Astrocytic interleukin-3 programs microglia and limits Alzheimer's disease.

Communication within the glial cell ecosystem is essential for neuronal and brain health1-3. The influence of glial cells on the accumulation and clearance of ß-amyloid (Aß) and neurofibrillary tau in the brains of individuals with Alzheimer's disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aß deposits, microglia increase their expression of IL-3Rα-the specific receptor for IL-3 (also known as CD123)-making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aß and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte-microglia cross-talk and a node for therapeutic intervention in AD.

Outcomes of Lung Transplantation in Patients With Right Ventricular Dysfunction: A Single-Center Retrospective Analysis Comparing ECMO Configurations in a Bridge-to-Transplant Setting.

This study aimed to assess the lung transplantation (LT) outcomes of patients with right ventricular dysfunction (RVD), focusing on the impact of various extracorporeal membrane oxygenation (ECMO) configurations. We included adult patients who underwent LT with ECMO as a bridge-to-transplant from 2011 to 2021 at a single center. Among patients with RVD (n = 67), veno-venous (V-V) ECMO was initially applied in 79% (53/67) and maintained until LT in 52% (35/67). Due to the worsening of RVD, the configuration was changed from V-V ECMO to veno-arterial (V-A) ECMO or a right ventricular assist device with an oxygenator (Oxy-RVAD) in 34% (18/67). They showed that lactic acid levels (2-6.1 mmol/L) and vasoactive inotropic score (6.6-22.6) increased. V-A ECMO or Oxy-RVAD was initiated and maintained until LT in 21% (14/67) of cases. There was no significant difference in the survival rates among the three configuration groups (V-V ECMO vs. configuration changed vs. V-A ECMO/Oxy-RVAD). Our findings suggest that the choice of ECMO configuration for LT candidates with RVD should be determined by the patient's current hemodynamic status. Vital sign stability supports the use of V-V ECMO, while increasing lactic acid levels and vasopressor needs may require a switch to V-A ECMO or Oxy-RVAD.

Degradation and inhibition of epigenetic regulatory protein BRD4 exacerbate Alzheimer's disease-related neuropathology in cell models.

Epigenetic regulation plays substantial roles in human pathophysiology, which provides opportunities for intervention in human disorders through the targeting of epigenetic pathways. Recently, emerging evidence from preclinical studies suggested the potential in developing therapeutics of Alzheimer's disease (AD) by targeting bromodomain containing protein 4 (BRD4), an epigenetic regulatory protein. However, further characterization of AD-related pathological events is urgently required. Here, we investigated the effects of pharmacological degradation or inhibition of BRD4 on AD cell models. Interestingly, we found that both degradation and inhibition of BRD4 by ARV-825 and JQ1, respectively, robustly increased the levels of amyloid-beta (Aß), which has been associated with the neuropathology of AD. Subsequently, we characterized the mechanisms by which downregulation of BRD4 increases Aß levels. We found that both degradation and inhibition of BRD4 increased the levels of BACE1, the enzyme responsible for cleavage of the amyloid-beta protein precursor (APP) to generate Aß. Consistent with Aß increase, we also found that downregulation of BRD4 increased AD-related phosphorylated Tau (pTau) protein in our 3D-AD human neural cell culture model. Therefore, our results suggest that downregulation of BRD4 would not be a viable strategy for AD intervention. Collectively, our study not only shows that BRD4 is a novel epigenetic component that regulates BACE1 and Aß levels, but also provides novel and translational insights into the targeting of BRD4 for potential clinical applications.

Adult neurogenesis in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of age-related dementia, characterized by progressive memory loss and cognitive disturbances. The hippocampus, where adult hippocampal neurogenesis (AHN), a relatively novel form of brain plasticity that refers to the birth of new neurons, occurs, is one of the first brain regions to be affected in AD patients. Recent studies showed that AHN persists throughout life in humans, but it drops sharply in AD patients. Next questions to consider would be whether AHN impairment is a contributing factor to learning and memory impairment in AD and whether restoring AHN could ameliorate or delay cognitive dysfunction. Here, we outline and discuss the current knowledge about the state of AHN in AD patients, AHN impairment as a potentially relevant mechanism underlying memory deficits in AD, therapeutic potential of activating AHN in AD, and the mechanisms of AHN impairment in AD.

