Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids.

Spinal opioid-induced itch, a prevalent side effect of pain management, has been proposed to result from pain inhibition. We now report that the µ-opioid receptor (MOR) isoform MOR1D is essential for morphine-induced scratching (MIS), whereas the isoform MOR1 is required only for morphine-induced analgesia (MIA). MOR1D heterodimerizes with gastrin-releasing peptide receptor (GRPR) in the spinal cord, relaying itch information. We show that morphine triggers internalization of both GRPR and MOR1D, whereas GRP specifically triggers GRPR internalization and morphine-independent scratching. Providing potential insight into opioid-induced itch prevention, we demonstrate that molecular and pharmacologic inhibition of PLCß3 and IP3R3, downstream effectors of GRPR, specifically block MIS but not MIA. In addition, blocking MOR1D-GRPR association attenuates MIS but not MIA. Together, these data suggest that opioid-induced itch is an active process concomitant with but independent of opioid analgesia, occurring via the unidirectional cross-activation of GRPR signaling by MOR1D heterodimerization.

LncRNA GABPB1-IT1 is upregulated in ischemia-induced acute kidney injury and downregulates miR-204-5p to promote hypoxia-induced human renal proximal tubular epithelial cell apoptosis.

INTRODUCTION: The present study investigated the role of long non-coding RNA (lncRNA) GABPB1-IT1 in ischemia-induced acute kidney injury (AKI). METHODS: The expression of GABPB1-IT1 in plasma of patients with ischemia-induced AKI and healthy controls was detected by RT-qPCR. GABPB1-IT1 and miR-204-5p were overexpressed in human renal proximal tubular epithelial cells (HRPTEpCs), followed by RT-qPCR to assess the overexpression effect and the regulatory relationship between GABPB1-IT1 and miR-204-5p. Methylation-specific PCR (MSP) was performed to assess the promoter methylation status of miR-204-5p. Additionally, cell apoptosis assay was carried out to evaluate the correlation between miR-204-5p and GABPB1-IT1 in the context of hypoxia-induced apoptosis of HRPTEpCs. RESULTS: GABPB1-IT1 was upregulated in plasma of patients with ischemia-induced AKI. In HRPTEpCs, hypoxia upregulated the expression of GABPB1-IT1. MiR-204-5p was downregulated in ischemia-induced AKI, and the expression of miR-204-5p was inversely correlated with GABPB1-IT1. In HRPTEpCs, overexpression of GABPB1-IT1 decreased the expression levels of miR-204-5p and increased miR-204-5p gene methylation. In addition, overexpression of GABPB1-IT1 reduced the inhibitory effects of miR-204-5p on the apoptosis of HRPTEpC induced by hypoxia. Furthermore, overexpression of GABPB1-IT1 promoted kidney injury, renal tissue injury scores, and the level of serum creatinine. However, miR-204-5p had the opposite effect. CONCLUSION: GABPB1-IT1 was upregulated in ischemia-induced AKI and may induce hypoxia-induced apoptosis of HRPTEpC by methylation of miR-204-5p.

Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas.

Bruton's tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC50 value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC50 = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations.

Nonpermissive Skin Environment Impairs Nerve Regeneration in Diabetes via Sec31a.

OBJECTIVE: Although the microenvironment for peripheral nerve regeneration is permissive, such a mechanism is defective in diabetes, and the molecular mediators remain elusive. [Correction added on May 11, 2022, after first online publication: In the preceding sentence, "is ok" was changed to "is defective".] This study aimed to (1) investigate the relationship between skin innervation and collagen pathology in diabetic neuropathy and to (2) clarify the molecular alterations that occur in response to hyperglycemia and their effects on axon regeneration. METHODS: We addressed this issue using two complementary systems: (1) human skin from patients with diabetic neuropathy and to (2) a coculture model of human dermal fibroblasts (HDFs) with rat dorsal root ganglia neurons in the context of intrinsic neuronal factor and extrinsic microenvironmental collagen and its biosynthetic pathways. RESULTS: In diabetic neuropathy, the skin innervation of intraepidermal nerve fiber density (IENFd), a measure of sensory nerve degeneration, was reduced with similar expression of a growth associated protein 43, a marker of nerve regeneration. In contrast, the content and packing of collagen in the diabetic skin became more rigid than the control skin. Sec31a, a protein that regulates the collagen biosynthetic pathway, was upregulated and inversely correlated with IENFd. In the cell model, activated HDFs exposed to high-glucose medium enhanced the expression of Sec31a and collagen I through the activation of transforming growth factor ß, a profibrotic molecule. Sec31a upregulation impaired neurite outgrowth. This effect was reversed by silencing Sec31a expression and neurite outgrowth was resumed. INTERPRETATION: The current study provides evidence that Sec31a plays a key role in inhibiting nerve regeneration in diabetic neuropathy. ANN NEUROL 2022;91:821-833.

