Diagnostic Performance of 18F-FDG Positron Emission Tomography/Computed Tomography and Blood Test Parameters for Pulmonary Inflammatory Pseudotumor.

PURPOSE: Pulmonary inflammatory pseudotumor (PIP) is an inflammatory proliferative tumor-like lesion that frequently exhibits hypermetabolism on 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography imaging (PET/CT) and is readily misdiagnosed as a malignant tumor. The purpose of this study was to identify PIP by combining PET/computed tomography metabolic and blood test characteristics with machine learning. PATIENTS AND METHODS: We recruited 27 patients with PIP and 28 patients with lung cancer (LC). The PET metabolic and blood test parameters were collected, and the differences between the groups were evaluated. In addition, we combined the support vector machine (SVM) classifier with the indicators that differed between the groups to classify PIP and LC. RESULTS: For PET metabolic parameters, our findings showed that, as compared with the LC group, maximal standardized uptake value (P< 0.001, t = -4.780), Mean standardized uptake value SUVmean, P< 0.001, t = -4.946), and SD40% (P< 0.001, t = -4.893) were considerably reduced in the PIP group, whereas CV40% (P= 0.004, t = 3.012) was significantly greater. For blood test parameters, the total white blood cell count (P< 0.001, t= 6.457) and absolute neutrophil count (P< 0.001, t= 6.992) were substantially higher in the PIP group than in the LC group. Furthermore, the performance of SVM trained solely on PET metabolic parameters (mean area under the curve [AUC] = 0.84) was comparable to that of SVM trained solely on blood test parameters (mean AUC = 0.86). Surprisingly, utilizing the combined parameters increased SVM performance significantly (mean AUC = 0.98). CONCLUSION: PET metabolic and blood test parameters differed significantly between the PIP and LC groups, and the SVM paradigm using these significantly different features has the potential to be used to classify PIP and LC, which has important clinical implications.

Efficacy and safety of stapokibart (CM310) in uncontrolled seasonal allergic rhinitis (MERAK): an investigator-initiated, placebo-controlled, randomised, double-blind, phase 2 trial.

Background: There is no trial to assess the benefits of periodically using biologics during the pollen season in patients with uncontrolled seasonal allergic rhinitis (SAR), who have moderate-to-severe symptoms even after standard-of-care. This trial aimed to evaluate the efficacy and safety of the add-on administration of stapokibart, a humanised monoclonal antibody that targets interleukin-4 receptor alpha, in patients with uncontrolled SAR. Methods: In this investigator-initiated, randomised, double-blind, placebo-controlled trial, eligible patients received either stapokibart 600-300 mg weekly (QW), every 2 weeks (Q2W), or placebo QW for 4 weeks. All patients were given mometasone furoate nasal spray and loratadine throughout the trial. The primary endpoint was the mean change from baseline in daily reflective total nasal symptom score (rTNSS) during 2-week treatment. Secondary efficacy outcomes included: the mean change from baseline in daily rTNSS during 4-week treatment; the mean changes and the mean percentage changes from baseline during 2-week and 4-week treatment in 1) daily rTNSS and reflective total ocular symptom score (rTOSS), 2) morning (AM)/evening (PM) rTNSS and rTOSS, 3) AM instantaneous total nasal symptom score (iTNSS) and instantaneous total ocular symptom score (iTOSS), 4) individual nasal and ocular symptoms; the change from baseline in Rhinoconjunctivitis Quality of-Life Questionnaire score during 4-week treatment. Exploratory endpoints included the change of prespecified markers related to type 2 inflammation pre- and post-treatment. Safety, immunogenicity, and pharmacokinetics were also evaluated. This study is registered with www.clinicaltrials.gov (NCT05470647). Findings: Between August 17, 2022, and December 28, 2022, 92 patients with uncontrolled SAR were enrolled from 4 centres in China and randomly assigned to receive stapokibart 600-300 mg QW (n = 31), stapokibart 600-300 mg Q2W (n = 30), or placebo QW (n = 31), of whom 86 (93%) completed the study. Both stapokibart Q2W and QW did not significantly improve mean change from baseline in daily rTNSS compared with placebo in 2 weeks. The least-squares (LS) mean differences (97.5% confidence interval [CI]) compared with placebo were -1.0 (-2.3, 0.2) in stapokibart Q2W group (p = 0.065) and -0.2 (-1.5, 1.0) in stapokibart QW group (p = 0.67). For the secondary outcomes, compared with placebo, stapokibart Q2W presented significant improvements in the mean percentage change from baseline in daily rTNSS in 2 weeks (LS mean difference -12.9%, 95% CI -25.3%, -0.4%, p = 0.043), as well as AM iTNSS over 2 weeks (LS mean difference -17.4%, 95% CI -31.0%, -3.8%, p = 0.013) and 4 weeks (LS mean difference -15.4%, 95% CI -29.0%, -1.9%, p = 0.026). Additionally, the nasal congestion score was significantly lower in stapokibart Q2W than placebo during 2-week (LS mean difference -0.4, 95% CI -0.7, -0.1, p = 0.014) and 4-week (LS mean difference -0.4, 95% CI -0.7, -0.04, p = 0.028) treatment. Treatment-emergent adverse events (TEAEs) occurred in 48% (15/31), 33% (10/30), and 61% (19/31) of patients receiving stapokibart QW, Q2W, and placebo, respectively. Most reported TEAEs were sinus bradycardia, hyperlipidaemia, and blood uric acid increased. Interpretation: In this phase 2 trial, both stapokibart regimens had an acceptable safety and tolerability profile but did not significantly improve daily rTNSS in patients with uncontrolled SAR. The efficacy of stapokibart in patients with uncontrolled SAR is being further investigated in ongoing phase 3 trials (clinicaltrials.gov, NCT05908032). Funding: Ministry of Science and Technology of the People's Republic of China; Ministry of Education of the People's Republic of China; National Natural Science Foundation of China; Chinese Academy of Medical Sciences.

