Transient receptor potential melastatin 2 (TRPM2) ion channel has an essential function in modulating cell survival following oxidant injury and is highly expressed in many cancers including ...neuroblastoma. Here, in xenografts generated from neuroblastoma cells in which TRPM2 was depleted with CRISPR/Cas9 technology and in in vitro experiments, tumor growth was significantly inhibited and doxorubicin sensitivity increased. The hypoxia-inducible transcription factor 1/2α (HIF-1/2α) signaling cascade including proteins involved in oxidant stress, glycolysis, and mitochondrial function was suppressed by TRPM2 depletion. TRPM2-depleted SH-SY5Y neuroblastoma cells demonstrated reduced oxygen consumption and ATP production after doxorubicin, confirming impaired cellular bioenergetics. In cells in which TRPM2 was depleted, mitochondrial superoxide production was significantly increased, particularly following doxorubicin. Ectopic expression of superoxide dismutase 2 (SOD2) reduced ROS and preserved viability of TRPM2-depleted cells, however, failed to restore ATP levels. Mitochondrial reactive oxygen species (ROS) were also significantly increased in cells in which TRPM2 function was inhibited by TRPM2-S, and pretreatment of these cells with the antioxidant MitoTEMPO significantly reduced ROS levels in response to doxorubicin and protected cell viability. Expression of the TRPM2 pore mutant E960D, in which calcium entry through TRPM2 is abolished, also resulted in significantly increased mitochondrial ROS following doxorubicin treatment, showing the critical role of TRPM2-mediated calcium entry. These findings demonstrate the important function of TRPM2 in modulation of cell survival through mitochondrial ROS, and the potential of targeted inhibition of TRPM2 as a therapeutic approach to reduce cellular bioenergetics, tumor growth, and enhance susceptibility to chemotherapeutic agents.
Abstract
BACKGROUND:
Optimal postoperative management paradigm for brain metastases remains controversial.
OBJECTIVE:
To conduct a systematic review of the literature to understand the role of ...postoperative stereotactic radiosurgery after resection of brain metastases.
METHODS:
We performed a MEDLINE search of the literature to identify series of patients with brain metastases treated with stereotactic radiosurgery after surgical resection. Outcomes including overall survival, local control, distant intracranial failure, and salvage therapy use were recorded. Patient, tumor, and treatment factors were correlated with outcomes through the use of the Pearson correlation and 2-way Student t test as appropriate.
RESULTS:
Fourteen studies involving 629 patients were included. Median survival for all studies was 14 months. Local control was correlated with the median volume treated with radiosurgery (r = −0.766, P < .05) and with the rate of gross total resection (r = .728, P < .03). Mean crude local control was 83%; 1-year local control was 85%. Distant intracranial failure occurred in 49% of cases, and salvage whole-brain radiation therapy was required in 29% of cases. Use of a radiosurgical margin did not lead to increased local control or overall survival.
CONCLUSION:
Our systematic review supports the use of radiosurgery as a safe and effective strategy for adjuvant treatment of brain metastases, particularly when gross total resection has been achieved. With all limitations of comparisons between studies, no increase in local recurrence or decrease in overall survival compared with rates with adjuvant whole-brain radiation therapy was found.
