Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma
, but the ...efficacy of CAR T cell therapy in solid tumours has been limited
. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more 'stem-like' phenotype and increased mitochondrial mass
. We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.
The identification of semen during a criminal investigation may be a critical component in the prosecution of a sexual assault. Commonly employed enzymatic and affinity‐based methods for detection ...lack specificity, are time‐consuming, and only provide a presumptive indication that semen is present where microscopic visualization is unable to meet the throughput demands. Contrary to traditional approaches, protein mass spectrometry provides true confirmatory results, but multiday sample preparation and nanoflow sample separation requirements have limited the practical applicability of these approaches. Aiming at streamlining sexual assault screening by mass spectrometry, the work here coupled a 60‐minute rapid tryptic digestion, semenogelin‐II peptide affinity purification on an Agilent AssayMap Bravo automation platform, and a 3‐minute targeted LC‐MS/MS method on an Agilent 6495 triple quadrupole mass spectrometer operating in multiple reaction monitoring mode for detecting semenogelin‐II peptides in sexual assault samples. The developed assay was assessed using casework‐type samples and was successful in detecting trace levels (0.0001 μl) of semen recovered from both cotton and vaginal swabs, as well as semen recovered from vaginal swabs during menses or adulterated with personal lubricants. This work represents a promising technique for high‐throughput seminal fluid identification in sexual assault‐type samples by mass spectrometry.
STUDY DESIGN.Comparative reliability and prospective validity.
OBJECTIVE.First, to evaluate the reliability of four methods of assessing magnetic resonance imaging (MRI) bone marrow edema (BMO) of ...the posterior vertebral arch of the lumbar vertebrae of elite junior fast bowlers. Second, to evaluate the validity of the most reliable method for the early detection of lumbar bone stress injury.
SUMMARY OF BACKGROUND DATA.MRI has demonstrated utility in identifying BMO in lumbar vertebrae. Methods to grade the severity of BMO may provide valuable insight to inform clinical management, particularly in elite athletes where detection of early-stage bone stress may prevent progression to more severe and costly bone stress injury.
METHODS.Sixty-five male elite junior fast bowlers had repeat MRI scans during a cricket season. A subset of 19 bowlers’ images were reassessed by experienced musculoskeletal radiologists to determine intra- and inter-rater reliability. All images were aligned with independent medical records of lower back symptoms and diagnosed bone stress injuries to establish the relationship of BMO and lumbar bone stress injury.
RESULTS.Clinical detection of abnormal BMO, whether the pars region of the vertebra was considered in its entirety or subdivided into regions, had fair-to-moderate inter-rater reliability, and fair-to-almost perfect intra-rater reliability. Measurement of BMO signal intensity using an imaging software tool had excellent intra-rater and inter-rater reliability (ICC = 0.848, 0.837). BMO signal intensity was positively associated with subsequent LBSI (P < 0.001), and differentiated between asymptomatic and symptomatic bowlers (P < 0.001).
CONCLUSION.Measurement of BMO signal intensity using an imaging software tool proved a reliable and valid measure of the severity of lumbar bone stress injury in elite junior fast bowlers.Level of Evidence2
IMPORTANCE: Refining eligibility guidelines may identify more appropriate patients to undergo useful medical procedures. OBJECTIVE: To improve cost-effectiveness in selecting patients with melanoma ...for sentinel lymph node biopsy (SLNB). DESIGN, SETTING, AND PARTICIPANTS: This hybrid prognostic study/decision analytical model was conducted among patients with melanoma who were eligible for SLNB at 2 melanoma centers from Australia and the US from 2000 to 2014. Participants consisted of 2 cohorts of patients with melanoma undergoing SLNB and a cohort of eligible patients without SLNB. Individualized probabilities of SLNB positivity generated by a patient-centered methodology (PCM) were compared with those generated by conventional multiple logistic regression analysis investigating 12 prognostic factors. Prognostic accuracy was assessed by the area under the receiver operating characteristic curve (AUROC) for each methodology and by matched-pair analyses. INTERVENTIONS: Triaging appropriate patients to undergo SLNB. MAIN OUTCOMES AND MEASURES: Total number of SLNBs performed (giving total cost) vs number of SLNB-positive outcomes (a measure of effectiveness) was evaluated. Improved cost-effectiveness through judicious patient selection was interpreted as increased