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Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with

Photon-number-resolving detectors are in high demand for applications in photonic quantum technology. In this study, we demonstrate the photon-number-resolving capabilities of our self-developed, highly efficient InGaAs/InAlAs single-photon avalanche diode. We achieved intrinsic photon number resolving by harnessing the high multiplication gain generated through an avalanche process in the InAlAs multiplication layer. With a maximum single-photon detection efficiency of 46%, we were able to distinguish photon number states up to 5 from the signal probability distribution without encountering avalanche saturation that could otherwise limit the capability of photon number resolving. We reasonably anticipate that the photon-number-resolving accuracy and capability can be further improved once the noise issue in such InGaAs/InAlAs SPADs is carefully managed. [ABSTRACT FROM AUTHOR]

To explore the effects of customized 3D-printed assistive technology (AT) on functional performance and feasibility in patients with neurological impairment. Patients with neurological impairment were recruited and randomized into customized 3D-printed assistive device group (group 1; n = 17) or standard device group (group 2; n = 14). The device was designed to assist their writing, spoon using, and typing. Each patient underwent 4-week intervention with the device (30 min per session, twice a week). We observed significant differences in shoulder abduction (p =.00), external rotation (p =.01), and internal rotation (p =.02) in group 1. And significant differences in abduction (p =.05) and external rotation (p =.05) between the 2 groups. Group 1 achieved significant improvements in writing without AT (p =.04) and with AT (p =.02), spoon use without AT (p =.02) and with AT (p =.03), and hemiplegia-side typing with AT (p =.00). Group 2 achieved significant improvements in writing without AT (p =.01), hemiplegia-side typing without AT (p =.01), and bil-side typing with AT (P =.05). Moreover, no significant differences were noted in other outcome measures. This study demonstrated that customized 3D-printed AT can improve shoulder active motion for patients with neurological impairment. A positive effect in functional hand tasks after AT intervention. Offering customized AT with specific training could enhance the efficacy of interventions. The feasibility of using 3D printing technology to produce customized AT, which has the potential to be cost-effective and efficient. 3D-printed assistive device incorporating a splint can improve shoulder active motion compared to conventional assistive device for patients with neurological impairment. A positive effect in functional hand tasks after assistive device intervention. [ABSTRACT FROM AUTHOR]

The ongoing COVID‐19 pandemic has had a profound worldwide impact on the laboratory hematology community. Nevertheless, the pace of COVID‐19 hematology‐related research has continued to accelerate and has established the role of laboratory hematology data for many purposes including disease prognosis and outcome. The purpose of this scoping review was to assess the current state of COVID‐19 laboratory hematology research. A comprehensive search of the literature published between December 1, 2019, and July 3, 2020, was performed, and we analyzed the sources, publication dates, study types, and topics of the retrieved studies. Overall, 402 studies were included in this scoping review. Approximately half of these studies (n = 202, 50.37%) originated in China. Retrospective cohort studies comprised the largest study type (n = 176, 43.89%). Prognosis/ risk factors, epidemiology, and coagulation were the most common topics. The number of studies published per day has increased through the end of May. The studies were heavily biased in favor of papers originating in China and on retrospective clinical studies with limited use of and reporting of laboratory data. Despite the major improvements in our understanding of the role of coagulation, automated hematology, and cell morphology in COVID‐19, there are gaps in the literature, including biosafety and the laboratory role in screening and prevention of COVID‐19. There is a gap in the publication of papers focused on guidelines for the laboratory. Our findings suggest that, despite the large number of publications related to laboratory data and their use in COVID‐19 disease, many areas remain unexplored or under‐reported. [ABSTRACT FROM AUTHOR]

The authors describe the impact of telephone calls to older people on later visits with a physician. They mention the effect of the COVID-19 pandemic in increasing the isolation of older people, the program of volunteers calling patients, and how the calls increased the likelihood of outpatient visits.