Treating patient populations with significant psychiatric and neurocognitive symptomatology can present a unique clinical dilemma: progress in psychotherapy can be significantly fettered by cognitive ...deficits, whereas neurocognitive rehabilitation efforts can be ineffective because of psychiatric overlay. Application of mindfulness-based interventions to address either cognitive or psychiatric symptoms in isolation appears efficacious in many contexts; however, it remains unclear whether this type of intervention might help address simultaneous neurocognitive and psychiatric symptomatology. In a pre-post mixed methods design pilot study, nine Veterans with post-traumatic stress disorder (PTSD) and a history of mild traumatic brain injury with chronic cognitive complaints participated in Mindfulness-Based Stress Reduction (MBSR). Clinical interview, questionnaires, and attention and PTSD measures were administered immediately before, immediately after, and 3 months after MBSR completion. Qualitative and quantitative findings suggest high levels of safety, feasibility, and acceptability. Measurement of attention revealed significant improvement immediately following MBSR (p < 0.05, d = 0.57) and largely sustained improvement 3 months after completion of MBSR (p < 0.10, d = 0.48). Significant reduction in PTSD symptoms was found immediately after MBSR (p < 0.05, d = -1.56), and was sustained 3 months following MBSR completion (p < 0.05, d = -0.93). These results warrant a randomized controlled trial follow-up. Potential mechanisms for the broad effects observed will be explored.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Detection methods that do not require nucleic acid amplification are advantageous for viral diagnostics due to their rapid results. These platforms could provide information for both accurate ...diagnoses and pandemic surveillance. Influenza virus is prone to pandemic-inducing genetic mutations, so there is a need to apply these detection platforms to influenza diagnostics. Here, we analyzed the Fast Evaluation of Viral Emerging Risks (FEVER) pipeline on ultrasensitive detection platforms, including a waveguide-based optical biosensor and a flow cytometry bead-based assay. The pipeline was also evaluated in silico for sequence coverage in comparison to the U.S. Centers for Disease Control and Prevention's (CDC) influenza A and B diagnostic assays. The influenza FEVER probe design had a higher tolerance for mismatched bases than the CDC's probes, and the FEVER probes altogether had a higher detection rate for influenza isolate sequences from GenBank. When formatted for use as molecular beacons, the FEVER probes detected influenza RNA as low as 50 nM on the waveguide-based optical biosensor and 1 nM on the flow cytometer. In addition to molecular beacons, which have an inherently high background signal we also developed an exonuclease selection method that could detect 500 pM of RNA. The combination of high-coverage probes developed using the FEVER pipeline coupled with ultrasensitive optical biosensors is a promising approach for future influenza diagnostic and biosurveillance applications.
Independent and chain coffee shops offer similar products, but differ in their organisational form and branding. We examine the entry and exit patterns of 4,768 coffee retailers in Melbourne between ...1991 and 2010. Panel logit regressions indicate that chain stores have no discernible effect on the exit or entry decisions of independent stores. However, chains and independents do increase the probability of exit for neighbouring stores of their own type. These findings imply that independents and chains operate almost as though they are in separate markets.
Viral pathogens can rapidly evolve, adapt to novel hosts, and evade human immunity. The early detection of emerging viral pathogens through biosurveillance coupled with rapid and accurate diagnostics ...are required to mitigate global pandemics. However, RNA viruses can mutate rapidly, hampering biosurveillance and diagnostic efforts. Here, we present a novel computational approach called FEVER (Fast Evaluation of Viral Emerging Risks) to design assays that simultaneously accomplish: 1) broad-coverage biosurveillance of an entire group of viruses, 2) accurate diagnosis of an outbreak strain, and 3) mutation typing to detect variants of public health importance. We demonstrate the application of FEVER to generate assays to simultaneously 1) detect sarbecoviruses for biosurveillance; 2) diagnose infections specifically caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); and 3) perform rapid mutation typing of the D614G SARS-CoV-2 spike variant associated with increased pathogen transmissibility. These FEVER assays had a high in silico recall (predicted positive) up to 99.7% of 525,708 SARS-CoV-2 sequences analyzed and displayed sensitivities and specificities as high as 92.4% and 100% respectively when validated in 100 clinical samples. The D614G SARS-CoV-2 spike mutation PCR test was able to identify the single nucleotide identity at position 23,403 in the viral genome of 96.6% SARS-CoV-2 positive samples without the need for sequencing. This study demonstrates the utility of FEVER to design assays for biosurveillance, diagnostics, and mutation typing to rapidly detect, track, and mitigate future outbreaks and pandemics caused by emerging viruses.
