Search

Abstract Objectives This study aimed to investigate the characteristics of patients with recurrent or advanced non‐small cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs) or immune‐checkpoint inhibitors (ICIs) who developed secondary malignancies, as well as evaluate the impact of these secondary malignancies on the course of lung cancer. Materials and Methods This study included 112 patients with postoperative recurrent or advanced NSCLC, who received TKIs, ICIs, or immune combination therapy as the primary treatment modality between April 1, 2013, and March 31, 2020, and achieved long‐term survival (≥2 years). Secondary malignancies were defined as newly diagnosed cancers in other organs occurring after NSCLC treatment initiation. Results Among the 112 patients, 10 (8.9%) developed 12 carcinomas, including third primary malignancies. Univariate analysis, considering secondary malignancies as the outcome, revealed a non‐significant trend towards a higher incidence of secondary malignancies in smokers compared to non‐smokers. Conclusion This study found that 8.9% of patients with advanced NSCLC who received TKIs, ICIs, or immune combination therapy and survived ≥2 years developed secondary malignancies. This underscores the importance of early diagnosis and treatment, even during lung cancer treatment, to identify suspicious lesions in other organs either via imaging or physical examinations.

Although the anatomical arrangement of brain regions and the functional structures within them are similar across individuals, the representation of neural information, such as recorded brain activity, varies among individuals owing to various factors. Therefore, appropriate conversion and translation of brain information is essential when decoding neural information using a model trained using another person’s data or to achieving brain-to-brain communication. We propose a brain representation transfer method that involves transforming a data representation obtained from one person’s brain into that obtained from another person’s brain, without relying on corresponding label information between the transferred datasets. We defined the requirements to enable such brain representation transfer and developed an algorithm that distills the assumption of common similarity structure across the brain datasets into a rotational and reflectional transformation across low-dimensional hyperspheres using encoders for non-linear dimensional reduction. We first validated our proposed method using data from artificial neural networks as substitute neural activity and examining various experimental factors. We then evaluated the applicability of our method to real brain activity using functional magnetic resonance imaging response data acquired from human participants. The results of these validation experiments showed that our method successfully performed representation transfer and achieved transformations in some cases that were similar to those obtained when using corresponding label information. Additionally, we reconstructed images from individuals’ data without training personalized decoders by performing brain representation transfer. The results suggest that our unsupervised transfer method is useful for the reapplication of existing models personalized to specific participants and datasets to decode brain information from other individuals. Our findings also serve as a proof of concept for the methodology, enabling the exchange of the latent properties of neural information representing individuals’ sensations.

IntroductionIn the early postoperative period after total knee arthroplasty (TKA), joint range of motion (ROM) limitation and increased stiffness due to pain are commonly observed. Previous studies have reported that a single bout of foam rolling (FR) can acutely increase ROM and pain threshold on the contralateral (non-intervention) side in healthy participants. In this study, we aimed to expand this knowledge for TKA rehabilitation and investigated the acute effects of FR intervention on the non-operative side on ROM, stiffness, and pain of the operative side in postoperative patients within the first week after TKA.Materials and methodsThe study employed a randomized crossover design: 20 patients (mean age 75.0 ± 7.8 years) in the first postoperative week after TKA were divided alternately into Roll_Break and Break_Roll groups in the order of prescription. In the Roll_Break group, after the initial evaluation, a 180-s (60-s × three sets) FR intervention using a roller massager by a physiotherapist for the knee extensors was performed on the contralateral side (non-operative side), followed by the measurement. Afterwards, after 180-s of supine at rest, the measurement was performed again (i.e., control phase). In the Break_Roll group, after the initial evaluation, each patient was placed in a seated resting position for 180-s, and then another measurement was performed (i.e., control phase). After this, the FR intervention was performed for 180-s, and then the measurement was performed again. The intensity of the FR intervention was set to the maximum intensity that did not cause pain. We measured pain using the visual analogue scale at rest and during the knee joint ROM measurements, knee joint active movement ROM, knee joint passive ROM, and stiffness during the knee joint active movement.ResultsAll outcome variables showed significant improvements after the FR intervention (intervention phase) when compared pre- to post-intervention, and significantly favourable effects were found compared to the control condition.ConclusionThe results showed significant improvements in ROM, pain, and stiffness of the operative side after the FR intervention on the non-operative side. For future therapy approaches for TKA patients, FR treatment of the non-operative side should be employed in the first weeks after surgery.