Alterations to the epigenetic landscape of diffuse large B-cell lymphoma (DLBCL) play a fundamental role in deregulating genes involved in normal lymphocyte differentiation. To determine whether targeted epigenetic therapy could reverse these pathogenic chromatin changes and suppress the expression of a lymphoma oncogene, we focused onBCL6, a transcriptional repressor whose aberrant expression is tightly linked to DLBCL proliferation and survival. We fused zinc-finger (ZF) domains specific for regulatory regions in theBCL6locus to a repressive epigenetic modifier, the Kruppel-associated box (KRAB) repressor domain. Distinct ZF–KRAB fusions repressed the local chromatin landscape, suppressedBCL6expression, significantly impaired DLBCL growth, and caused widespread cell death in aBCL6-dependent manner. Importantly, expression of ectopicBCL6protein rescued ZF–KRAB-induced cell death, demonstrating the modifiers’ specificity. We show that sequence-specific epigenetic modifiers can alter oncogene expression and induce apoptosis in cancer cells, underscoring their potential for future development as targeted epigenetic protein therapies. [ABSTRACT FROM AUTHOR]

We present an experimental study of charge persistence effect in InGaAs/InP single-photon avalanche diodes based on their dark and illuminated characteristics. It is well known that the sources of dark carriers mainly originate from thermal generation, trap-assisted tunneling, and afterpulsing, where these mechanisms are dominant in the dark count rate performance at different temperature ranges. In this letter, besides the above-mentioned mechanisms, we further address an additional mechanism involved that competes with suppression of thermal carriers when the temperature is decreased. A good correspondence is observed by comparing the dark characteristics with the illuminated characteristics, showing that the additional spurious signals occurred at intermediate temperature range originate from the charge persistence effect. [ABSTRACT FROM AUTHOR]

The article discusses research which investigated functional responses of cytokine-induced memory-like natural killer (NK) cells against acute myeloid leukemia (AML) target cells. Topics explored include the prognosis and lack of treatment options for AML patients, the use of mass cytometry to differentiate memory-like from control NK cells, and the antileukemia functionality observed in memory-like NK cells.

Infection is a common cause of morbidity and mortality in chronic lymphocytic leukemia and should be considered when examining bone marrow specimens to identify a potentially treatable pathogen. [ABSTRACT FROM AUTHOR]

Resveratrol has been reported to exhibit neuroprotective activities in vitro and in vivo. However, little is known about resveratrol tetramers of hopeaphenol, vitisin A, and vitisin B with the same molecular mass in the improvement of degenerative disorders. In this study, two 95% ethanol extracts (95EE) from stem parts of Vitis thunbergii Sieb. & Zucc. (VT-95EE) and from the root (R) parts of Vitis thunbergii var. taiwaniana (VTT-R-95EE) showed comparable acetylcholinesterase (AChE) inhibitory activities. It was found that VT-95EE and VTT-R-95EE showed different distribution patterns of identified resveratrol and resveratrol tetramers of hopeaphenol, vitisin A, and vitisin B based on the analyses of HPLC chromatographic profiles. The hopeaphenol, vitisin A, and vitisin B, showed AChE and monoamine oxidase-B inhibitions in a dose-dependent manner, among which vitisin B and vitisin A exhibited much better activities than those of resveratrol, and had neuroprotective activities against methylglyoxal-induced SH-SY5Y cell deaths. The scopolamine-induced amnesiac ICR mice treated with VT-95EE and its ethyl acetate-partitioned fraction (VT-95EE-EA) at doses of 200 and 400 mg/kg, or vitisin A at a dose of 40 mg/kg, but not vitisin B (40 mg/kg), were shown significantly to improve the impaired learning behaviors by passive avoidance tests compared to those in the control without drug treatments (p < 0.05). Compared to mice in the control group, the brain extracts in the vitisin A-treated mice or donepezil-treated mice showed significant reductions in AChE activities and malondialdehyde levels (p < 0.05), and elevated the reduced protein expressions of brain-derived neurotrophic factor (BDNF) and BDNF receptor, tropomyosin receptor kinase B (TrkB). These results revealed that vitisin A was the active constituent in the VT-95EE and VTT-95EE, and the VT medicinal plant and that the endemic variety of VTT has potential in developing functional foods for an unmet medical need for neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Agricultural waste from the hulls of water caltrop (Trapa taiwanesis Nakai, TT-hull) was extracted by either steeping them in cold 95% ethanol (C95E), refluxing 95E, refluxing 50E, or refluxing hot water (HW) to obtain C95EE, 95EE, 50EE, and HWE, respectively. These four extracts showed acetylcholinesterase (AChE) inhibitory activities and free radical scavenging activities, as well as anti-non-enzymatic protein glycation in vitro. Eight compounds were isolated from TT-hull-50EE and were used to plot the chromatographic fingerprints of the TT-hull extracts, among which tellimagrandin-I, tellimagrandin-II, and 1,2,3,6-tetra-galloylglucose showed the strongest AChE inhibitory activities, and they also exhibited anti-amyloid β peptide aggregations. The scopolamine-induced amnesiac ICR mice that were fed with TT-hull-50EE or TT-hull-HWE (100 and 200 mg/kg) or tellimagrandin-II (100 and 200 mg/kg) showed improved learning behavior when evaluated using passive avoidance or water maze evaluation, and they showed significant differences (p < 0.05) compared to those in the control group. The enriched hydrolysable tannins of the recycled TT-hull may be developed as functional foods for the treatment of degenerative disorders. [ABSTRACT FROM AUTHOR]

