Interstitial pneumonitis associated with combined regimen of immunotherapy and conventional therapies-pharmacovigilance database analysis with real-world data validation.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy combined with conventional therapies is being broadly applied in non-small cell lung cancer (NSCLC) patients. However, the risk of interstitial pneumonitis (IP) following a combined regimen is incompletely characterized. METHODS: A total of 46,127 NSCLC patients were extracted for disproportionality analyses of IP from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database. A total of 1108 NSCLC patients who received ICI treatment at Nanfang Hospital of Southern Medical University were collected and utilized for real-world validation. RESULTS: Of the 46,127 patients with NSCLC, 3830 cases (8.3%; 95% confidence interval [CI], 8.05-8.56) developed IP. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with radiation (RT) was the highest (121.69; 95% CI, 83.60-184.96; P < 0.0001) among all therapies, while that of ICI combined with chemotherapy (CHEMO) or targeted therapy (TARGET) was 0.90 (95% CI, 0.78-1.04; P = 0.160) and 1.49 (95% CI, 0.95-2.23; P = 0.065), respectively, using ICI monotherapy as reference. Furthermore, analyses from our validation cohort of 1108 cases showed that the adjusted odds ratio of ICI combined with RT was the highest (12.25; 95% CI, 3.34-50.22; P < 0.01) among all the therapies, while that of ICI combined with CHEMO or TARGET was 2.32 (95% CI, 0.89-7.92; P = 0.12) and 0.66 (95% CI, 0.03-4.55; P = 0.71), respectively, using ICI monotherapy as reference. CONCLUSIONS: Compared with ICI monotherapy, ICI combined with RT, rather than with CHEMO or TARGET, is associated with a higher risk of IP in NSCLC patients. Hence, patients receiving these treatments should be carefully monitored for IP.

Organ-specific metastatic landscape dissects PD-(L)1 blockade efficacy in advanced non-small cell lung cancer: applicability from clinical trials to real-world practice.

BACKGROUND: Organ-specific metastatic context has not been incorporated into the clinical practice of guiding programmed death-(ligand) 1 [PD-(L)1] blockade, due to a lack of understanding of its predictive versus prognostic value. We aim at delineating and then incorporating both the predictive and prognostic effects of the metastatic-organ landscape to dissect PD-(L)1 blockade efficacy in non-small cell lung cancer (NSCLC). METHODS: A total of 2062 NSCLC patients from a double-arm randomized trial (OAK), two immunotherapy trials (FIR, BIRCH), and a real-world cohort (NFyy) were included. The metastatic organs were stratified into two categories based on their treatment-dependent predictive significance versus treatment-independent prognosis. A metastasis-based scoring system (METscore) was developed and validated for guiding PD-(L)1 blockade in clinical trials and real-world practice. RESULTS: Patients harboring various organ-specific metastases presented significantly different responses to immunotherapy, and those with brain and adrenal gland metastases survived longer than others [overall survival (OS), p = 0.0105; progression-free survival (PFS), p = 0.0167]. In contrast, survival outcomes were similar in chemotherapy-treated patients regardless of metastatic sites (OS, p = 0.3742; PFS, p = 0.8242). Intriguingly, the immunotherapeutic predictive significance of the metastatic-organ landscape was specifically presented in PD-L1-positive populations (PD-L1 > 1%). Among them, a paradoxical coexistence of a favorable predictive effect coupled with an unfavorable prognostic effect was observed in metastases to adrenal glands, brain, and liver (category I organs), whereas metastases to bone, pleura, pleural effusion, and mediastinum yielded consistent unfavorable predictive and prognostic effects (category II organs). METscore was capable of integrating both predictive and prognostic effects of the entire landscape and dissected OS outcome of NSCLC patients received PD-(L)1 blockade (p < 0.0001) but not chemotherapy (p = 0.0805) in the OAK training cohort. Meanwhile, general performance of METscore was first validated in FIR (p = 0.0350) and BIRCH (p < 0.0001), and then in the real-world NFyy cohort (p = 0.0181). Notably, METscore was also applicable to patients received PD-(L)1 blockade as first-line treatment both in the clinical trials (OS, p = 0.0087; PFS, p = 0.0290) and in the real-world practice (OS, p = 0.0182; PFS, p = 0.0045). CONCLUSIONS: Organ-specific metastatic landscape served as a potential predictor of immunotherapy, and METscore might enable noninvasive forecast of PD-(L)1 blockade efficacy using baseline radiologic assessments in advanced NSCLC.

