Diagnosis and Prognostic Implications of Primary Intraosseous Carcinoma: A Case Report and Literature Review.

Primary Intraosseous Carcinoma (PIOC) is a rare and aggressive squamous cell carcinoma (SCC) derived from remnants of odontogenic epithelium with no initial connection to oral mucosa. Due to the rarity of the disease, etiology and epidemiology are not clearly defined. The most affected site is the posterior mandible, and clinical features include swelling of the jaw, jaw pain, and sensory disturbances. Given the similarities of PIOC to other odontogenic carcinomas, diagnosis is often difficult, resulting in delays in intervention. Treatment of PIOC of the mandible includes surgery alone, surgery with adjuvant radiotherapy or chemotherapy, and free flap reconstruction. PIOC prognosis is poor, with the lymph nodal status acting as an important indicator. We present a case of a 60-year-old female who presented with a left submandibular mass initially thought to be SCC of unknown primary origin. Further investigation led to a final diagnosis of PIOC of the mandible. Clinical, radiological, and histological features of PIOC will be discussed.

Transcriptomic analysis reveals Streptococcus agalactiae activation of oncogenic pathways in cervical adenocarcinoma.

Cervical adenocarcinoma (AC), a subtype of uterine cervical cancer (CC), poses a challenge due to its resistance to therapy and poor prognosis compared with squamous cervical carcinoma. Streptococcus agalactiae [group B Streptococcus (GBS)], a Gram-positive coccus, has been associated with cervical intraepithelial neoplasia in CC. However, the underlying mechanism interaction between GBS and CC, particularly AC, remains elusive. Leveraging The Cancer Genome Atlas public data and time-series transcriptomic data, the present study investigated the interaction between GBS and AC, revealing activation of two pivotal pathways: 'MAPK signaling pathway' and 'mTORC1 signaling'. Western blotting, reverse transcription-quantitative PCR and cell viability assays were performed to validate the activation of these pathways and their role in promoting cancer cell proliferation. Subsequently, the present study evaluated the efficacy of two anticancer drugs targeting these pathways (binimetinib and ridaforolimus) in AC cell treatment. Binimetinib demonstrated a cytostatic effect, while ridaforolimus had a modest impact on HeLa cells after 48 h of treatment, as observed in both cell viability and cytotoxicity assays. The combination of binimetinib and ridaforolimus resulted in a significantly greater cytotoxic effect compared to binimetinib or ridaforolimus monotherapy, although the synergy score indicated an additive effect. In general, the MAPK and mTORC1 signaling pathways were identified as the main pathways associated with GBS and AC cells. The combination of binimetinib and ridaforolimus could be a potential AC treatment.

Lesson from COVID-19 outbreak; importance of standard precautions to febrile neutropenia prevention in patients with breast cancer who received adjuvant chemotherapy: a retrospective observational study.

Purpose: Intensive cytotoxic chemotherapy increases the risk of infection in patients with cancer by inducing bone marrow suppression and mucosal injury. Febrile neutropenia (FN) is the most important clinical adverse event in patients with cancer receiving cytotoxic chemotherapy. To prevent FN, standard precautions including hand and respiratory hygiene are generally recommended, but the exact effect of non-pharmacologic intervention has not been clearly proven in the clinical setting. We aimed to compare the incidence of FN between the pre-coronavirus disease 19 (COVID-19) era vs. the post-COVID-19 era. Methods: We retrospectively enrolled patients with breast cancer who received an adriamycin and cyclophosphamide (AC) regimen containing adjuvant chemotherapy at Jeju National University Hospital. We compared the incidence of FN between the pre- and post-COVID-19 period and analyzed characteristics of the event and other clinical risk factors. Results: In total, 149 patients were enrolled, including 94 who received AC chemotherapy in the pre-COVID-19 era and 55 who received it in the post-COVID-19 era. Sixteen patients (10.7%) experienced FN. Fourteen (14.9%) and 2 events (3.6%) occurred in pre-COVID-19 and post-COVID-19 eras, respectively. The post-COVID-19 era was the only risk factor for FN (P = 0.032). Conclusion: We found an association between FN occurrence and the COVID-19 outbreak, providing indirect evidence of the importance of non-pharmacological measures to reduce FN risk in patients with breast cancer. Further research is required to confirm the standard precautions for FN prevention in patients with cancer.