• VEW-MWPLS is proposed to enhance the prediction performance of NOx emission. • With adjustable forgetting factor, VEW-MWPLS can change modeling data window. • An efficient updated scheme with detailed derivations is provided. • Computational efficiency of VEW-MWPLS and past methods are analyzed and compared. The efficiency of selective catalytic reduction denitrification heavily depends on the amount of ammonia injection, which is determined by the emission of nitrogen oxides (NOx) in flue gas. To accurately predict NOx emission of the coal-fired boiler with strong variable correlations, nonlinear and time-varying characteristics for determining the amount of injected ammonia, a soft sensor modeling method based on the moving window partial least squares (MWPLS) and locally weighted regression, referred to as variable exponentially weighted MWPLS (VEW-MWPLS), is proposed. It adjusts the window size in disguised form by automatically strengthen or weaken the information in the selected window according to the prediction errors of the current model. In this work, with the added new sample and the removed old sample, a series of rank-1 modification formulations are used to calculate both, the means and standard deviations among the input and output variables and the covariance and cross-covariance matrices so that a quick and adaptive update can be done for the PLS model. The numerical results have demonstrated that VEW-MWPLS algorithm can reduce the mean and standard deviation of prediction errors by one order of magnitude, and reduce the computational complexity by two orders of magnitude when being compared with other algorithms. Thus the proposed VEW-MWPLS is more suitable for predicting NOx emission online. [ABSTRACT FROM AUTHOR]

In this work, we demonstrate In0.52Al0.48As top/backside-illuminated avalanche photodiodes (APD) with dual multiplication layers for high-speed and wide dynamic range performances. Our fabricated top-illuminated APDs, with a partially depleted p-type In0.53Ga0.47As absorber layer and thin In0.52Al0.48As dual multiplication (M-) layer (60 and 88 nm), exhibit a wide optical-to-electrical bandwidth (16 GHz) with high responsivity (2.5 A/W) under strong light illumination (around 1 mW). The measured bias dependent 3-dB O-E bandwidth was pinned at 16 GHz without any serious degradation near the saturation current output. To further increase the speed, we downscaled the active diameter and adopted a back-side illuminated structure with flip-chip bonding for batter optical alignment tolerance. A significant improvement in maximum bandwidth was demonstrated (25 versus 18 GHz). On the other hand, we adopted a thick dual M-layer (200 and 300 nm) and 2 μm absorber layer in the APD design to circumvent the problem of serious bandwidth degradation under high gain (>100) and high-power operation which significantly enhanced the dynamic range. Due to dual M-layer, the carriers could be energized in the first M-layer then propagate to the second M-layer to trigger the avalanche process. In both cases, despite variation in thickness of the absorber and M-layer, the cascade avalanche process leads to values close to the ultra-high gain bandwidth product (GBP) of around 460 GHz with a responsivity of 0.4 and 1 A/W at unit gain for the thin and thick M-layer devices, respectively. We successfully achieved a good sensitivity of around −20.6 dBm optical modulation amplitude (OMA) at a data rate of 25.78 Gb/s, by packaging the fabricated APDs (thin dual M-layer (60 and 88 nm) version) with a 25 Gb/s trans-impedance amplifier in a 100 Gb/s ROSA package. The results show that, the incorporation of a dual multiplication (M) layer structure in the APD opens a new window to obtaining the higher GBP in order to meet the requirements for high-speed transmission without the need of further downscaling the multiplication layer. [ABSTRACT FROM AUTHOR]