Introduction: Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein overexpressed in various cancer types. Although TROP2-targeting therapy is currently attracting attention, little is known about TROP2 expression in thymic carcinoma. Methods: TROP2 gene expression in thymic epithelial tumors was analyzed using RNA-sequencing (RNA-seq) data for 122 cases obtained from The Cancer Genome Atlas. Immunohistochemistry (IHC) staining with anti-TROP2 antibody (SP295) was performed in 26 cases of thymic carcinoma tissues surgically resected at Juntendo University. Results: RNA-seq data analysis from The Cancer Genome Atlas revealed that TACSTD2 (gene encoding TROP2) expression was significantly higher in thymic carcinoma than in thymoma (adjusted p = 6.64e-05). There was also a trend of increasing expression in the order of thymoma type B1, B2, B3, and thymic carcinoma. As for IHC in thymic carcinoma, TROP2 expression was localized to the membrane of cancer cells. Intensity 0, 1, and 2 was observed in six (23.1%), 11 (42.3%), and nine (34.6%) cases, respectively, leading to TROP2 positivity in 20 cases (76.9%). The median proportion of TROP2-positive tumor cells and the median H-score were 25.0% (range: 0%–100%) and 25.0 (range: 0–200), respectively. No relevant factors were identified in the analysis of TROP2 expression and patient background. Although not significant, high TROP2 expression (H-score ≥ 50) tended to be associated with shorter survival. Conclusions: TROP2 expression in thymic carcinoma was confirmed by both RNA-seq and IHC, with high expression observed in IHC for intensity (76.9%) and proportion. TROP2 could be a potential target in thymic carcinoma.

As the apparent intelligence of artificial neural networks (ANNs) advances, they are increasingly likened to the functional networks and information processing capabilities of the human brain. Such comparisons have typically focused on particular modalities, such as vision or language. The next frontier is to use the latest advances in ANNs to design and investigate scalable models of higher-level cognitive processes, such as conscious information access, which have historically lacked concrete and specific hypotheses for scientific evaluation. In this work, we propose and then empirically assess an embodied agent with a structure based on global workspace theory (GWT) as specified in the recently proposed “indicator properties” of consciousness. In contrast to prior works on GWT which utilized single modalities, our agent is trained to navigate 3D environments based on realistic audiovisual inputs. We find that the global workspace architecture performs better and more robustly at smaller working memory sizes, as compared to a standard recurrent architecture. Beyond performance, we perform a series of analyses on the learned representations of our architecture and share findings that point to task complexity and regularization being essential for feature learning and the development of meaningful attentional patterns within the workspace.

Abstract Childhood abuse reduces hippocampal and amygdala volumes and impairs social cognition, including the ability to recognize facial expressions. However, these associations have been studied primarily in individuals with a history of severe abuse and psychiatric symptoms; researchers have not determined whether these associations can also be observed in healthy adults. In the present study, we analyzed data from 400 healthy adults (208 men and 192 women) at Tamagawa University. Parental rejection reflecting childhood abuse was assessed using the short form of Egna Minnen Beträffande Uppfostran, while social cognition was assessed using the “Fake Smile Detection Task.” Hippocampal and amygdala volumes were extracted from T1-weighted magnetic resonance imaging data using FreeSurfer. We found that greater parental rejection resulted in smaller hippocampal and amygdala volumes and poorer performance in the Fake Smile Detection Task. Structural equation modeling analysis supported the model that hippocampal volume mediates maternal rejection effect on performance on the Fake Smile Detection Task, with involvement of the amygdala. These findings are in line with the structural and functional connectivity found between the hippocampus and amygdala and their joint involvement in social cognition. Therefore, parental rejection may affect hippocampal and amygdala volumes and social cognitive function even in symptom-free adults.

Abstract How the human brain represents millisecond unit of time is far from clear. A recent neuroimaging study revealed the existence in the human premotor cortex of a topographic representation of time i.e., neuronal units selectively responsive to specific durations and topographically organized on the cortical surface. By using high resolution functional Magnetic Resonance Images here, we go beyond this previous work, showing duration preferences across a wide network of cortical and subcortical brain areas: from cerebellum to primary visual, parietal, premotor and prefrontal cortices. Most importantly, we identify the effective connectivity structure between these different brain areas and their duration selective neural units. The results highlight the role of the cerebellum as the network hub and that of medial premotor cortex as the final stage of duration recognition. Interestingly, when a specific duration is presented, only the communication strength between the units selective to that specific duration and to the neighboring durations is affected. These findings link for the first time, duration preferences within single brain region with connectivity dynamics between regions, suggesting a communication mode that is partially duration specific.

Abstract Docetaxel-induced fluid retention (DIFR) cumulatively occurs and is one of the most troublesome adverse effects. This study aimed to determine whether high dose dexamethasone (DEX) could prevent DIFR during breast cancer treatment. Breast cancer patients receiving docetaxel (75 mg/m2)-containing regimens were divided into 4 and 8 mg/day DEX groups, with each DEX dose administered on days 2–4 and retrospectively assessed. Incidence of greater than or equal to grade 2 DIFR was significantly lower in the 8 mg group (13.0%) compared to the 4 mg group (39.6%, P = 0.001). All-grade DIFR was also less in the 8 mg group (P = 0.01). Furthermore, the maximum variation of body weight was significantly lower in the 8 mg group (P = 0.0003). These results were also confirmed in the propensity score-matched population. Additionally, time-related DIFR incidence was also significantly delayed in the 8 mg group (P = 0.0005). Our study revealed that high dose DEX prevents DIFR. Therefore, further studies on its management are required for less onerous chemotherapy provision with better DIFR control.