High-dose chemotherapy followed by autologous stem cell transplantation in pediatric patients with relapsed osteosarcoma.

BACKGROUND: Patients with relapsed osteosarcoma have poor treatment outcomes. High-dose chemotherapy with autologous stem cell transplantation (HDCT/ASCT) has been used in several high-risk malignant solid tumors; however, few studies have evaluated their role in treating osteosarcoma. We evaluated the effectiveness of HDCT/ASCT in relapsed pediatric osteosarcoma cases. PROCEDURE: We retrospectively reviewed the medical records of 40 patients diagnosed with and treated for relapsed osteosarcoma at Asan Medical Center and Samsung Medical Center from January 1996 to July 2019. RESULTS: The median age of this cohort was 13.4 years (range: 6.1-18.2). The cohort's 5-year overall survival (OS) was 51.0% ± 0.1% during a median follow-up period of 67.5 months. Twenty-five patients (62.5%) achieved complete remission (CR) with salvage treatment, and the 5-year OS was 82.4% ± 0.1%, whereas none of the remaining 15 patients who did not achieve CR survived (p < .0001). Of the 25 CR cases, 15 underwent subsequent HDCT/ASCT. We compared the effect of HDCT/ASCT among patients who achieved CR. There were no significant differences in the 5-year OS outcomes between patients who did and did not receive HDCT/ASCT (83.9% ± 0.1%, 13/15 vs. 80.0% ± 0.1%, 8/10, respectively; p = .923). CONCLUSION: To our knowledge, we report the first comparative cohort study that proved HDCT/ASCT does not significantly improve survival outcomes in relapsed osteosarcoma. Achievement of CR remains the most crucial factor for good survival outcomes.

Right Ventricular Assist Device With Extracorporeal Membrane Oxygenation for Bridging Right Ventricular Heart Failure to Lung Transplantation: A Single-Center Case Series and Literature Review.

OBJECTIVE: Right ventricular heart failure (RVHF) is a critical complication in patients with respiratory failure, particularly among those who transitioned to lung transplantation using venovenous (VV) extracorporeal membrane oxygenation (ECMO). In these patients, both cardiac and respiratory functions are supported using venoarterial or venoarterial-venous ECMO. However, these modalities increase the risk of device-related complications, such as thromboembolism, bleeding, and limb ischemia, and they may disturb early rehabilitation. Due to these limitations, a right ventricular assist device with an oxygenator (Oxy-RVAD) using ECMO may be considered for patients with RVHF with VV ECMO. DESIGN: A retrospective case series and literature review. SETTING: A single tertiary care university hospital. PARTICIPANTS: The study comprised lung transplantation candidates on ECMO bridging who developed right-sided heart failure. INTERVENTIONS: An RVAD with ECMO. MEASUREMENTS AND MAIN RESULTS: Of eight patients who underwent the study protocol, seven were bridged successfully to lung transplantation (BTT), and all patients with BTT were discharged, with a 30-day survival rate of 100% (7/7 patients). The 180-day survival rate was 85% (6/7 patients). CONCLUSIONS: The study suggested that Oxy-RVAD using ECMO may be a viable option for bridging patients with RVHF to lung transplantation. TRIAL REGISTRATION: Retrospectively registered.

A three-dimensional human neural cell culture model of Alzheimer's disease.

Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-ß plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-ß peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-ß-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-ß species and phosphorylated tau but did not demonstrate amyloid-ß plaques or neurofibrillary tangles. Here we report that FAD mutations in ß-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-ß, including amyloid-ß plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-ß generation with ß- or γ-secretase inhibitors not only decreased amyloid-ß pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-ß-mediated tau phosphorylation. We have successfully recapitulated amyloid-ß and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer's disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders.