Cardio-Oncology and Heart Failure: A Scientific Statement from the Heart Failure Society of America.

Heart failure and cancer remain two of the leading causes of morbidity and mortality and the two disease entities are linked in a complex manner. Patients with cancer are at increased risk of cardiovascular complications related to the cancer therapies. The presence of cardiomyopathy or heart failure in a patient with new cancer diagnosis portends a high risk for adverse oncology and cardiovascular outcomes. With the rapid growth of cancer therapies, many of which interfere with cardiovascular homeostasis, heart failure practitioners need to be familiar with prevention, risk stratification, diagnosis, and management strategies in cardio-oncology. This Heart Failure Society of America statement addresses the complexities of heart failure care among patients with active cancer diagnosis and cancer survivors. Risk stratification, monitoring, and management of cardiotoxicity are presented across Stages A through D heart failure, with focused discussion on heart failure preserved ejection fraction and special populations such as survivors of childhood and young adulthood cancers. We provide an overview of the shared risk factors between cancer and heart failure, highlighting heart failure as a form of cardiotoxicity associated with many different cancer therapeutics. Finally, we discuss disparities in the care of patients with cancer and cardiac disease and present a framework for a multidisciplinary team approach and critical collaboration between heart failure, oncology, palliative care, pharmacy, and nursing teams in the management of these complex patients.

Improving Identification of At-Risk Behaviors in Adolescents with Rheumatic Disease.

BACKGROUND/OBJECTIVE: Many adolescent patients view their rheumatologist as their primary physician and therefore it is important to screen youth for sexual activity and substance use as recommended by the American Academy of Pediatrics. We implemented an electronic social history questionnaire (SHQ) and alert system to identify at-risk behaviors in adolescents with rheumatic disease. METHODS: The SHQ was administered to adolescents 14 years and older with a goal to survey patients' sexual activity, and alcohol, tobacco, and drug use. The SHQ was given via tablet at each rheumatology outpatient visit. A positive response triggered a best practice advisory (BPA) alert when the chart was opened to remind the clinician to discuss these results privately. RESULTS: A total of 877 unique patients were surveyed. Ninety patients (12%) reported being sexually active, and sexually active patients were significantly older than those who were not (17.2 vs 15 years, p<0.001). Seventy-two percent of patients were female, and the mean age was 15.8 years. Sexually active patients were more likely to be smokers, drink alcohol, and use other drugs (p<0.001). Strong associations were observed between alcohol use and male sex (p = 0.0227), White race (p = 0.0052), and public insurance (p = 0.0021). CONCLUSION: Overall, 12% of patients reported being sexually active, underscoring the need to screen adolescents for sexual activity given many rheumatology patients take teratogenic medication. A smaller proportion used substances. Implementing an EMR-based SHQ can help identify patients most at-risk, and the BPA served as a useful tool to remind clinicians to discuss the SHQ privately.

Adoption, acceptance, and use of a decision support tool to promote timely investigations for cancer in primary care.

BACKGROUND: The complexities of diagnosing cancer in general practice has driven the development of quality improvement (QI) interventions, including clinical decision support (CDS) and auditing tools. Future Health Today (FHT) is a novel QI tool, consisting of CDS at the point-of-care, practice population-level auditing, recall, and the monitoring of QI activities. OBJECTIVES: Explore the acceptability and usability of the FHT cancer module, which flags patients with abnormal test results that may be indicative of undiagnosed cancer. METHODS: Interviews were conducted with general practitioners (GPs) and general practice nurses (GPNs), from practices participating in a randomized trial evaluating the appropriate follow-up of patients. Clinical Performance Feedback Intervention Theory (CP-FIT) was used to analyse and interpret the data. RESULTS: The majority of practices reported not using the auditing and QI components of the tool, only the CDS which was delivered at the point-of-care. The tool was used primarily by GPs; GPNs did not perceive the clinical recommendations to be within their role. For the CDS, facilitators for use included a good workflow fit, ease of use, low time cost, importance, and perceived knowledge gain. Barriers for use of the CDS included accuracy, competing priorities, and the patient population. CONCLUSIONS: The CDS aligned with the clinical workflow of GPs, was considered non-disruptive to the consultation and easy to implement into usual care. By applying the CP-FIT theory, we were able to demonstrate the key drivers for GPs using the tool, and what limited the use by GPNs.