[Effect of the NF-κB/iNOS Signaling Pathway on Spiral Ganglion in Mouse Model of Sensorineural Hearing Loss].

Objective: To explore the effect of changes in the expression level of necorsis factor (NF)-κB/inducible nitric oxide synthase (iNOS) signaling pathway on hearing loss in a mouse model of sensorineural hearing loss (SNHL) induced by 3-nitropropionic acid (3-NP). Methods: The animal model was established by tympanic injection. C57BL/6 male mice were divided into three groups, 3-NP group receiving tympanic injection of 3-NP solution, 3-NP+EVP4593 group receiving tympanic injection of 3-NP solution and intraperitoneal injection of EVP4593 solution, and a control group receiving tympanic injection of phosphate buffered saline (PBS). Auditory brainstem response (ABR) was tested before and after injection. After 4 weeks, the cochlea was harvested and immunohistochemistry and qRT-PCR of NF-κB p65, RelB, iNOS, and Caspase-3 were conducted accordingly. Results: The hearing thresholds of the 3-NP group were higher than those of the control group and the 3-NP+EVP4593 group ( P<0.05), and the hearing thresholds of the 3-NP+EVP4593 group were also higher than those of the control group ( P<0.05). Immunofluorescence staining and qRT-PCR results showed that 3-NP exposure caused an increase in the expressions of NF-κB p65, RelB, and iNOS in the spiral ganglion in comparison with those of the control group ( P<0.05), and their expressions decreased with the administration of EVP4593 ( P<0.05). The expression of Caspase-3 in the spiral ganglion cells in the 3-NP group was higher than that in the control group, while in the 3-NP+EVP4593 group, it was lower than that in the 3-NP group ( P<0.05). Conclusion: This study found that, by activating the NF-κB/iNOS signaling pathway, 3-NP may cause inflammation in the spiral ganglion of the cochlear in the SNHL model mice, which may play an important role in the pathogenesis of SNHL.

[Effect of Connexin on Cochlear Blood-Labyrinth Barrier in a Mouse Model of Endolymphatic Hydrops].

Objective: To examine the expression of tight-junction connexin ZO-1 in the stria vascularis tissue of the cochlea by using spontaneous endolymphatic hydrops animal model constructed with PHEX gene mutant mice, and to analyze the dynamic changes of the gene mutant mice in pathology, imaging, and hearing function. Methods: Male Hyp-Duk/Y mice with PHEX gene mutation were selected as the experimental group at three time points, 21 days post birth (P21), 90 days post birth (P90) and 120 days post birth (P120), and wild-type male mice of the same ages were selected as the control groups. The cochlear sections were HE-stained in order to observe whether endolymphatic hydrops was present or absent and to assess its severity. The expression of connexin ZO-1 in both groups was evaluated through immunohistochemical staining of cochlear sections. Auditory-evoked brainstem response (ABR) was induced in both groups at P90 and gadolinium-enhanced MRI was conducted in vivo to observe the middle-order endolymphatic dilatation of cochlea in experimental and control mice aged P21, P90 and P120. Results: HE staining of pathological sections of PHEX Hyp-Duk/Y mice aged P90 and P120 showed increased endolymphatic hydronephrosis. The level of striae ZO-1 in PHEX Hyp-Duk/Y mice aged P90 and P120 was significantly lower than that of the controls of the same age (P<0.05). The expression level of ZO-1 was significantly negatively correlated with the degree of endolymphatic hydronephrosis (r=-0.939, P<0.01). The bilateral ABR threshold of PHEX Hyp-Duk/Y mice aged P90 was higher than that of the wild-type mice of the same age, and the mutant mice showed asymmetric hearing loss on both sides. Severe endolymphatic hydronephrosis was observed in PHEX Hyp-Duk/Y mice aged P90 and P120 through in vivo MRI gadolinium imaging. Conclusion: PHEX Hyp-Duk/Y can be used as a sound model for basic research of Ménière's disease. Compared with wild-type mice, PHEX Hyp-Duk/Y mice showed decreased expression of connexin protein ZO-1, which damaged the function of the blood-labyrinth barrier in stria vascularis, and was involved in the formation of endolymphatic hydrops. 7.0 T MRI gadolinium imaging can be used to observe the changes of severe endolymphatic hydrops in mice in vivo, providing imaging basis for the diagnosis of Ménière's disease.