numbers of SLNB-positive outcomes achieved, decreased numbers of SLNBs performed, or both outcomes simultaneously. RESULTS: Among 7331 patients with melanoma, SLNB outcomes were assessed in 3640 Australian patients (2212 males 60.8%; 2447 aged >50 years 67.2%) and 1342 US patients (774 males 57.7%; 885 aged >50 years 66.0%); 2349 patients eligible for SLNB who did not undergo the procedure were included in the simulation. PCM-generated probabilities achieved an AUROC of 0.803 in predicting SLNB positivity in the Australian cohort and 0.826 in the US cohort, higher than corresponding AUROCs generated by conventional logistic regression analysis. In simulation, adopting many SLNB-positive probabilities as minimally acceptable patient-selection criteria resulted in fewer procedures performed or increased the expected numbers of positive SLNBs. A minimally acceptable PCM-generated probability of 8.7% elicited the same number of SLNBs as historically performed (3640 SLNBs), with 1066 positive SLNBs (29.3%), constituting an improvement of 287 additional positive SLNBs compared with 779 actual positive SLNBs (36.8% improvement). In contrast, adopting a 23.7% PCM-generated minimum cutoff probability resulted in performing 1825 SLNBs, or 1815 fewer SLNBs than the actual experience (49.9%). It resulted in the same expected number of positive results (779 SLNBs), for a 42.7% positivity rate. CONCLUSIONS AND RELEVANCE: This prognostic study/decision analytical model found that the PCM approach outperformed conventional multiple logistic regression analysis in predicting which patients would have positive results on SLNB. These findings suggest that systematically producing and exploiting more accurate SLNB-positivity probabilities could improve the selection of patients with melanoma for SLNB compared with using established guidelines, thus improving the cost-effectiveness of the selection process. Eligibility guidelines to undergo SLNB should include a context-tailored minimum cutoff probability.
Abstract
We report on fabrication and characterization of layered, tungsten doped, spherical about 2 mm diameter microcrystalline diamond ablator shells for inertial confinement fusion (ICF) ...experiments at the National Ignition Facility. As previously reported, diamond ICF ablator shells can be fabricated by chemical vapor deposition (CVD) on solid spherical silicon mandrels using an ellipsoidal microwave plasma reactor. In the present work, we further developed these ablator shells by embedding a
W
-doped diamond layer sandwiched between two undoped diamond regions.
W
incorporation in diamond was achieved by adding tungsten hexacarbonyl to the CH
4
/H
2
CVD feed gas. We observe that the
W
doping concentration decreases with increasing deposition rate which, in turn, is controlled by adjusting the total gas pressure. Cross sectional microstructural analysis reveals sharp interfaces between doped and undoped regions of the diamond shell and uniform
W
distribution with concentrations up to about 0.3 at.%. At higher
W
concentrations (>0.3 at.%) formation of tungsten carbide precipitates is observed. Using a 3‐shock 1.6 MJ laser pulse, the targets described in this work produced the first laser driven implosion to break the 1 × 10
16
neutron yield barrier, followed by experiments (described in future publications) with similar targets and slightly more laser energy producing yields as high as 4 × 10
17
.
Background
The effects of conflict and displacement on adolescent mental health and protection are profound and can have lasting consequences. We aimed to investigate the effectiveness of two ...group‐based psychosocial interventions on mental health and protection of South Sudanese refugee adolescents.
Methods
A randomized controlled trial was done in four villages within the Omugo extension of Rhino Camp refugee settlement in the West Nile region of Uganda. Male and female adolescents (aged 9–14 years) were randomly assigned to attend 12 weeks of either a Standard psychosocial intervention delivered in a child‐friendly space (CFS) or a more structured sequential delivery of psychosocial sessions guided by a newly developed Toolkit for Child‐Friendly Spaces in Humanitarian Settings. The primary outcomes were psychological distress and resilience 12 months after baseline assessment. The trial is registered with ClinicalTrials.gov, NCT03897894.
Results
Between May 28, 2019, and February 20, 2020, 1,280 eligible adolescents were recruited. With 70.2% retention at follow‐up, 214 assigned to the Standard, 211 assigned to the Toolkit, and 370 assigned to the waitlist control were included in the intention‐to‐treat and as‐treated analysis. Both the Toolkit and Standard approaches were more effective in reducing psychological distress and perceived protection risks reported by adolescents compared to no intervention. Differential intervention impacts are indicated in subgroup analyses.