Sustainable phosphorus adsorption and recovery from aqueous solution by a novel recyclable Ca-PAC-CTS.

Phosphorus removal has been explored for a long time, however sustainable phosphorus adsorption and recovery with adsorbents recycling is rarely reported. This work proposes a sustainable phosphorus recycling route with calcium-modified powdered activated carbon with chitosan (Ca-PAC-CTS). The morphology, functional groups and crystal structure of Ca-PAC-CTS were characterized. The maximum phosphorus adsorption capacity was 16.73 mg/g Ca-PAC-CTS with Langmuir model at 298 K. Stable phosphorus sorption on Ca-PAC-CTS could be observed at the large range of pH (4- 10) when coexisting with NO3-, SO42-, Cl- and F-, except HCO3-. 98.95 % The recovery of adsorbed phosphorus could get to 98.95 % using 0.05 M sulfuric acid solution, and the phosphate adsorption efficiency through Ca-PAC-CTS remained to be more than 80 % after five adsorption-desorption cycles, suggesting that Ca-PAC-CTS was one of the promising adsorbents for sustainable removal and recovery of phosphorus in aqueous solution.

[Segmentation of prostate region in magnetic resonance images based on improved V-Net].

Magnetic resonance (MR) imaging is an important tool for prostate cancer diagnosis, and accurate segmentation of MR prostate regions by computer-aided diagnostic techniques is important for the diagnosis of prostate cancer. In this paper, we propose an improved end-to-end three-dimensional image segmentation network using a deep learning approach to the traditional V-Net network (V-Net) network in order to provide more accurate image segmentation results. Firstly, we fused the soft attention mechanism into the traditional V-Net's jump connection, and combined short jump connection and small convolutional kernel to further improve the network segmentation accuracy. Then the prostate region was segmented using the Prostate MR Image Segmentation 2012 (PROMISE 12) challenge dataset, and the model was evaluated using the dice similarity coefficient (DSC) and Hausdorff distance (HD). The DSC and HD values of the segmented model could reach 0.903 and 3.912 mm, respectively. The experimental results show that the algorithm in this paper can provide more accurate three-dimensional segmentation results, which can accurately and efficiently segment prostate MR images and provide a reliable basis for clinical diagnosis and treatment.