Expression Profiling of Coding and Noncoding RNAs in the Endometrium of Patients with Endometriosis.

The aim of this study was to identify differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) in the endometrium of individuals with and without endometriosis (EMS) during the proliferative (P) and secretory (S) phases of the menstrual cycle. Tissues were obtained from 18 control (CT; P-phase [pCT], n = 8; S-phase [sCT], n = 13) and 23 EMS patients (P-phase [pEMS], n = 13; S-phase [sEMS], n = 12). DElncRNAs and DEmRNAs were analyzed using total RNA-sequencing. In P-phase, expression of NONHSAG019742.2 and NONHSAT120701.2 was significantly higher in EMS than control patients, that of while NONHSAG048398.2 and NONHSAG016560.2 was lower in EMS patients. In S-phase, expression of NONHSAT000959.2, NONHSAT203423.1, and NONHSAG053769.2 was significantly increased in EMS patients, while that of NONHSAG012105.2 and NONHSAG020839.2 was lower. In addition, the expression of HSD11B2, THBS1, GPX3, and SHISA6 was similar to that of neighboring lncRNAs in both P- and S-phases. In contrast, ELP3 and NR4A1, respectively, were up- or downregulated in pEMS tissues. In sEMS, expression of LAMB3 and HIF1A was increased, while expression of PAM was reduced. Our findings on lncRNAs and mRNAs encourage not only exploration of the potential clinical applications of lncRNAs and mRNAs as prognostic or diagnostic biomarkers for EMS but also to gain valuable insights into its pathogenesis.

Inhibitory Effects of Reynoutria japonica Houtt. on Pain and Cartilage Breakdown in Osteoarthritis Based on Its Multifaceted Anti-Inflammatory Activity: An In Vivo and In Vitro Approach.

In the past 30 years, the number of years lived with disability due to osteoarthritis (OA) has doubled, making it an increasing global health burden. To address this issue, interventions that inhibit the progressive pathology driven by age-related low-grade inflammation, the primary mechanism of OA, are being actively pursued. Recent investigations have focused on modulating the age-related low-grade inflammatory pathology of this disease as a therapeutic target. However, no agent has successfully halted the disease's progression or reversed its irreversible course. Reynoutria japonica Houtt. (RJ), a promising East Asian herbal medicine, has been utilized for several diseases due to its potent anti-inflammatory activity. This study aims to determine RJ's capacity to inhibit OA symptoms and associated inflammation, exploring its potential for further development. In vivo and in vitro experiments demonstrated RJ's anti-OA activity and modulation of multifaceted inflammatory targets. RJ significantly inhibited pain, gait deterioration, and cartilage destruction in a monosodium iodoacetate-induced OA rat model, with its analgesic effect further confirmed in an acetic acid-induced writhing model. RJ exhibited consistent anti-inflammatory activity against multiple targets in serum and cartilage of the OA rat model and lipopolysaccharide-induced RAW 264.7 cells. The inhibition of inflammatory cytokines, including interleukin-1ß, interleukin-6, matrix metalloproteinase-13, tumor necrosis factor-α, and nitric oxide synthase 2, suggests that RJ's alleviation of OA manifestations relates to its multifaceted anti-inflammatory activity. These results indicate that RJ merits further investigation as a disease-modifying drug candidate targeting OA's inflammatory pathology. To further characterize the pharmacological properties of RJ, future studies with expanded designs are warranted.

Piperonylic Acid Promotes Hair Growth by Activation of EGFR and Wnt/ß-Catenin Pathway.