Surgical Outcome of Colon Interposition in Esophageal Cancer Surgery: Analysis of Risk Factors for Conduit-Related Morbidity.

BACKGROUND: We aimed to assess the feasibility, surgical outcomes, and conduit-related complications of colon interposition in patients with esophageal cancer. METHODS: Patients with esophageal cancer who underwent colon interposition for esophageal reconstruction between June 2000 and June 2013 were retrospectively reviewed. RESULTS: A total of 67 consecutive patients (mean age, 62.2 ± 7.9 years) were enrolled. During this time period, 944 patients underwent esophageal reconstruction using gastric conduit. Twelve patients (17.9%) also received neoadjuvant chemoradiotherapy (nCRT). The median follow-up duration was 44 months (range, 1-168 months); median survival duration was 63 months (range, 1-168 months); and 3- and 5-year overall survival rates were 61.6 and 49.4%, respectively. A total of 43 patients (64.2%) experienced at least 1 postoperative morbidity. According to the Clavien-Dindo grading system, 36 patients (54%) experienced postoperative morbidity of higher than Grade III. Pulmonary complications were most commonly observed complications among the patients (18 patients, 26.9%). Anastomosis site leakage developed in 11 patients (16.4%), and 3 of these patients (6.0%) eventually experienced graft failure. On multivariate analysis, nCRT was determined as a significant risk factor for conduit-related complications (leakage, graft failure, fistula, and stricture). CONCLUSION: Colon interposition is associated with relatively high complication rates, whereas nCRT is associated with conduit morbidity.

Surgical Outcomes after Pulmonary Resection for Non-Small Cell Lung Cancer with Localized Pleural Seeding First Detected during Surgery.

OBJECTIVES: Curative resection is not indicated for non-small cell lung cancer (NSCLC) with pleural seeding, which is classified as stage IV (M1a) disease. However, some patients with a presumably resectable main tumor are diagnosed with localized pleural seeding during surgery. METHODS: A retrospective analysis was performed of 3,975 patients who underwent surgery for NSCLC from 2000 to 2011. Among these cases, 78 (2.0%) patients had unexpected pleural seeding detected during surgery. Exploration with pleural biopsy was performed in 42 of these patients (exploration-only group) and pulmonary resection, including for the main tumor, was performed in 36 cases (resection group; sublobar resection in 12, lobectomy in 21, and pneumonectomy in 3 patients). Survival and cancer progression rates were estimated using the Kaplan-Meier method. Cox proportional hazard regression was used to evaluate prognostic factors associated with survival. RESULTS: Adenocarcinoma was the predominant histological type in both the exploration and resection groups (88.1 and 86.1%, respectively). Epidermal growth factor receptor expression was detected in 22 (52.4%) patients of the exploration group and 21 (58.3%) patients of the resection group. Baseline characteristics including age, sex, comorbidity, pulmonary function, and clinical T/N status were not significantly different between the two groups. There were no postoperative deaths in either group but postoperative complications occurred in two (4.8%) patients of the exploration group and three (8.3%) patients of the resection group. The overall 3- and 5-year survival rates in the exploration group were 41.1 and 15.2%, respectively, with a median survival time (MST) of 33 months, whereas they were 66.7 and 42.7%, respectively, in the resection group, with a 52-month MST (p = 0.012). Local and regional progression-free rates were significantly different (p < 0.001 and p = 0.029, respectively) between groups, whereas no difference was seen in the distant metastasis rates (p = 0.957). In multivariate survival analysis, surgical resection was the only significant prognostic factor (p = 0.01). CONCLUSIONS: Pulmonary resection including the main tumor, regardless of resection extent, may increase long-term survival for NSCLC patients with localized pleural seeding first detected during surgery, without a significant increase in hospital mortality or morbidity.

Doubling time of thymic epithelial tumours on CT: correlation with histological subtype.