Electrochemiluminescent bioassay based on Ru@Zr-BTC-MOFs nanoparticles for determination of let-7a miRNA using the hybridization chain reaction.

Carboxyl-rich tris(4,4'-dicarboxylic acid-2,2'-bipyridyl) ruthenium(II) ([Ru(dcbpy)3]2+) and 1,3,5-phenyl tricarboxylic acid (H3BTC) were used as the organic ligand to synthesize the metal-organic frameworks by a simple one-pot hydrothermal method with ZrCl4 as metal ion source. Subsequently, the excellent electrochemiluminescence (ECL) luminophore (denoted as Ru@Zr-BTC-MOFs) was obtained. The Ru@Zr-BTC-MOFs displayed outstanding ECL properties, and a sensitive ECL bioassay based on Ru@Zr-BTC-MOFs was designed for the detection of let-7a microRNA (miRNA) using hybrid chain reaction (HCR). Under the optimal experimental conditions, the proposed bioassay exhibited a good linear relationship in the range from 50.0 fM to 5.00 × 102 pM with a detection limit of 3.71 fM. Besides, the proposed sensor exhibited satisfactory performance in real samples. The recovery was 91 ~ 108%, and the relative standard deviation was less than 5.6%. It might have potential clinical applications for detecting miRNA in biomedical research and clinical diagnosis. The schematic diagram of the preparation of Ru@Zr-BTC-MOFs (a) and ECL sensor for detecting let -7a (b).

Antibacterial oxygenated ergostane-type steroids produced by the marine sponge-derived fungus Aspergillus sp.

Two oxygenated ergostane-type steroids including one new compound, 3ß-hydroxy-5α,6ß-methoxyergosta-7,22-dien-15-one (1) along with a known analogue ergosta-6,22-dien-3ß,5α,8α-triol (2) were isolated from the crude extracts of the marine sponge-derived fungus Aspergillus sp. Their structures were elucidated on the basis of combined NMR and MS spectroscopic methods. Compound 1 was a marine ergostane-type steroid with two methoxy groups at C-5 and C-6, respectively. These oxygenated ergostane-type steroids were evaluated for their antibacterial activities against human or aquatic pathogens. Among them, compound 1 exhibited antibacterial activity against Staphylococcus aureus.

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OBJECTIVES: To explore the association between maternal gestational diabetes mellitus (GDM) exposure and the development of autism spectrum disorder (ASD) in offspring. METHODS: A case-control study was conducted, recruiting 221 children with ASD and 400 healthy children as controls. Questionnaires and interviews were used to collect information on general characteristics of the children, socio-economic characteristics of the family, maternal pregnancy history, and maternal disease exposure during pregnancy. Multivariate logistic regression analysis was used to investigate the association between maternal GDM exposure and the development of ASD in offspring. The potential interaction between offspring gender and maternal GDM exposure on the development of ASD in offspring was explored. RESULTS: The proportion of maternal GDM was significantly higher in the ASD group compared to the control group (16.3% vs 9.4%, P=0.014). After adjusting for variables such as gender, gestational age, mode of delivery, parity, and maternal education level, maternal GDM exposure was a risk factor for ASD in offspring (OR=2.18, 95%CI: 1.04-4.54, P=0.038). On the basis of adjusting the above variables, after further adjusting the variables including prenatal intake of multivitamins, folic acid intake in the first three months of pregnancy, and assisted reproduction the result trend did not change, but no statistical significance was observed (OR=1.94, 95%CI: 0.74-5.11, P=0.183). There was an interaction between maternal GDM exposure and offspring gender on the development of ASD in offspring (P<0.001). Gender stratified analysis showed that only in male offspring of mothers with GDM, the risk of ASD was significantly increased (OR=3.67, 95%CI: 1.16-11.65, P=0.027). CONCLUSIONS: Maternal GDM exposure might increase the risk of ASD in offspring. There is an interaction between GDM exposure and offspring gender in the development of ASD in offspring.