Simultaneous ammonium and phosphate removal with Mg-loaded chitosan carbonized microsphere: Influencing factors and removal mechanism.

A novel Mg-loaded chitosan carbonized microsphere (MCCM) was prepared for simultaneous adsorption of ammonium and phosphate in this study, through the investigation of preparation procedures, addition ratio, and preparation temperature. Pollutants removals by MCCM were more acceptable with 64.71% for ammonium and 99.26% for phosphorus, compared with chitosan carbonized microspheres (CCM), Mg-loaded chitosan hydrogel beads (MCH) and MgCl2·6H2O. Addition ratio of 0.6:1 (mchitosan: mMgCl2) and preparation temperature of 400 °C in MCCM preparation were responsible for pollutant removal and yield. The effect analysis of MCCM dosage, solution pH, pollutant concentration, adsorption mode and coexisting ions on the removal for both ammonium and phosphate indicated that pollutants removals were increased with increasing MCCM dosages, and achieved the peak at pH 8.5, but presented to be stable with Na+, K+, Ca2+, Cl-, NO3-, CO32- and SO42-, except for Fe3+.Adsorption mechanisms discussion implied that simultaneous ammonium and phosphate removal with MCCM was attributed to struvite precipitation, ion exchange, hydrogen bonding, electrostatic attraction and Mg-P complexation, suggesting that MCCM presents a new way for simultaneous concentrated ammonium and phosphate removal in wastewater treatment.

Plasma Core Alzheimer's Disease Biomarkers Predict Amyloid Deposition Burden by Positron Emission Tomography in Chinese Individuals with Cognitive Decline.

Blood-based biomarkers have been considered as a promising method for the diagnosis of Alzheimer's disease (AD). The reliability and accuracy of plasma core AD biomarkers, including phosphorylated tau (P-tau181), total tau (T-tau), Aß42, and Aß40, have also been confirmed in diagnosing AD and predicting cerebral ß-amyloid (Aß) deposition in Western populations, while fewer research studies have ever been conducted in China's Han population. In this study, we investigated the capability of plasma core AD biomarkers in predicting cerebral Aß deposition burden among the China Aging and Neurodegenerative Disorder Initiative (CANDI) cohort consisting of cognitively normal (CN), mild cognitive impairment (MCI), AD dementia, and non-Alzheimer's dementia disease (Non-ADD). Body fluid (plasma and CSF) AD core biomarkers were measured via single-molecule array (Simoa) immunoassay. The global standard uptake value ratio (SUVR) was then calculated by 18F-florbetapir PET, which was divided into positive (+) and negative (-). The most significant correlation between plasma and CSF was plasma P-tau181 (r = 0.526, P < 0.0001). Plasma P-tau181 and P-tau181/T-tau ratio were positively correlated with global SUVR (r = 0.257, P < 0.0001; r = 0.263, P < 0.0001, respectively), while Aß42 and Aß42/Aß40 ratio were negatively correlated with global SUVR (r = -0.346, P < 0.0001; r = -0.407, P < 0.0001, respectively). Interestingly, voxel-wise analysis showed that plasma P-tau181 and P-tau181/T-tau ratio were negatively related to 18F-florbetapir PET in the hippocampus and parahippocampal cortex. The optimal predictive capability in distinguishing all Aß+ participants from Aß- participants and MCI+ from MCI- subgroups was the plasma P-tau181/T-tau ratio (AUC = 0.825 and 0.834, respectively). Our study suggested that plasma P-tau181 and P-tau181/T-tau ratio possessed better diagnostic and predictive values than plasma Aß42 and Aß42/Aß40 in this cohort, a finding that may be useful in clinical practices and trials in China.

Design, synthesis, and preliminary evaluation of [18F]-aryl flurosulfates PET radiotracers via SuFEx methods for ß-amyloid plaques in Alzheimer's disease.

