Tumor-associated macrophages (TAMs) usually express an M2 phenotype, which enables them to perform immunosuppressive and tumor-promoting functions. Reprogramming these TAMs toward an M1 phenotype ...could thwart their pro-cancer activities and unleash anti-tumor immunity, but efforts to accomplish this are nonspecific and elicit systemic inflammation. Here we describe a targeted nanocarrier that can deliver in vitro-transcribed mRNA encoding M1-polarizing transcription factors to reprogram TAMs without causing systemic toxicity. We demonstrate in models of ovarian cancer, melanoma, and glioblastoma that infusions of nanoparticles formulated with mRNAs encoding interferon regulatory factor 5 in combination with its activating kinase IKKβ reverse the immunosuppressive, tumor-supporting state of TAMs and reprogram them to a phenotype that induces anti-tumor immunity and promotes tumor regression. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this immunotherapy could enable physicians to obviate suppressive tumors while avoiding systemic treatments that disrupt immune homeostasis.
Therapies based on immune cells have been applied for diseases ranging from cancer to diabetes. However, the viral and electroporation methods used to create cytoreagents are complex and expensive. ...Consequently, we develop targeted mRNA nanocarriers that are simply mixed with cells to reprogram them via transient expression. Here, we describe three examples to establish that the approach is simple and generalizable. First, we demonstrate that nanocarriers delivering mRNA encoding a genome-editing agent can efficiently knock-out selected genes in anti-cancer T-cells. Second, we imprint a long-lived phenotype exhibiting improved antitumor activities into T-cells by transfecting them with mRNAs that encode a key transcription factor of memory formation. Third, we show how mRNA nanocarriers can program hematopoietic stem cells with improved self-renewal properties. The simplicity of the approach contrasts with the complex protocols currently used to program therapeutic cells, so our methods will likely facilitate manufacturing of cytoreagents.Current widely used viral and electroporation methods for creating therapeutic cell-based products are complex and expensive. Here, the authors develop targeted mRNA nanocarriers that can transiently program gene expression by simply mixing them with cells, to improve their therapeutic potential.
Rethinking Individualism and Collectivism Oyserman, Daphna; Coon, Heather M; Kemmelmeier, Markus
Psychological bulletin,
01/2002, Letnik:
128, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Are Americans more individualistic and less collectivistic than members of other
groups? The authors summarize plausible psychological implications of
individualism-collectivism (IND-COL), ...meta-analyze cross-national and
within-United States IND-COL differences, and review evidence for effects of
IND-COL on self-concept, well-being, cognition, and relationality. European
Americans were found to be both more individualistic-valuing personal
independence more-and less collectivistic-feeling duty to
in-groups less-than others. However, European Americans were not more
individualistic than African Americans, or Latinos, and not less collectivistic
than Japanese or Koreans. Among Asians, only Chinese showed large effects, being
both less individualistic and more collectivistic. Moderate IND-COL effects were
found on self-concept and relationality, and large effects were found on
attribution and cognitive style.
is amplified in 20% to 25% of neuroblastoma, and
-amplified neuroblastoma contributes to a large percent of pediatric cancer-related deaths. Therapy improvements for this subtype of cancer are a high ...priority. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified
rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1. Accumulating iron causes reactive oxygen species (ROS) production, and
-amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. This dependence creates a marked vulnerability to targeting the system Xc-/glutathione (GSH) pathway with ferroptosis inducers. This reliance can be exploited through therapy with FDA-approved rheumatoid arthritis drugs sulfasalazine (SAS) and auranofin: in
-amplified, patient-derived xenograft models, both therapies blocked growth and induced ferroptosis. SAS and auranofin activity was largely mitigated by the ferroptosis inhibitor ferrostatin-1, antioxidants like N-acetyl-L-cysteine, or by the iron scavenger deferoxamine (DFO). DFO reduced auranofin-induced ROS, further linking increased iron capture in
-amplified neuroblastoma to a therapeutic vulnerability to ROS-inducing drugs. These data uncover an oncogene vulnerability to ferroptosis caused by increased iron accumulation and subsequent reliance on the system Xc-/GSH pathway. SIGNIFICANCE: This study shows how MYCN increases intracellular iron levels and subsequent GSH pathway activity and demonstrates the antitumor activity of FDA-approved SAS and auranofin in patient-derived xenograft models of
-amplified neuroblastoma.
To determine the innervation pattern to the thumb carpometacarpal (CMC) joint and assess the safety and efficacy of selective joint denervation for the treatment of pain and impairment associated ...with thumb CMC arthritis.
Cadaveric dissections were performed in 10 fresh upper extremities to better define the innervation patterns to the CMC joint and guide the surgical approach for CMC joint denervation. Histologic confirmation of candidate nerves was performed with hematoxylin and eosin staining. Results from a series of 12 patients with symptomatic thumb CMC arthritis who underwent selective denervation were retrospectively evaluated to determine the safety and efficacy of this treatment approach. Differences in preoperative and postoperative measurements of grip and key-pinch strength as well as subjective reporting of symptoms were compared.
Nerve branches to the thumb CMC joint were found to arise from the lateral antebrachial cutaneous nerve (10 of 10 specimens), the palmar cutaneous branch of the median nerve (7 of 10 specimens), and the radial sensory nerve (4 of 10 specimens). With an average follow-up time of 15 months, 11 of 12 patients (92%) reported complete or near-complete relief of pain. Average improvements in grip and lateral key-pinch strength were 4.1 ± 3.0 kg (18% ± 12% from baseline) and 1.7 ± 0.5 kg (37% ± 11% from baseline), respectively. One patient experienced the onset of new pain consistent with a neuroma that resolved with steroid injection. All patients were released to light activity at 1 week after surgery, and all activity restrictions were lifted by 6 weeks after surgery.