OBJECTIVES: We retrospectively evaluated the doubling time (DT) of thymic epithelial tumours (TET) according to the histological subtype on CT. METHODS: From January 2005 to June 2016, we enrolled 53 patients who had pathologically confirmed TET and at least two CT scans. Tumour size was measured using a two-dimensional method, and the DT was calculated. DTs were compared among histological subtypes, and factors associated with rapid tumour growth (DT <180 days) were assessed. RESULTS: In 42 of the 53 patients (79.2%) the tumours showed interval growth (>2 mm) during follow-up. The median DT for all tumours was 400 days (range 48-1,964 days). There were no significant differences in DT in relation to histological subtype (p = 0.177). When TETs were recategorized into three groups, i.e. low-risk thymomas (types A, AB, B1), high-risk thymomas (types B2, B3), and thymic carcinoma, DT was significantly different among the groups (median DT 436, 381 and 189 days, respectively; p = 0.031). Histological subtype (type B3 and thymic carcinoma) was the single independent predictor of rapid tumour growth. CONCLUSIONS: The majority of TETs grew during follow-up with variable and relatively slow growth rates. Histological features of aggressive behaviour significantly correlated with a decreased DT and rapid growth. KEY POINTS: • The majority of thymic epithelial tumours grew during follow-up (79.2%, 42/53). • Doubling times of thymic epithelial tumours were highly variable (median 400 days). • Histological features of aggressive behaviour significantly correlated with a decreased doubling time.

Alzheimer's in 3D culture: challenges and perspectives.

Alzheimer's disease (AD) is the most common cause of dementia, and there is currently no cure. The "ß-amyloid cascade hypothesis" of AD is the basis of current understanding of AD pathogenesis and drug discovery. However, no AD models have fully validated this hypothesis. We recently developed a human stem cell culture model of AD by cultivating genetically modified human neural stem cells in a three-dimensional (3D) cell culture system. These cells were able to recapitulate key events of AD pathology including ß-amyloid plaques and neurofibrillary tangles. In this review, we will discuss the progress and current limitations of AD mouse models and human stem cell models as well as explore the breakthroughs of 3D cell culture systems. We will also share our perspective on the potential of dish models of neurodegenerative diseases for studying pathogenic cascades and therapeutic drug discovery.

The Different Clinical Aspects of Pediatric Primary Airway Tumors in the Larynx, Trachea, and Bronchi.

Primary airway tumors are rare in children and no literature reviewed their characteristics each location. We evaluate the clinical characteristics and outcomes of Korean children with primary airway tumors, from the larynx to bronchi. A retrospective chart review of children with primary tumors of the larynx, trachea, and bronchi at Asan Medical Center from January 2000 to July 2016 was conducted. Nineteen children were diagnosed with primary airway tumors of the larynx (47.4%), trachea (10.5%), and bronchi (42.1%). Median follow-up duration was 2.8 years and there were recurrences in 21.1%. Laryngeal tumors were associated with a younger median age at onset (2 months) and diagnosis (4 months), and most were relatively small (median size = 5.3 mm) and symptomatic. Tracheal and bronchial tumors were found in older children (age at onset and diagnosis > 11 years) and large (> 15.0 mm). Most (75%) patients with bronchial tumors were asymptomatic and all the patients with tracheal tumors were symptomatic. This study suggests that we should consider different the locations in primary airway tumor based on the age at onset and diagnosis, initial symptoms or signs, and size of tumor.

Predictive factors for a long-term response duration in non-squamous cell lung cancer patients treated with pemetrexed.