[Research advances in multimodal magnetic resonance for cognitive impairment in children with benign childhood epilepsy with centrotemporal spikes].

Cognitive impairment in children with benign childhood epilepsy with centrotemporal spikes (BECT) has complex etiologies and is closely associated abnormal neural networks. Multimodal magnetic resonance imaging of brain structure and function is a powerful tool for studying abnormal neural networks of cognitive impairment in epilepsy and can explore the pathogenesis of cognitive impairment in epilepsy at the level of brain structure and function by analyzing the imaging features of brain structure and function. This article reviews the research advances in multimodal magnetic resonance for cognitive impairment in children with BECT.

Associated and predictive factors of quality of life in patients with temporal lobe epilepsy.

OBJECTIVE: Identifying the factors that are correlated with and predictive of reduced quality of life (QOL) is essential to optimize the treatment of epilepsy and the management of comorbidities. METHODS: We analyzed the independent associations between the Quality of Life in Epilepsy-31 (QOLIE-31) inventory and the demographic, clinical, psychiatric, and cognitive variables of 47 consecutive patients with temporal lobe epilepsy (TLE). Predictors of the correlated variables were analyzed by multiple linear regression analysis. RESULTS: The QOLIE-31 total score was positively correlated with occupational status and Mini-Mental State Examination (MMSE) scores (r = 0.290 and 0.295, respectively; P < 0.05) and negatively correlated with the duration of seizures, adverse effects of antiepileptic drugs (AEDs), and the Pittsburgh Sleep Quality Inventory (PSQI), Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS) scores (r = -0.357, 0.321, 0.328, -0.672, and -0.565, respectively; P < 0.05; P < 0.01 for the SAS and SDS). In the final multivariate regression model, anxiety, long durations of seizures, adverse effects of AEDs, and depression explained approximately 60.6% (adjusted R2 = 0.606, R coefficient = 0.800) of the QOLIE-31 overall score variance. CONCLUSION: Anxiety, long durations of seizures, adverse effects of AEDs, and depression were significant predictors of QOL, and these variables had relatively high prediction capacities for the overall QOLIE-31 in the regression model. Comorbid anxiety is the most powerful negative determinant of the QOLIE-31.

Common variants of APOE are associated with anti-epileptic drugs resistance in Han Chinese patients.

Purpose/aim of the study: Apolipoprotein E (APOE) has been implicated as one of the susceptibility genes for some subtypes of epilepsy and may be related to anti-epileptic drugs resistance. The purpose of this study was to investigate the possible association between APOE variants and the anti-epileptic drugs resistance in Chinese population. MATERIALS AND METHODS: APOE gene rs429358 and rs7412 variants were genotyped for ϵ2, ϵ3, ϵ4 alleles using amplification refractory mutation system in 480 subjects including 207 anti-epileptic drugs-resistant patients and 273 drug-responsive patients. RESULTS: We found that the frequency of APOE gene rs429358 C allele in the drug resistant patients is higher than that in the drug-responsive patients (14.98% vs. 10.1%, OR = 1.25[1.02 - 1.52], p = 0.017). Moreover, according to the two variants, we analyzed the distributions of -ϵ4 and +ϵ4 alleles of APOE gene and found that there were higher frequencies of +ϵ4 allele in drug-resistant epileptic patients than that in drug-responsive patients (31.8% vs. 13.2%, OR = 1.15[1.05 - 1.25], p = 0.002). CONCLUSIONS: Our study demonstrated that APOE rs429358 variant C allele and ϵ4 allele were associated with the anti-epileptic drugs resistance in Han Chinese patients.

[Role of video electroencephalogram in diagnosis and localization of epilepsy in children].

