Associations of Serum Insulin and Related Measures With Neuropathology and Cognition in Older Persons With and Without Diabetes.

OBJECTIVE: To examine associations of serum insulin and related measures with neuropathology and cognition in older persons. METHODS: We studied 192 older persons (96 with diabetes and 96 without, matched by sex and balanced by age-at-death, education, and postmortem interval) from a community-based, clinical-pathologic study of aging, with annual evaluations including neuropsychological testing (summarized into global cognition and 5 cognitive domains) and postmortem autopsy. We assessed serum insulin, glucose, leptin, adiponectin, hemoglobin A1C, advanced glycation-end products (AGEs), and receptors for advanced glycation-end products, and calculated the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and adiponectin-to-leptin ratio. Using adjusted regression analyses, we examined the associations of serum measures with neuropathology of cerebrovascular disease and Alzheimer's disease, and with the level of cognition proximate-to-death. RESULTS: Higher HOMA-IR was associated with the presence of brain infarcts and specifically microinfarcts, and higher HOMA-IR and leptin were each associated with subcortical infarcts. Further, higher leptin levels and lower adiponectin-to-leptin ratios were associated with the presence of moderate-to-severe atherosclerosis. Serum insulin and related measures were not associated with the level of Alzheimer's disease pathology, as assessed by global, as well as amyloid burden or tau tangle density scores. Regarding cognitive outcomes, higher insulin and leptin levels, and lower adiponectin and receptors for advanced glycation-end products levels, respectively, were each associated with lower levels of global cognition. INTERPRETATION: Peripheral insulin resistance indicated by HOMA-IR and related serum measures was associated with a greater burden of cerebrovascular neuropathology and lower cognition. ANN NEUROL 2024;95:665-676.

Low expression of exosomal miR-150 predicts poor prognosis in colorectal cancer patients after surgical resections.

Liver metastasis is a leading indicator of poor prognosis in patients with colorectal cancer (CRC). Exosomal intercellular communication has been reported to play an important role in cancer invasion and metastasis. Here, we characterized exosomal miRNAs underlying liver metastasis in CRC patients (Cohort 1, n = 30) using miRNA arrays. Exosomal miR-150 was found to be downregulated in CRC patients with liver metastases compared to those without (P = 0.025, fold change [FC] = 2.01). These results were then validated using another independent cohort of CRC patients (Cohort 2, n = 64). Patients with low expression of exosomal miR-150 had significantly shorter overall survival (OS) time (33.3 months versus 43.3 months, P = 0.002). In addition, the low expression of exosomal miR-150 was significantly correlated with advanced tumor node metastasis staging (P = 0.013), higher CA199 level (P = 0.018), and the presence of liver metastasis (P = 0.048). Multivariate analysis showed that low expression of exosomal miR-150 (P = 0.035) and liver metastasis (P < 0.001) were independent prognostic factors for overall survival. In vivo and in vitro studies showed that the viability and invasion of CRC cells were both significantly suppressed by ExomiR-150. Target-prediction assessment and dual-luciferase reporter assay indicated that FTO (the fat mass and obesity-associated gene) was a direct target for miR-150. This study first demonstrated that exosomal miR-150 may be a potential prognostic factor and treatment target for CRC.

Spatial and Frequency Specific Artifact Reduction in Optically Pumped Magnetometer Recordings.