Hearing loss is the most prevalent hereditary sensory disorder in children. Approximately 2 in 1000 infants are affected by genetic hearing loss. The PJVK gene, which encodes the pejvakin protein, has been linked to autosomal recessive non-syndromic hearing loss DFNB59. Previous clinical studies have revealed that PJVK mutations might be associated with a wide spectrum of auditory manifestations, ranging from hearing loss of pure cochlear origin to that involving the retrocochlear central auditory pathway. The phenotypic variety makes the pathogenesis of this disease difficult to determine. Similarly, mouse models carrying different Pjvk defects show phenotypic variability and inconsistency. In this study, we generated a knockin mouse model carrying the c.874G > A (p.G292R) variant to model and investigate the auditory and vestibular phenotypes of DFNB59. • A mouse model of DFNB59 with the Pjvk c.874G > A mutation was established by CRISPR/Cas9 approach. • Pjvk c.874G > A mutant mice exhibited progressive hearing loss, with cochlear hair cell and spiral ganglion degeneration. • Vestibular dysfunction with progressive loss of vestibular ganglion neurons was observed in Pjvk c.874G > A mutant mice. [ABSTRACT FROM AUTHOR]

Abstract Background Endoplasmic reticulum (ER) stress plays a crucial role in cell death decisions in context of various diseases. Although it is known that ER stress occurs in livers subjected to hemorrhagic shock and reperfusion (HS/R), there is no understanding about the influence of the liver architecture on ER stress and the activation of the unfolded protein response (UPR). Materials and methods Mice were subjected to a pressure-controlled HS (30 ± 5 mmHg) for 90 min. Mice were sacrificed 2, 4, 6, 8, 10, 14, 18, and 24 h after shock induction. Plasma levels of inflammatory cytokines (IL-6, CXCL1, CXCL9, CXCL10, CCL2, CCL3) and transaminases were measured. Hematoxylin and eosin stains of paraffin-embedded liver tissue sections were evaluated for liver damage. Immunohistochemistry was used to analyze the hepatic topography of ER stress marker binding immunoglobulin protein and the activation of the three major pathways of the UPR. Results Compared with sham-operated mice, HS/R led to profound liver damage and an elevation of inflammatory cytokines. We found time-dependent topographical changes of ER stress in the livers. Furthermore, the three major pathways of the UPR represented by protein kinase RNA-like ER kinase, activating transcription factor 6, and inositol-requiring enzyme 1 were activated in differing ways dependent on the zonation within the liver acinus. Conclusions These findings show that the liver architecture must be taken into account when investigating the role of ER stress and the UPR in ischemia-reperfusion injury after HS/R. [ABSTRACT FROM AUTHOR]

