The role of radiotherapy in patients with refractory Hodgkin's lymphoma after treatment with brentuximab vedotin and/or immune checkpoint inhibitors.

Background: Approximately 10%-30% of patients with Hodgkin's lymphoma (HL) experience relapse or refractory (R/R) disease after first-line standard therapy. Brentuximab vedotin (BV) and immune checkpoint inhibitors (ICIs) have important roles in the salvage treatment of R/R HL. However, subsequent treatment for HL refractory to BV and/or ICI treatment is challenging. Methods: We retrospectively analyzed patients in two institutions who had R/R HL, experienced BV or ICI treatment failure, and received radiotherapy (RT) thereafter. The overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were analyzed. Results: Overall, 19 patients were enrolled. First-line systemic therapy comprised doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD, 84.2%); AVD plus ICIs (10.5%); and bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP, 5.3%). After first-line therapy, 15 (78.9%) and four patients (21.1%) had refractory disease and relapsed, respectively. After R/R HL diagnosis, six (31.6%), two (10.5%), and 11 (57.9%) patients received BV and ICIs concurrently, BV monotherapy, and ICI monotherapy, respectively. All patients received intensity-modulated RT (n = 12, 63.2%) or volumetric modulated arc therapy (VMAT; n = 7, 36.8%). The ORR as well as the complete response (CR) rate was 100%; the median DOR to RT was 17.2 months (range, 7.9-46.7 months). Two patients showed progression outside the radiation field; one patient had extensive in-field, out-of-field, nodal, and extranodal relapse. With a median follow-up time of 16.2 months (range, 9.2-23.2 months), the 1-year PFS and OS were 84.4% and 100%, respectively. PFS was associated with extranodal involvement (P = 0.019) and gross tumor volume (P = 0.044). All patients tolerated RT well without adverse events of grade ≥ 3. Conclusion: RT is effective and safe for treating HL refractory to BV or ICIs and has the potential to be part of a comprehensive strategy for HL.

Effect of WeChat-Based Medication Guidance on Symptoms and Serological Parameters in Children with Mycoplasma Pneumoniae.

Objective: The aim of this study was to assess the effect of microsoft-based medication guidance on the level of symptoms and serological indicators in children receiving budesonide nebulisation combined with terbutaline for the treatment of Mycoplasma pneumoniae pneumoniae (MPP). Methods: A total of 109 children with MPP treated in The First Affiliated Hospital of Ningbo University of China between October 2022 and April 2023 were divided into the conventional group (n=54, with medication guidance by telephone follow-up) and the WeChat group (n=55, with medication guidance based on the WeChat platform) using a randomized number table. The time to resolution of symptoms, serological index levels, incidence of adverse drug events, medication adherence scores and satisfaction rate of family guidance were compared between the two groups. Results: The disappearance time of symptoms such as wheezing and cough in the WeChat group was shorter than that in the conventional group (P < .05). After treatment, the C-reactive protein (CRP), interleukin-6 (IL-6) and calcitoninogen (PCT) levels and the incidence of adverse drug events were lower in the WeChat group than in the conventional group (P < .05). After treatment, the levels of forceful spirometry (FVC), 1st-second expiratory volume (FEV1), peak expiratory flow rate (PEF), medication compliance score and family guidance satisfaction rate were higher in the WeChat group than in the conventional group (P < .05). Conclusion: WeChat-based medication guidance can optimize the therapeutic effect of MPP, improve children's medication compliance and satisfaction rate of family guidance, and reduce the occurrence of adverse drug events.

Myelodysplasia-related gene mutations are associated with favorable prognosis in patients with TP53-mutant acute myeloid leukemia.