BACKGROUND: Pemetrexed is widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSCLC). However, factors that can predict the benefits of pemetrexed therapy have not yet been defined. METHODS: We compared the clinical and molecule pathological characteristics of good and poor responders among a cohort of 1,848 non-squamous NSCLC patients who had received at least two cycles of pemetrexed therapy between November 2006 and February 2015. Among these cases, 92 good responders who were the top 5 % in terms of progression-free survival (PFS) and 222 poor responders who had progressive disease after only 2 cycles of therapy were selected for the analysis. RESULTS: The median PFS of the good responders was 29.9 months (range; 20.9-90.0) and the median number of cycle was 37 (range; 18-129). Although 53.5 % of patients showed stable disease (SD), this response was sustained (median PFS in SD, 29.6 months). A never-smoking status was related to better survival outcome, whereas EGFR mutation, two or more metastatic sites, and intra-abdominal metastasis were each associated with a poor PFS. ALK translocation showed a tendency for a positive impact on response to pemetrexed, whereas metastatic lesion to liver, adrenal gland or bone showed a tendency for a negative impact despite not reaching our threshold for statistical significance. CONCLUSIONS: Predictive factors, such as smoking status, the status of genetic alteration and tumor burden, should be considered when administering pemetrexed therapy for non-squamous NSCLC.

Clinical results of surgical resection of mediastinal teratoma: efficacy of video-assisted thoracic surgery.

BACKGROUND: In patients with a mediastinal tumor, video-assisted thoracic surgery (VATS) is considered to be associated with more postoperative advantages compared to open procedures. However, open procedures are still preferred in cases with large or malignant tumors. Therefore, in order to determine the appropriate surgical strategies for resection of teratomas, we here review our experience with such cases. METHODS: Between January 2000 and February 2014, we experienced 132 patients diagnosed with mediastinal teratoma. By using data from a retrospective review of the patients' medical records, we compared the demographic characteristics, hospital stay duration, chest tube indwelling time, operative time, and mass size of the VATS group with those of the patients in the open group. Moreover, we also analyzed the postoperative complications and recurrence. Finally, based on our findings, we created a '∆V (volume of the mass-volume of the cyst in the mass)' capable of determining the appropriate surgical strategy, measured by preoperative computed tomography scan. RESULTS: We excised the mass using VATS in 79 patients, while 53 patients underwent open procedures, including thoracotomy (n = 10) and median sternotomy (n = 43). The operative times, the hospital stay duration, and the chest tube indwelling time were significantly shorter in the VATS group compared to in the open group (Table 1). Four cases were converted to thoracotomy. The mean mass sizes were 6.53 ± 2.20 cm and 8.58 ± 3.45 cm in the VATS and open groups, respectively. The '∆V' of the VATS group was higher than that of the open group. There were three postoperative complications. Table 1 Comparison of the perioperative variables between the VATS group and open groups VATS (n = 79) Open (n = 53) p value Preoperative variables Age (years) 32.34  ±  13.44 29.30 ± 14.76 0.223 Female 63 28 0.001 BMI 22.07 ± 3.34 22.59 ± 3.91 0.409 ASA class 0.272 Class 1 39 21 Class 2 40 32 Mass size (cm) 6.53 ± 2.20 8.58 ± 3.45 <0.001 ∆V (cm(3)) 988.15 ± 1590.85 3093.22 ± 4947.33 0.001 Intraoperative variable Operative time (min) 129 ± 46 170 ± 45 <0.001 Postoperative variable Hospitalization (days) 6.00 ± 3.03 8.94 ± 3.99 <0.001 ICU stay (days) 0 0.42 ± 0.50 <0.001 CTD time (days) 2.00 ± 1.24 3.8 ± 3.63 <0.001 Median F/U duration (months) 47.16 ± 43.60 27.52 ± 34.00 The data are presented as mean ± standard deviation VATS video-assisted thoracic surgery, CTD chest tube indwelling CONCLUSION: VATS for mediastinal teratoma can be performed safely in selected patients with large or malignant masses. The proposed '∆V' appears to be a useful method for determining the appropriate surgical strategy in the large size teratoma cases.

Recurrence Risk-Scoring Model for Stage I Adenocarcinoma of the Lung.