Dermal papilla cells (DPCs) are located at the bottom of the hair follicle and play a critical role in hair growth, shape, and cycle. Epidermal growth factor receptor (EGFR) and Wnt/ß-catenin signaling pathways are essential in promoting keratinocyte activation as well as hair follicle formation in DPCs. Piperonylic acid is a small molecule that induces EGFR activation in keratinocytes. However, the effects of piperonylic acid on DPCs in regard to the stimulation of hair growth have not been studied. In the present study, piperonylic acid was shown to activate the Wnt/ß-catenin signaling pathway in addition to the EGFR signaling pathway in DPCs. Piperonylic acid suppressed DKK1 expression, which presumably promoted the accumulation of ß-catenin in the nucleus. In addition, piperonylic acid promoted cyclin D upregulation and cell growth and increased the expression of alkaline phosphatase (ALP), a DPC marker. In a clinical study, the group that applied a formulation containing piperonylic acid had a significantly higher number of hairs per unit area than the placebo group. These results identify piperonylic acid as a promising new candidate for hair loss treatment.

Absence of canonical mutations in pediatric essential thrombocytosis: a case series.

Essential thrombocytosis (ET) is a rare myeloproliferative disease in children, and there are few standard management guidelines. We herein report a case series of 10 pediatric patients with ET diagnosed at our institution over a period of 13 years. All patients fulfilled the World Health Organization diagnostic criteria for ET, and none harbored the canonical ET mutations JAK2 V617F, CALR, or MPL. Overall, 7 of the 10 patients received treatment for ET, and during follow-up, 3 of these 7 patients discontinued cytoreductive therapy. No patient experienced hemorrhagic or thrombotic complications. Our case series emphasizes that the genetic features of pediatric ET may differ significantly from those of adult ET, and that treatment cessation is a possibility for some patients.

National trends in type 2 diabetes mellitus stratified by central adiposity using waist-to-height ratio in South Korea, 2005-2022.

Studies investigating the association between type 2 diabetes mellitus and central adiposity are lacking. Therefore, this study aimed to investigate trends in type 2 diabetes mellitus stratified by central adiposity using waist-to-height ratio (WHtR). Trends in type 2 diabetes mellitus were examined by central adiposity, using WHtR, with data from the Korea National Health and Nutrition Examination Survey (2005-2022). Individuals aged 30 years and over who participated in the survey were selected. Type 2 diabetes mellitus was identified based on serum glucose or HbA1c levels, the use of diabetes medications, or a prior diagnosis by a physician. Weighted ß-coefficients or odd ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess changes in disease prevalence. A total of 79,368 participants were included in the database (female: 45,163 [56.9%]). from 2005 to 2022, the prevalence of type 2 diabetes mellitus increased from 3.3 to 5.8% in the healthy central adiposity group, from 11.2 to 17.1% in the increased central adiposity group, and from 18.0 to 26.7% in the high central adiposity group. Males, older population, lower education level, lower household income, and smoking are associated with a higher risk of type 2 diabetes. In the high central adiposity group, overweight and obese individuals had higher susceptibility than underweight or normal-weight individuals, with ORs of 5.85 (95% CI, 2.54-13.47) and 8.24 (3.79-17.94), respectively. The prevalence of type 2 diabetes mellitus has increased in all central adiposity groups in the past decade. This underscores the need for tailored interventions to address disparities and improve diabetes management in at-risk populations.

Preparing for responsive management versus preparing for renal dialysis in multimorbid older people with advanced chronic kidney disease (Prepare for Kidney Care): Study protocol for a randomised controlled trial.