BACKGROUND: Magnetoencephalography (MEG) based on optically pumped magnetometers (OPMs) opens up new opportunities for brain research. However, OPM recordings are associated with artifacts. We describe a new artifact reduction method, frequency specific signal space classification (FSSSC), to improve the signal-to-noise ratio of OPM recordings. METHODS: FSSSC was based on time-frequency analysis and signal space classification (SSC). SSC was accomplished by computing the orthogonality of the brain signal and artifact. A dipole phantom was used to determine if the method could remove artifacts and improve accuracy of source localization. Auditory evoked magnetic fields (AEFs) from human subjects were used to assess the usefulness of artifact reduction in the study of brain function because bilateral AEFs have proven a good benchmark for testing new methods. OPM data from empty room recordings were used to estimate magnetic artifacts. The effectiveness of FSSSC was assessed in waveforms, spectrograms, and covariance domains. RESULTS: MEG recordings from phantom tests show that FSSSC can remove artifacts, normalize waveforms, and significantly improve source localization accuracy. MEG signals from human subjects show that FSSC can reveal auditory evoked magnetic responses overshadowed and distorted by artifacts. The present study demonstrates FSSSC is effective at removing artifacts in OPM recordings. This can facilitate the analyses of waveforms, spectrograms, and covariance. The accuracy of source localization of OPM recordings can be significantly improved by FSSSC. CONCLUSIONS: Brain responses distorted by artifacts can be restored. The results of the present study strongly support that artifact reduction is very important in order for OPMs to become a viable alternative to conventional MEG.

Delirium Among Hospitalized Older Adults With Acute Heart Failure Exacerbation.

BACKGROUND: Delirium among older adults hospitalized with acute heart failure is associated with increased mortality. However, studies concomitantly assessing the association of delirium with both clinical and economic outcomes in this population, such as mortality, hospital cost, or length of stay, are lacking. METHODS AND RESULTS: We conducted a retrospective observational study using National Inpatient Sample data from 2011 to 2014. Using multivariable logistic regression, we assessed the association of delirium with in-hospital mortality, then estimated the incremental hospital cost and excessive length of stay adjusting for demographic and clinical factors using multivariable generalized linear regression. The association of other medical complications on clinical and economic outcomes was also assessed. A total of 568,565 (weighted N = 2,826,131) hospitalizations of patients 65 years or older with acute heart failure from 2011 to 2014 were included in the final analysis. The reported prevalence of delirium was 4.53%. After multivariable adjustment, delirium was associated with a 2.35-fold increase in the odds of in-hospital mortality (95% confidence interval [CI] 2.23-2.47), which was lower than the odds ratio for sepsis/septicemia (5.36; 95% CI, 5.02-5.72) or respiratory failure (4.53; 95% CI, 4.38-4.69), but similar to that for acute kidney injury (2.39; 95% CI, 2.31-2.48) and higher than for non-ST elevation myocardial infarct (1.57; 95% CI, 1.46-1.68). Delirium increased the total hospital cost by $4,262 (95% CI, $4,002-4,521) and the length of stay by 1.73 days (95% CI, 1.68-1.78), which was slightly lower than, but similar to, acute kidney injury ($4,771; 95% CI, $4,644-4,897) and 1.82 days (95% CI, 1.79-1.84), and higher than non-ST elevation myocardial infarct ($1,907; 95% CI, $1,629-2,185) and 0.31 days (95% CI, 0.25-0.37). CONCLUSIONS: Delirium was associated with increased in-hospital mortality, total hospital cost, and length of stay, and the magnitude of the effect was similar to that for acute kidney injury. Enhanced efforts to prevent delirium are needed to decrease its adverse impact on clinical and economic outcomes for hospitalized older adults with acute heart failure.

Provider-Patient Discussions About Smoking and the Impact of Lung Cancer Screening Guidelines: NHIS 2011-2015.

BACKGROUND: Clinical practice guidelines for treating tobacco use and lung cancer screening guidelines recommend smoking cessation counseling to current smokers by health care professionals. OBJECTIVE: Our objective was to determine the contemporary patterns of current smokers' discussions about smoking with their health care professionals in the USA. DESIGN, SETTING, AND PARTICIPANTS: We conducted an observational study of 30,132 current smokers (weighted sample 40,126,006) for the years 2011 to 2015 using data from the National Health Interview Survey. MAIN MEASURES: Our main outcome was the proportion of current smokers who had discussions about smoking with their health care professionals. We used the Cochran-Armitage trend test to evaluate the temporal trends in current smokers' discussions about smoking, and used a multivariable logistic model to determine the predictors of discussions about smoking, controlling for smokers' demographics, health status, and receipts of lung cancer screening. KEY RESULTS: Our study found the proportion of current smokers who had discussions about smoking with their health care professionals increased from 51.3% in 2011 to 55.4% in 2015 (P-trend < 0.0001). However, about 15% of current smokers who underwent lung cancer screening did not have or could not recall discussions about smoking with their health care professionals. In multivariable analyses and sensitivity analysis, the predictors of discussions about smoking were being a heavy smoker, receipt of lung cancer screening, being non-Hispanic white, having a physician office visit in the past year, being diagnosed with respiratory conditions, having fair or poor health, and having insurance coverage. CONCLUSIONS: The results demonstrated a steady but slow increase in current smokers' discussions about smoking with their health care professionals in recent years, especially among heavy smokers. More than 40% of current smokers did not have or could not recall any discussions about smoking with their health care professionals.

