressed in a number of cell types that functions not only in intercellular communication, but also in the extracellular matrix (ECM). OPN/SPP1 possesses cytokine, chemokine, and signal transduction functions by virtue of modular structural motifs that provide interaction surfaces for integrins and CD44-variant receptors. In humans, there are three experimentally verified splice variants of OPN/SPP1 and CD44's ten exons are also alternatively spiced in a cell/tissue-specific manner, although very little is known about how this is regulated in the central nervous system (CNS). Post-translational modifications of phosphorylation, glycosylation, and localized cleavage by specific proteases in the cells and tissues where OPN/SPP1 functions, provides additional layers of specificity. However, the former make elucidating the exact molecular mechanisms of OPN/SPP1 function more complex. Flexibility in OPN/SPP1 structure and its engagement with integrins having the ability to transmit signals in inside-out and outside-in direction, is likely why OPN/SPP1 can serve as an early detector of inflammation and ongoing tissue damage in response to cancer, stroke, traumatic brain injury, pathogenic infection, and neurodegeneration, processes that impair tissue homeostasis. This review will focus on what is currently known about OPN/SPP1 function in the brain.

GPR183 antagonism reduces macrophage infiltration in influenza and SARS-CoV-2 infection.

RATIONALE: Severe viral respiratory infections are often characterised by extensive myeloid cell infiltration and activation and persistent lung tissue injury. However, the immunological mechanisms driving excessive inflammation in the lung remain poorly understood. OBJECTIVES: To identify the mechanisms that drive immune cell recruitment in the lung during viral respiratory infections and identify novel drug targets to reduce inflammation and disease severity. METHODS: Preclinical murine models of influenza A virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. RESULTS: Oxidised cholesterols and the oxysterol-sensing receptor GPR183 were identified as drivers of monocyte/macrophage infiltration to the lung during influenza A virus (IAV) and SARS-CoV-2 infection. Both IAV and SARS-CoV-2 infection upregulated the enzymes cholesterol 25-hydroxylase (CH25H) and cytochrome P450 family 7 subfamily member B1 (CYP7B1) in the lung, resulting in local production of the oxidised cholesterols 25-hydroxycholesterol (25-OHC) and 7α,25-dihydroxycholesterol (7α,25-OHC). Loss-of-function mutation of Gpr183 or treatment with a GPR183 antagonist reduced macrophage infiltration and inflammatory cytokine production in the lungs of IAV- or SARS-CoV-2-infected mice. The GPR183 antagonist significantly attenuated the severity of SARS-CoV-2 infection and viral loads. Analysis of single-cell RNA-sequencing data on bronchoalveolar lavage samples from healthy controls and COVID-19 patients with moderate and severe disease revealed that CH25H, CYP7B1 and GPR183 are significantly upregulated in macrophages during COVID-19. CONCLUSION: This study demonstrates that oxysterols drive inflammation in the lung via GPR183 and provides the first preclinical evidence for the therapeutic benefit of targeting GPR183 during severe viral respiratory infections.

Hip Arthroscopy for Femoroacetabular Impingement Is Associated With Improved Sexual Function And Quality of Life.

PURPOSE: The purpose of this study was to investigate changes in sexual function and activity after arthroscopic hip surgery for femoroacetabular impingement using the United Kingdom Non-Arthroplasty Hip Registry dataset. Subanalyses were performed between males and females, and patients over 40 and under 40 years old. METHODS: Patients who had arthroscopic hip surgery between January 1, 2012, and October 31, 2020, were aged over 16, and completed the relevant patient-reported outcome measures were included. Question 9 of the International Hip Outcome Tool-12 (sexual activity question [SAQ]) refers to problems with sexual activity, and responses to this were compared before surgery and at 6 and 12 months after surgery. Subanalyses were also performed, including SAQ scores by patients' sex or age. SAQ scores were correlated with Euroqol-5 dimension-5 level self-reporting tool (EQ-5D-5L) scores using Spearman's rank coefficient. RESULTS: SAQ was answered by 2,547 patients before and at 6 months after surgery (62.3% female, median age = 36.2, interquartile range [IQR] = 29-44 years) and by 2,314 at 12 months (61.9% female, median age = 36.2, IQR = 29-44 years). Scores for sexual activity increased from 35.0 before surgery to 70.0 at 6 months (P < .001) and were maintained at 12 months (P < .001). Female patients demonstrated a significantly greater improvement in their scores for sexual function from before surgery (median = 30.0, IQR = 14-50) to 6 months (median = 60, IQR = 28-86, P < .001) and 12 months (median = 62.0, IQR = 29-90, P < .001), compared to male patients (preoperative median = 50.0, IQR 25-84; 6-month median = 80, IQR = 45-97; 12-month median = 80, IQR = 41-98). The effect of age on improvements in sexual function did not demonstrate a significant difference. A significant positive correlation was found between improvements in sexual function and quality of life, as measured by the EQ-5D-5L, at 6 and 12 months (P < .001). CONCLUSION: Hip arthroscopy for symptomatic femoroacetabular impingement produces an improvement in sexual function and activity. Scores for sexual function improved regardless of patient age or sex; however, female patients experienced a greater improvement in sexual function than males. LEVEL OF EVIDENCE: Level III (Retrospective cohort study).