[18F]BAY-94-9172, [18F]AV-45, and [18F]GE-067 were FDA approved positron emission tomography (PET) imaging radiotracer of ß-amyloid plaques (Aß) in Alzheimer's disease (AD). However, the radiochemical synthesis requires multi-step reactions and complex procedure. Recently, a protocol for radiochemical synthesis of sulfur fluoride exchange (SuFEx) using ultrafast 19F/18F isotopic exchange had been reported. We developed three pairs of novel 18F-labeled radiotracers by the "SuFEx" method for PET imaging Aß plaques. The 18F labeling reaction can be completed quickly (30 s) at room temperature and purified using solid-phase extraction (SPE). The radiochemical purity (RCP) of the products was all greater than 95 %. In vitro fluorescent staining using Aß-transgenesis mice section preliminary verified the affinity of tracers with Aß. Competitive binding assay displayed high affinity of tracers for towards artificial Aß1-42 aggregates (Ki values ranging from 3.53 ± 0.39 to 42.0 ± 4.24 nM). In vivo biodistribution and Micro-PET imaging showed that [18F]-Sulfur Fluoride ß-Amyloid ([18F]SFA 1-6) could penetration the blood-brain barrier (BBB) in wild-type mice, and [18F]SFA 5-6 had a high initial brain uptake value (3.65 ± 0.9 % and 5.07 ± 0.1 % ID/g, respectively) and a fast washout (Brain uptake2 min/60 min = 4.15 and 4.61, respectively) from the brain. In vitro autoradiography demonstrated the affinity of the [18F]SFA 5-6 to Aß plaques in AD human brain tissues. Our results suggested that [18F]SFA maybe a potential PET radiotracers for detecting Aß in Alzheimer's disease.

Au Wire Ball Welding and Its Reliability Test for High-Temperature Environment.

The long-term application of sensors in a high-temperature environment needs to address several challenges, such as stability at high temperatures for a long time, better wiring interconnection of sensors, and reliable and steady connection of the sensor and its external equipment. In order to systematically investigate the reliability of thin coatings at high temperatures for a long time, Au and Cr layers were deposited on silicon substrates by magnetron sputtering. Additionally, samples with different electrode thicknesses were annealed at different temperatures for a varied duration to study the effect of electrode thickness, temperature, and duration on the reliability of samples. The results of tensile and probe tests before and after heat treatment revealed that the mechanical strength and electrical properties have changed after annealing. In addition, the bonding interface was analyzed by a cross-sectional electron microscope. The analysis showed that long-term continuous high-temperature exposure would result in thinning of the electrode, formation of pores, recrystallization, and grain growth, all of which can affect the mechanical strength and electrical properties. In addition, it was observed that increasing the thickness of the gold layer will improve reliability, and the test results show that although the thin metal layer sample is in poor condition, it is still usable. The present study provides theoretical support for the application of thin coatings in high temperatures and harsh environments.

Case report: Revealing a special and rare autoimmune GFAP astrocytopathy in the spinal cord succeeding Neurobrucellosis infection.

Brucellosis, a zoonosis, can cause an inflammatory response in most organs and continues to be a public health problem in some endemic areas, whereas neurobrucellosis is a morbid form of brucellosis that affects the central nervous system (CNS) with poor prognosis. Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an autoimmune disease, and there have been no reports of a Brucella infection, leading to GFAP astrocytopathy. We report the case of a patient with a positive and high level of GFAP antibodies in the cerebrospinal fluid (CSF), following a Brucella infection. Although this patient did not show any responsible lesions in the diffusion sequence of the magnetic resonant imaging (MRI) scan, we found an evidence of thoracolumbar (T12) involvement on fluorodeoxyglucose (FDG) positron emission tomography (PET). The symptoms of spinal cord involvement were only partly relieved after initial treatment [doxycycline (0.1 g Bid) and rifampicin (0.6 g Qd) for 6 weeks]; however, they markedly improved after the subsequent immunosuppressive therapy [intravenous methylprednisolone (1,000 mg for 3 days)], followed by a 50% reduction from the preceding dose after 3 days, and subsequently, oral prednisone tablets (60 mg/day) was started, which was then gradually tapered [reduced to 10 mg/day every 1-2 weeks)]. The positive response to immunosuppressive therapy and treatment outcome strongly indicated the presence of an autoimmune neurological disease probably triggered by some infectious factors. Therefore, our findings reveal that a Brucella infection is one of the causes of autoimmune GFAP astrocytopathy, and when this infection is difficult to be identified by regular MRI, FDG PET can be used as a supplementary method for diagnosis and treatment.