Background: Severe injury and associated hemorrhagic shock lead to an inflammatory response and subsequent increased tissue damage. Numerous reports have shown that injury-induced inflammation and the associated end-organ damage is driven by Toll-like receptor 4 (TLR4) activation via damage-associated molecular patterns. We examined the effectiveness of Eritoran tetrasodium (E5564), an inhibitor of TLR4 function, in reducing inflammation induced during hemorrhagic shock with resuscitation (HS/R) or after peripheral tissue injury (bilateral femur fracture, BFF). Material and methods: Mice underwent HS/R or BFF with or without injection of Eritoran (5 mg/kg body weight) or vehicle control given before, both before and after, or only after HS/R or BFF. Mice were sacrificed after 6 h and plasma and tissue cytokines, liver damage (histology; aspartate aminotransferase/alanine aminotransferase), and inflammation (NF-κB) and gut permeability were assessed. Results: In HS/R Eritoran significantly reduced liver damage (values ± SEM: alanine aminotransferase 9910 ± 3680 U/L versus 1239 ± 327 U/L and aspartate aminotransferase 5863 ± 2000 U/L versus 1246 ± 243 U/L, P < 0.01) at 6 h compared with control when given just before HS and again just prior to resuscitation. Eritoran administration also led to lower IL-6 levels in plasma and liver and less NF-κB activation in liver. Increases in gut barrier permeability induced by HS/R were also prevented with Eritoran. Eritoran similarly diminished BFF-mediated systemic inflammatory responses. Conclusion: These data suggest Eritoran can inhibit tissue damage and inflammation induced via TLR4/myeloid differentiation factor 2 signaling from damage-associated molecular patterns released during HS/R or BFF. Eritoran may represent a promising therapeutic for trauma patients to prevent multiple organ failure. [ABSTRACT FROM AUTHOR]

Three-dimensional-printed assistive devices hold promise for improving writing abilities, yet factors influencing device selection and their impact on satisfaction and effectiveness remain unclear, especially in adults, as they are typically tested on children. The aim of this article is to assess the efficacy and satisfaction with a writing assistive device at different angles among individuals with brain injury and explore device selection factors. Twenty-six participants with brain injuries selected their preferred device angle. Writing speed, quality, and satisfaction were recorded. Immediate speed improvements were significant at 5° and 30° ( p = .006, .013, respectively). Satisfaction scores did not significantly differ among angles. Normotonia in elbow ( p < .001; odds ratio: 3.403) and wrist ( p ≤ .001; odds ratio: 2.695) muscles increased the likelihood of selecting the 5° device. Immediate speed improvements at specific angles highlight the influence of muscle normotonia on device selection, vital for tailored brain injury rehabilitation., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Postzygotic (somatic) variants in the mTOR pathway genes cause a spectrum of distinct developmental abnormalities. Accurate classification of somatic variants in this group of disorders is crucial for affected individuals and their families., Methods: The ClinGen Brain Malformation Variant Curation Expert Panel was formed to curate somatic variants associated with developmental brain malformations. We selected the genes AKT3, MTOR, PIK3CA, and PIK3R2 as the first set of genes to provide additional specifications to the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) sequence variant interpretation guidelines, which currently focus solely on germline variants., Results: A total of 24 of the original 28 ACMG/AMP criteria required modification. Several modifications used could be applied to other genes and disorders in which somatic variants play a role: 1) using variant allele fraction differences as evidence that somatic mutagenesis occurred as a proxy for de novo variation, 2) incorporating both somatic and germline evidence, and 3) delineating phenotype on the basis of variable tissue expression., Conclusion: We have established a framework for rigorous interpretation of somatic mosaic variants, addressing issues unique to somatic variants that will be applicable to many genes and conditions., Competing Interests: Conflict of Interest D.T.M. has received honoraria from Ambry Genetics and PreventionGenetics. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: The most common B-cell cancers, chronic lymphocytic leukemia/lymphoma (CLL), follicular and diffuse large B-cell (FL, DLBCL) lymphomas, have distinct clinical courses, yet overlapping "cell-of-origin". Dynamic changes to the epigenome are essential regulators of B-cell differentiation. Therefore, we reasoned that these distinct cancers may be driven by shared mechanisms of disruption in transcriptional circuitry., Methods: We compared purified malignant B-cells from 52 patients with normal B-cell subsets (germinal center centrocytes and centroblasts, naïve and memory B-cells) from 36 donor tonsils using >325 high-resolution molecular profiling assays for histone modifications, open chromatin (ChIP-, FAIRE-seq), transcriptome (RNA-seq), transcription factor (TF) binding, and genome copy number (microarrays)., Findings: From the resulting data, we identified gains in active chromatin in enhancers/super-enhancers that likely promote unchecked B-cell receptor signaling, including one we validated near the immunoglobulin superfamily receptors FCMR and PIGR. More striking and pervasive was the profound loss of key B-cell identity TFs, tumor suppressors and their super-enhancers, including EBF1, OCT2(POU2F2), and RUNX3. Using a novel approach to identify transcriptional feedback, we showed that these core transcriptional circuitries are self-regulating. Their selective gain and loss form a complex, iterative, and interactive process that likely curbs B-cell maturation and spurs proliferation., Interpretation: Our study is the first to map the transcriptional circuitry of the most common blood cancers. We demonstrate that a critical subset of B-cell TFs and their cognate enhancers form self-regulatory transcriptional feedback loops whose disruption is a shared mechanism underlying these diverse subtypes of B-cell lymphoma., Funding: National Institute of Health, Siteman Cancer Center, Barnes-Jewish Hospital Foundation, Doris Duke Foundation., Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Macroscopic coherence of Bose condensates is a fundamental and practical phenomenon in many-body systems, such as the long-range correlation of exciton-polariton condensates with a dipole density typically below the exciton Mott-transition limit. Here we extend the macroscopic coherence of electron-hole-photon interacting systems to a new region in the phase diagram-the high-density plasma region, where long-range correlation is generally assumed to be broken due to the rapid dephasing. Nonetheless, a cooperative state of electron-hole plasma does emerge through the sharing of the superfluorescence field in an optical microcavity. In addition to the in situ coherence of e-h plasma, a long-range correlation is formed between two 8-μm-spaced plasma ensembles even at room temperature. Quantized and self-modulated correlation modes are generated for e-h ensembles in the plasma region. By controlling the distance between the two ensembles, multiple coupling regimes are revealed, from strong correlation to perturbative phase correlation and finally to an incoherent classical case, which has potential implications for tunable and high-temperature-compatible quantum devices.