Selective denervation of the CMC joint is an effective approach to treat pain and alleviate impairment associated with CMC arthritis. The procedure is well tolerated, with faster recovery as compared with trapeziectomy. Branches arising from the lateral antebrachial cutaneous nerve, palmar cutaneous branch of the median nerve, and radial sensory nerve can be identified and resected with a single-incision Wagner approach.
Therapeutic V.
Total knee arthroplasty (TKA) has evolved during the past 30 years to a well-defined technical surgery with excellent results for as many as 20 years of followup. The concepts of exposure, ligament ...balancing, and joint alignment have been established clearly by Insall and others. In the early 1990s, Repicci introduced minimally invasive surgery for unicondylar knee arthroplasty. This approach suggested that less invasive surgery could accomplish similar results to those of standard unicondylar knee arthroplasty. Early reports in the literature support these conclusions. It only was logical that the minimally invasive surgery approach eventually would be applied to TKA. It is extremely important to establish a clear definition of the minimally invasive surgery and, then, to follow the results. We have completed 70 minimally-invasive TKAs during the past 9 months with early results that indicate less intraoperative blood loss, shorter length of stay, increased range of motion (ROM), with similar implant accuracy to standard TKA. These new procedures will require thorough evaluation as with any new clinical endeavor. It also is of paramount importance to remember that the main goal of any new technology is to advance the science of medicine without compromising the ultimate result for the patient. The early findings are encouraging for the future of minimally invasive TKA and we hope to improve the technology during the next few years.
The construct of individualism–collectivism (IND-COL) has become the definitive standard in cross-cultural psychology, management, and related fields. It is also among the most controversial, in ...particular, with regard to the ambiguity of its dimensionality: Some view IND and COL as the opposites of a single continuum, whereas others argue that the two are independent constructs. We explored the issue through seven different tests using original individual-level data from 50 studies and meta-analytic data from 149 empirical publications yielding a total of 295 sample-level observations that were collected using six established instruments for assessing IND and COL as separate constructs. Results indicated that the dimensionality of IND-COL may depend on (a) the specific instrument used to collect the data, (b) the sample characteristics and the cultural region from which the data were collected, and (c) the level of analysis. We also review inconsistencies, deficiencies, and challenges of conceptualizing IND-COL and provide guidelines for developing and selecting instruments for measuring the construct, and for reporting and meta-analyzing results from this line of research.
Introduction
Robotic-arm assisted unicompartmental knee arthroplasty (RA-UKA) has demonstrated accurate component positioning and excellent outcomes for medial components. However, there is a paucity ...of literature on lateral compartment RA-UKA. The purpose of our study was to assess the midterm clinical outcomes and survivorship of lateral RA-UKA.
Methods
This study was a retrospective review of a single-center prospectively maintained cohort of 33 patients (36 knees) indicated for lateral UKA. Perioperative, and postoperative two- and five-year Knee injury Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Score (WOMAC), and Forgotten Joint Score (FJS) patient reported outcome measures were collected. Five-year follow-up was recorded in 29 patients (32 knees).
Results
Mean follow up was 5.1 ± 0.1 years. Mean age and BMI was 70.9 ± 7.2 years and 29.0 ± 4.2 kg/m2, respectively. At discharge, mean distance walked was 273.4 ± 70.4 feet, and mean pain score was 2.0 ± 2.5. At 2-year follow up, mean KOOS, WOMAC, and FJS were 75.1 ± 13.5, 15.0 ± 7.2, and 81.0 ± 23.3, respectively. At 5-year follow up, mean KOOS, WOMAC, and FJS were 75.3 ± 14.6, 14.9 ± 5.0, and 75.8 ± 27.4, respectively. Mean change in KOOS and WOMAC were 35.6 ± 27.1 and 11.7 ± 13.4 (p< .001 and p< .001). 94% of patients were very satisfied/satisfied, 3% neutral, and 3% dissatisfied. 91% met activity expectations, and 59% were more active than before. Survivorship was 100% at 5 years.
Discussion
In this study, lateral RA-UKA demonstrated significantly improved clinical outcomes, high patient satisfaction, met expectations, and excellent functional recovery at midterm follow up. Comparative studies are needed to determine differences between robotic-assisted and conventional lateral UKA, as well as TKA.
Earwax is a readily accessible biological matrix that has the potential to be used in disease diagnostics. However, its semisolid nature and high chemical complexity have hampered efforts to ...investigate its potential to reveal disease markers. This is because more conventional methods of analysis such as gas chromatography–mass spectrometry (GC–MS) and liquid chromatography–mass spectrometry yield unsatisfactory results due to the presence of many nonvolatile and/or coeluting compounds, which in some cases have very similar mass spectrometric profiles. In addition, these routine methods often require the sample to be saponified, which dramatically increases the complexity of the analysis and makes it difficult to determine which compounds are actually present versus those that are produced by saponification. In this study, two-dimensional GC mass spectrometry (GC × GC–MS) was successfully applied for the characterization of the chemical components of earwax from healthy donors using nonpolar (primary) and midpolar (secondary) columns without saponification. Over 35 of the compounds that were identified are reported for the first time to be detected in unsaponified earwax. The resulting GC × GC–MS contour plots revealed visually recognizable compound class clusters of previously reported groups including alkanes, alkenes, fatty acids, esters, triglycerides, and cholesterol esters, as well as cholesterol and squalene. The application of GC × GC–MS revealed results that provide a foundation upon which future studies aimed at comparing healthy donor earwax to that from individuals exhibiting various disease states can be accomplished.
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