This study aimed to examine the characteristics and treatment outcomes of patients with TP53-mutant acute myeloid leukaemia (AML) and to explore potential prognostic factors. This retrospective analysis included 130 patients diagnosed with TP53-mutant AML at the Fujian Medical University Union Hospital between January 2016 and June 2023. Patients' ages ranged from 17 to 80 years, with a median age of 59 years. The proportions of de novo, therapy-related, and secondary AML cases were 71.5%, 7.7%, and 20.8%, respectively. Complex karyotypes were observed in 60.6% of patients, and the proportions of -5 or del(5q), -7 or del(7q), and - 17 or del(17p) were 41.7%, 27.9% and 14.4%, respectively. DNA methylation- and myelodysplasia-related (MR) gene mutations were observed in 36.9% and 25.4% of patients, respectively. These patients showed poor survival, with a median overall survival (OS) of 4.5 months, a 1-year OS rate of 32.5%, a 3-year OS rate of 18.8%, and a 5-year OS rate of 11.3%. The complete response rates for intensive chemotherapy (IC), hypomethylating agent (HMAs)-based therapies, and azacitidine plus venetoclax were 35.7%, 22.2%, and 37.5%, respectively. Patients who did or did not receive allogeneic haematopoietic stem cell transplantation (allo-HSCT) had similar prognoses (median OS: 6.0 vs. 3.9 months; P = 0.6415). Multivariate analysis indicated that MR gene mutations is an independent favorable prognostic factor of OS (HR = 0.366, 95% CI: 0.181-0.738, P = 0.005). In conclusion, patients with TP53-mutant AML have poor prognoses under current treatment strategies and MR gene mutations are associated with a more favorable survival. Therefore, further studies are needed to improve the survival rates in this population.

Hypofractionated radiotherapy for refractory or relapsed aggressive B-cell lymphoma in the rituximab era.

BACKGROUND: Radiotherapy (RT) is an effective and available local treatment for patients with refractory or relapsed (R/R) aggressive B-cell lymphomas. However, the value of hypofractionated RT in this setting has not been confirmed. METHODS: We retrospectively analyzed patients with R/R aggressive B-cell lymphoma who received hypofractionated RT between January 2020 and August 2022 at a single institution. The objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and acute side effects were analyzed. RESULTS: A total of 30 patients were included. The median dose for residual disease was 36 Gy, at a dose per fraction of 2.3-5 Gy. After RT, the ORR and complete response (CR) rates were 90% and 80%, respectively. With a median follow-up of 10 months (range, 2-27 months), 10 patients (33.3%) experienced disease progression and three died. The 1-year OS and PFS rates for all patients were 81.8% and 66.3%, respectively. The majority (8/10) of post-RT progressions involved out-of-field relapses. Patients with relapsed diseases, no response to systemic therapy, multiple lesions at the time of RT, and no response to RT were associated with out-of-field relapses. PFS was associated with response to RT (P = 0.001) and numbers of residual sites (P < 0.001). No serious non-hematological adverse effects (≥ grade 3) associated with RT were reported. CONCLUSION: These data suggest that hypofractionated RT was effective and tolerable for patients with R/R aggressive B-cell lymphoma, especially for those that exhibited localized residual disease.

Pulmonary infection associated with immune dysfunction is associated with poor prognosis in patients with myelodysplastic syndrome accompanied by TP53 abnormalities.

The aim of this study was to examine the characteristics and prognosis of patients with myelodysplastic syndrome (MDS) accompanied by TP53 abnormalities and explore potential prognostic factors and treatment responses. This retrospective analysis included 95 patients with MDS and TP53 abnormalities and 173 patients with MDS without TP53 abnormalities at the Fujian Medical University Union Hospital between January 2016 and June 2023. Among patients with TP53 abnormalities, 26 (27.4%) developed AML during the disease course, with a median transformation time of 5.7 months. Complex karyotypes were observed in 73.1% of patients, and the proportions of -5 or del(5q), -7 or del(7q), +8, and -20 or del(20q) were 81.8%, 54.5%, 30.7%, and 25.0%, respectively. These patients exhibited poor survival, with a median overall survival (OS) of 7.3 months, and had 1- and 2-year OS rates of 42.2% and 21.5%, respectively. The complete response rates for azacitidine monotherapy, venetoclax combined with azacitidine, decitabine monotherapy, and decitabine combined with low-dose chemotherapy were 9.1%, 41.7%, 37.5%, and 33.3%, respectively. Long-term survival was similar among the four treatment groups. Patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) had a median OS of 21.3 months, which trended to be longer than that of patients who did not undergo allo-HSCT (5.6 months; P = 0.1449). Patients with pulmonary infection at diagnosis experienced worse OS than those without pulmonary infection (2.3 months vs. 15.4 months; P < 0.0001). Moreover, 61.9% of patients with pulmonary infection had immune dysfunction, with a ratio of CD4+ to CD8+ T lymphocytes below two. Pulmonary infections and complex karyotypes were independent adverse prognostic factors for OS. In conclusion, TP53 abnormalities in patients with MDS were frequently accompanied by complex karyotypes, and treatments based on hypomethylating agents or venetoclax have limited efficacy. Pulmonary infections associated with immune dysfunction is associated with poor prognosis.