Here, we describe a case of temporary severe neutropenia after atezolizumab monotherapy and its treatment course. Atezolizumab monotherapy was introduced as a 6th-line treatment for a man in his late 60s, who was diagnosed with stage Ⅳ lung adenocarcinoma. The first treatment cycle was administered during hospitalization, and the patient presented with a fever of 37.8°C on the first day. The fever resolved after the administration of acetaminophen and naproxen, and the white blood cell count, neutrophil count, and other white blood cell fractions were normal. However, grade 3 leukopenia and grade 4 neutropenia appeared at the beginning of the third cycle, and treatment was discontinued. After treatment, monocyte count in the leukocyte fraction increased from approximately 10% to 25.6%. Lenograstim 100 μg subcutaneous injection and oral levofloxacin 500 mg once daily were started of onset of neutropenia, and he was hospitalized the next day. Laboratory findings upon admission showed a significant improvement to 5,300/µL for leukocytes and 3,376/µL for neutrophils. Lenograstim was discontinued, with no further decrease in the neutrophil count. Atezolizumab therapy was resumed, and there was no further reduction in leukocyte, neutrophil, or leukocyte fractions over about a 2-year period. Concomitant drugs were maintained during the atezolizumab treatment, suggesting that they did not induce neutropenia. In conclusion, we observed temporary severe neutropenia during atezolizumab monotherapy. Neutrophil recovery with cautious monitoring has enabled longer efficacy. We should consider temporary symptom occurrence in cases of haematological immune-related adverse events.

Abstract Characterization of inter-regional interactions in brain is essential for understanding the mechanism relevant to normal brain function and neurological disease. The recently developed flexible micro (μ)-electrocorticography (μECoG) device is one prominent method used to examine large-scale cortical activity across multiple regions. The sheet-shaped μECoG electrodes arrays can be placed on a relatively wide area of cortical surface beneath the skull by inserting the device into the space between skull and brain. Although rats and mice are useful tools for neuroscience, current μECoG recording methods in these animals are limited to the parietal region of cerebral cortex. Recording cortical activity from the temporal region of cortex in mice has proven difficult because of surgical barriers created by the skull and surrounding temporalis muscle anatomy. Here, we developed a sheet-shaped 64-channel μECoG device that allows access to the mouse temporal cortex, and we determined the factor determining the appropriate bending stiffness for the μECoG electrode array. We also established a surgical technique to implant the electrode arrays into the epidural space over a wide area of cerebral cortex covering from the barrel field to olfactory (piriform) cortex, which is the deepest region of the cerebral cortex. Using histology and computed tomography (CT) images, we confirmed that the tip of the μECoG device reached to the most ventral part of cerebral cortex without causing noticeable damage to the brain surface. Moreover, the device simultaneously recorded somatosensory and odor stimulus-evoked neural activity from dorsal and ventral parts of cerebral cortex in awake and anesthetized mice. These data indicate that our μECoG device and surgical techniques enable the recording of large-scale cortical activity from the parietal to temporal cortex in mice, including somatosensory and olfactory cortices. This system will provide more opportunities for the investigation of physiological functions from wider areas of the mouse cerebral cortex than those currently available with existing ECoG techniques.

Abstract Trust attitude is a social personality trait linked with the estimation of others’ trustworthiness. Trusting others, however, can have substantial negative effects on mental health, such as the development of depression. Despite significant progress in understanding the neurobiology of trust, whether the neuroanatomy of trust is linked with depression vulnerability remains unknown. To investigate a link between the neuroanatomy of trust and depression vulnerability, we assessed trust and depressive symptoms and employed neuroimaging to acquire brain structure data of healthy participants. A high depressive symptom score was used as an indicator of depression vulnerability. The neuroanatomical results observed with the healthy sample were validated in a sample of clinically diagnosed depressive patients. We found significantly higher depressive symptoms among low trusters than among high trusters. Neuroanatomically, low trusters and depressive patients showed similar volume reduction in brain regions implicated in social cognition, including the dorsolateral prefrontal cortex (DLPFC), dorsomedial PFC, posterior cingulate, precuneus, and angular gyrus. Furthermore, the reduced volume of the DLPFC and precuneus mediated the relationship between trust and depressive symptoms. These findings contribute to understanding social- and neural-markers of depression vulnerability and may inform the development of social interventions to prevent pathological depression.