The evaluation of comprehensive medication management for chronic diseases in primary care clinics, a Texas delivery system reform incentive payment program.

BACKGROUND: The Institute of Medicine reported that more than 1.5 million preventable adverse drug events occur annually in the United States. Comprehensive Medication Management (CMM) is the medication review process to improve clinical outcomes, enhance patient adherence, reduce drug therapy problems and reduce health care costs. University of Texas (UT) Physicians implemented a CMM program in several community-based clinics. We evaluated the effectiveness of CMM to reduce drug therapy problems and achieve medical cost savings. METHODS: This was a retrospective, observational study of CMM participants from October 2015 to September 2016. Program participants included patients aged 18 years or older who had taken more than 4 prescribed medications and were diagnosed with at least one of the following chronic diseases: hypertension, congestive heart failure, chronic obstructive pulmonary disease, asthma or diabetes. Under the CMM program, a clinical pharmacist reviewed patients' electronic health records and created action plans to resolve identified drug problems. As part of the evaluation of the clinical process, two independent physicians conducted peer review on the recommendations issued by the pharmacist in order to establish inter-rater reliability of drug therapy problems and potential consequent medical services. The drug therapy problems were identified and classified into four categories: indication, effectiveness, safety and/or compliance. The average cost of avoided medical services was obtained based on cost extrapolations from the literature, combined with hospital discharge data. Potential medical services avoided were linked to the average cost of those services to calculate the total cost savings of the program from the payers' perspective. RESULTS: By reviewing electronic health records of 3280 patients, the pharmacist identified 301 drug therapy problems and resolved 49.8% of these problems with collaboration from the patient's primary care physician or care team. The most commonly identified drug problems were related to potentially adverse drug reactions or inappropriate drug dosage. The CMM program resulted in potential cost savings of $1,143,015. CONCLUSIONS: The CMM program resolved medication therapy problems among program participants and achieved significant health care cost savings.

LncRNA UCA1/miR-124 axis modulates TGFß1-induced epithelial-mesenchymal transition and invasion of tongue cancer cells through JAG1/Notch signaling.

Tongue cancer remains a massive threat to public health due to the high rate of metastasis. Tumor cell epithelial-mesenchymal transition (EMT), which can be induced by transforming growth factor ß1 (TGFß1), has been regarded as a significant contributor to cancer invasion and migration. In our previous study, long noncoding RNA (lncRNA) MALAT1/miR-124/JAG1 axis modulates the growth of tongue cancer. In addition to metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), another lncRNA, urothelial cancer associated 1 (UCA1), can promote EMT and cancer metastasis. In the present study, UCA1 was overexpressed in tongue cancer tissues and cell lines. UCA1 overexpression was correlated to the poorer prognosis of patients with tongue cancer. UCA1 knockdown significantly suppressed TGFß1-induced tongue cancer cell invasion and EMT by decreasing vimentin and increasing E-cadherin. Regarding the molecular mechanism, UCA1 could directly bind to microRNA-124 (miR-124) and negatively regulate each other. UCA1 knockdown ameliorated, whereas miR-124 inhibition exacerbated TGFß1-induced EMT and invasion in tongue cancer cells through miR-124 downstream jagged 1 (JAG1) and Notch signaling. Moreover, miR-124 inhibition partially impaired the effect of UCA1 knockdown. In tongue cancer tissues, miR-124 expression was remarkably decreased, whereas JAG1 mRNA expression was increased. miR-124 was negatively correlated with UCA1 and JAG1. UCA1 and JAG1 were positively correlated. In summary, we provided a novel mechanism by which the EMT process and cancer cell invasion in tongue cancer could be modulated from the perspective of lncRNA-miRNA-mRNA regulation.