Dynamic Prediction of Survival for Sinonasal Extranodal Natural Killer/T-cell Lymphoma.

BACKGROUND: Extranodal natural killer/ T-cell lymphoma (ENKTL) is a rare malignant tumor. This study aimed to develop a predictive nomogram and a web-based survival rate calculator for dynamically predicting the survival of patients with sinonasal ENKTL (SN-ENKTL). METHODS: This study investigated patients (n = 134) with SN-ENKTL who had been initially treated in our hospital between Jan 2008 and Dec 2016. The patients were randomly divided into training and validation cohorts, in a 7:3 ratio. Independent prognostic factors were identified and integrated to build a predictive nomogram and a web-based calculator using the Cox-regression model. The nomogram was evaluated by consistency index and calibration curve. RESULTS: Age, lactate dehydrogenase, hemoglobin, Epstein-Barr virus DNA, and Ann Arbor stage were identified as independent risk factors. We constructed a predictive nomogram for survival and a web-based calculator (https://taiqinwang.shinyapps.io/DynNomapp/). CONCLUSION: This study developed a prognostic model and a web-based calculator specifically focused on SN-ENKTL for otolaryngologists to use to facilitate timely treatment decisions for the disease. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:1645-1651, 2023.

Plasmonic Enhanced Nanocrystal Infrared Photodetectors.

Low-dimensional nanomaterials are widely investigated in infrared photodetectors (PDs) due to their excellent optical and electrical properties. To further improve the PDs property like quantum efficiency, metallic microstructures are commonly used, which could squeeze light into sub-diffraction volumes for enhanced absorption through surface plasma exciton resonance effects. In recent years, plasmonic enhanced nanocrystal infrared PDs have shown excellent performance and attracted much research interest. In this paper, we summarize the progress in plasmonic enhanced nanocrystal infrared PDs based on different metallic structures. We also discuss challenges and prospects in this field.

Micro Spectrometers Based on Materials Nanoarchitectonics.

Spectral analysis is an important tool that is widely used in scientific research and industry. Although the performance of benchtop spectrometers is very high, miniaturization and portability are more important indicators in some applications, such as on-site detection and real-time monitoring. Since the 1990s, micro spectrometers have emerged and developed. Meanwhile, with the development of nanotechnology, nanomaterials have been applied in the design of various micro spectrometers in recent years, further reducing the size of the spectrometers. In this paper, we review the research progress of micro spectrometers based on nanomaterials. We also discuss the main limitations and perspectives on micro spectrometers.

Home Care System for Mobility Disabilities Based on Intelligent Perception.

In order to explore how to realize home care for the elderly with mobility difficulties, this paper proposes a home care system for the elderly with mobility difficulties based on intelligent perception. This method explores the research of home care for mobility disabilities by recommending key technical problems and solutions based on information represented by intelligent perception. The research shows that the home care system based on intelligent perception can effectively solve the nursing problems of the elderly, which is about 60% more efficient than the traditional methods. The combination of intelligent perception and reasonable home care mode will improve the social and economic benefits of health services and promote the balance between supply and demand of the whole health services.

Building Flexible Escherichia coli Modules for Bifunctionalizing n-Octanol: The Byproduct of Oleic Acid Biorefinery.

Artificial biorefinery of oleic acid into 1,10-decanedioic acid represents a revolutionizing route to the sustainable production of chemically difficult-to-make bifunctional chemicals. However, the carbon atom economy is extremely low (56%) due to the formation of unifunctional n-octanol. Here, we report a panel of recombinant Escherichia coli modules for diverse bifunctionalization, where the desired genetic parts are well distributed into different modules that can be flexibly combined in a plug-and-play manner. The designed ω-functionalizing modules could achieve ω-hydroxylation, consecutive ω-oxidation, or ω-amination of n-octanoic acid. By integrating these advanced modules with the reported oleic acid-cleaving modules, high-value C8 and C10 products, including ω-hydroxy acid, ω-amino acid, and α,ω-dicarboxylic acid, were produced with 100% carbon atom economy. These ω-functionalizing modules enabled the complete use of all of the carbon atoms from oleic acid (released from plant oil) for the green synthesis of structurally diverse bifunctional chemicals.

SIRT1 deficiency increases O-GlcNAcylation of tau, mediating synaptic tauopathy.