Introduction: Pembrolizumab is a programmed death-ligand 1 inhibitor that was initially indicated for monotherapy in patients with advanced lung cancer. The Japanese Lung Cancer Society conducted an observational study on pembrolizumab using confirmative data obtained through postmarketing all-case surveillance (PMACS), which was performed by a pharmaceutical company under the Japanese law in 2017. Methods: This multicenter observational study was conducted by the Japanese Lung Cancer Society using PMACS data with the newly created central registration system regarding patients with NSCLC who received pembrolizumab monotherapy between February 1, 2017 and June 30, 2017; a new database was created by adding the clinical information regarding prognosis for 3 years after therapy to the existing data collected by PMACS. Results: A total of 300 patients from 43 facilities were enrolled in this study. The median overall survival and progression-free survival after pembrolizumab initiation were 558 and 188 days, respectively. Moreover, the 1- and 3-year survival rates were 58.9% and 33.7%, respectively. Results of multivariate analysis revealed performance status (p < 0.0001), histology (p = 0.0118), previous chemotherapy (p = 0.0007), programmed death-ligand 1 expression status (p = 0.0195), and previous steroid use (p = 0.0460) as significant factors that affected overall survival. The toxicity profile was similar to that previously reported. Conclusions: In this first attempt to use PMACS data, we successfully collected clinical information and found the real-world efficacy and safety of pembrolizumab.

We investigated the effects of long-term repeated treatments with a sustainable gonadotropin-releasing hormone (GnRH) antagonist, degarelix acetate, on testicular hormonal secretion, size, ultrasound images, histology and spermatogenesis in goats to assess its efficacy as a chemical castration method. Male Shiba goats (3–6 months of age) were treated subcutaneously with degarelix acetate every 4 weeks for 24 weeks. Plasma testosterone and insulin-like peptide 3 concentrations decreased (P < 0.05) within 2 days after the first treatment and remained low until 29 weeks (P < 0.05). Scrotal circumference and testicular pixel intensity were lower from 2–6 months and from 1–6 months, respectively, compared to the pretreatment values (P < 0.05). The testis and epididymis weights were lower at 24 weeks compared to those in untreated goats (P < 0.05). There were no sperm in the seminiferous tubules of testicular tissue sections or in homogenates of the epididymis at 24 weeks. These results suggest that repeated treatment with degarelix acetate is an effective chemical castration method for goats.

Powder metallurgical processing of Tungsten (W) followed by thermomechanical treatment, including rolling and stress relief (SR) heat treatment, is a candidate fabrication process for W materials for fusion applications. Helium (He) is insoluble in almost all metals, and grain boundary embrittlement occurs on the accumulation of He on their grain boundaries. In this study, the effects of He concentration, test temperature, and strain rate on the mechanical properties of SR-W were investigated using tensile tests. The He effects were studied by the uniform implantation of high-energy He-ions into specimens by cyclotron accelerator irradiation and by tensile tests from 300 °C to 1300 °C. The examined He concentration was below 20 appm. Vickers hardness tests on an isochronal annealed specimen up to 1500 °C showed that the threshold concentration of He for suppressing the recovery and recrystallization of the microstructure of SR-W by annealing was between 2 and 20 appm. The tensile test showed a slight increase in the ultimate tensile strength (UTS) at He concentrations up to 20 appm; however, no clear effect on the elongation or fracture mode was observed. The results of the tensile test conducted at 1300 °C on a 20-appm He-implanted specimen showed that its softening and ductility by recrystallization were suppressed; however, there was no observation of grain boundary embrittlement by He implantation. The results suggest that the mechanism of the mechanical response of He-implanted SR-W was He suppression of the recovery and recrystallization of the layered structure unique to SR-W up to 1500 °C. Moreover, at the level of He concentration introduced by nuclear transmutation in the divertor of a fusion reactor without displacement damage, no severe effect occurred to promote the embrittlement of SR-W.

Limited salvage chemotherapies are available for relapsed/refractory acute myeloid leukemia. Herein, we described successful reinduction chemotherapy, involving a combination of clofarabine, cyclophosphamide, and etoposide, in a 12-year-old male with relapsed acute myeloid leukemia prior to allogeneic bone marrow transplantation from his father. Although treatment with a combination of fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin, and gemtuzumab ozogamicin had no positive effects, the aforementioned clofarabine-based chemotherapy induced complete remission and allowed the transplantation to go ahead. The abovementioned regimen may be useful for induction chemotherapy prior to hematopoietic stem cell transplantation for refractory/relapsed acute myeloid leukemia.

Pediatric acute lymphoblastic leukemia regimens include large L-asparaginase dosages and steroids, which are associated with an increased risk of venous thromboemboli in adolescents and young adults. Herein, we report the case of an 18-year-old male with acute lymphoblastic leukemia, who was treated with the pediatric regimen, in which edoxaban was employed as a prophylaxis against cerebral sinus venous thrombosis. The event happened on day 20 of induction therapy, when brain magnetic resonance imaging demonstrated a cerebral sinus venous thrombosis in the superior sagittal sinus. Anticoagulation therapy was initiated, and the patient’s symptoms disappeared 3 days later. The induction therapy was restarted after an interruption of 16 days, and the consolidation therapies, which included L-asparaginase and steroids, were completed. Edoxaban was administered as a prophylaxis during the consolidation therapy. There were no further adverse events. Edoxaban could be an effective prophylaxis for coagulation complications in adolescents and young adults with acute lymphoblastic leukemia.