Comparative Effectiveness of Computed Tomography- Versus Ultrasound-Guided Percutaneous Radiofrequency Ablation Among Medicare Patients 65 Years of Age or Older With Hepatocellular Carcinoma.

BACKGROUND: For patients with hepatocellular carcinoma (HCC) not eligible for surgical resection, radiofrequency ablation (RFA) is a promising technique that reduces the risk of disease progression. OBJECTIVES: To evaluate whether the trend of image guidance for RFA is moving toward the more expensive computed tomography (CT) technology and to determine the clinical benefits of CT guidance over the ultrasound (US) guidance. METHODS: A cohort of 463 patients was identified from the Surveillance, Epidemiology, and End Results and Medicare-linked database. The temporal trends in use of image guidance were assessed using the Cochrane-Armitage test. The associations between modality of image guidance and survival, complications, and costs were assessed using the Cox regression model, the logistic regression model, and the generalized linear model, respectively. RESULTS: The use of CT-guided RFA increased sharply, from 20.7% in 2002 to 75.9% in 2011. Compared with CT-guided RFA, those who received US-guided RFA had comparable risk of periprocedural and delayed postprocedural complications. Stratified analyses by tumor size also showed no statistically significant difference. In adjusted survival analysis, no statistically significant difference was observed in overall and cancer-specific survival. Nevertheless, the cost of CT-guided RFA ($2847) was higher than that of US-guided RFA ($1862). CONCLUSIONS: Despite its rapid adoption over time, CT-guided RFA incurred higher procedural costs than US-guided RFA but did not significantly improve postprocedural complications and survival. Echoing the American Board of Internal Medicine's Choosing Wisely campaign and the American Society of Clinical Oncology's Value of Cancer Care initiative, findings from our study call for critical evaluation of whether CT-guided RFA provides high-value care for patients with HCC.

Hierarchical Self-Assembly and Chiroptical Studies of Luminescent 4d-4f Cages.

Multinuclear lanthanide-containing supramolecular cages have received increasing attention recently because of their unique electroptical and magnetic properties. Here we report the hierarchical self-assembly and chiroptical studies of a group of 4d-4f heterometallic cages synthesized from a preformed dimetalloligand [(bpy)2Pd212]2+ (2) (bpy = 2,2-bipyridine) and a variety of trivalent lanthanide ions (Ln = NdIII, EuIII, YbIII). The programmable self-assembly process leading to the trigonal bipyramidal cages formulated as {Ln2[(bpy)2Pd212]3}12+ (3) has been confirmed by one- and two-dimensional NMR, electro-spray-ionization time-of-flight mass-spectroscopy, and in one typical case by single-crystal X-ray diffraction studies. Circular dichroism and circular polarized luminescence spectra confirmed the strict control of stereoselectivity on the heterometallic cages, dictated by the chiral amide groups on the ligands. Excitation (up to 420 nm) on the dipalladium chromophores on these cages leads to the characteristic lanthanide luminescence at both the visible and the near-infrared regions, depending on the lanthanide ions used. Through the assembly-disassembly process, luminescent turn-off sensing toward penicillin among several widely used antibiotics has also been demonstrated with the Europium cage, featuring a limit of detection as low as 0.88 ppb (S/N = 3). Our results pave the way for the construction of chiral 4d-4f supramolecular cages which may find potential applications in luminescent sensing and/or labeling reagents.

Budget Impact Analysis of Against Colorectal Cancer In Our Neighborhoods (ACCION): A Successful Community-Based Colorectal Cancer Screening Program for a Medically Underserved Minority Population.