Pleomorphic Leiomyosarcoma Presenting as a Upper Back Epidermal Inclusion Cyst.

ABSTRACT: Leiomyosarcoma is a common sarcoma of both organs and soft tissues; however, large intradermal tumors are extremely rare. Presented is a pleomorphic leiomyosarcoma in a 64-year-old man, initially considered to be a ruptured epidermal inclusion cyst. The patient had a mildly tender, enlarging soft-tissue mass with a central pore on his right upper back. Incomplete extirpation showed a 5 × 5 cm heterogeneous, predominantly pleomorphic sarcoma with areas of fascicular and storiform spindled cells infiltrating the subcutaneous soft tissue to the underlying fascia and extending upward into the middle and upper dermis with prominent extension into pilosebaceous units. There were small foci with myxoid stroma and large areas of necrosis. CD31 demonstrated thin-walled curvilinear vessels throughout the tumor. The first desmin immunohistochemical stain near areas with myxoid stroma was negative but smooth muscle actin positive. However, desmin positivity was strong and diffuse in the spindled and more pleomorphic areas on 2 additional tissue sections. No rhabdomyoblasts or striated muscle fibers were seen. A diagnosis of pleomorphic leiomyosarcoma was rendered. This case highlights a unique clinical and histological presentation of a leiomyosarcoma initially mistaken to be a ruptured epidermal inclusion cyst, and the need to sometimes apply ancillary immunohistochemical studies to sections from more than one tissue block to accurately differentiate heterogeneous sarcomas with similar histologic features.

Characterization of a Clival Chordoma Xenograft Model Reveals Tumor Genomic Instability.

Patient-derived xenografts retain the genotype of the parent tumors more readily than tumor cells maintained in culture. The two previously reported clival chordoma xenografts were derived from recurrent tumors after radiation. To study the genetics of clival chordoma in the absence of prior radiation exposure we established a patient-derived xenograft at primary resection of a clival chordoma. Epicranial grafting of clival chordoma collected during surgery was performed. Tumor growth was established in a nonobese diabetic/severe combined immunodeficiency mouse and tumors have been passaged serially for seven generations. Physaliferous cell architecture was shown in the regenerated tumors, which stained positive for Brachyury, cytokeratin, and S100 protein. The tumors showed bone invasion. Single-nucleotide polymorphism analysis of the tumor xenograft was compared with the parental tumor. Copy number gain of the T gene (brachyury) and heterozygous loss of cyclin dependent kinase inhibitor 2A (CDKN2A) was observed. Heterozygous loss of the tumor-suppressor fragile histidine triad (FHIT) gene also was observed, although protein expression was preserved. Accumulation of copy number losses and gains as well as increased growth rate was observed over three generations. The patient-derived xenograft reproduces the phenotype of clival chordoma. This model can be used in the future to study chordoma biology and to assess novel treatments.