BACKGROUND: Chronic kidney disease (CKD) prevalence is steadily increasing, in part due to increased multimorbidity in our aging global population. When progression to kidney failure cannot be avoided, people need unbiased information to inform decisions about whether to start dialysis, if or when indicated, or continue with holistic person-centred care without dialysis (conservative kidney management). Comparisons suggest that while there may be some survival benefit from dialysis over conservative kidney management, in people aged 80 years and over, or with multiple health problems or frailty, this may be at the expense of quality of life, hospitalisations, symptom burden and preferred place of death. Prepare for Kidney Care aims to compare preparation for a renal dialysis pathway with preparation for a conservative kidney management pathway, in relation to quantity and quality of life in multimorbid, frail, older people with advanced CKD. METHODS: This is a two-arm, superiority, parallel group, non-blinded, individual-level, multi-centre, pragmatic trial, set in United Kingdom National Health Service (NHS) kidney units. Patients with advanced CKD (estimated glomerular filtration rate < 15 mL/min/1.73 m2, not due to acute kidney injury) who are (a) 80 years of age and over regardless of frailty or multimorbidity, or (b) 65-79 years of age if they are frail or multimorbid, are randomised 1:1 to 'prepare for responsive management', a protocolised form of conservative kidney management, or 'prepare for renal dialysis'. An integrated QuinteT Recruitment Intervention is included. The primary outcome is mean total number of quality-adjusted life years during an average follow-up of 3 years. The primary analysis is a modified intention-to-treat including all participants contributing at least one quality of life measurement. Secondary outcomes include survival, patient-reported outcomes, physical functioning, relative/carer reported outcomes and qualitative assessments of treatment arm acceptability. Cost-effectiveness is estimated from (i) NHS and personal social services and (ii) societal perspectives. DISCUSSION: This randomised study is designed to provide high-quality evidence for frail, multimorbid, older patients with advanced CKD choosing between preparing for dialysis or conservative kidney management, and healthcare professionals and policy makers planning the related services. TRIAL REGISTRATION: ISRCTN, ISRCTN17133653 ( https://doi.org/10.1186/ISRCTN17133653 ). Registered 31 May 2017.

KCNB1-Leptin receptor complexes couple electric and endocrine function in the melanocortin neurons of the hypothalamus.

The neurons of the melanocortin system regulate feeding and energy homeostasis through a combination of electrical and endocrine mechanisms. However, the molecular basis for this functional heterogeneity is poorly understood. Here, a voltage-gated potassium (Kv+) channel named KCNB1 (alias Kv2.1) forms stable complexes with the leptin receptor (LepR) in a subset of hypothalamic neurons including proopiomelanocortin (POMC) expressing neurons of the Arcuate nucleus (ARHPOMC). Mice lacking functional KCNB1 channels (NULL mice) have less adipose tissue and circulating leptin than WT animals and are insensitive to anorexic stimuli induced by leptin administration. NULL mice produce aberrant amounts of POMC at any developmental stage. Canonical LepR-STAT3 signaling-which underlies POMC production-is impaired, whereas non-canonical insulin receptor substrate PI3K/Akt/FOXO1 and ERK signaling are constitutively upregulated in NULL hypothalami. The levels of proto-oncogene c-Fos-that provides an indirect measure of neuronal activity-are higher in arcuate NULL neurons compared to WT and most importantly do not increase in the former upon leptin stimulation. Hence, a Kv channel provides a molecular link between neuronal excitability and endocrine function in hypothalamic neurons.

Activation of Gs signaling in mouse enteroendocrine K-cells greatly improves obesity- and diabetes-related metabolic deficits.

Following a meal, glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), the two major incretins promoting insulin release, are secreted from specialized enteroendocrine cells (L- and K-cells, respectively). Although GIP is the dominant incretin in humans, the detailed molecular mechanisms governing its release remain to be explored. GIP secretion is regulated by the activity of G protein-coupled receptors (GPCRs) expressed by K-cells. GPCRs couple to one or more specific classes of heterotrimeric G proteins. In the present study, we focused on the potential metabolic roles of K-cell Gs. First, we generated a mouse model that allowed us to selectively stimulate K-cell Gs signaling. Second, we generated a mouse strain harboring an inactivating mutation of Gnas, the gene encoding the alpha-subunit of Gs, selectively in K-cells. Metabolic phenotyping studies showed that acute or chronic stimulation of K-cell Gs signaling greatly improved impaired glucose homeostasis in obese mice and in a mouse model of type 2 diabetes, due to enhanced GIP secretion. In contrast, K-cell-specific Gnas knockout mice displayed markedly reduced plasma GIP levels. These data strongly suggest that strategies aimed at enhancing K-cell Gs signaling may prove useful for the treatment of diabetes and related metabolic diseases.

Ubiquitin regulatory X (UBX) domain-containing protein 6 is essential for autophagy induction and inflammation control in macrophages.