OBJECTIVE: To study the role of video electroencephalogram (VEEG) versus regular electroencephalogram (REEG) in the diagnosis of epilepsy and localization of origin of epileptic discharge in children through a comparative analysis. METHODS: A retrospective analysis was performed for the clinical data of 223 children with clinical paroxysmal symptoms in the past and suspected epilepsy. VEEG and REEG were compared from the aspects of monitoring of clinical seizures, interictal epileptiform discharge (IED), localization of the origin of IED, and identification of non-epileptic seizures, and the detection rate of IED during awakening and sleep stages was also compared. RESULTS: Compared with REEG, VEEG had significantly higher detection rates of IED and synchronous clinical seizures in children with epileptiform discharge (P<0.01). Of all children, 86 were diagnosed with epilepsy, 78 were diagnosed with epilepsy syndrome, 31 were diagnosed with non-epileptic seizures, and 81 had a definite location of the origin of epileptic discharge according to the VEEG. The detection rate of IED in the sleep stage was higher than that in the awakening stage (46% vs 13.2%; P<0.01), and IED was mainly detected in the NREM I-II stages according to the VEEG. CONCLUSIONS: VEEG has a significantly better performance than REEG in the diagnosis and localization of epilepsy in children and has a high value in clinical practice.

[Effects of temporal lobe epilepsy and idiopathic epilepsy on cognitive function and emotion in children].

OBJECTIVE: To investigate the effects of temporal lobe epilepsy and idiopathic epilepsy on cognitive function and emotion in children and the risk factors for cognitive impairment. METHODS: A retrospective analysis was performed for the clinical data of 38 children with temporal lobe epilepsy and 40 children with idiopathic epilepsy. The controls were 42 healthy children. All subjects received the following neuropsychological tests: Montreal Cognitive Assessment (MoCA) scale, verbal fluency test, digit span test, block design test, Social Anxiety Scale for Children (SASC), and Depression Self-rating Scale for Children (DSRSC). RESULTS: Compared with the control group, the temporal lobe epilepsy and idiopathic epilepsy groups showed significantly lower scores of MoCA, verbal fluency, digit span, and block design (P<0.05) and significantly higher scores on SASC and DSRSC (P<0.05). Compared with the idiopathic epilepsy group, the temporal lobe epilepsy group showed significantly lower scores of MoCA, verbal fluency, digit span, and block design (P<0.05) and significantly higher scores on SASC and DSRSC (P<0.05). In the temporal lobe epilepsy group, MoCA score was negatively correlated with SASC score, DSRSC score, and seizure frequency (r=-0.571, -0.529, and -0.545 respectively; P<0.01). In the idiopathic epilepsy group, MoCA score was also negatively correlated with SASC score, DSRSC score, and seizure frequency (r=-0.542, -0.487, and -0.555 respectively; P<0.01). CONCLUSIONS: Children with temporal lobe epilepsy and idiopathic epilepsy show impaired whole cognition, verbal fluency, memory, and executive function and have anxiety and depression, which are more significant in children with temporal lobe epilepsy. High levels of anxiety, depression, and seizure frequency are risk factors for impaired cognitive function.

A quantum dot probe conjugated with aß antibody for molecular imaging of Alzheimer's disease in a mouse model.

The treatment of Alzheimer's disease (AD) has been hampered by a lack of sensitive and specific non-invasive diagnostic methods. Quantum dots (QD) are nano-crystals with unique photo-physical properties that bypass some of the limitations of conventional dyes and imaging tools. This study is aimed to evaluate the fluorescence properties of a QD probe conjugated with an anti-Aß antibody (QD-Aß-Ab). Healthy mice and mice bearing mutated human APP695swe and APP717 V-F transgenes received intracerebroventricular injection of the probe for subsequent imaging. Immunohistochemistry revealed that Aß1-42 was distributed in the hippocampus CA1 area in the APP transgenic mice. Fluorescence microscopy demonstrated that fluorescence was mainly observed in the hippocampus area, the cerebral cortex, sagittal septum and striatum of APP transgenic mice. In vivo imaging of mice receiving the QD-Aß-Ab probe showed that healthy mice exhibited a narrow range of fluorescence and lower fluorescence intensity compared with APP transgenic mice. The mean fluorescence intensity of brain tissues of healthy C57BL mice was 12.3784 ± 3.9826, which was significantly lower than that of 10- and 16-month-old APP transgenic mice (45.03 ± 2.66 and 46.69 ± 3.22, respectively; P < 0.05). In this study we present the first direct evidence that QD-Aß-Ab conjugate probes can track in vivo state of Aß accumulation in mice and the findings suggest that such probes may be of potential use for early molecular diagnostic imaging of AD.

Plasticity at axon initial segment of hippocampal CA3 neurons in rat after status epilepticus induced by lithium-pilocarpine.