Conclusions
The trial found that both psychosocial interventions when implemented in a CFS are well suited as a first‐line mental health and violence prevention intervention for adolescent populations exposed to conflict and forced displacement. Where feasible, CFS should be implemented as a primary response strategy soon after displacement to improve psychological health and reduce the risk environment for adolescents.
Political and economic transitions have had substantial impacts on forest conservation. Where transitions are underway or anticipated, historical precedent and methods for systematically assessing ...future trends should be used to anticipate likely threats to forest conservation and design appropriate and prescient policy measures to counteract them. Myanmar is transitioning from an authoritarian, centralized state with a highly regulated economy to a more decentralized and economically liberal democracy and is working to end a long-running civil war. With these transitions in mind, we used a horizon-scanning approach to assess the 40 emerging issues most affecting Myanmar's forests, including internal conflict, land-tenure insecurity, large-scale agricultural development, demise of state timber enterprises, shortfalls in government revenue and capacity, and opening of new deforestation frontiers with new roads, mines, and hydroelectric dams. Averting these threats will require, for example, overhauling governance models, building capacity, improving infrastructure- and energy-project planning, and reforming land-tenure and environmental-protection laws. Although challenges to conservation in Myanmar are daunting, the political transition offers an opportunity for conservationists and researchers to help shape a future that enhances Myanmar's social, economic, and environmental potential while learning and applying lessons from other countries. Our approach and results are relevant to other countries undergoing similar transitions. Las transiciones políticas y económicas han tenido impactos sustanciales sobre la conservación de los bosques. En los lugares donde se estén llevando a cabo las transiciones o donde se anticipen se deberían utilizar los precedentes históricos y los métodos para evaluar sistemáticamente lasfuturas tendencias para anticipar las amenazas probables a la conservación de los bosques y para diseñar medidas políticas apropiadas que se anticipen a las amenazas y las contrarresten. Myanmar está en una transición entre un estado autoritario centralizado con una economía altamente regulada y una democracia más descentralizada y liberal, además de estar trabajando para terminar con una guerra civil de larga duración. Con estas transiciones en mente utilizamos una estrategia de escaneo de horizonte para evaluar los 40 temas emergentes que más afectan a los bosques de Myanmar, incluyendo al conflicto interno, la inseguridad de la tenencia, el desarrollo agrícola a gran escala, la desaparición de las empresas estatales de madera, la escasez de ingresos públicos y capacidad, y la apertura de nuevas fronteras de deforestación con nuevas carreteras, minas y presas hidroeléctricas. Para evitar estas amenazas se requerirá de la revisión de los modelos de gobemanza, la capacidad de construcción, la mejora de la planeación de proyectos de energía e infraestructura, y la reforma de las leyes de tenencia y de protección ambiental, por citar algunos ejemplos. Aunque en Myanmar los retos para la conservación son abrumadores, la transición política ofrece una oportunidad para que los conservacionistas y los investigadores ayuden a formar un futuro que mejore el potencial social, económico y ambiental de Myanmar mientras se aprenden y aplican lecciones de otros países. Nuestra estrategia y sus resultados son relevantes para otros países pasando por transiciones similares.
IFITMs are broad antiviral factors that block incoming virions in endosomal vesicles, protecting target cells from infection. In the case of HIV-1, we and others reported the existence of an ...additional antiviral mechanism through which IFITMs lead to the production of virions of reduced infectivity. However, whether this second mechanism of inhibition is unique to HIV or extends to other viruses is currently unknown. To address this question, we have analyzed the susceptibility of a broad spectrum of viruses to the negative imprinting of the virion particles infectivity by IFITMs. The results we have gathered indicate that this second antiviral property of IFITMs extends well beyond HIV and we were able to identify viruses susceptible to the three IFITMs altogether (HIV-1, SIV, MLV, MPMV, VSV, MeV, EBOV, WNV), as well as viruses that displayed a member-specific susceptibility (EBV, DUGV), or were resistant to all IFITMs (HCV, RVFV, MOPV, AAV). The swapping of genetic elements between resistant and susceptible viruses allowed us to point to specificities in the viral mode of assembly, rather than glycoproteins as dominant factors of susceptibility. However, we also show that, contrarily to X4-, R5-tropic HIV-1 envelopes confer resistance against IFITM3, suggesting that viral receptors add an additional layer of complexity in the IFITMs-HIV interplay. Lastly, we show that the overall antiviral effects ascribed to IFITMs during spreading infections, are the result of a bimodal inhibition in which IFITMs act both by protecting target cells from incoming viruses and in driving the production of virions of reduced infectivity. Overall, our study reports for the first time that the negative imprinting of the virion particles infectivity is a conserved antiviral property of IFITMs and establishes IFITMs as a paradigm of restriction factor capable of interfering with two distinct phases of a virus life cycle.