LS-106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo.

With the wide clinical use of the third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC), acquired resistance caused by EGFR C797S tertiary mutation has become a concern. Therefore, fourth-generation EGFR inhibitors that could overcome this mutation have gained increasing attention in recent years. Here, we identified LS-106 as a novel EGFR inhibitor against C797S mutation and evaluated its antitumor activity both in vitro and in vivo. In cell-free assay, LS-106 potently inhibited the kinase activities of EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S with IC50 values of 2.4 nmol/L and 3.1 nmol/L, respectively, which was more potent than osimertinib. Meanwhile, LS-106 exhibited comparable kinase inhibitory effect to osimertinib on EGFRL858R/T790M and wild-type EGFR. Results from cellular experiments demonstrated that LS-106 potently blocked the phosphorylation of EGFR C797S triple mutations in the constructed BaF3 cells that highly expressed EGFR19del/T790M/C797S or EGFRL858R/T790M/C797S , and thus inhibited the proliferation of these cells. We also constructed tumor cells harboring EGFR19del/T790M/C797S (named PC-9-OR cells) using the CRISPR/Cas9 system and found that LS-106 markedly suppressed the activation of EGFR19del/T790M/C797S and the proliferation of PC-9-OR cells. Moreover, cells harboring EGFR19del/T790M/C797S underwent remarkable apoptosis upon LS-106 treatment. In vivo experiments further demonstrated that oral administration of LS-106 caused significant tumor regression in a PC-9-OR xenograft model, with a tumor growth inhibition rate (TGI) of 83.5% and 136.6% at doses of 30 and 60 mg/kg, respectively. Taken together, we identified LS-106 as a novel fourth-generation EGFR inhibitor against C797S mutation and confirmed its preclinical antitumor effects in C797S-triple-mutant tumor models.

Distinct Alterations in Tricarboxylic Acid Cycle Metabolites Associate with Cancer and Autism Phenotypes in Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome.

Germline heterozygous PTEN mutations cause subsets of Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS); these subsets are characterized by high risks of breast, thyroid, and other cancers and, in one subset, autism spectrum disorder (ASD). Up to 10% of individuals with PTENMUT CS, CS-like syndrome, or BRRS have germline SDHx (succinate dehydrogenase, mitochondrial complex II) variants, which modify cancer risk. PTEN contributes to metabolic reprogramming; this is a well-established role in a cancer context. Relatedly, SDH sits at the crossroad of the electron transport chain and tricarboxylic acid (TCA) cycle, two central bioenergetic pathways. Intriguingly, PTENMUT and SDHMUT individuals have reduced SDH catalytic activity, resulting in succinate accumulation; this indicates a common genotype-independent biochemical alteration. Here, we conducted a TCA targeted metabolomics study on 511 individuals with CS, CS-like syndrome, or BRRS with various genotypes (PTEN or SDHx, mutant or wild type [WT]) and phenotypes (cancer or ASD) and a series of 187 population controls. We found consistent TCA cycle metabolite alterations in cases with various genotypes and phenotypes compared to controls, and we found unique correlations of individual metabolites with particular genotype-phenotype combinations. Notably, increased isocitrate (p = 1.2 × 10-3), but reduced citrate (p = 5.0 × 10-4), were found to be associated with breast cancer in individuals with PTENMUT/SDHxWT. Conversely, increased lactate was associated with neurodevelopmental disorders regardless of genotype (p = 9.7 × 10-3); this finding was replicated in an independent validation series (n = 171) enriched for idiopathic ASD (PTENWT, p = 5.6 × 10-4). Importantly, we identified fumarate (p = 1.9 × 10-2) as a pertinent metabolite, distinguishing individuals who develop ASD from those who develop cancer. Our observations suggest that TCA cycle metabolite alterations are germane to the pathobiology of PTEN-related CS and BRRS, as well as genotype-independent ASD, with implications for potential biomarker and/or therapeutic value.