A Novel Crossbeam Structure with Graphene Sensing Element for N/MEMS Mechanical Sensors.

A graphene membrane acts as a highly sensitive element in a nano/micro-electro-mechanical system (N/MEMS) due to its unique physical and chemical properties. Here, a novel crossbeam structure with a graphene varistor protected by Si3N4 is presented for N/MEMS mechanical sensors. It substantially overcomes the poor reliability of previous sensors with suspended graphene and exhibits excellent mechanoelectrical coupling performance, as graphene is placed on the root of the crossbeam. By performing basic mechanical electrical measurements, a preferable gauge factor of ~1.35 is obtained. The sensitivity of the graphene pressure sensor based on the crossbeam structure chip is 33.13 mV/V/MPa in a wide range of 0~20 MPa. Other static specifications, including hysteresis error, nonlinear error, and repeatability error, are 2.0119%, 3.3622%, and 4.0271%, respectively. We conclude that a crossbeam structure with a graphene sensing element can be an application for the N/MEMS mechanical sensor.

Detection of plasma exosomal miRNA-205 as a biomarker for early diagnosis and an adjuvant indicator of ovarian cancer staging.

BACKGROUND: Ovarian cancer (OC) is one of the serious threats to the health of women worldwide, and accurate biomarkers are urgently demanded for early diagnosis of OC. We have previously confirmed that miR-205 promotes the invasion and metastasis of OC cells by inhibiting the expression of the tumor suppressor gene TCF21. In this study, we used liquid biopsy technology to detect the expression levels of the four genes, miR-205, CA125, HE4 and TCF21, in the exosomes of plasma of OC patients. Combined with analysis of clinicopathological parameters of OC patients, we aimed to provide efficient and non-invasive laboratory biomarkers for early diagnosis of OC. METHODS: 36 OC patients who were diagnosed in local hospitals from September 2020 to July 2021 were selected as OC group, 31 cases of surgically diagnosed with ovarian benign lesions were selected as benign group, and 32 healthy people who underwent physical examination during the same period were selected as a control group. We employed transmission electron microscope (TEM), Western blotting (WB), and nanoparticle tracking analysis (NTA) to identify biomarkers in the exosomes extracted from plasma of the three groups. The RNA levels of miR-205, CA125, HE4 and TCF21 genes in plasma exosomes were detected by real-time quantitative PCR (qRT-PCR) method. We used clinical pathological parameters and the Receiver Operating Characteristic (ROC) curves to evaluate the diagnostic efficacy for the genes detected in plasma exosomes. RESULTS: We found that the expression level of miR-205 in plasma exosomes of the OC group was significantly higher than that of the benign and control groups (P <  0.05), and the level of miR-205 was elevated during the III-IV periods of OC and lymph node metastasis. CONCLUSION: The level of miR-205 in plasma exosomes is a valuable tumor biomarker to improve OC diagnosis.

ITSN1: a novel candidate gene involved in autosomal dominant neurodevelopmental disorder spectrum.