BACKGROUND: The axon initial segment (AIS) is a specialized membrane region in the axon of neurons wherein numerous specific voltage-gated sodium channels (VGSCs) are clustered and action potentials are initiated. The AIS is currently considered as a new plastic hotspot. METHODS: We investigated the alterations in Nav1.6 (SCN8A) and its adapter protein ankyrin G in the AIS of the hippocampal cornu ammonis 3 (CA3) pyramidal cells of rat after status epilepticus induced by lithium-pilocarpine (PISE). RESULTS: Nav1.6 and ankyrin G were colocalized in the AIS of hippocampal CA3 pyramidal neurons. Compared with the control group, the protein and mRNA expression of Nav1.6 increased within 24 h and 60 days after PISE. By contrast, ankyrin G protein expression decreased slightly within 24 h but increased within 60 days, whereas ankyrin G mRNA increased within 24 h and 60 days after PISE. However, the protein and mRNA expression levels of Nav1.6 and ankyrin G within 7 days after PISE did not differ significantly with those of the control. CONCLUSIONS: Nav1.6 and ankyrin G may participate in the plastic changes in the AIS of hippocampus CA3 neurons after PISE and play potential roles in epileptogenesis by regulating neuronal excitability.

PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer.

Contradictory characteristics of elevated mutational burden and a "cold" tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)-mutant non-small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation-mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically "hot" TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC. SIGNIFICANCE: Targeting PARP exerts dual effects to overcome LKB1 loss-driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.

CDK4/6 inhibition triggers ICAM1-driven immune response and sensitizes LKB1 mutant lung cancer to immunotherapy.

Liver kinase B1 (LKB1) mutation is prevalent and a driver of resistance to immune checkpoint blockade (ICB) therapy for lung adenocarcinoma. Here leveraging single cell RNA sequencing data, we demonstrate that trafficking and adhesion process of activated T cells are defected in genetically engineered Kras-driven mouse model with Lkb1 conditional knockout. LKB1 mutant cancer cells result in marked suppression of intercellular adhesion molecule-1 (ICAM1). Ectopic expression of Icam1 in Lkb1-deficient tumor increases homing and activation of adoptively transferred SIINFEKL-specific CD8+ T cells, reactivates tumor-effector cell interactions and re-sensitises tumors to ICB. Further discovery proves that CDK4/6 inhibitors upregulate ICAM1 transcription by inhibiting phosphorylation of retinoblastoma protein RB in LKB1 deficient cancer cells. Finally, a tailored combination strategy using CDK4/6 inhibitors and anti-PD-1 antibodies promotes ICAM1-triggered immune response in multiple Lkb1-deficient murine models. Our findings renovate that ICAM1 on tumor cells orchestrates anti-tumor immune response, especially for adaptive immunity.

MicroRNA expression profile of the hippocampus in a rat model of temporal lobe epilepsy and miR-34a-targeted neuroprotection against hippocampal neurone cell apoptosis post-status epilepticus.

BACKGROUND: The expression pattern and function of miRNAs in the rat model of temporal lobe epilepsy have not been well defined. Profiling miRNA expression in the rat model of temporal lobe epilepsy and investigating the function of specific miRNAs in epilepsy offers the prospect of a deeper understanding of the mechanisms of epilepsy. METHODS: The lithium-pilocarpine-induced status epilepticus model and the temporal lobe epilepsy model were established in Sprague-Dawley rats. Samples were analysed to detect deregulated miRNAs in the hippocampal temporal lobe, and several of these deregulated miRNAs were confirmed by qPCR. The expression of the pro-apoptotic miR-34a was detected at 1 day, 7 days and 2 weeks post-status epilepticus and at 2 months after temporal lobe epilepsy. The antagomir of miR-34a was then utilised. The expression of miR-34a after targeting and the expression change of activated caspase-3 protein were examined. The effects of altering the expression of miR-34a and activated caspase-3 protein on neuronal survival and neuronal death or apoptosis post-status epilepticus were assessed. RESULTS: The miRNA microarray detected 9 up-regulated miRNAs (miR-146a, -211, -203, -210, -152, -31, -23a, -34a, -27a) and 15 down-regulated miRNAs (miR-138*, -301a, -136, -153, -19a, -135b, -325-5p, -380, -190, -542-3p, -33, -144, -542-5p, -543, -296*). Some of the deregulated miRNAs (miR-146a, miR-210, miR-27a, miR-135b and miR-33) were confirmed using qPCR. Furthermore, an increase in expression of the pro-apoptotic miR-34a was demonstrated in the post-status epilepticus rat hippocampus. miR-34a was significantly up-regulated at 1 day, 7 days and 2 weeks post-status epilepticus and at 2 months after temporal lobe epilepsy. Experiments with the miR-34a antagomir revealed that targeting miR-34a led to an inhibition of activated caspase-3 protein expression, which may contribute to increased neuronal survival and reduced neuronal death or apoptosis. CONCLUSIONS: Our study showed the expression profile of miRNAs in the hippocampus in a rat model of temporal lobe epilepsy and an increase in the expression of the pro-apoptotic miR-34a in post-status epilepticus rats. The results show that miR-34a is up-regulated during seizure-induced neuronal death or apoptosis, and targeting miR-34a is neuroprotective and is associated with an inhibition of an increase in activated caspase-3 protein.