Maladaptive motor cortical excitability and connectivity in polyneuropathy with neuropathic pain.

BACKGROUND AND PURPOSE: Sensory symptoms, especially neuropathic pain, are common in polyneuropathy. Conventional diagnostic tools can evaluate structural or functional impairment of nerves but cannot reveal mechanisms of neuropathic pain. Changes in the brain after polyneuropathy may play roles in the genesis of neuropathic pain. METHODS: This cross-sectional study investigated changes of cortical excitability within left primary motor cortex (M1) by measuring resting motor thresholds, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and afferent inhibition between polyneuropathy patients and controls, and investigated the correlates of these parameters with neuropathic pain and M1 structural and functional connectivity assessed by diffusion tractography imaging and functional magnetic resonance imaging. RESULTS: Thirty-three painful and 15 nonpainful neuropathic patients and 21 controls were enrolled. There were no differences in intraepidermal nerve fiber density, nerve conduction studies, thermal thresholds, or autonomic functional tests between patients with and without neuropathic pain. Compared to controls, neuropathic patients exhibited similar resting motor thresholds or afferent inhibition, but attenuated SICI and augmented ICF, especially in painful patients. Changes of intracortical excitability in neuropathic patients were correlated with intensities of neuropathic pain, and different presentations of SICI and ICF were noted between patients with and without thermal paresthesia. Additionally, short-latency afferent inhibition at an interstimulus interval of 20 ms was associated with structural connectivity of left M1 with brain areas associated with pain perception. CONCLUSIONS: Maladaptive cortical excitability with altered structural connectivity in left M1 developed after peripheral nerve degeneration and was associated with neuropathic pain and sensory symptoms in polyneuropathy.

Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as novel and potent TBK1 inhibitors: design, synthesis, biological evaluation, and molecular docking study.

sABSTRACTTANK-binding kinase 1 (TBK1), a noncanonical member of the inhibitor-kappaB kinases (IKKs) family, plays a vital role in coordinating the signalling pathways of innate immunity, involving in the process of neuroinflammation, autophagy, and oncogenesis. In current study, based on rational drug design strategy, we discovered a series of 1H-pyrazolo[3,4-b]pyridine derivatives as potent TBK1 inhibitors and dissected the structure-activity relationships (SARs). Through the several rounds of optimisation, compound 15y stood out as a potent inhibitor on TBK1 with an IC50 value of 0.2 nM and also displayed good selectivity. The mRNA detection of TBK1 downstream genes showed that compound 15y effectively inhibited TBK1 downstream IFN signalling in stimulated THP-1 and RAW264.7 cells. Meanwhile, compound 15y exhibited a micromolar antiproliferation effect on A172, U87MG, A375, A2058, and Panc0504 cell lines. Together, current results provided a promising TBK1 inhibitor 15y as lead compound for immune- and cancer-related drug discovery.

Risk and outcome of subsequent malignancies after radioactive iodine treatment in differentiated thyroid cancer patients.

