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.
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.
EGFR inhibitors (EGFRi) are effective against
mutant lung cancers. The efficacy of these drugs however is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired ...mutation in EGFR,
We recently demonstrated that
can arise
during treatment (Hata et al.,
2016); it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells (referred to as drug tolerant cells (DTCs)) prior to acquiring secondary mutations like
Experimental Design: We have developed DTCs to EGFRi in
mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhibitors to eliminate DTCs and shrink
mutant lung cancer tumors
Results: We demonstrate surviving
mutant lung cancers upregulate the anti-apoptotic protein MCL-1 in response to short-term EGFRi treatment. Mechanistically, DTCs undergo a protein biosynthesis enrichment resulting in increased mTORC1-mediated mRNA translation of MCL-1, revealing a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors. Moreover, MCL-1 is a key molecule governing the emergence of early
mutant DTCs to EGFRi and we demonstrate it can be effectively co-targeted with clinically-emerging MCL-1 inhibitors both
and
Conclusions: Altogether, these data reveal that this novel therapeutic combination may delay the acquisition of secondary mutations, therefore prolonging therapy efficacy.
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.
Per- and Polyfluorinated alkyl substances (PFAS) are a broad class of synthetic compounds that have fluorine substituted for hydrogen in several or all locations and are globally categorized as PFCs ...(perfluorochemicals; commonly called fluorinated chemicals). These compounds have unique chemical and physical properties that enable their use in non-stick surfaces, fire-fighting efforts, and as slick coatings. However, recent concerns over the health effects of such compounds, specifically perfluorooctanoic acid and perfluorooctane sulfonic acid (PFOA, PFOS; PFOA/S), have led to increased attention and research by the global community into degradation methods. In this study, soil samples from PFAS-contamination sites were cultured and screened for microbes with PFOA/S degradation potential, which led to the identification of Delftia acidovorans. It was found that D. acidovorans isolated from PFAS-contaminated soils was capable of growth in minimal media with PFOA as a sole carbon resource, and an observable fluoride concentration increase was observed when cells were exposed to PFOA. This suggests potential activity of a dehalogenase enzyme that may be of use in PFOA or PFAS microbial remediation efforts. Several associated haloacid dehalogenases have been identified in the D. acidovorans genome and have been engineered for expression in Escherichia coli for rapid production and purification. These enzymes have shown potential for enzymatic defluorination, a significant step in biological degradation and removal of PFOA/S from the environment. We hypothesize that bioremediation of PFAS using naturally occurring microbial degradation pathways may represent a novel approach to remove PFAS contamination.
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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