PURPOSE: The aim of this retrospective, multicenter study was to develop a recurrence risk-scoring model in patients with curatively resected stage I lung adenocarcinoma (ADC). METHODS: Clinicopathologic and outcome data for a development cohort of 1,700 patients with pathologic stage I ADC from four institutions resected between January 2000 and December 2009 were evaluated. A phantom study was performed for correction of inter-institutional differences in positron emission tomography-standardized uptake value (PET-SUV). A nomogram for recurrence prediction was developed using Cox proportional hazards regression. This model was validated in a cohort of 460 patients in two other hospitals. The recurrence rate was 21.0 % for the development cohort and 22.1 % for the validation cohort. RESULTS: In multivariable analysis, three independent predictors for recurrence were identified: pathologic tumor size (hazard ratio [HR] 1.03, 95 % CI 1.017-1.048; p < 0.001), corrected PET-SUV (HR 1.08, 95 % CI 1.051-1.105; p < 0.001), and lymphovascular invasion (HR 1.65, 95 % CI 1.17-2.33; p = 0.004). The nomogram was made based on these factors and a calculated risk score was accorded to each patient. Kaplan-Meier analysis of the development cohort showed a 5-year recurrence-free survival (RFS) of 83 % (95 % CI 0.80-0.86) in low-risk patients and 59 % (95 % CI 0.54-0.66) in high-risk patients with the highest 30 percentile scores. The concordance index was 0.632 by external validation. CONCLUSIONS: This recurrence risk-scoring model can be used to predict the RFS for pathologic stage I ADC patients using the above three easily measurable factors. High-risk patients need close follow-up and can be candidates for adjuvant chemotherapy.

Value of flexible bronchoscopy for the preoperative assessment of NSCLC diagnosed using percutaneous core needle biopsy.

BACKGROUND: We aimed to investigate the value of routine flexible bronchoscopy (FB) for the preoperative assessment of early-stage non-small cell lung cancer (NSCLC) diagnosed using percutaneous core needle biopsy (PCNB). METHODS: We enrolled 688 NSCLC patients who were treated at our hospital between January 2003 and December 2012 and who met the following criteria: (1) early-stage lung cancer (stage I or II); (2) lung cancer had been diagnosed using PCNB; and (3) no evidence of endobronchial disease in the airways other than the primary cancer site on both chest computed tomography (CT) and positron emission tomography-CT (PET-CT). All NSCLC patients were from the same tertiary referral center, where FB is routinely performed preoperatively for this disease, and their medical records were reviewed retrospectively. RESULTS: Of the 688 patients included in the study, 451 (65.6%) were male and the median age was 65 years. Pathology analysis revealed that adenocarcinoma was the most frequently observed cell type (516/688, 75.0%). The distribution of preoperative clinical staging for the 688 patients was (1) IA (54.5%, 375/688); (2) IB (22.1%, 152/688); (3) IIA (18.2%, 125/688); and (4) IIB (5.2%, 36/688). The majority of these patients (95.2%, 655/688) underwent surgical resection. Unsuspected malignant endobronchial lesion on FB was found in only two cases (0.3%), and the surgical strategy had to be modified for both of these patients. CONCLUSION: Preoperative FB is not beneficial for screening the airways of almost any patient with early-stage NSCLC, provided that neither PET-CT nor CT reveal any evidence of endobronchial malignant involvement other than at the primary cancer site.

Structure-Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology.