Hyperphosphorylation of the microtubule associated protein tau is associated with several neurodegenerative diseases including Alzheimer's Disease (AD), collectively referred to as tauopathies. However, the mechanisms by which tau is linked to synaptic dysfunction and memory impairment remain unclear. To address this question, we constructed a mouse model with brain-specific deficiency of SIRT1 (SIRT1 flox/Cre + ). Here, we show that increase of site-specific phosphorylation of tau is coupled with the strengthened O-GlcNAcylation of tau triggered by reduced O-GlcNAcase (OGA) and increased O-GlcNAc transferase (OGT) protein level in the brain of SIRT1 flox/Cre+ mice. SIRT1 deletion in mice brain changes the synaptosomal distribution of site-specific phospho-tau. Learning and memory deficiency induced by dendritic spine deficits and synaptic dysfunction are revealed via SIRT1 flox/Cre+ mice. Our results provide evidence for SIRT1 as a potential therapeutic target in clinical tauopathies.

Tau Acts in Concert With Kinase/Phosphatase Underlying Synaptic Dysfunction.

Alzheimer's disease (AD) is characterized by two pathological features: neurofibrillary tangles (NFTs), formed by microtubule-associated protein tau, and abnormal accumulation of amyloid-ß (Aß). Multiple evidence placed synaptic tau as the vital fact of AD pathology, especially at the very early stage of AD. In the present review, we discuss tau phosphorylation, which is critical for the dendritic localization of tau and synaptic plasticity. We review the related kinases and phosphatases implicated in the synaptic function of tau. We also review the synergistic effects of these kinases and phosphatases on tau-associated synaptic deficits. We aim to open a new perspective on the treatment of AD.

SEPT6_TRIM33 Gene Fusion and Mutated TP53 Pathway Associate With Unfavorable Prognosis in Patients With B-Cell Lymphomas.

BACKGROUND: Mounting studies have sought to identify novel mutation biomarkers having diagnostic and prognostic potentials. Nevertheless, the understanding of the mutated pathways related to development and prognosis of B-cell lymphoma is still lacking. We aimed to comprehensively analyze the mutation alterations in genes of canonical signaling pathways and their impacts on the clinic outcomes of patients with B-cell lymphoma. METHODS: Circulating cell-free DNA (cfDNA) samples from 79 patients with B-cell lymphomas were used for targeted sequencing with a 560-gene panel for depicting mutation landscapes and identifying gene fusion events. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses of mutated genes were performed. The associations of mutation status of genes and seven canonical oncogenic pathways with progression-free survival (PFS) were assessed using Kaplan-Meier test and multivariate Cox analysis. The variant allele frequencies (VAFs) of genes in TP53 and Hippo pathways in paired baseline and post-treatment samples from 18 B-cell lymphoma patients were compared. Finally, the associations of identified fusion genes, mutated genes, and pathways with treatment response were evaluated based on objective response rates (ORRs) comparisons of groups. RESULTS: We identified 666 mutations from 262 genes in baseline cfDNAs from 79 B-cell lymphoma patients, and found some genes were preferentially mutated in our cohort such as GNAQ, GNAS, H3F3A, DNMT3A, HLA-A, and HLA-B. These frequently mutated genes were significantly associated with negative "regulation of gene expression, epigenetic" and virus infections such as cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus 1 infections. We detected five fusion genes in at least two patients with B-cell lymphoma, and among them, TCF7L2_WT1 gene fusion was most frequently detected in 30.4% of patients (24 of 79 cases). SEPT6_TRIM33 gene fusion, mutated TP53 and Hippo pathways were significantly associated with poor PFS, and SEPT6_TRIM33 fusion gene and mutated TP53 pathway were independent prognostic factors for B-cell lymphoma. A decreased VAF of TP53 p.Y88C and LATS2 p.F972L was detected in patients with complete response to treatments. Moreover, a significant difference in ORR was observed in patients with NPM1_NR4A3 and SEPT6_TRIM33 fusions. CONCLUSIONS: SEPT6_TRIM33 gene fusion and mutated TP53 and Hippo pathways may serve as prognostic makers for B-cell lymphoma patients.

Exosomal miR-122-5p is Related to the Degree of Myelosuppression Caused by Chemotherapy in Patients with Colorectal Cancer.