Enhancing glioblastoma treatment using cisplatin-gold-nanoparticle conjugates and targeted delivery with magnetic resonance-guided focused ultrasound.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor resulting in high rates of morbidity and mortality. A strategy to increase the efficacy of available drugs and enhance the delivery of chemotherapeutics through the blood brain barrier (BBB) is desperately needed. We investigated the potential of Cisplatin conjugated gold nanoparticle (GNP-UP-Cis) in combination with MR-guided Focused Ultrasound (MRgFUS) to intensify GBM treatment. Viability assays demonstrated that GNP-UP-Cis greatly inhibits the growth of GBM cells compared to free cisplatin and shows marked synergy with radiation therapy. Additionally, increased DNA damage through γH2AX phosphorylation was observed in GNP-UP-Cis treated cells, along with enhanced platinum concentrations. In vivo, GNP-UP-Cis greatly reduced the growth of GBM tumors and MRgFUS led to increased BBB permeability and GNP-drug delivery in brain tissue. Our studies suggest that GNP-Cis conjugates and MRgFUS can be used to focally enhance the delivery of targeted chemotherapeutics to brain tumors.

Diagnosis of glenoid labral tears using 3-tesla MRI vs. 3-tesla MRA: a systematic review and meta-analysis.

BACKGROUND: Various protocols exist for magnetic resonance arthrogram (MRA) of the shoulder, including 3D isotropic scanning and positioning in neutral (2D neutral MRA), or abduction-external-rotation (ABER). HYPOTHESIS: MRA does not improve diagnostic accuracy for labral tears when compared to magnetic resonance imaging (MRI) performed using 3-Tesla (3T) magnets. METHOD: Systematic review of the Cochrane, MEDLINE, and PubMed databases according to PRISMA guidelines. Included studies compared 3T MRI or 3T MRA (index tests) to arthroscopic findings (reference test). Methodological appraisal performed using QUADAS-2. Pooled sensitivity and specificity were calculated. RESULTS: Ten studies including 929 patients were included. Index test bias and applicability were a concern in the majority of studies. The use of arthroscopy as the reference test raised concern of verification bias in all studies. For anterior labral lesions, 3T MRI was less sensitive (0.83 vs. 0.87 p = 0.083) than 3T 2D neutral MRA. Compared to 3T 2D neutral MRA, both 3T 3D Isotropic MRA and 3T ABER MRA significantly improved sensitivity (0.87 vs. 0.95 vs. 0.94). For SLAP lesions, 3T 2D neutral MRA was of similar sensitivity to 3T MRI (0.84 vs. 0.83, p = 0.575), but less specific (0.99 vs. 0.92 p < 0.0001). For posterior labral lesions, 3T 2D neutral MRA had greater sensitivity than 3T 3D Isotropic MRA and 3T MRI (0.90 vs. 0.83 vs. 0.83). CONCLUSIONS: At 3-T, MRA improved sensitivity for diagnosis of anterior and posterior labral lesions, but reduced specificity in diagnosis of SLAP tears. 3T MRA with ABER positioning further improved sensitivity in diagnosis of anterior labral tears. LEVEL OF EVIDENCE: IV.

Epithelial Cell Transforming 2 and Aurora Kinase B Modulate Formation of Stress Granule-Containing Transcripts from Diverse Cellular Pathways in Astrocytoma Cells.

Stress granules are small RNA-protein granules that modify the translational landscape during cellular stress to promote survival. The RhoGTPase RhoA is implicated in the formation of RNA stress granules. Our data demonstrate that the cytokinetic proteins epithelial cell transforming 2 and Aurora kinase B (AurkB) are localized to stress granules in human astrocytoma cells. AurkB and its downstream target histone-3 are phosphorylated during arsenite-induced stress. Chemical (AZD1152-HQPA) and siRNA inhibition of AurkB results in fewer and smaller stress granules when analyzed using high-throughput fluorescent-based cellomics assays. RNA immunoprecipitation with the known stress granule aggregates TIAR and G3BP1 was performed on astrocytoma cells, and subsequent analysis revealed that astrocytoma stress granules harbor unique mRNAs for various cellular pathways, including cellular migration, metabolism, translation, and transcriptional regulation. Human astrocytoma cell stress granules contain mRNAs that are known to be involved in glioma signaling and the mammalian target of rapamycin pathway. These data provide evidence that RNA stress granules are a novel form of epigenetic regulation in astrocytoma cells, which may be targetable by chemical inhibitors and enhance astrocytoma susceptibility to conventional therapy, such as radiation and chemotherapy.