BACKGROUND: We identified differentiated thyroid cancer (DTC) survivors from SEER registries and performed Poisson regression to calculate the relative risks (RRs) of subsequent malignancies (SMs) by different sites associated with radioactive iodine (RAI) treatment, and the attributable risk proportion of RAI for developing different SMs. RESULTS: We identified 4628 of 104,026 DTC patients developing a SM after two years of their DTC diagnosis, with a medium follow-up time of 113 months. The adjusted RRs of developing SM associated with RAI varied from 0.98 (0.58-1.65) for neurologic SMs to 1.37 (1.13-1.66) for hematologic SMs. The RRs of developing all cancer combined SMs generally increased with age at DTC diagnosis and decreased with the latency time. We estimated that the attributable risk proportion of RAI treatment is only 0.9% for all cancer combined SMs and 20% for hematologic SMs, which is the highest among all SMs. The tumor features and mortalities in patients treated with and without RAI are generally comparable. CONCLUSION: With the large population based analyses, we concluded that a low percentage of DTC survivors would develop SMs during their follow-up. Although the adjusted RR of SMs development increased slightly in patients receiving RAI, the attributable risk proportion associated with RAI was low, suggesting the absolute number of SMs induced by RAI in DTC survivors would be low. The attributable risk proportion of RAI treatment is the highest in hematological SMs, but when in consideration of its low incidence among all DTC survivors, the absolute number of hematological SMs was low.

Early changes of nerve integrity in preclinical carriers of hereditary transthyretin Ala117Ser amyloidosis with polyneuropathy.

BACKGROUND AND PURPOSE: Disease-modifying therapies provide new horizons for hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) to slow neuropathic progression. Initiating treatment at the earliest time requires biomarkers reflecting both small- and large-fiber degeneration in carriers. METHODS: This study included examinations of pathology (intraepidermal nerve fiber [IENF] density), physiology (nerve conduction studies, autonomic function test, and nerve excitability), and psychophysics (thermal thresholds) in carriers to compare to healthy controls and asymptomatic diabetic patients. RESULTS: There were 43 carriers (44.2 ± 11.4 years, p.Ala117Ser in 42 carriers), 43 controls (43.4 ± 12.7 years) including 26 noncarrier families, and 50 asymptomatic diabetic patients (58.1 ± 9.5 years). Carriers had lower IENF densities than controls and similar densities as diabetic patients. Median nerve conduction parameters, especially distal motor latency, were the most frequent neurophysiological abnormality in carriers, could differentiate carriers from controls and diabetic patients, were correlated with IENF densities in carriers but not in controls and diabetic patients, and were correlated with nerve excitability parameters in carriers but not in controls. Fifteen carriers (34.9%) with electrophysiological evidence of median nerve entrapment at the wrist had lower IENF densities and more abnormal conduction parameters than carriers without. We defined nerve dysfunction index-the ratio of median distal motor latency to IENF density-which differentiated carriers from controls. CONCLUSIONS: In late-onset ATTRv-PN carriers with predominant p.Ala117Ser, median conduction parameters were the most common neurophysiological abnormalities and served as surrogate signatures of small- and large-fiber impairment. Combination of median distal motor latency and IENF density can reflect early neuropathy in carriers.

Radical 1,5-Chloropentafluorosulfanylation of Unactivated Vinylcyclopropanes and Transformation into α-SF5 Ketones.

The radical 1,5-chloropentafluorosulfanylation of vinyl cyclopropanes (VCPs) initiated by Et3B/O2 affords allylic pentafluorosulfanyl/homoallylic chloride products through the ring-strain release of the cyclopropane. The VCP substitution pattern was investigated. The utility of this reaction was illustrated in post-transformation of the C═C bond by ozonolysis, giving access to valuable α-SF5 carbonyl compounds.

Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with activating EGFR mutations initially respond to first-generation EGFR inhibitors; however, the efficacy of these drugs is limited by acquired resistance driven by the EGFR T790M mutation. The discovery of third-generation EGFR inhibitors overcoming EGFR T790M and their new resistance mechanisms have attracted much attention. METHODS: We examined the antitumor activities and potential resistance mechanism of a novel EGFR third-generation inhibitor in vitro and in vivo using ELISA, SRB assay, immunoblotting, flow cytometric analysis, kinase array, qRT-PCR and tumor xenograft models. The clinical effect on a patient was evaluated by computed tomography scan. RESULTS: We identified compound ASK120067 as a novel inhibitor of EGFR T790M, with selectivity over EGFR WT. ASK120067 exhibited potent anti-proliferation activity in tumor cells harboring EGFR T790M (NCI-H1975) and sensitizing mutations (PC-9 and HCC827) while showed moderate or weak inhibition in cells expressing EGFR WT. Oral administration of ASK120067 induced tumor regression in NSCLC xenograft models and in a PDX model harboring EGFR T790M. The treatment of one patient with advanced EGFR T790M-positive NSCLC was described as proof of principle. Moreover, we found that hyperphosphorylation of Ack1 and the subsequent activation of antiapoptotic signaling via the AKT pathway contributed to ASK120067 resistance. Concomitant targeting of EGFR and Ack1 effectively overrode the acquired resistance of ASK120067 both in vitro and in vivo. CONCLUSIONS: Our results idenfity ASK120067 as a promising third-generation EGFR inhibitor and reveal for the first time that Ack1 activation as a novel resistance mechanism to EGFR inhibitors that guide to potential combination strategy.