The characteristics of a fine-bubble plume passing through two tandem cylinders are investigated. Fine-bubbles with a mean diameter of 0.055 mm are released by water electrolysis from electrodes placed at the bottom of a tank. They induce an upward water flow around them with rising due to buoyancy. Orthogonally to the axis of such fine–bubble plume, two cylinders with a diameter D of 30 mm are arranged in tandem. The distance between the cylinders, L, ranges between 1.5D and 3D. This study visualizes the bubbles and water flow around the cylinders. It also measures the bubble velocity distribution. The experiments reveal the water and bubble shear layers originating at the sides of the lower cylinder and make clear their behavior around the upper cylinder. This study elucidates the effects of L on the characteristics of the fine-bubble plume, such as the stagnant bubbly flow and the bubbly wake around the cylinders.

Information processing in neural systems can be described and analyzed at multiple spatiotemporal scales. Generally, information at lower levels is more fine-grained but can be coarse-grained at higher levels. However, only information processed at specific scales of coarse-graining appears to be available for conscious awareness. We do not have direct experience of information available at the scale of individual neurons, which is noisy and highly stochastic. Neither do we have experience of more macro-scale interactions, such as interpersonal communications. Neurophysiological evidence suggests that conscious experiences co-vary with information encoded in coarse-grained neural states such as the firing pattern of a population of neurons. In this article, we introduce a new informational theory of consciousness: Information Closure Theory of Consciousness (ICT). We hypothesize that conscious processes are processes which form non-trivial informational closure (NTIC) with respect to the environment at certain coarse-grained scales. This hypothesis implies that conscious experience is confined due to informational closure from conscious processing to other coarse-grained scales. Information Closure Theory of Consciousness (ICT) proposes new quantitative definitions of both conscious content and conscious level. With the parsimonious definitions and a hypothesize, ICT provides explanations and predictions of various phenomena associated with consciousness. The implications of ICT naturally reconcile issues in many existing theories of consciousness and provides explanations for many of our intuitions about consciousness. Most importantly, ICT demonstrates that information can be the common language between consciousness and physical reality.

The purpose of this project is to examine the notch sensitivity to the strength of a mechanical metamaterial comprising a periodic arrangement of snapping units. A unit cell of the metamaterial consists of two centrally connected wavy-shape segment (a snapping segment and a bearing segment). Since the unit cell possesses two stable deformation states in a certain load range, the nominal strain is rapidly increased by snap-through instabilities (snap-through deformation) when the applied load reaches a critical value. In the tensile experiment of specimens comprised of 30×30 unit cells under quasi-stick conditions, the cells on a certain row snap, and this results in a macroscopic load drop. As the applied deformation increases the snap-through deformation propagates to the adjacent cell. The cells snap through row-by-row with relatively small increases and decreases, until fracture occurs in the specimen. This process brings about a large macroscopic ductility of the metamaterial. Subsequently, a center-hole notch is introduced into the specimen and tensile experiments are performed. Although the snap-through deformation preferentially occurs at the notch root, it propagates to the other cells row-by-row without fracture because a stress concentration at the notch root is relaxed by the snapping. The snapping metamaterial possesses low defect susceptibility and high embrace as a structural material.

Prognosis in pediatric patients with refractory/relapsed acute myeloid leukemia (AML) is grim, and there is no standard treatment for such patients. Combined treatment with intensive chemotherapy and gemtuzumab ozogamicin (GO), a monoclonal anti-CD33 antibody conjugated with calicheamicin, is useful as reinduction therapy in refractory/relapsed AML. Here, we describe three cases of pediatric refractory/relapsed AML that were successfully managed with FLAG-IDA (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin), with or without GO, as reinduction therapy before a KIR-ligand-mismatched cord blood transplant. This strategy relies on the fact that killer cell immunoglobulin-like receptors (KIR) on cord blood natural killer (NK) cells recognize human leukocyte antigen (HLA) class I alleles, and that donor KIR-ligand incompatibility may be associated with lower incidence of relapse and improved survival in AML, as cells that lack these inhibitory HLA ligands can activate NK cells. All three patients are currently alive and have been disease-free for 24–65 months, although one patient developed severe sinusoidal obstructive syndrome (SOS). Thus, our strategy can result in excellent outcomes in pediatric patients with refractory/relapsed AML.

Modality-invariant categorical representations, i.e., shared representation, is thought to play a key role in learning to categorize multi-modal information. We have investigated how a bimodal autoencoder can form a shared representation in an unsupervised manner with multi-modal data. We explored whether altering the depth of the network and mixing the multi-modal inputs at the input layer affect the development of the shared representations. Based on the activation of units in the hidden layers, we classified them into four different types: visual cells, auditory cells, inconsistent visual and auditory cells, and consistent visual and auditory cells. Our results show that the number and quality of the last type (i.e., shared representation) significantly differ depending on the depth of the network and are enhanced when the network receives mixed inputs as opposed to separate inputs for each modality, as occurs in typical two-stage frameworks. In the present work, we present a way to utilize information theory to understand the abstract representations formed in the hidden layers of the network. We believe that such an information theoretic approach could potentially provide insights into the development of more efficient and cost-effective ways to train neural networks using qualitative measures of the representations that cannot be captured by analyzing only the final outputs of the networks.