The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants.

Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth.

Diagnostic Efficacy of 3-T MRI for Knee Injuries Using Arthroscopy as a Reference Standard: A Meta-Analysis.

OBJECTIVE: The objectives of our study were to assess the evidence for the diagnostic efficacy of 3-T MRI for meniscal and anterior cruciate ligament (ACL) injuries in the knee using arthroscopy as the reference standard and to compare these results with the results of a previous meta-analysis assessing 1.5-T MRI. MATERIALS AND METHODS: The online Cochrane Library, MEDLINE, and PubMed databases were searched using the following terms: MRI AND ((3 OR three) AND (Tesla OR T)) AND knee AND arthroscopy AND (menisc* OR ligament). Patient demographics, patient characteristics, MRI scanning details, and diagnostic results were investigated. The methodologic quality of the included studies was assessed using the revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. A meta-analysis of studies using 3-T MRI was performed, and the results were compared with a previous meta-analysis of studies using 1.5-T MRI. RESULTS: One hundred one studies were identified by the search strategy, and 13 studies were included in our review. Twelve studies were considered to have level 1b evidence, and one study was considered to have level 2b evidence. All 13 studies had high methodologic integrity and low risk of bias using the QUADAS-2 tool. The studies included 1197 patients with a mean age of 41.9 years. Ten of the 13 studies were eligible for meta-analysis. The mean sensitivity and mean specificity of 3-T MRI for knee injuries by location were as follows: medial meniscus, 0.94 (95% CI, 0.91-0.96) and 0.79 (95% CI, 0.75-0.83), respectively; lateral meniscus, 0.81 (95% CI, 0.75-0.85) and 0.87 (95% CI, 0.84-0.89); and ACL, 0.92 (95% CI, 0.83-0.96) and 0.99 (95% CI, 0.96-1.00). The specificity of 3-T MRI for injuries of the lateral meniscus was significantly lower than that of 1.5-T MRI (p = 0.0013). CONCLUSION: This study does not provide evidence that 3-T scanners have superior diagnostic efficacy for meniscal damage and ACL integrity when compared with previous studies of 1.5-T machines.

Medulloblastoma: Tumor Biology and Relevance to Treatment and Prognosis Paradigm.

Medulloblastoma is a malignant embryonic brain tumor arising in the posterior fossa and typically occurring in pediatric patients. Current multimodal treatment regimes have significantly improved the survival rates; however, a marked heterogeneity in therapy response is observed, and one third of all patients die within 5 years after diagnosis. Large-scale genetic and transcriptome analysis revealed four medulloblastoma subgroups (WNT, SHH, Group 3, and Group 4) associated with different demographic parameters, tumor manifestation, and clinical behavior. Future treatment protocols will integrate molecular classification schemes to evaluate subgroup-specific intensification or de-escalation of adjuvant therapies aimed to increase tumor control and reduce iatrogenic induced morbidity. Furthermore, the identification of genetic drivers allows assessing target therapies in order to increase the chemotherapeutic armamentarium. This review highlights the biology behind the current classification system and elucidates relevant aspects of the disease influencing forthcoming clinical trials.

Dual band sensitivity enhancements of a VO(x) microbolometer array using a patterned gold black absorber.

Infrared-absorbing gold black has been selectively patterned onto the active surfaces of a vanadium-oxide-based infrared bolometer array. Patterning by metal lift-off relies on protection of the fragile gold black with an evaporated oxide, which preserves much of gold black's high absorptance. This patterned gold black also survives the dry-etch removal of the sacrificial polyimide used to fabricate the air-bridge bolometers. For our fabricated devices, infrared responsivity is improved 22% in the long-wave IR and 70% in the mid-wave IR by the gold black coating, with no significant change in detector noise, using a 300°C blackbody and 80 Hz chopping rate. The increase in the time constant caused by the additional mass of gold black is ∼15%.

Diagnosis of rotator cuff tears using 3-Tesla MRI versus 3-Tesla MRA: a systematic review and meta-analysis.