General Synthesis of Tri-Carbo-Substituted N2-Aryl-1,2,3-triazoles via Cu-Catalyzed Annulation of Azirines with Aryldiazonium Salts.

The general synthesis of fully substituted N2-aryl-1,2,3-triazoles is hitherto challenging compared with that of the N1-aryl counterparts. Herein, we describe a Cu-catalyzed annulation reaction of azirines and aryldiazonium salts. This regiospecific method allows access to a broad spectrum of tri-carbo N2-aryl-1,2,3-triazoles substituted with diverse aryl and alkyl moieties. Its utility is highlighted by the synthesis of several triazole precursors applicable in drug discovery, as well as novel chiral binaphthyl ligands bearing triazole moieties.

Metastatic pancreatic adenocarcinomas could be classified into M1a and M1b category by the number of metastatic organs.

BACKGROUND: With the improvement of treatment and prognosis for patients with late malignant diseases, certain malignancies with distant metastasis (M1 category) have been further classified into M1a (single metastatic site) and M1b (multiple metastatic sites) category in the staging system. We aimed to assess the feasibility of sub-classifying metastatic pancreatic adenocarcinoma (mPA) into M1a and M1b category depending on the number of metastatic organs. METHODS: Patient records were collected from the Surveillance, Epidemiology, and End Results (SEER) database (2010-2015). Univariable and multivariable analyses were performed using the Cox regression model. Then survival analysis was determined using the Kaplan-Meier method. RESULTS: A total of 11,885 patients were included in this analysis, including 9425 patients with single metastasis and 2460 patients with multiple metastases. Multivariable analysis showed that gender, age, marital status, grade, surgery, chemotherapy, and radiotherapy were independent prognostic factors for patients with single metastasis; gender, age, marital status, grade, chemotherapy and radiotherapy were independent prognostic factors for patients with multiple metastases. Notably, surgery was an independent prognostic factor for patients with single metastasis (P < 0.001) but not for patients with multiple metastases (P = 0.134). Kaplan-Meier analysis showed that patients with single metastasis (M1a) had better survival outcomes than patients with multiple metastases (M1b) (P < 0.001). CONCLUSIONS: PA patients with M1 diseases could be divided into M1a (single metastasis) category and M1b (multiple metastases) category by the number of metastatic organs. The subclassification would facilitate individualized treatment for late PA patients. Surgery was associated with lower mortality in M1a patients but not significantly in M1b patients.

An impedimetric immunosensor for determination of porcine epidemic diarrhea virus based on the nanocomposite consisting of molybdenum disulfide/reduced graphene oxide decorated with gold nanoparticles.

An electrochemical immunosensor for the determination of porcine epidemic diarrhea virus (PEDV) is described. It was manufactured by using gold nanoparticles/molybdenum disulfide/reduced graphene oxide nanocomposites modified on the surface of a glassy carbon electrode (GCE). The independently developed monoclonal antibody of PEDV-2C11 was immobilized on the modified electrode at site of gold nanoparticles provided in the nanocomposites. The concentration of PEDV was quantified by measuring the changes in the charge transfer resistance of the electrode before and after the immunoreaction between antigen-antibody by using hexacyanoferrate(II)/(III) as the redox probe. The frequency range was 10-1 to 105 Hz at the amplitude of 10 mV and an applied potential of + 0.180 V. Based on the immunoreaction between PEDV antigen and PEDV-2C11 antibody in 0.1 M phosphate buffer containing 0.1 M KCl at 37.5 °C for 140 min, the relative change in impedance was proportional to the logarithmic value of PEDV concentrations in the range of 82.5 to 1.65 × 104 TCID50 mL-1. Good reproducibility, stability, and specificity of the proposed immunosensor were obtained. It was successfully applied to the determination of PEDV in the spiked sample. Graphical abstractSchematic representation. a The preparation of AuNP/MoS2/rGO composites. b Representation of modification and functioning of the label-free electrochemical immunosensor and the electrochemical impedimetric response obtained before (a) and after (b) incubation of PEDV.