Abstract Background Interstitial lung diseases induced by anticancer agents (ILD-AA) are rare adverse effects of anticancer therapy. However, prognostic biomarkers for ILD-AA have not been identified in patients with advanced lung cancer. Our aim was to analyze the association between serum biomarkers sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), and clinical characteristics in patients diagnosed with ILD-AA. Methods Between April 2011 and March 2016, 1224 advanced lung cancer patients received cytotoxic agents and epidermal growth factor receptor tyrosine kinase inhibitors at Juntendo University Hospital and Juntendo University Urayasu Hospital. Of these patients, those diagnosed with ILD-AA were enrolled in this case control study. ΔKL-6 and ΔSP-D were defined as the difference between the levels at the onset of ILD-AA and their respective levels prior to development of ILD-AA. We evaluated KL-6 and SP-D at the onset of ILD-AA, ΔKL-6 and ΔSP-D, the risk factors for death related to ILD-AA, the chest high resolution computed tomography (HRCT) findings, and survival time in patients diagnosed with ILD-AA. Results Thirty-six patients diagnosed with ILD-AA were enrolled in this study. Among them, 14 patients died of ILD-AA. ΔSP-D in the patients who died was significantly higher than that in the patients who survived. However, ΔKL-6 did not differ significantly between the two groups. Moreover, ΔSP-D in patients who exhibited diffuse alveolar damage was significantly higher than that in the other patterns on HRCT. Receiver operating characteristic curve analysis was used to set the optimal cut off value for ΔSP-D at 398 ng/mL. Survival time for patients with high ΔSP-D (≥ 398 ng/mL) was significantly shorter than that for patients with low ΔSP-D. Multivariate analysis revealed that ΔSP-D was a significant prognostic factor of ILD-AA. Conclusions This is the first research to evaluate high ΔSP-D (≥ 398 ng/mL) in patients with ILD-AA and to determine the risk factors for ILD-AA in advanced lung cancer patients. ΔSP-D might be a serum prognostic biomarker of ILD-AA. Clinicians should evaluate serum SP-D during chemotherapy and should carefully monitor the clinical course in patients with high ΔSP-D.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by rapid progression. The mechanisms that lead to a shift from initial therapeutic sensitivity to ultimate therapeutic resistance are poorly understood. Although the SCLC genomic landscape led to the discovery of promising agents targeting genetic alterations that were already under investigation, results have been disappointing. Achievements in targeted therapeutics have not been observed for over 30 years. Therefore, the underlying disease biology and novel targets urgently require a better understanding. Epigenetic regulation is deeply involved in the cellular plasticity that could shift tumor cells to the malignant phenotype. We have focused on a histone modifier, LSD1, that is overexpressed in SCLC and is a potent therapeutic target. Interestingly, the LSD1 splice variant LSD1+8a, the expression of which has been reported to be restricted to neural tissue, was detected and was involved in the expression of neuroendocrine marker genes in SCLC cell lines. Cells with high expression of LSD1+8a were resistant to CDDP and LSD1 inhibitor. Moreover, suppression of LSD1+8a inhibited cell proliferation, indicating that LSD1+8a could play a critical role in SCLC. These findings suggest that LSD1+8a should be considered a novel therapeutic target in SCLC.

The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.

Time is a fundamental dimension of everyday experiences. We can unmistakably sense its passage and adjust our behavior accordingly. Despite its ubiquity, the neuronal mechanisms underlying the capacity to perceive time remains unclear. Here, in two experiments using ultrahigh-field 7-Tesla (7T) functional magnetic resonance imaging (fMRI), we show that in the medial premotor cortex (supplementary motor area [SMA]) of the human brain, neural units tuned to different durations are orderly mapped in contiguous portions of the cortical surface so as to form chronomaps. The response of each portion in a chronomap is enhanced by neighboring durations and suppressed by nonpreferred durations represented in distant portions of the map. These findings suggest duration-sensitive tuning as a possible neural mechanism underlying the recognition of time and demonstrate, for the first time, that the representation of an abstract feature such as time can be instantiated by a topographical arrangement of duration-sensitive neural populations.

This paper presents the Homeo-Heterostatic Value Gradients (HHVG) algorithm as a formal account on the constructive interplay between boredom and curiosity which gives rise to effective exploration and superior forward model learning. We offer an instrumental view of action selection, in which an action serves to disclose outcomes that have intrinsic meaningfulness to an agent itself. This motivated two central algorithmic ingredients: devaluation and devaluation progress, both underpin agent's cognition concerning intrinsically generated rewards. The two serve as an instantiation of homeostatic and heterostatic intrinsic motivation. A key insight from our algorithm is that the two seemingly opposite motivations can be reconciled—without which exploration and information-gathering cannot be effectively carried out. We supported this claim with empirical evidence, showing that boredom-enabled agents consistently outperformed other curious or explorative agent variants in model building benchmarks based on self-assisted experience accumulation.