Experimental Study of the Propagation Process of Dissection Using an Aortic Silicone Phantom.

BACKGROUND: The mortality of acute aortic dissection (AD) can reach 65~70%. However, it is challenging to follow the progress of AD formation. The purpose of this work was to observe the process of dissection development using a novel tear-embedded silicone phantom. METHODS: Silicone phantoms were fabricated by embedding a torn area and primary tear feature on the inner layer. CT scanning and laser lightening were conducted to observe the variations in thickness and volume of the true lumen (TL) and false lumen (FL) during development. RESULTS: The model with a larger interlayer adhesion damage required a lower pressure to trigger the development of dissection. At the initiation stage of dissection, the volume of TL increased by 25.5%, accompanied by a 19.5% enlargement of tear size. The force analysis based on the change of tear size verified the deduction of the process of interlaminar separation from the earlier studies. CONCLUSIONS: The primary tear and the weakening adhesion of the vessel layers are key factors in AD development, suggesting that some forms of primary damage to the arterial wall, in particular, the lumen morphology of vessels with straight inner lumen, should be considered as early risk predictors of AD.

[Neuronal synaptic reconstruction in hippocampus in chronic phase of pilocarpine-treated rats].

OBJECTIVE: To explore the aberrant formation of excitatory and inhibitory circuit rearrangements of hippocampus in temporal lobe epilepsy. METHODS: Pilocarpine-induced animal model was established. At around Day 60 post-modeling, retrograde tracer fluorogold (FG) was injected in vivo into CA1 and CA3 areas of hippocampus by stereotaxic apparatus. Immunohistochemistry of FG was used to observe the aberrant excitatory circuit rearrangements. Double immunofluorescence with NPY (neuropeptide Y) and FG was performed to observe the aberrant inhibitory circuit rearrangements. RESULTS: After an injection of FG into CA1 area, the FG-labeled pyramidal cells could be observed distantly from the zone of dye spread in CA1 area, CA3 area and subiculm. And the FG-labeled non-principal neurons could be seen in stratum oriens of CA1 and hilus in experimental group. Double immunofluorescence revealed that the FG-labeled NPY interneurons were located distantly from the zone of dye spread in CA1 area, CA3 area and hilus in experimental rats. When injection was administered in CA3 area, the FG-labeled pyramidal cells were visible in the whole CA3 area and hilus in both groups. Some pyramidal cells were present in CA1 in experimental group. Also some FG-labeled non-principle cells were found in hilus and distantly from the zone of dye spread in CA1 area. And the FG-labeled NPY neurons could be seen in hilus in experimental rats. CONCLUSION: Aberrant excitatory and inhibitory synaptic reconstruction exist in hippocampus in chronic phase of temporal lobe epilepsy, including excitatory synaptic connections among pyramidal cells in CA1 area, pyramidal cells between CA1 and subiculum and pyramidal cells between CA1 and CA3, inhibitory synaptic connections among dendritic interneurons in CA1 area, CA3 to CA1, hilus to CA1 and hilus to CA3 area. These circuit arrangements may play an important role in the pathogenesis of epilepsy.

De Novo Mutation in Non-Tyrosine Kinase Domain of ROS1 as a Potential Predictor of Immune Checkpoint Inhibitors in Melanoma.