Abstract Background & purpose The cervicothoracic differentiation test (CTDT), cervical and thoracic unloading are used clinically to guide treatment. This study sought to determine the reliability ...and diagnostic accuracy of these tests. Methods A prospective diagnostic accuracy study was performed at two outpatient clinics and one university research center. A convenience sample of 48 individuals with neck pain was recruited. Cervical and thoracic unloading tests and CTDT were performed with symptom relief considered a positive test. Pain was assessed using a visual analog pain scale (VAS) at rest and during provocative movements. The reference standard was pain relief following thoracic manipulation. Change in pain was used to identify improvement at the MCID (15 mm) and 50% improvement thresholds. Results All three tests demonstrated high levels of inter-rater reliability, K = 0.900.77–1.00. Of 48 individuals who completed the study, 39 (81.3%) were improved ≥ MCID; compared to 34 (70.8%) at the 50% threshold. As a single test, the CTDT yielded the strongest diagnostic utility (at MCID threshold) based on ROC curve: AUC 0.791 s.e. 0.078; with high specificity (0.8951.75–99.72); LR+ 6.23 0.97–40; LR- 0.35 0.20–0.58; and PPV 96.43. Unloading tests demonstrated high sensitivity, but poor specificity and likelihood ratios. Composite tests improved specificity, but with lower accuracy and minimal changes in ROC area compared to the CTDT in isolation. Conclusions The CTDT is a specific test with significant diagnostic utility to identify individuals who will experience immediate pain relief following thoracic manipulation. The CTDT should be considered during the clinical decision making process when treating individuals with neck pain.
This study determines the reproducibility of magnetic resonance elastography (MRE) derived brain stiffness in normal volunteers and compares it against pseudotumor patients before and after lumbar ...puncture (LP).
MRE was performed on 10 normal volunteers for reproducibility and 14 pseudotumor patients before and after LP. During LP, opening and closing cerebrospinal fluid (CSF) pressures were recorded before and after removal of CSF and correlated to brain stiffness.
Stiffness reproducibility was observed (r > 0.78; p < 0.008). Whole brain opening LP stiffness was significantly (p = 0.04) higher than normals, but no significant difference (p = 0.11) in closing LP measurements. No significant correlation was observed between opening and closing pressure and brain stiffness.
Display omitted
•MRE-derived stiffness measurements of the brain are reproducible.•MRE brain stiffness in pseudotumor patients before and after LP was investigated.•MRE stiffness was significantly higher in IIH patients before LP compared to normal healthy volunteers.•No correlation was observed between opening and closing pressure and stiffness.
Across the world, the housing crisis is escalating. Mass migration to cities has led to rapid urbanisation on an unprecedented scale, while the withdrawal of public funding from social housing ...provision in Western countries, and widening income inequality, have further compounded the situation. In prosperous US and European cities, middle- and low-income residents are being pushed out of housing markets increasingly dominated by luxury investors. The average London tenant, for example, now pays an unaffordable 49 per cent of his or her pre-tax income in rent. Parts of the developing world and areas of forced migration are experiencing insufficient affordable housing stock coupled with rapidly shifting ways of life. In response to this context, forward-thinking architects are taking the lead with a collaborative approach. By partnering with allied fields, working with residents, developing new forms of housing, and leveraging new funding systems and policies, they are providing strategic leadership for what many consider to be our cities' most pressing crisis. Amidst growing economic and health disparities, this issue of AD asks how housing projects, and the design processes behind them, might be interventions towards greater social equity, and how collaborative work in housing might reposition the architectural profession at large. Recommended by Fast Company as one of the best reads of 2018 and included in their list of 9 books designers should read in 2019! Contributors include: Cynthia Barton, Deborah Gans, and Rosamund Palmer; Neeraj Bhatia and Antje Steinmuller; Dana Cuff; Fatou Dieye; Robert Fishman; Na Fu; Paul Karakusevic; Kaja Kühl and Julie Behrens; Matthew Gordon Lasner; Meir Lobaton Corona; Marc Norman; Julia Park; Brian Phillips and Deb Katz; Pollyanna Rhee; Emily Schmidt and Rosalie Genevro Featured architects: Architects for Social Housing, ShigeruBan Architects, Tatiana Bilbao ESTUDIO, cityLAB, Frédéric Druot Architecture, ERA Architects, GANS studio, Garrison Architects, HOWOGE, Interface Studio Architects, Karakusevic Carson Architects, Lacaton & Vassal, Light Earth Designs, NHDM, PYATOK architecture + urban design, Urbanus, and Urban Works Agency
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