We summarize the original formulation of the free energy principle and highlight some technical issues. We discuss how these issues affect related results involving generalised coordinates and, where appropriate, mention consequences for and reveal, up to now unacknowledged, differences from newer formulations of the free energy principle. In particular, we reveal that various definitions of the “Markov blanket” proposed in different works are not equivalent. We show that crucial steps in the free energy argument, which involve rewriting the equations of motion of systems with Markov blankets, are not generally correct without additional (previously unstated) assumptions. We prove by counterexamples that the original free energy lemma, when taken at face value, is wrong. We show further that this free energy lemma, when it does hold, implies the equality of variational density and ergodic conditional density. The interpretation in terms of Bayesian inference hinges on this point, and we hence conclude that it is not sufficiently justified. Additionally, we highlight that the variational densities presented in newer formulations of the free energy principle and lemma are parametrised by different variables than in older works, leading to a substantially different interpretation of the theory. Note that we only highlight some specific problems in the discussed publications. These problems do not rule out conclusively that the general ideas behind the free energy principle are worth pursuing.

Recent MRI studies have shown that schizophrenia is characterized by reductions in brain gray matter, which progress in the acute state of the disease. Cortical circuitry abnormalities in gamma oscillations, such as deficits in the auditory steady state response (ASSR) to gamma frequency (>30-Hz) stimulation, have also been reported in schizophrenia patients. In the current study, we investigated neural responses during click stimulation by BOLD signals. We acquired BOLD responses elicited by click trains of 20, 30, 40 and 80-Hz frequencies from 15 patients with acute episode schizophrenia (AESZ), 14 symptom-severity-matched patients with non-acute episode schizophrenia (NASZ), and 24 healthy controls (HC), assessed via a standard general linear-model-based analysis. The AESZ group showed significantly increased ASSR-BOLD signals to 80-Hz stimuli in the left auditory cortex compared with the HC and NASZ groups. In addition, enhanced 80-Hz ASSR-BOLD signals were associated with more severe auditory hallucination experiences in AESZ participants. The present results indicate that neural over activation occurs during 80-Hz auditory stimulation of the left auditory cortex in individuals with acute state schizophrenia. Given the possible association between abnormal gamma activity and increased glutamate levels, our data may reflect glutamate toxicity in the auditory cortex in the acute state of schizophrenia, which might lead to progressive changes in the left transverse temporal gyrus.

Wiskott–Aldrich syndrome is a rare X-linked recessive disease resulting from variations in the WAS gene. Wiskott–Aldrich syndrome is sometimes difficult to differentiate from immune thrombocytopenic purpura. A 2-month-old boy was admitted to our hospital for purpura and thrombocytopenia. His mean platelet volume was reported to be normal. Treatment with intravenous immunoglobulins failed to improve the patient’s platelet count. Subsequently, an acute cytomegalovirus infection was confirmed by serological testing and antigenemia. The patient was diagnosed with immune thrombocytopenic purpura secondary to a cytomegalovirus infection. However, based on the patient’s clinical course and the refractoriness of his condition, Wiskott–Aldrich syndrome was strongly suspected. Through direct sequencing of the genomic DNA of the Wiskott–Aldrich syndrome protein (WASP) gene, we identified a novel missense mutation in exon 3 of the patient’s WASP gene (c. 343 C>T, p. H115T), and the patient was diagnosed with Wiskott–Aldrich syndrome at 3 months after onset. Children with Wiskott–Aldrich syndrome are often initially diagnosed with immune thrombocytopenic purpura, which can lead to inappropriate treatment and delays to life-saving definitive therapy. Our findings imply that Wiskott–Aldrich syndrome should be considered as a differential diagnosis in cases of refractory immune thrombocytopenic purpura combined with a cytomegalovirus infection.

The ability to integrate information in the brain is considered to be an essential property for cognition and consciousness. Integrated Information Theory (IIT) hypothesizes that the amount of integrated information ( Φ ) in the brain is related to the level of consciousness. IIT proposes that, to quantify information integration in a system as a whole, integrated information should be measured across the partition of the system at which information loss caused by partitioning is minimized, called the Minimum Information Partition (MIP). The computational cost for exhaustively searching for the MIP grows exponentially with system size, making it difficult to apply IIT to real neural data. It has been previously shown that, if a measure of Φ satisfies a mathematical property, submodularity, the MIP can be found in a polynomial order by an optimization algorithm. However, although the first version of Φ is submodular, the later versions are not. In this study, we empirically explore to what extent the algorithm can be applied to the non-submodular measures of Φ by evaluating the accuracy of the algorithm in simulated data and real neural data. We find that the algorithm identifies the MIP in a nearly perfect manner even for the non-submodular measures. Our results show that the algorithm allows us to measure Φ in large systems within a practical amount of time.