OBJECTIVE: To compare the diagnostic accuracy of magnetic resonance imaging (MRI), 2-dimensional magnetic resonance arthrogram (MRA) and 3-dimensional isotropic MRA in the diagnosis of rotator cuff tears when performed exclusively at 3-T. MATERIALS AND METHODS: A systematic review was undertaken of the Cochrane, MEDLINE and PubMed databases in accordance with the PRISMA guidelines. Studies comparing 3-T MRI or 3-T MRA (index tests) to arthroscopic surgical findings (reference test) were included. Methodological appraisal was performed using QUADAS 2. Pooled sensitivity and specificity were calculated and summary receiver-operating curves generated. Kappa coefficients quantified inter-observer reliability. RESULTS: Fourteen studies comprising 1332 patients were identified for inclusion. Twelve studies were retrospective and there were concerns regarding index test bias and applicability in nine and six studies respectively. Reference test bias was a concern in all studies. Both 3-T MRI and 3-T MRA showed similar excellent diagnostic accuracy for full-thickness supraspinatus tears. Concerning partial-thickness supraspinatus tears, 3-T 2D MRA was significantly more sensitive (86.6 vs. 80.5 %, p = 0.014) but significantly less specific (95.2 vs. 100 %, p < 0.001). There was a trend towards greater accuracy in the diagnosis of subscapularis tears with 3-T MRA. Three-Tesla 3D isotropic MRA showed similar accuracy to 3-T conventional 2D MRA. CONCLUSION: Three-Tesla MRI appeared equivalent to 3-T MRA in the diagnosis of full- and partial-thickness tears, although there was a trend towards greater accuracy in the diagnosis of subscapularis tears with 3-T MRA. Three-Tesla 3D isotropic MRA appears equivalent to 3-T 2D MRA for all types of tears.

Divergent immunity and energetic programs in the gills of migratory and resident Oncorhynchus mykiss.

Divergent life history strategies occur in steelhead or rainbow trout Oncorhynchus mykiss, and many populations produce both migrant (anadromous fish that move to the ocean after rearing) and resident (do not migrate and remain in fresh water) individuals. Mechanisms leading to each type are only partially understood; while the general tendency of a population is heritable, individual tendency may be plastic, influenced by local environment. Steelhead hatchery programmes aim to mitigate losses in wild stocks by producing trout that will migrate to the ocean and not compete with wild trout for limited freshwater resources. To increase our understanding of gill function in these migratory or resident phenotypes, here we compare gill transcriptome profiles of hatchery-released fish either at the release site (residents) or five river kilometres downstream while still in full fresh water (migrants). To test whether any of these genes can be used as predictive markers for smoltification, we compared these genes between migrant-like and undifferentiated trout while still in the hatchery in a common environment (prerelease). Results confirmed the gradual process of smoltification, and the importance of energetics, gill remodelling and ion transport capacity for migrants. Additionally, residents overexpressed transcripts involved in antiviral defences, potentially for immune surveillance via dendritic cells in the gills. The best smoltification marker candidate was protein s100a4, expression of which was highly correlated with Na(+) , K(+) ATPase (NKA) activity and smolt-like morphology in pre- and postrelease trout gills.

The role of drebrin in glioma migration and invasion.

Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite current advances in therapy consisting of surgery followed by chemotherapy and radiation, the overall survival rate still remains poor. Therapeutic failures are partly attributable to the highly infiltrative nature of tumor adjacent to normal brain parenchyma. Recently, evidence is mounting to suggest that actin cytoskeleton dynamics are critical components of the cell invasion process. Drebrin is an actin-binding protein involved in the regulation of actin filament organization, and plays a significant role in cell motility; however, the role of drebrin in glioma cell invasiveness has not yet been fully elucidated. Therefore, this study was aimed to clarify the role of drebrin in glioma cell morphology and cell motility. Here we show that drebrin is expressed in glioma cell lines and in operative specimens of GBM. We demonstrate that stable overexpression of drebrin in U87 cells leads to alterations in cell morphology, and induces increased invasiveness in vitro while knockdown of drebrin in U87 cells by small interfering RNA (siRNA) decreases invasion and migration. In addition, we show that depletion of drebrin by siRNA alters glioma cell morphology in A172 GBM cell line. Our results suggest that drebrin contributes to the maintenance of cell shape, and may play an important role in glioma cell motility.

Testing advances in molecular discrimination among Chinook salmon life histories: evidence from a blind test.

