Background
An elevated neutrophil‐to‐lymphocyte ratio (NLR) is associated with poor survival in patients with cancer, including those who receive immunotherapies. The authors sought to investigate ...NLR as a biomarker of treatment outcomes in patients with melanoma who were treated with PD‐1 inhibition.
Methods
Patients undergoing initial treatment with PD‐1 inhibitor monotherapy for stage IV melanoma at a single center from 2012 to 2015 were included. Clinical characteristics and the NLR at baseline and before subsequent treatment cycles were collected. The time to treatment failure (TTF) and overall survival (OS) were evaluated using Kaplan‐Meier and landmark analyses.
Results
Among 224 study patients, 63 (28%) had a baseline NLR ≥5. The baseline NLR was significantly associated with Eastern Cooperative Oncology Group performance status and the number of involved metastatic sites. With a median follow‐up of 39 months in survivors, a baseline NLR ≥5 was independently associated with shorter OS (hazard ratio, 2.0; 95% CI, 1.3‐2.9) and TTF (hazard ratio, 1.7; 95% CI, 1.2‐2.4). An NLR increase ≥30% during the first 2 cycles of treatment was associated with worse OS (median, 47 vs 13.5 months; P < .001) and a trend toward shorter TTF (12.8 vs 5.9 months; P = .05). A combined baseline NLR ≥5 and an NLR increase ≥30% identified a small cohort with markedly shortened OS (median, 5.8 months) and TTF (median, 1.8 months).
Conclusions
Elevated baseline NLR and an increased NLR early during treatment are prognostic for TTF and OS in patients who have melanoma treated with PD‐1 inhibitor monotherapy. Combined, these biomarkers can widely risk‐stratify patients for treatment failure and survival.
A pretreatment neutrophil‐to‐lymphocyte ratio (NLR) ≥5 and an increase ≥30% in the NLR are independently prognostic for treatment failure and worse overall survival in patients who have melanoma treated with PD‐1 inhibitor monotherapy. The pretreatment NLR is associated with both tumor and host factors, suggesting that the NLR reflects a complex interaction between the tumor and the host immune response.
Structural differences in pathological and functional amyloid fibrils have been investigated by Raman microspectroscopy. Second-derivative analyses of amide-I and amide-III bands distinguish parallel ...in-register β-sheets from a β-solenoid. Further, spatially resolved Raman spectra reveal molecular heterogeneity in amyloid structures.
The greatly enhanced fields near metal nanoparticles have demonstrated remarkable optical properties and are promising for applications from solar energy to biosensing. However, direct experimental ...study of these light-matter interactions at the nanoscale has remained difficult due to the limitations of optical microscopy. Here, we use single-molecule fluorescence imaging to probe how a plasmonic nanoantenna modifies the fluorescence emission from a dipole emitter. We show that the apparent fluorophore emission position is strongly shifted upon coupling to an antenna and that the emission of dyes located up to 90 nm away is affected by this coupling. To predict this long-ranged effect, we present a framework based on a distance-dependent partial coupling of the dye emission to the antenna. Our direct interpretation of these light-matter interactions will enable more predictably optimized, designed, and controlled plasmonic devices and will permit reliable plasmon-enhanced single-molecule nanoscopy.
Parkinson’s disease (PD) is associated with the formation of α-synuclein amyloid fibrils. Elucidating the role of these β-sheet-rich fibrils in disease progression is crucial; however, collecting ...detailed structural information on amyloids is inherently difficult because of their insoluble, non-crystalline, and polymorphic nature. Here, we show that Raman spectroscopy is a facile technique for characterizing structural features of α-synuclein fibrils. Combining Raman spectroscopy with aggregation kinetics and transmission electron microscopy, we examined the effects of pH and ionic strength as well as four PD–related mutations (A30P, E46K, G51D, and A53T) on α-synuclein fibrils. Raman spectral differences were observed in the amide-I, amide-III, and fingerprint regions, indicating that secondary structure and tertiary contacts are influenced by pH and to a lesser extent by NaCl. Faster aggregation times appear to facilitate unique fibril structure as determined by the highly reproducible amide-I band widths, linking aggregation propensity and fibril polymorphism. Importantly, Raman spectroscopy revealed molecular-level perturbations of fibril conformation by the PD–related mutations that are not apparent through transmission electron microscopy or limited proteolysis. The amide-III band was found to be particularly sensitive, with G51D exhibiting the most distinctive features, followed by A53T and E46K. Relating to a cellular environment, our data would suggest that fibril polymorphs can be formed in different cellular compartments and potentially result in distinct phenotypes. Our work sets a foundation toward future cellular Raman studies of amyloids.
Emotions are highly influential to many psychological processes. Indeed, research employing emotional stimuli is rapidly escalating across the field of psychology. However, challenges remain ...regarding discrete evocation of frequently co-elicited emotions such as amusement and happiness, or anger and disgust. Further, as much contemporary work in emotion employs college students, we sought to additionally evaluate the efficacy of film clips to discretely elicit these more challenging emotions in a young adult population using an online medium. The internet is an important tool for investigating responses to emotional stimuli, but validations of emotionally evocative film clips across laboratory and web-based settings are limited in the literature. An additional obstacle is identifying stimuli amidst the numerous film clip validation studies. During our investigation, we recognized the lack of a categorical database to facilitate rapid identification of useful film clips for individual researchers’ unique investigations. Consequently, here we also sought to produce the first
compilation
of such stimuli into an accessible and comprehensive catalog. We based our catalog upon prior work as well as our own, and identified 24 articles and 295 film clips from four decades of research. We present information on the validation of these clips in addition to our own research validating six clips using online administration settings. The results of our search in the literature and our own study are presented in tables designed to facilitate and improve a selection of highly valid film stimuli for future research.