Disorders of somatic mosaicism (DoSM) are a diverse group of syndromic and non-syndromic conditions caused by mosaic variants in genes that regulate cell survival and proliferation. Despite overlap in gene space and technical requirements, few clinical labs specialize in DoSM compared to oncology. We adapted a high-sensitivity next-generation sequencing cancer assay for DoSM in 2014. Some 343 individuals have been tested over the past 5 years, 58% of which had pathogenic and likely pathogenic (P/LP) findings, for a total of 206 P/LP variants in 22 genes. Parameters associated with the high diagnostic yield were: (1) deep sequencing (∼2,000× coverage), (2) a broad gene set, and (3) testing affected tissues. Fresh and formalin-fixed paraffin embedded tissues performed equivalently for identification of P/LP variants (62% and 71% of individuals, respectively). Comparing cultured fibroblasts to skin biopsies suggested that culturing might boost the allelic fraction of variants that confer a growth advantage, specifically gain-of-function variants in PIK3CA. Buccal swabs showed high diagnostic sensitivity in case subjects where disease phenotypes manifested in the head or brain. Peripheral blood was useful as an unaffected comparator tissue to determine somatic versus constitutional origin but had poor diagnostic sensitivity. Descriptions of all tested individuals, specimens, and P/LP variants included in this cohort are available to further the study of the DoSM population., (Copyright © 2019. Published by Elsevier Inc.)