OBJECTIVES: Given the uncertain cost of delivering community-based cancer screening programs, we developed a Markov simulation model to project the budget impact of implementing a comprehensive colorectal cancer (CRC) prevention program compared with the status quo. METHODS: The study modeled the impacts on the costs of clinical services, materials, and staff expenditures for recruitment, education, fecal immunochemical testing (FIT), colonoscopy, follow-up, navigation, and initial treatment. We used data from the Against Colorectal Cancer In Our Neighborhoods comprehensive CRC prevention program implemented in El Paso, Texas, since 2012. We projected the 3-year financial consequences of the presence and absence of the CRC prevention program for a hypothetical population cohort of 10,000 Hispanic medically underserved individuals. RESULTS: The intervention cohort experienced a 23.4% higher test completion rate for CRC prevention, 8 additional CRC diagnoses, and 84 adenomas. The incremental 3-year cost was $1.74 million compared with the status quo. The program cost per person was $261 compared with $86 for the status quo. The costs were sensitive to the proportion of high-risk participants and the frequency of colonoscopy screening and diagnostic procedures. CONCLUSIONS: The budget impact mainly derived from colonoscopy-related costs incurred for the high-risk group. The effectiveness of FIT to detect CRC was critically dependent on follow-up after positive FIT. Community cancer prevention programs need reliable estimates of the cost of CRC screening promotion and the added budget impact of screening with colonoscopy.

Preliminary investigation of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives as a novel series of mGlu5 receptor positive allosteric modulators with efficacy in preclinical models of schizophrenia.

As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives. From these efforts, compound 4k emerged as a potent and selective mGlu5 PAM displaying overall attractive in vitro (pharmacological and ADMET) and PK profiles combined with in vivo efficacy in preclinical models of schizophrenia. However, further advancement of the compound was precluded due to severely limiting CNS-related side-effects confirming the previously reported association between excessive mGlu5 activation and target-related toxicities.

Discovery and SAR of novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5).

We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.

Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency.

We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) from a 5,6-bicyclic class of dihydropyrazolo[1,5-a]pyridin-4(5H)-ones containing a phenoxymethyl linker. Studies focused on a survey of non-amide containing hydrogen bond accepting (HBA) pharmacophore replacements. A highly potent and selective PAM, 2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (11, VU0462054), bearing a simple ketone moiety, was identified (LE=0.52, LELP=3.2). In addition, hydroxyl, difluoro, ether, and amino variations were examined. Despite promising lead properties and exploration of alternative core heterocycles, linkers, and ketone replacements, oxidative metabolism and in vivo clearance remained problematic for the series.

Reduced Cortico-Cortical Resting-State Connectivity in Sensory Systems Related to Bodily Pain in Juvenile Fibromyalgia.

OBJECTIVE: Juvenile-onset fibromyalgia (JFM) is a paradigmatic chronic pain condition for which the underlying neurobiological substrates are poorly understood. This study examined, for the first time, data-driven resting-state functional connectivity (rsFC) alterations in 37 female adolescents with JFM compared with 43 healthy female adolescents and identified associations with bodily pain. METHODS: Whole-brain voxel-wise rsFC alterations were assessed using the intrinsic connectivity contrast, a measure of node centrality at each voxel, and seed-based analyses for interpretability. We studied the relationship between rsFC alterations in somatosensory systems and the location and extension of bodily pain. RESULTS: Adolescents with JFM had voxel-wise rsFC reductions in the paracentral lobule (PCL)/primary somatosensory cortex (S1) (T = 4.89, family-wise error corrected p-value (pFWE) < 0.001) and left midcingulate cortex (T = 4.67, pFWE = 0.043). Post hoc analyses revealed reduced rsFC spanning major cortical sensory hubs (T > 4.4, pFWE < 0.030). Cortico-cortical rsFC reductions within PCL/S1 in JFM occurred in locations innervated by bodily areas where the pain was most frequent (F = 3.15; positive false discovery rate = 0.029) and predicted widespread pain (T > 4.4, pFWE < 0.045). Conversely, adolescents with JFM had increases in PCL/S1-thalamus (T = 4.75, pFWE = 0.046) and PCL/S1-anterior insula rsFC (T = 5.13, pFWE = 0.039). CONCLUSION: Reduced cortico-cortical sensory integration involving PCL/S1 and spanning the sensory systems may underly critical pain sensory features in youth with JFM. Reduced sensory integration is paralleled by augmented cross-talk between sensory and affective/salience-processing regions, potentially indicating a shift toward more affectively colored sensory experiences to the detriment of specific sensory discrimination.