ITSN1 plays an important role in brain development. Recent studies in large cohorts of subjects with neurodevelopmental disorders have identified de novo variants in ITSN1 gene thereby suggesting that this gene is involved in the development of such disorders. The aim of this study is to provide further proof of such a link. We performed trio exome sequencing in a patient presenting autism, intellectual disability, and severe behavioral difficulties. Additional affected patients with a neurodevelopmental disorder harboring a heterozygous variant in ITSN1 (NM_003024.2) were collected through a worldwide collaboration. All patients underwent detailed phenotypic and genetic assessment and data was collected and shared by healthcare givers. We identified ten novel patients from eight families with heterozygous truncating or missense variants in ITSN1 gene. In addition, four previously published patients from large meta-analysis studies were included. In total, 7/14 patients presented a de novo variant in ITSN1. All patients showed neurodevelopmental disorders from autism spectrum disorders (90%), intellectual disability (86%), and epilepsy (30%). We demonstrated that truncating variants are in the first half of ITSN1 whereas missense variants are clustered in C-terminal region. We suggest ITSN1 gene is involved in development of an autism spectrum disorder with variable additional neurodevelopmental deficiency, thus confirming the hypothesis that ITSN1 is important for brain development.

Pre-Operative Prediction of Mediastinal Node Metastasis Using Radiomics Model Based on 18F-FDG PET/CT of the Primary Tumor in Non-Small Cell Lung Cancer Patients.

Purpose: We investigated whether a fluorine-18-fluorodeoxy glucose positron emission tomography/computed tomography (18F-FDG PET/CT)-based radiomics model (RM) could predict the pathological mediastinal lymph node staging (pN staging) in patients with non-small cell lung cancer (NSCLC) undergoing surgery. Methods: A total of 716 patients with a clinicopathological diagnosis of NSCLC were included in this retrospective study. The prediction model was developed in a training cohort that consisted of 501 patients. Radiomics features were extracted from the 18F-FDG PET/CT of the primary tumor. Support vector machine and extremely randomized trees were used to build the RM. Internal validation was assessed. An independent testing cohort contained the remaining 215 patients. The performances of the RM and clinical node staging (cN staging) in predicting pN staging (pN0 vs. pN1 and N2) were compared for each cohort. The area under the curve (AUC) of the receiver operating characteristic curve was applied to assess the model's performance. Results: The AUC of the RM [0.81 (95% CI, 0.771-0.848); sensitivity: 0.794; specificity: 0.704] for the predictive performance of pN1 and N2 was significantly better than that of cN in the training cohort [0.685 (95% CI, 0.644-0.728); sensitivity: 0.804; specificity: 0.568], (P-value = 8.29e-07, as assessed by the Delong test). In the testing cohort, the AUC of the RM [0.766 (95% CI, 0.702-0.830); sensitivity: 0.688; specificity: 0.704] was also significantly higher than that of cN [0.685 (95% CI, 0.619-0.747); sensitivity: 0.799; specificity: 0.568], (P = 0.0371, Delong test). Conclusions: The RM based on 18F-FDG PET/CT has a potential for the pN staging in patients with NSCLC, suggesting that therapeutic planning could be tailored according to the predictions.

Individual Brain Metabolic Connectome Indicator Based on Jensen-Shannon Divergence Similarity Estimation Predicts Seizure Outcomes of Temporal Lobe Epilepsy.

Objective: We aimed to use an individual metabolic connectome method, the Jensen-Shannon Divergence Similarity Estimation (JSSE), to characterize the aberrant connectivity patterns and topological alterations of the individual-level brain metabolic connectome and predict the long-term surgical outcomes in temporal lobe epilepsy (TLE). Methods: A total of 128 patients with TLE (63 females, 65 males; 25.07 ± 12.01 years) who underwent Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) imaging were enrolled. Patients were classified either as experiencing seizure recurrence (SZR) or seizure free (SZF) at least 1 year after surgery. Each individual's metabolic brain network was ascertained using the proposed JSSE method. We compared the similarity and difference in the JSSE network and its topological measurements between the two groups. The two groups were then classified by combining the information from connection and topological metrics, which was conducted by the multiple kernel support vector machine. The validation was performed using the nested leave-one-out cross-validation strategy to confirm the performance of the methods. Results: With a median follow-up of 33 months, 50% of patients achieved SZF. No relevant differences in clinical features were found between the two groups except age at onset. The proposed JSSE method showed marked degree reductions in IFGoperc.R, ROL. R, IPL. R, and SMG. R; and betweenness reductions in ORBsup.R and IOG. R; meanwhile, it found increases in the degree analysis of CAL. L and PCL. L, and in the betweenness analysis of PreCG.R, IOG. R, PoCG.R, PCL. L and PCL.R. Exploring consensus significant metabolic connections, we observed that the most involved metabolic motor networks were the INS-TPOmid.L, MTG. R-SMG. R, and MTG. R-IPL.R pathways between the two groups, and yielded another detailed individual pathological connectivity in the PHG. R-CAU.L, PHG. R-HIP.L, TPOmid.L-LING.R, TPOmid.L-DCG.R, MOG. R-MTG.R, MOG. R-ANG.R, and IPL. R-IFGoperc.L pathways. These aberrant functional network measures exhibited ideal classification performance in predicting SZF individuals from SZR ones at a sensitivity of 75.00%, a specificity of 92.79%, and an accuracy of 83.59%. Conclusion: The JSSE method indicator can identify abnormal brain networks in predicting an individual's long-term surgical outcome of TLE, thus potentially constituting a clinically applicable imaging biomarker. The results highlight the biological meaning of the estimated individual brain metabolic connectome.

Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency.

PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated. RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. CONCLUSIONS: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.

Phosphorylation of RAB7 by TBK1/IKKε Regulates Innate Immune Signaling in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous disease enriched for mutations in PTEN and dysregulation of innate immune signaling. Here, we demonstrate that Rab7, a recently identified substrate of PTEN phosphatase activity, is also a substrate of the innate immune signaling kinases TANK-binding kinase 1 (TBK1)/IκB kinase ε (IKKε) on the same serine-72 (S72) site. An unbiased search for novel TBK1/IKKε substrates using stable isotope labeling with amino acids in cell culture phosphoproteomic analysis identified Rab7-S72 as a top hit. PTEN-null TNBC cells expressing a phosphomimetic version of Rab7-S72 exhibited diffuse cytosolic Rab7 localization and enhanced innate immune signaling, in contrast to a kinase-resistant version, which localized to active puncta that promote lysosomal-mediated stimulator of interferon genes (STING) degradation. Thus, convergence of PTEN loss and TBK1/IKKε activation on Rab7-S72 phosphorylation limited STING turnover and increased downstream production of IRF3 targets including CXCL10, CCL5, and IFNß. Consistent with this data, PTEN-null TNBC tumors expressed higher levels of STING, and PTEN-null TNBC cell lines were hyperresponsive to STING agonists. Together, these findings begin to uncover how innate immune signaling is dysregulated downstream of TBK1/IKKε in a subset of TNBCs and reveals previously unrecognized cross-talk with STING recycling that may have implications for STING agonism in the clinic. SIGNIFICANCE: These findings identify Rab7 as a substrate for TBK1 for regulation of innate immune signaling, thereby providing important insight for strategies aimed at manipulating the immune response to enhance therapeutic efficacy in TNBC.

Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature.

PURPOSE: To define the clinical characteristics of patients with variants in TCF20, we describe 27 patients, 26 of whom were identified via exome sequencing. We compare detailed clinical data with 17 previously reported patients. METHODS: Patients were ascertained through molecular testing laboratories performing exome sequencing (and other testing) with orthogonal confirmation; collaborating referring clinicians provided detailed clinical information. RESULTS: The cohort of 27 patients all had novel variants, and ranged in age from 2 to 68 years. All had developmental delay/intellectual disability. Autism spectrum disorders/autistic features were reported in 69%, attention disorders or hyperactivity in 67%, craniofacial features (no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Additional features affecting various organ systems were described in 93%. In a majority of patients, we did not observe previously reported findings of postnatal overgrowth or craniosynostosis, in comparison with earlier reports. CONCLUSION: We provide valuable data regarding the prognosis and clinical manifestations of patients with variants in TCF20.

Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS.