Metabolic tumor burden on baseline 18F-FDG PET/CT improves risk stratification in pediatric patients with mature B-cell lymphoma.

PURPOSE: In order to better identify patients most at risk of treatment failure and disease progression in pediatric mature B-cell non-Hodgkin lymphoma (B-NHL), the prognostic role of metabolic tumor burden measured on baseline 18F-FDG PET/CT scan, including total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG), was investigated. METHODS: Pretreatment 18F-FDG PET/CT scans from 46 consecutive pediatric patients (median age 7 years; range 2-18 years) with newly diagnosed B-NHL were retrospectively analyzed. Clinicopathological parameters and imaging characteristics, including TMTV, TLG, and bone marrow (BM) involvement detected by PET/CT were compared to predict progression-free survival (PFS) and overall survival (OS). RESULTS: The median follow-up time was 31 months. Areas under the curve of TMTV and TLG to predict events were 0.820 and 0.816, respectively. The 2-year PFS and OS were 29% and 43% in 7 patients with high TLG (> 5797 g) vs. 93% and 96% in those with low TLG (P < 0.001). High TMTV (> 524 cm3) was present in ten patients and predicted a significantly inferior outcome (PFS: 50% vs. 92%, P = 0.001; OS: 60% vs. 96%, P = 0.002). In multivariate analysis, TMTV and TLG outperformed other clinicopathological factors, including serum lactate dehydrogenase and BM involvement on biopsy, and remained the most robust predictors of survival. Furthermore, TLG sub-stratified patients with distinct outcomes efficiently within high- or intermediate-risk groups, with the negative predictive value of 100% and 92% and the positive predictive value of 100% and 50% for high-risk and intermediate-risk patients, respectively. On the other hand, BM involvement identified only by PET demonstrated an inferior prognostic value in comparison with BM biopsy. CONCLUSIONS: Baseline TMTV and TLG are both strong independent prognostic factors for pediatric B-NHL and provide a potential approach to aid in risk sub-stratification, especially in patients with high-risk disease.

Tacrolimus combined with corticosteroids effectively improved the outcome of a cohort of patients with immune-mediated necrotising myopathy.

OBJECTIVES: To assess the efficacy and safety of tacrolimus in combination with corticosteroids in patients with immune-mediated necrotising myopathy. METHODS: The medical records of 20 hospitalised patients with immune-mediated necrotising myopathy (IMNM) who had received tacrolimus combined with oral prednisone from January 2014 to August 2017 were retrospectively reviewed. The recruited patients were shifted to the combined therapy because they failed to respond well to monotherapy with oral prednisone. The clinical efficacy during an average follow-up of 21 months (range, 14-24 months) was assessed by evaluating the changes of serum creatine kinase (CK) levels, the Medical Research Council (MRC) grading of the weakest muscle groups and dosage of oral prednisone. Adverse effects were monitored to assess the safety of tacrolimus. RESULTS: After starting tacrolimus, most of the 20 patients showed significant improvement in muscle strength and remarkable decline in serum CK levels at the follow-up points (p<0.0001). In addition, the daily dosage of prednisone was statistically significantly reduced (p<0.0001) after the combination therapy. No serious adverse events attributable to tacrolimus occurred in the patients. CONCLUSIONS: Early co-administration of tacrolimus with corticosteroid promoted the remission and recovery of patients with IMNM and seemed to be a relatively safe treatment programme for physician managing immune-mediated necrotising myopathy.