Ubiquitin regulatory X (UBX) domain-containing protein 6 (UBXN6) is an essential cofactor for the activity of the valosin-containing protein p97, an adenosine triphosphatase associated with diverse cellular activities. Nonetheless, its role in cells of the innate immune system remains largely unexplored. In this study, we report that UBXN6 is upregulated in humans with sepsis and may serve as a pivotal regulator of inflammatory responses via the activation of autophagy. Notably, the upregulation of UBXN6 in sepsis patients was negatively correlated with inflammatory gene profiles but positively correlated with the expression of Forkhead box O3, an autophagy-driving transcription factor. Compared with those of control mice, the macrophages of mice subjected to myeloid cell-specific UBXN6 depletion exhibited exacerbated inflammation, increased mitochondrial oxidative stress, and greater impairment of autophagy and endoplasmic reticulum-associated degradation pathways. UBXN6-deficient macrophages also exhibited immunometabolic remodeling, characterized by a shift to aerobic glycolysis and elevated levels of branched-chain amino acids. These metabolic shifts amplify mammalian target of rapamycin pathway signaling, in turn reducing the nuclear translocation of the transcription factor EB and impairing lysosomal biogenesis. Together, these data reveal that UBXN6 serves as an activator of autophagy and regulates inflammation to maintain immune system suppression during human sepsis.

Opportunistic offering of self-sampling to non-attenders within the English cervical screening programme: a pragmatic, multicentre, implementation feasibility trial with randomly allocated cluster intervention start dates (YouScreen).

Background: Self-sampling has game-changing potential to tackle the declining participation and inequities seen in many organised cervical screening programmes. Wide variation in uptake between settings and mode of kit offer highlight the importance of local piloting. Furthermore, harnessing the benefits of self-sampling in real-world settings has been surprisingly challenging. The YouScreen study estimated the impact of offering self-sampling to non-attenders within the English Programme and evaluated large-scale opportunistic offering of self-sampling in primary care. Methods: A pragmatic modified stepped-wedge implementation feasibility trial with randomly-allocated cluster intervention start dates at primary care practices in England (133 participating, 62 non-participating). Eligible women were aged 25-64 years and ≥6 months overdue for screening ("non-attenders"). Between January 13, 2021 and 30 November, 2021 self-sampling kits were distributed to non-attenders via an opportunistic offer in primary care when they consulted for any reason and direct mailout to those unscreened 15-months after routine invitation. Primary outcomes were the proportion of non-attenders screened each month; change in coverage; and uptake (90 days). YouScreen is registered with ISRCTN:12759467. Findings: 8338 women provided self-samples following recruitment between January 13, 2021 and 30 November, 2021. Self-samples were returned from 65.5% (6061/9248) who accepted an opportunistically offered kit and 12.9% (2777/17,604) directly-mailed kits. Responders were representative of the ethnically diverse and deprived underlying non-attendee population (64% ethnic minority groups, 60% from the two most deprived national quintiles). The self-sampling intervention resulted in a 22% (95% CI 18-26) increase in non-attenders screened per month (per-protocol analysis) and 12% (95% CI 9-15) (intention-to-treat analysis). Change in coverage at participating (mean intervention duration 7.5 months) vs non-participating practices was 1.6% (95% CI 0.4-2.8). Adverse effects were not formally collected. Interpretation: Opportunistically offering self-sampling to under-screened women in primary care could increase coverage in England and potentially reach underserved populations. Funding: North Central London and North East London Cancer Alliance.

Development of Polar BODIPY-Tetrazines for Rapid Pretargeted Fluorescence Imaging.

Polar BODIPY-tetrazine dyes were developed and clicked in vivo to a preaccumulated trans-cyclooctene-modified anti-TAG72 monoclonal antibody CC49 (CC49-TCO). The in vivo click performance was evaluated using an in-house developed ex vivo blocking assay. All tested polar BODIPY structures exhibited excellent in vivo binding, confirming that the turn-on tetrazine dyes successfully clicked in vivo to pretargeted CC49-TCO. Fluorescence imaging showed high tumor-to-muscle ratios of 4:1. This proof-of-concept study indicates that the pretargeting concept based on turn-on probes could be used for cancer treatments, such as photodynamic or -thermal therapy.

Erlotinib regulates short-term memory, tau/Aß pathology, and astrogliosis in mouse models of AD.