Folate receptor α (FRα) is a well-studied tumor biomarker highly expressed in many epithelial tumors such as breast, ovarian, and lung cancers. Mirvetuximab soravtansine (IMGN853) is the antibody-drug conjugate of FRα-binding humanized monoclonal antibody M9346A and cytotoxic maytansinoid drug DM4. IMGN853 is currently being evaluated in multiple clinical trials, in which the immunohistochemical evaluation of an archival tumor or biopsy specimen is used for patient screening. However, limited tissue collection may lead to inaccurate diagnosis due to tumor heterogeneity. Herein, we developed a zirconium-89 ( 89 Zr)-radiolabeled M9346A ( 89 Zr-M9346A) as an immuno-positron emission tomography (immuno-PET) radiotracer to evaluate FRα expression in triple-negative breast cancer (TNBC) patients, providing a novel means to guide intervention with therapeutic IMGN853. In this study, we verified the binding specificity and immunoreactivity of 89 Zr-M9346A by in vitro studies in FRα high cells (HeLa) and FRα low cells (OVCAR-3). In vivo PET/computed tomography (PET/CT) imaging in HeLa xenografts and TNBC patient-derived xenograft (PDX) mouse models with various levels of FRα expression demonstrated its targeting specificity and sensitivity. Following PET imaging, the treatment efficiencies of IMGN853, pemetrexed, IMGN853 + pemetrexed, paclitaxel, and saline were assessed in FRα high and FRα low TNBC PDX models. The correlation between 89 Zr-M9346A tumor uptake and treatment response using IMGN853 in FRα high TNBC PDX model suggested the potential of 89 Zr-M9346A PET as a noninvasive tool to prescreen patients based on the in vivo PET imaging for IMGN853-targeted treatment.

Background: The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear., Methods: We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols., Results: Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles., Conclusions: Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).

Background: Although the role of TLR4 in driving inflammation and organ injury after hemorrhagic shock and resuscitation (H/R) is well established, the role of TLR2-another receptor for damage-associated molecular pattern (DAMP) molecules-is not. In this study, we used a combination of TLR2 and wild type (WT) mice treated with anti-TLR2 and anti-TLR4 neutralizing monoclonal antibodies (mAb) to discern the contribution of TLR2 relative to TLR4 to the systemic inflammatory response in murine H/R., Material and Methods: WT mice, TLR2, and WT mice receiving an anti-TLR2 or an anti-TLR4 mAB (given as a pretreatment) were sacrificed at 6 or 20 h post-H/R. Bone marrow TLR2/WT chimeric mice were created to assess the importance of immune and nonimmune cell-associated TLR2., Results: TLR2 mice subjected to H/R exhibited significantly less liver damage and lower markers of systemic inflammation only at 20 h. Bone marrow chimeric mice using combinations of TLR2 mice and WT mice demonstrated that TLR2 on non-bone marrow derived cells played a dominant role in the differences at 20 h. Interestingly, WT mice treated with anti-TLR2 mAB demonstrated a reduction in organ damage and systemic inflammation at both 6 and 20 h following H/R. A combination of anti-TLR2 mAB and anti-TLR4 mAB showed that both receptors drive IP-10 and KC levels and that there is cooperation for increases in IL-6, MIG, and MCP-1 levels between TLR2 and TLR4., Conclusion: These data also support the conclusion that TLR2 and TLR4 act in concert as important receptors in the host immune response to H/R., Competing Interests: The authors declare that they have no conflict-of-interest in presenting this manuscript for publication.

We demonstrate a combined experimental and theoretical investigation of the polarization properties of the strong coupling between fine structure-split excitons and anisotropy-split cavity modes. While the temperature is varied to control the light-matter coupling, we observe a notable change in the emission polarization for the branch of the exciton-like polariton. The exciton dephasing is introduced in order to explain the temperature-sensitive effect on the emission polarization. We apply the medium-dependent Green function approach involving the polarization-dependent exciton dephasing to model the emission spectra, which shows qualitative agreement with our experimental results.

We demonstrate sequential lasing at two well-separated energies in a highly photoexcited planar microcavity at room temperature. Two spatially overlapped lasing states with distinct polarization properties appear at energies more than 5 meV apart. Under a circularly polarized nonresonant 2 ps pulse excitation, a sub-10-ps transient circularly polarized high-energy (HE) state emerges within 10 ps after the pulse excitation. This HE state is followed by a pulsed state that lasts for 20-50 ps at a low energy (LE) state. The HE state is highly circularly polarized as a result of a spin-preserving stimulated process, while the LE state shows a significantly reduced circular polarization because of a diminishing spin imbalance.