[This corrects the article DOI: 10.1371/journal.pbio.1002262.].

Although psychological and computational models of time estimation have postulated the existence of neural representations tuned for specific durations, empirical evidence of this notion has been lacking. Here, using a functional magnetic resonance imaging (fMRI) adaptation paradigm, we show that the inferior parietal lobule (IPL) (corresponding to the supramarginal gyrus) exhibited reduction in neural activity due to adaptation when a visual stimulus of the same duration was repeatedly presented. Adaptation was strongest when stimuli of identical durations were repeated, and it gradually decreased as the difference between the reference and test durations increased. This tuning property generalized across a broad range of durations, indicating the presence of general time-representation mechanisms in the IPL. Furthermore, adaptation was observed irrespective of the subject's attention to time. Repetition of a nontemporal aspect of the stimulus (i.e., shape) did not produce neural adaptation in the IPL. These results provide neural evidence for duration-tuned representations in the human brain.

Media multitasking, or the concurrent consumption of multiple media forms, is increasingly prevalent in today's society and has been associated with negative psychosocial and cognitive impacts. Individuals who engage in heavier media-multitasking are found to perform worse on cognitive control tasks and exhibit more socio-emotional difficulties. However, the neural processes associated with media multi-tasking remain unexplored. The present study investigated relationships between media multitasking activity and brain structure. Research has demonstrated that brain structure can be altered upon prolonged exposure to novel environments and experience. Thus, we expected differential engagements in media multitasking to correlate with brain structure variability. This was confirmed via Voxel-Based Morphometry (VBM) analyses: Individuals with higher Media Multitasking Index (MMI) scores had smaller gray matter density in the anterior cingulate cortex (ACC). Functional connectivity between this ACC region and the precuneus was negatively associated with MMI. Our findings suggest a possible structural correlate for the observed decreased cognitive control performance and socio-emotional regulation in heavy media-multitaskers. While the cross-sectional nature of our study does not allow us to specify the direction of causality, our results brought to light novel associations between individual media multitasking behaviors and ACC structure differences.

Can subjective belief about one's own perceptual competence change one's perception? To address this question, we investigated the influence of self-efficacy on sensory discrimination in two low-level visual tasks: contrast and orientation discrimination. We utilised a pre-post manipulation approach whereby two experimental groups (high and low self-efficacy) and a control group made objective perceptual judgments on the contrast or the orientation of the visual stimuli. High and low self-efficacy were induced by the provision of fake social-comparative performance feedback and fictional research findings. Subsequently, the post-manipulation phase was performed to assess changes in visual discrimination thresholds as a function of the self-efficacy manipulations. The results showed that the high self-efficacy group demonstrated greater improvement in visual discrimination sensitivity compared to both the low self-efficacy and control groups. These findings suggest that subjective beliefs about one's own perceptual competence can affect low-level visual processing.

The oxidation of Ag nanostructures has been studied as a key step for their degradation under the guiding principle in the previous paper that they are stable when their Fermi level is lower than those of their surroundings. The drop of the Fermi level of a thin Ag layer was caused by the formation of self-assembled monolayers (SAMs) of certain organic compounds including those of photographic interest and a monolayer of AgI, and attributed to the formation of dielectric layers, whose positive charges were closer to the Ag layer than negative charges. A consideration is given on further examinations needed to realize the above guiding principle in individual devices. [ABSTRACT FROM AUTHOR]

Across cultures, social relationships are often thought of, described, and acted out in terms of physical space (e.g. "close friends" "high lord"). Does this cognitive mapping of social concepts arise from shared brain resources for processing social and physical relationships? Using fMRI, we found that the tasks of evaluating social compatibility and of evaluating physical distances engage a common brain substrate in the parietal cortex. The present study shows the possibility of an analytic brain mechanism to process and represent complex networks of social relationships. Given parietal cortex's known role in constructing egocentric maps of physical space, our present findings may help to explain the linguistic, psychological and behavioural links between social and physical space.

When visual input is inconclusive, does previous experience aid the visual system in attaining an accurate perceptual interpretation? Prolonged viewing of a visually ambiguous stimulus causes perception to alternate between conflicting interpretations. When viewed intermittently, however, ambiguous stimuli tend to evoke the same percept on many consecutive presentations. This perceptual stabilization has been suggested to reflect persistence of the most recent percept throughout the blank that separates two presentations. Here we show that the memory trace that causes stabilization reflects not just the latest percept, but perception during a much longer period. That is, the choice between competing percepts at stimulus reappearance is determined by an elaborate history of prior perception. Specifically, we demonstrate a seconds-long influence of the latest percept, as well as a more persistent influence based on the relative proportion of dominance during a preceding period of at least one minute. In case short-term perceptual history and long-term perceptual history are opposed (because perception has recently switched after prolonged stabilization), the long-term influence recovers after the effect of the latest percept has worn off, indicating independence between time scales. We accommodate these results by adding two positive adaptation terms, one with a short time constant and one with a long time constant, to a standard model of perceptual switching.