PURPOSE: As rapidly dividing cells are usually the target of anticancer chemotherapy, it is inevitable that rapidly dividing normal cells become damaged, with myelosuppressive effects being a serious side effect of this therapy. Many recent studies have found that exosomal microRNAs (miRNAs) are related to the occurrence of some diseases. PATIENTS AND METHODS: Small RNA sequencing was used to investigate differential exosomal miRNAs with the same expression trend between groups after chemotherapy: MildA (before chemotherapy in patients with mild myelosuppression) and MildB (after chemotherapy in patients with mild myelosuppression); SevereA (before chemotherapy in patients with severe myelosuppression) and SevereB (after chemotherapy in patients with severe myelosuppression). A Venn diagram was generated to screen exosomal miRNAs related to chemotherapy. Small RNA sequencing was also used to investigate differentially expressed exosomal miRNAs among these groups, and exosomal miRNAs related to myelosuppression after chemotherapy was explored using a Venn diagram. RT-qPCR was applied to further verify the sequencing results. We performed target gene prediction and functional analysis for candidate exosomal miRNAs. RESULTS: Compared with that in the MildA or SevereA group, an increase in exosomal miR-122-5p was found in the MildB or SevereB group, and the expression level was lower in the SevereB group than in the MildB group. However, we found no notable difference in its expression level between the MildA and SevereA groups. Similar results were not obtained for the remaining miRNAs. RT-qPCR confirmed the screening results. Further analyses indicated that exosomal miR-122-5p targets CDK4 to inhibit the cell cycle. CONCLUSION: The expression level of exosomal miR-122-5p in the serum of patients with colorectal cancer correlates with the severity of myelosuppression caused by chemotherapy, and miR-122-5p targets CDK4 to inhibit cell cycle progression.

SIRT1 Regulates Tau Expression and Tau Synaptic Pathology.

BACKGROUND: Amyloid plaques and neurofibrillary tangles are two pathological hallmarks of Alzheimer's disease (AD). However, synaptic deficits occur much earlier and correlate stronger with cognitive decline than amyloid plaques and neurofibrillary tangles. Mislocalization of tau is an early hallmark of neurodegeneration and precedes aggregations. Sirtuin type 1 (SIRT1) is a deacetylase which acts on proteins including transcriptional factors and associates closely with AD. OBJECTIVE: The present study investigated the association between SIRT1 and tau expression/tau localization in cells and in mice brains. METHODS: Western blot was performed to detected tau, SIRT1, C/EBPα, and GAPDH protein levels. Immunological fluorescence assay was used to assess tau localization in primary cortical neuronal cells. Golgi staining was performed to evaluated dendritic spine morphology in mice brains. RESULTS: In the present study, we found that SIRT1 negatively regulates expression of tau at the transcriptional level through transcriptional factor C/EBPα. Inhibition of the activity of SIRT1 limits the distribution of tau to the neurites. In the meantime, the alteration of dendritic spine morphology is also observed in the brains of SIRT1+/- mice. CONCLUSION: SIRT1 may be a potential drug target for early intervention in AD.

Bufalin suppresses tumour microenvironment-mediated angiogenesis by inhibiting the STAT3 signalling pathway.

BACKGROUND: Antiangiogenic therapy has increasingly become an important strategy for the treatment of colorectal cancer. Recent studies have shown that the tumour microenvironment (TME) promotes tumour angiogenesis. Bufalin is an active antitumour compound whose efficacy has been indicated by previous studies. However, there are very few studies on the antiangiogenic effects of bufalin. METHODS: Herein, human umbilical vein endothelial cell (HUVEC) tube formation, migration and adhesion tests were used to assess angiogenesis in vitro. Western blotting and quantitative PCR were used to detect relevant protein levels and mRNA expression levels. A subcutaneous xenograft tumour model and a hepatic metastasis model were established in mice to investigate the influence of bufalin on angiogenesis mediated by the TME in vivo. RESULTS: We found that angiogenesis mediated by cells in the TME was significantly inhibited in the presence of bufalin. The results demonstrated that the proangiogenic genes in HUVECs, such as VEGF, PDGFA, E-selectin and P-selectin, were downregulated by bufalin and that this downregulation was mediated by inhibition of the STAT3 pathway. Overexpression of STAT3 reversed the inhibitory effects of bufalin on angiogenesis. Furthermore, there was little reduction in angiogenesis when bufalin directly acted on the cells in the tumour microenvironment. CONCLUSION: Our findings demonstrate that bufalin suppresses tumour microenvironment-mediated angiogenesis by inhibiting the STAT3 signalling pathway in vascular endothelial cells, revealing that bufalin may be used as a new antiangiogenic adjuvant therapy medicine to treat colorectal cancer.

The Role of Amyloid-Beta and Tau in the Early Pathogenesis of Alzheimer's Disease.