Influenza hemagglutinin (HA) is the primary target of the humoral response during infection/vaccination. Current influenza vaccines typically fail to elicit/boost broadly neutralizing antibodies ...(bnAbs), thereby limiting their efficacy. Although several bnAbs bind to the conserved stem domain of HA, focusing the immune response to this conserved stem in the presence of the immunodominant, variable head domain of HA is challenging. We report the design of a thermotolerant, disulfide-free, and trimeric HA stem-fragment immunogen which mimics the native, prefusion conformation of HA and binds conformation specific bnAbs with high affinity. The immunogen elicited bnAbs that neutralized highly divergent group 1 (H1 and H5 subtypes) and 2 (H3 subtype) influenza virus strains in vitro. Stem immunogens designed from unmatched, highly drifted influenza strains conferred robust protection against a lethal heterologous A/Puerto Rico/8/34 virus challenge in vivo. Soluble, bacterial expression of such designed immunogens allows for rapid scale-up during pandemic outbreaks.
Suppression of emotional expression has been associated with depressive symptoms. However, men suppress emotions more than women but women experience more symptoms of depression. The present study ...examined gender and emotional non-acceptance (thinking of emotions as bad and to be avoided) as moderators of the suppression-depression relationship. Participants were males (
n
=
118) and females (
n
=
210) aged 17–24. As expected, men reported suppressing emotions more than women and women reported more depressive symptoms. However, suppression was only related to depression in men and not women. Hierarchical regressions revealed a 3-way interaction among gender, suppression, and non-acceptance. Lower acceptance of emotions was associated with the highest depressive symptoms regardless of suppression or gender. With greater acceptance of emotions, suppression was related to more depressive symptoms in men but fewer depressive symptoms in women. These findings suggest that suppressing emotions may have different functions and may be more useful for understanding depressive symptoms in men rather than women.
Skin color patterns are ubiquitous in nature, impact social behavior, predator avoidance, and protection from ultraviolet irradiation. A leading model system for vertebrate skin patterning is the ...zebrafish; its alternating blue stripes and yellow interstripes depend on light-reflecting cells called iridophores. It was suggested that the zebrafish's color pattern arises from a single type of iridophore migrating differentially to stripes and interstripes. However, here we find that iridophores do not migrate between stripes and interstripes but instead differentiate and proliferate in-place, based on their micro-environment. RNA-sequencing analysis further reveals that stripe and interstripe iridophores have different transcriptomic states, while cryogenic-scanning-electron-microscopy and micro-X-ray diffraction identify different crystal-arrays architectures, indicating that stripe and interstripe iridophores are different cell types. Based on these results, we present an alternative model of skin patterning in zebrafish in which distinct iridophore crystallotypes containing specialized, physiologically responsive, organelles arise in stripe and interstripe by in-situ differentiation.
Coupling to metal nanoparticles can increase the fluorescence intensity and photostability of fluorescent probes, and this plasmon-enhanced fluorescence is particularly promising for the dimmer ...fluorescent proteins common in biological imaging. Here, we measure the intensity distribution of single Cy3.5 dye molecules and mCherry fluorescent proteins one at a time as they adsorb on a conformal surface 4.8–61.0 nm thick over a gold nanorod (NR). The emission intensities for both types of fluorophores depend nonmonotonically on the spacer thickness, and an optimal spacer thickness of ∼10 nm is observed for both fluorophores using two different spacer layer materials. Emission from fluorophores coupled to metal nanoparticles is affected by two competing processes: an enhanced spontaneous decay rate and quenching via nonradiative antenna modes. After averaging over a conformal surface, the product of the simulated enhanced local electric field intensity and the quantum efficiency modification reproduces the experimental 10 nm ideal spacer thickness. Overall, up to a 3.4-fold average enhancement in fluorescence intensity was achieved despite the simple geometry, based on biocompatible, tunable, and economic colloidal gold NRs. This study of the distance dependence of single-molecule plasmon-enhanced fluorescence shows promise for super-resolving cellular membrane proteins naturally positioned above an extracellular substrate.
Tumor-intrinsic features may render large B-cell lymphoma (LBCL) insensitive to CD19-directed chimeric antigen receptor T cells (CAR-T). We hypothesized that TP53 genomic alterations are detrimental ...to response outcomes in LBCL treated with CD19-CAR-T.
Patients with LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing was performed on pre-CAR-T tumor samples in a subset of patients. Response and survival rates by histologic, cytogenetic, and molecular features were assessed. Within a cohort of newly diagnosed LBCL with genomic and transcriptomic profiling, we studied interactions between cellular pathways and
status.
We included 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T (axicabtagene ciloleucel 50%, tisagenlecleucel 32%, and lisocabtagene maraleucel 18%). Outcomes echoed pivotal trials: complete response (CR) rate 54%, median overall survival (OS) 21.1 months (95% CI, 14.8 to not reached), and progression-free survival 6 months (3.4 to 9.7). Histologic and cytogenetic LBCL features were not predictive of CR. In a subset of 82 patients with next-generation sequencing profiling, CR and OS rates were comparable with the unsequenced cohort.
alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariable and multivariable regression models; the 1-year OS in
-altered LBCL was 44% (95% CI, 29 to 67) versus 76% (65 to 89) in wild-type (
= .012). Transcriptomic profiling from a separate cohort of patients with newly diagnosed lymphoma (n = 562) demonstrated that
alterations are associated with dysregulation of pathways related to CAR-T-cell cytotoxicity, including interferon and death receptor signaling pathway and reduced CD8 T-cell tumor infiltration.
is a potent tumor-intrinsic biomarker that can inform risk stratification and clinical trial design in patients with LBCL treated with CD19-CAR-T. The role of TP53 should be further validated in independent cohorts.
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