The application of DNA-based markers toward the task of discriminating among alternate salmon runs has evolved in accordance with ongoing genomic developments and increasingly has enabled resolution of which genetic markers associate with important life-history differences. Accurate and efficient identification of the most likely origin for salmon encountered during ocean fisheries, or at salvage from fresh water diversion and monitoring facilities, has far-reaching consequences for improving measures for management, restoration and conservation. Near-real-time provision of high-resolution identity information enables prompt response to changes in encounter rates. We thus continue to develop new tools to provide the greatest statistical power for run identification. As a proof of concept for genetic identification improvements, we conducted simulation and blind tests for 623 known-origin Chinook salmon (Oncorhynchus tshawytscha) to compare and contrast the accuracy of different population sampling baselines and microsatellite loci panels. This test included 35 microsatellite loci (1266 alleles), some known to be associated with specific coding regions of functional significance, such as the circadian rhythm cryptochrome genes, and others not known to be associated with any functional importance. The identification of fall run with unprecedented accuracy was demonstrated. Overall, the top performing panel and baseline (HMSC21) were predicted to have a success rate of 98%, but the blind-test success rate was 84%. Findings for bias or non-bias are discussed to target primary areas for further research and resolution.

Focused ultrasound delivery of Raman nanoparticles across the blood-brain barrier: potential for targeting experimental brain tumors.

Spectral mapping of nanoparticles with surface enhanced Raman scattering (SERS) capability in the near-infrared range is an emerging molecular imaging technique. We used magnetic resonance image-guided transcranial focused ultrasound (TcMRgFUS) to reversibly disrupt the blood-brain barrier (BBB) adjacent to brain tumor margins in rats. Glioma cells were found to internalize SERS capable nanoparticles of 50nm or 120nm physical diameter. Surface coating with anti-epidermal growth factor receptor antibody or non-specific human immunoglobulin G, resulted in enhanced cell uptake of nanoparticles in-vitro compared to nanoparticles with methyl terminated 12-unit polyethylene glycol surface. BBB disruption permitted the delivery of SERS capable spherical 50 or 120nm gold nanoparticles to the tumor margins. Thus, nanoparticles with SERS imaging capability can be delivered across the BBB non-invasively using TcMRgFUS and have the potential to be used as optical tracking agents at the invasive front of malignant brain tumors. FROM THE CLINICAL EDITOR: This study demonstrates the use of magnetic resonance image-guided transcranial focused ultrasound to open the BBB and enable spectral mapping of nanoparticles with surface enhanced Raman scattering (SERS)-based molecular imaging for experimental tumor tracking.

The use of the ligament augmentation and reconstruction system (LARS) for posterior cruciate reconstruction.

PURPOSE: To systematically review and assess the use of the Ligament Advanced Reinforcement System (LARS; Surgical Implants and Devices, Arc-sur-Tille, France) for posterior cruciate ligament (PCL) reconstruction. METHODS: A search of multiple databases was conducted using the following terms: (LARS[All Fields] AND posterior[All Fields]) OR (LARS[All Fields] AND PCL[All Fields]). The methodologic quality of each article was assessed by use of abridged Downs and Black criteria. RESULTS: Fifty-four studies were found from the database search, of which 5 were included in the final review (4 case series and 1 case-control study). One hundred twenty-nine PCL reconstructions with LARS were performed. The mean patient age was 32.2 years, with 89 male and 40 female patients included. The mean follow-up time ranged from 10.5 to 44 months. Lysholm scores improved from a mean of 64.8 preoperatively to 89.8 postoperatively. No patients had International Knee Documentation Committee grade 1 or 2 preoperatively, with 93.0% achieving this postoperatively. Only 1 case of synovitis and 1 case of graft rupture were reported. CONCLUSIONS: There is little evidence on the effectiveness of PCL reconstructions using LARS ligaments. What data there are show great promise, with short- and medium-term outcome data appearing favorable to autograft reconstruction. Complication rates are encouragingly low. CLINICAL RELEVANCE: LARS has great potential for PCL reconstruction. Further studies are needed regarding the use of LARS ligaments during PCL reconstruction, including longer follow-up periods and investigation into the optimal timing for reconstruction. This may be best achieved by way of a multicenter study.