The abnormal accumulation of amyloid-b (Ab) and neurofibrillary tangles (NFTs) containing phosphorylated tau proteins are the main histopathological feature of Alzheimer's disease (AD). Synaptic damage and loss are earlier events than amyloid plaques and NFTs in AD progress and best correlate with cognitive deficits in AD patients. Soluble oligomeric Aß initiates the progression of AD and tau mediates the subsequent synaptic impairments at an early stage of AD. In this review we discuss how Ab or/and tau causes synaptic dysfunction. Ab oligomers gather at synapses and give rise to synaptic death in a variety of ways such as regulating receptors and receptor tyrosine kinases, unbalancing calcium homeostasis, and activating caspases and calcineurin. A large amount of hyperphosphorylated tau exists in the synapse of the AD brain. Aß-triggered synaptic deficits are dependent on tau. Soluble, hyperphosphorylated tau is much more correlated to cognitive decline in AD patients. Tau-targeted therapies have received more attention because the treatments targeting Aß failed in AD. Here, we also review the therapy strategies used to intervene in the very early stages of AD. Soluble hyperphosphorylated tau forms a complex with cell surface receptors, scaffold proteins, or intracellular signaling molecules to damage synaptic function. Therefore, therapeutic strategies targeting synaptic tau at the early stage of AD may ameliorating pathology in AD. This review aims to provide an update on the role of oligomeric Ab and soluble hyperphosphorylated tau in the early pathogenesis of Alzheimer's disease and to develop a new treatment strategy based on this.

IgD multiple myeloma with central nervous system involvement: A case report and literature review.

Central nervous system (CNS) involvement is a rare manifestation of multiple myeloma (MM) and the optimal management strategies have yet to be determined. The aim of the present study was to describe the case of a 47-year-old male patient with immunoglobulin D-λ MM who presented with multiple extramedullary infiltrations at diagnosis. This patient achieved stringent complete response after 9 cycles of treatment with bortezomib, lenalidomide and dexamethasone, and then received lenalidomide as maintenance therapy. CNS involvement and extramedullary relapse developed 3 months after the last chemotherapy cycle. Despite receiving a second-line treatment protocol, the patient succumbed to the disease within 1 month after recurrence. The characteristics and treatment options for CNS MM are discussed in this case report.

Dendritic/Post-synaptic Tau and Early Pathology of Alzheimer's Disease.

Microtubule-associated protein tau forms insoluble neurofibrillary tangles (NFTs), which is one of the major histopathological hallmarks of Alzheimer's disease (AD). Many studies have demonstrated that tau causes early functional deficits prior to the formation of neurofibrillary aggregates. The redistribution of tau from axons to the somatodendritic compartment of neurons and dendritic spines causes synaptic impairment, and then leads to the loss of synaptic contacts that correlates better with cognitive deficits than amyloid-ß (Aß) aggregates do in AD patients. In this review, we discuss the underlying mechanisms by which tau is mislocalized to dendritic spines and contributes to synaptic dysfunction in AD. We also discuss the synergistic effects of tau and oligomeric forms of Aß on promoting synaptic dysfunction in AD.

PGE2-JNK signaling axis non-canonically promotes Gli activation by protecting Gli2 from ubiquitin-proteasomal degradation.

Both bench and bedside investigations have challenged the supportive role of Hedgehog (Hh) activity in the progression of colorectal cancers, thus raising a critical need to further deeply determine the contribution of Hh to the growth of colorectal cancer. Combining multiple complementary means, including in vitro and in vivo inflammatory colorectal cancer models, and pathological analysis of clinical colorectal cancer patients samples. We report that colorectal cancer cells hijack prostaglandin E2 (PGE2) to non-canonically promote Hh transcriptional factor Gli activity and Gli-dependent proliferation of colorectal cancer cells in a Smo-independent manner. Mechanistically, PGE2 activates c-Jun N-terminal kinase (JNK), which in turn enables Gli2 to evade ubiquitin-proteasomal degradation by phosphorylating Gli2 at Thr1546. This study not only presents evidence for understanding the contribution of Hh to colorectal cancers, but also provides a novel molecular portrait underlying how PGE2-activated JNK fine-tunes the evasion of Gli2 from ubiquitin-proteasomal degradation. Therefore, it proposes a rationale for the future evaluation of chemopreventive and selective therapeutic strategies for colorectal cancers by targeting PGE2-JNK-Gli signaling route.