Introduction: Erlotinib is an epidermal growth factor receptor (EGFR) inhibitor that is approved by the FDA to treat non-small cell lung cancer (NSCLC). Several membrane receptors, including EGFR, interact with amyloid ß (Aß), raising the possibility that erlotinib could have therapeutic effects on Alzheimer's disease (AD). However, the effects of erlotinib on Aß/tau-related pathology and cognitive function in mouse models of AD and its mechanisms of action have not been examined in detail. Methods: To investigate the effects of erlotinib on cognitive function and AD pathology, 3 to 6-month-old PS19 mice and 3 to 3.5-month-old 5xFAD mice and WT mice were injected with vehicle (5% DMSO + 10% PEG + 20% Tween80 + 65% D.W.) or erlotinib (20 mg/kg, i.p.) daily for 14 or 21 days. Then, behavioral tests, Golgi staining, immunofluorescence staining, western blotting ELISA, and real-time PCR were conducted. Results and discussion: We found that erlotinib significantly enhanced short-term spatial memory and dendritic spine formation in 6-month-old P301S tau transgenic (PS19) mice. Importantly, erlotinib administration reduced tau phosphorylation at Ser202/Thr205 (AT8) and Thr231 (AT180) and further aggregation of tau into paired helical fragments (PHFs) and neurofibrillary tangles (NFTs) in 3-month-old and/or 6-month-old PS19 mice by suppressing the expression of the tau kinase DYRK1A. Moreover, erlotinib treatment decreased astrogliosis in 6-month-old PS19 mice and reduced proinflammatory responses in primary astrocytes (PACs) from PS19 mice. In 3- to 3.5-month-old 5xFAD mice, erlotinib treatment improved short-term spatial memory and hippocampal dendritic spine number and diminished Aß plaque deposition and tau hyperphosphorylation. Furthermore, erlotinib-treated 5xFAD mice exhibited significant downregulation of astrocyte activation, and treating PACs from 5xFAD mice with erlotinib markedly reduced cxcl10 (reactive astrocyte marker) and gbp2 (A1 astrocyte marker) mRNA levels and proinflammatory cytokine mRNA and protein levels. Taken together, our results suggest that erlotinib regulates tau/Aß-induced AD pathology, cognitive function, and Aß/tau-evoked astrogliosis and therefore could be a potent therapeutic drug for ameliorating AD symptoms.

Gut microbiota and their relationship with circulating adipokines in an acute hepatic encephalopathy mouse model induced by surgical bile duct ligation.

Background and aims: Various studies have shown the importance of the gut microbiota in human health. However, little is known about gut microbiome patterns and their effect on circulating adipo-myokine levels in hepatic encephalopathy (HE). We investigated the relationship between the gut microbiota and adipo-myokine levels using a mouse model of HE induced by surgical bile duct ligation (BDL). Methods and results: Wild-type C57BL/6J mice were subjected to sham surgery or BDL. Severe body weight loss, suppressed feed intake, and liver failure were observed in BDL mice compared with sham control mice. Additionally, changes in gut microbial communities and serum adipo-myokine levels were noted in BDL mice. In the BDL mouse gut, we identified 15 differentially abundant taxa including the phylum Verrucomicrobiota, the classes Actinomycetes and Verrucomicrobiae, the order Verrucomicrobiales, the families Akkermansiaceae, Bacteroidaceae, Rikenellaceae, and Oscillospiraceae, the genera Alistipes, Akkermansia, Muribaculum, and Phocaeicola, and the species Akkermansia muciniphila, Alistipes okayasuensis, and Muribaculum gordoncarteri by LEfSe analysis (LDA score≥4.0). Higher levels of certain adipo-myokines such as BDNF were detected in the serum of BDL mice. Spearman correlation analysis revealed that certain adipo-myokines (e.g., FSTL1) were positively correlated with the class Actinomycetes, the family Rikenellaceae, the genus Alistipes, and the species Alistipes okayasuensis. Interestingly, A. okayasuensis and M. gordoncarteri, recently isolated microbes, showed richness in the gut of BDL mice and demonstrated positive correlations with adipo-myokines such as FGF21. Conclusions: Overall, our results suggest that alteration of the gut microbiota in patients with HE may be closely correlated to the levels of adipo-myokines in the blood.