Despite extensive efforts, oncogenic KRAS remains resistant to targeted therapy. Combined downstream RAL-TBK1 and MEK inhibition induces only transient lung tumor shrinkage in KRAS-driven genetically engineered mouse models (GEMMs). Using the sensitive KRAS;LKB1 (KL) mutant background, we identify YAP1 upregulation and a therapy-induced secretome as mediators of acquired resistance. This program is reversible, associated with H3K27 promoter acetylation, and suppressed by BET inhibition, resensitizing resistant KL cells to TBK1/MEK inhibition. Constitutive YAP1 signaling promotes intrinsic resistance in KRAS;TP53 (KP) mutant lung cancer. Intermittent treatment with the BET inhibitor JQ1 thus overcomes resistance to combined pathway inhibition in KL and KP GEMMs. Using potent and selective TBK1 and BET inhibitors we further develop an effective therapeutic strategy with potential translatability to the clinic.

Evaluation of neurotensin receptor 1 as a potential imaging target in pancreatic ductal adenocarcinoma.

Pancreatic cancer is one of the deadliest human malignancies and lack of effective diagnostic and therapeutic methods. Accumulating evidence suggests that the neurotensin (NT) and neurotensin receptors (NTRs) play key roles in pancreatic adenocarcinoma growth and survival. In this study, we not only evaluate the NTR1 expression in pancreatic cancer patient samples, but also explore the PET and fluorescence imaging of NTR1 expression in pancreatic cancer animal models. The NTR1 expression was evaluated by immunohistochemistry staining in clinical patient tissue samples with pancreatic ductal adenocarcinoma, insulinoma, and pancreatitis. The results showed 79.4% positive rate of NRT1 expression in pancreatic ductal adenocarcinoma, compared with 33.3 and 22.7% in insulinoma and pancreatitis samples, respectively. High NTR1 gene expression was also found in Panc-1 cells and confirmed by cell immunofluorescence. 64Cu-AmBaSar-NT and IRDye800-NT were synthesized as imaging probes and maintained the majority of NTR1-binding affinity. In vivo imaging demonstrated that 64Cu-AmBaSar-NT has prominent tumor uptake (3.76 ± 1.45 and 2.29 ± 0.10%ID/g at 1 and 4 h post-injection). NIR fluorescent imaging with IRDye800-NT demonstrated good tumor-to-background contrast (8.09 ± 0.38 × 108 and 6.67 ± 0.43 × 108 (p/s/cm2/sr)/(µW/cm2) at 30 and 60 min post-injection). Fluorescence guided surgery was also performed as a proof of principle experiment. In summary, our results indicated that NTR1 is a promising target for pancreatic ductal adenocarcinoma imaging and therapy. The imaging probes reported here may not only be considered for improved diagnosis of pancreatic ductal adenocarcinoma, but also has the potential to be fully integrated into patient screening and treatment monitoring of future NTR1 targeted therapies.

Autophagy Inhibition Dysregulates TBK1 Signaling and Promotes Pancreatic Inflammation.

Autophagy promotes tumor progression downstream of oncogenic KRAS, yet also restrains inflammation and dysplasia through mechanisms that remain incompletely characterized. Understanding the basis of this paradox has important implications for the optimal targeting of autophagy in cancer. Using a mouse model of cerulein-induced pancreatitis, we found that loss of autophagy by deletion of Atg5 enhanced activation of the IκB kinase (IKK)-related kinase TBK1 in vivo, associated with increased neutrophil and T-cell infiltration and PD-L1 upregulation. Consistent with this observation, pharmacologic or genetic inhibition of autophagy in pancreatic ductal adenocarcinoma cells, including suppression of the autophagy receptors NDP52 or p62, prolonged TBK1 activation and increased expression of CCL5, IL6, and several other T-cell and neutrophil chemotactic cytokines in vitro Defective autophagy also promoted PD-L1 upregulation, which is particularly pronounced downstream of IFNγ signaling and involves JAK pathway activation. Treatment with the TBK1/IKKε/JAK inhibitor CYT387 (also known as momelotinib) not only inhibits autophagy, but also suppresses this feedback inflammation and reduces PD-L1 expression, limiting KRAS-driven pancreatic dysplasia. These findings could contribute to the dual role of autophagy in oncogenesis and have important consequences for its therapeutic targeting. Cancer Immunol Res; 4(6); 520-30. ©2016 AACR.