IMPORTANCE: The recently published ADAURA study has posed a significant dilemma for clinicians in selecting patients for adjuvant osimertinib. Risk factors for recurrence in early-stage epidermal ...growth factor receptor (EGFR)–positive non–small cell lung cancer (NSCLC) also remain undefined. OBJECTIVE: To determine clinicopathologic characteristics and recurrence patterns of resected early-stage EGFR-positive NSCLC, using wildtype EGFR as a comparator cohort, and identify features associated with recurrence. DESIGN, SETTING, AND PARTICIPANTS: This is a cohort study including patients diagnosed with AJCC7 Stage IA to IIIA NSCLC between January 1, 2010, and June 30, 2018, who underwent curative surgical procedures at a specialist cancer center in Singapore. The cutoff for data analysis was October 15, 2020. Patient demographic characteristics, treatment history, and survival data were collated. In exploratory analysis, whole-exome sequencing was performed in a subset of 86 patients. Data were analyzed from September 3, 2020, to June 6, 2021. EXPOSURES: Adjuvant treatment was administered per investigator’s discretion. MAIN OUTCOMES AND MEASURES: The main outcome was 2-year disease-free survival (DFS). RESULTS: A total of 723 patients were included (389 patients with EGFR-positive NSCLC; 334 patients with wildtype EGFR NSCLC). There were 366 women (50.6%) and 357 men (49.4%), and the median (range) age was 64 (22-88) years. A total of 299 patients (41.4%) had stage IA NSCLC, 155 patients (21.4%) had stage IB NSCLC, 141 patients (19.5%) had stage II NSCLC, and 125 patients (17.3%) had stage IIIA NSCLC. Compared with patients with wildtype EGFR NSCLC, patients with EGFR-positive NSCLC were more likely to be women (106 women 31.7% vs 251 women 64.5%) and never smokers (121 never smokers 36.2% vs 317 never smokers 81.5%). At median (range) follow up of 46 (0-123) months, 299 patients (41.4%) had cancer recurrence. There was no statistically significant difference in 2-year DFS for EGFR-positive and wildtype EGFR NSCLC (70.2% 95% CI, 65.3%-74.5% vs 67.6% 95% CI, 62.2%-72.4%; P = .70), although patients with EGFR-positive NSCLC had significantly better 5-year overall survival (77.7% 95% CI, 72.4%-82.1% vs 66.6% 95% CI, 60.5%-72.0%; P = .004). Among patients with EGFR-positive NSCLC, 2-year DFS was 81.0% (95% CI, 74.0%-86.3%) for stage IA, 78.4% (95% CI, 68.2%-85.6%) for stage IB, 57.1% (95% CI, 43.7%-68.4%) for stage II, and 46.6% (95% CI, 34.7%-57.7%) for stage IIIA. Overall, 5-year DFS among patients with stage IB through IIIA was 37.2% (95% CI, 30.1%-44.3%). Sites of disease at recurrence were similar between EGFR-positive and wildtype EGFR NSCLC, with locoregional (64 patients 16.5% vs 56 patients 16.8%), lung (41 patients 10.5% vs 40 patients 12.0%), and intracranial (37 patients 9.5% vs 22 patients 6.6%) metastases being the most common. A risk estimation model incorporating genomic data and an individual patient nomogram using clinicopathologic features for stage I EGFR-positive NSCLC was developed to improve risk stratification. CONCLUSIONS AND RELEVANCE: This cohort study found that recurrence rates were high in early-stage EGFR-positive NSCLC including stage IA, yet 37.2% of patients with stage IB through IIIA were cured without adjuvant osimertinib. Further studies are needed to elucidate individualized surveillance and adjuvant treatment strategies for early-stage EGFR-positive NSCLC.
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