Histone deacetylase 6 (HDAC6) is one of the key histone deacetylases (HDACs) that regulates various cellular functions including clearance of misfolded protein and immunological responses. Considerable evidence suggests that HDAC6 is closely related to amyloid and tau pathology, the two primary hallmarks of Alzheimer's disease (AD). It is still unclear whether HDAC6 expression changes with amyloid deposition in AD during disease progression or HDAC6 may be regulating amyloid phagocytosis or neuroinflammation or other neuropathological changes in AD. In this work, the pathological accumulation of HDAC6 in AD brains over age as well as the relationship of its regulatory activity - with amyloid pathogenesis and pathophysiological alterations is aimed to be enlightened using the newly developed HDAC6 inhibitor (HDAC6i) PB118 in microglia BV2 cell and 3D-AD human neural culture model. Results suggest that the structure-based rational design led to biologically compelling HDAC6i PB118 with multiple mechanisms that clear Aß deposits by upregulating phagocytosis, improve tubulin/microtubule network by enhancing acetyl α-tubulin levels, regulate different cytokines and chemokines responsible for inflammation, and significantly reduce phospho-tau (p-tau) levels associated with AD. These findings indicate that HDAC6 plays key roles in the pathophysiology of AD and potentially serves as a suitable pharmacological target through chemical biology-based drug discovery in AD.

Development of a New Positron Emission Tomography Imaging Radioligand Targeting RIPK1 in the Brain and Characterization in Alzheimer's Disease.

Targeting receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic stratagem for neurodegenerative disorders, particularly Alzheimer's disease (AD). A positron emission tomography (PET) probe enabling brain RIPK1 imaging can provide a powerful tool to unveil the neuropathology associated with RIPK1. Herein, the development of a new PET radioligand, [11C]CNY-10 is reported, which may enable brain RIPK1 imaging. [11C]CNY-10 is radiosynthesized with a high radiochemical yield (41.8%) and molar activity (305 GBq/µmol). [11C]CNY-10 is characterized by PET imaging in rodents and a non-human primate, demonstrating good brain penetration, binding specificity, and a suitable clearance kinetic profile. It is performed autoradiography of [11C]CNY-10 in human AD and healthy control postmortem brain tissues, which shows strong radiosignal in AD brains higher than healthy controls. Subsequently, it is conducted further characterization of RIPK1 in AD using [11C]CNY-10-based PET studies in combination with immunohistochemistry leveraging the 5xFAD mouse model. It is found that AD mice revealed RIPK1 brain signal significantly higher than WT control mice and that RIPK1 is closely related to amyloid plaques in the brain. The studies enable further translational studies of [11C]CNY-10 for AD and potentially other RIPK1-related human studies.

Esophageal Cancer Associated with Multiple Primary Cancers: Surgical Approaches and Long-term Survival.

BACKGROUND: The presence of multiple primary cancers (MPCs) in patients with esophageal cancer often presents physicians with a difficult therapeutic decision, because little is known about the appropriate treatment and long-term survival. The purpose of this study was to evaluate appropriate surgical approaches and long-term survival after surgery for esophageal cancer associated with MPCs. METHODS: Data from 622 patients who underwent surgery for primary esophageal cancer between 1989 and 2008 were reviewed retrospectively to identify the presence of MPCs. RESULTS: A total of 96 MPCs were identified in 90 (14.5 %) patients. The three leading MPCs were stomach cancer (n = 36, 37.5 %), head and neck cancer (n = 18, 18.8 %), and lung cancer (n = 18, 18.8 %). The rate of curative resections for both esophageal cancer and MPCs was 87.5 % (28/32) in patients with stomach cancer, 47.1 % (8/17) in head and neck cancer, and 52.9 % (9/17) in lung cancer (P = 0.006). The 5-year survival rates after surgery for esophageal cancer in patients associated with stomach, lung, and head and neck cancer were 52.7, 27.0, and 9.2 %, respectively (P = 0.011). CONCLUSIONS: A range of surgical approaches for esophageal cancer is available in patients associated with MPCs. However, curative resections for primary esophageal cancer associated with MPCs are feasible in highly selected patients. Therefore, a multidisciplinary team management approach is essential for customized treatment strategies in patients with esophageal cancer associated with MPCs.

Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance.

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation in AD could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, and clinical data and critically discuss the multicellular complexity of the AHN niche in relation to AD pathophysiology. We further present a roadmap toward a better understanding of the role of AHN in AD by probing the promises and caveats of the latest technological advancements in the field and addressing the conceptual and methodological challenges ahead.