PURPOSE: Despite the success of targeted therapy in c-ros oncogene 1 (ROS1)-rearranged cancers, especially non-small cell lung cancer (NSCLC), the clinical significance of ROS1 de novo mutation has not yet been understood. We sought to elucidate the predictive effect of ROS1 mutation for immune checkpoint inhibitor (ICI) therapy in melanoma. METHODS: The Cancer Genome Atlas [TCGA (n = 10967)] and Memorial Sloan Kettering Cancer Center [MSK (n = 10,945)] datasets, as well as two clinical cohorts of melanoma received ICI [CA209-038 (n = 73) and MEL-IPI (n = 110)], were included to explore the prevalence, prognostic effect, and immunotherapeutic predictive effect of ROS1 mutation in melanoma. Overall survival (OS) was defined as the primary outcome. RESULTS: Overall, melanoma accounted for the highest proportion of ROS1 mutation (~20%) which made up the majority (~95%) of the ROS1-alterated cases. Remarkably, ROS1 mutation yielded longer OS from ICI than the wild-type counterpart in the MSK melanoma population [hazard ratio (HR) 0.47, 95% confidence interval (CI) 0.30-0.74], and two external melanoma cohorts (CA209-038: HR 0.42, 95% CI 0.20-0.89; MEL-IPI: HR 0.55, 95% CI 0.34-0.91), without affecting the prognosis of patients. Elevated tumor mutational burden and enrichment of DNA damage repair was observed in ROS1 mutated patients, providing an explanation for the favorable responses to ICI therapy. Precisely, ROS1 mutation in non-protein tyrosine kinase (PTK) domain but not PTK mutation was responsible for the immunotherapy-specific responses of the ROS1 mutated patients in melanoma. CONCLUSIONS: Collectively, ROS1 mutation, specifically the non-PTK mutation, is a potential predictor of ICI therapy in melanoma, which is distinct from the well-established role of ROS1 rearrangement for targeted therapy in NSCLC.

Integrative evaluation of primary and metastatic lesion spectrum to guide anti-PD-L1 therapy of non-small cell lung cancer: results from two randomized studies.

Objectives: Clinical benefits of immune-checkpoint blockade (ICB) versus standard chemotherapy have been established in unselected non-small cell lung cancer (NSCLC). However, the response to ICB therapy among patients is heterogeneous in clinical practice. Materials and Methods: We retrospectively assessed the predicitive effect of the primary and metastatic lesion spectrum (baseline sum of the longest diameters [SLD], number of metastatic sites and specific organ metastases) on the efficacy of atezolizumab over docetaxel in OAK and POPLAR trial cohorts. A decision model, termed DSO (Diameter-Site-Organ), based on the spectrum was developed and validated for guiding ICB. Results: Higher SLD (>38 mm) and more metastatic sites (≥2) were characterized with pronounced overall survival (OS) benefits from atezolizumab versus docetaxel. Specifically, adrenal gland and brain metastases were identified as favorable predictors of atezolizumab treatment. The DSO model was developed in the discovery cohort to integrate the directive effect of the primary and metastatic lesion spectrum. Remarkably, a general pattern of enhanced efficacy of atezolizumab versus docetaxel was observed along with the increase of the DSO score. For patients with DSO score > 0, atezolizumab yielded a significantly prolonged OS than docetaxel, whereas OS was generally similar between two treatments in patients with DSO score ≤ 0. Equivalent findings were also seen in the internal and external validation cohorts. Conclusions: The response to anti-PD-L1 therapy among patients varied with the primary and metastatic lesion spectrum. The DSO-based system might provide promising medication guidance for ICB treatment in NSCLC patients.

Predicting the morbidity of chronic obstructive pulmonary disease based on multiple locally weighted linear regression model with K-means clustering.

Chronic Obstructive Pulmonary Disease (COPD) is a common chronic respiratory disease related to inflammation affected by harmful gas and particulate matter in the air. Mathematical prediction models between COPD and air pollutants are helpful for early identification, individualized interventions to slow disease progression, and for reduction of medical expenditures. The aim was to build a regression prediction model for the occurrence of COPD acute exacerbation. We collected hospital admissions for COPD in 2015-2018 from ten hospitals in Chongqing, China, used the increment per week as response, and the local sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO) and particulate matter 2.5 (PM2.5) concentrations as predictor variables to build a multiple prediction model. The Mean Absolute Percentage Error (MAPE) was used to evaluate the efficiency. We found that PM2.5 and SO2 are the most important factors contributing to the improvement of prediction accuracy. Multiple locally weighted linear regression (LWLR) Model based on integrated kernel framework with the K-means algorithm demonstrated minimum prediction error of 9.03 %(k=11).