Neurophysiology of Resilience in Juvenile Fibromyalgia.

Objective: Juvenile fibromyalgia (JFM) is a chronic pain syndrome predominantly affecting adolescent girls. Resilience may be a protective factor in coping with pain, reducing affective burden, and promoting positive outlooks. Brain regions affected in JFM overlap with those linked to resilience, particularly in the default-mode network (DMN). We investigate the role of resilience on core somatic and affective symptoms in JFM and assess the neurophysiological substrates for the first time. Methods: Forty-one girls with JFM and 40 pain-free adolescents completed a resting-state fMRI assessment and self-report questionnaires. We used clustering analyses to group JFM participants based on resilience, and principal component analyses to summarize core somatic and affective symptoms. We estimated whole-brain and within-DMN connectivity and assessed differences between higher and lower resilience JFM groups and compared their connectivity patterns to pain-free participants. Results: The higher resilience JFM group had less affective (T=4.03; p<.001) but similar core somatic symptoms (T=1.05; p=.302) than the lower resilience JFM group. They had increased whole-brain (T's>3.90, pFDR's<.03) and within-DMN (T=2.20, p=.03) connectivity strength, and higher connectivity between DMN nodes and self-referential, regulatory, and reward-processing regions. Conversely, higher DMN-premotor connectivity was observed in the lower resilience group. Conclusion: JFM participants with higher resilience were protected affectively but not in core somatic symptoms. Greater resilience was accompanied by higher signal integration within the DMN, a network central to internally oriented attention and flexible attention shifting. Crucially, the connectivity pattern in highly resilient patients resembled that of pain-free adolescents, which was not the case for the lower resilience group.

Associations of renin-angiotensin system inhibitor use with brain insulin signaling and neuropathology.

OBJECTIVE: To examine the associations of renin-angiotensin system (RAS) inhibitor use with postmortem brain insulin signaling and neuropathology. METHODS: Among Religious Orders Study participants, 150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had measurements of insulin receptor substrate-1 (IRS-1) and RAC-alpha serine/threonine protein kinase (AKT1) collected in the prefrontal cortex using ELISA and immunohistochemistry. Alzheimer's disease (AD), brain infarcts, and cerebral vessel pathology data were assessed by systematic neuropathologic evaluations. RAS inhibitor use was determined based on visual inspection of medication containers during study visits. The associations of RAS inhibitor use with brain insulin signaling measures and neuropathology were examined using adjusted regression analyses. RESULTS: Of the 90 RAS inhibitor users (54 with diabetes), 65 had used only angiotensin-converting enzyme inhibitors, 11 only angiotensin II receptor blockers, and 14 used both. RAS inhibitor use was associated with lower pT308AKT1/total AKT1, but not with pS307IRS-1/total IRS-1 or the density of cells stained positive for pS616 IRS-1. RAS inhibitor use was not associated with the level of global AD pathology or amyloid beta burden, but it was associated with a lower tau-neurofibrillary tangle density. Additionally, we found a significant interaction between diabetes and RAS inhibitors on tangle density. Furthermore, AKT1 phosphorylation partially mediated the association of RAS inhibitor use with tau tangle density. Lastly, RAS inhibitor use was associated with more atherosclerosis, but not with other cerebral blood vessel pathologies or cerebral infarcts. INTERPRETATION: Late-life RAS inhibitor use may be associated with lower brain AKT1 phosphorylation and fewer neurofibrillary tangles.

Suppression of tongue squamous cell carcinoma growth by inhibition of Jagged1 in vitro and in vivo.

BACKGROUND: The changes in Notch signaling are closely related to the occurrence and development of many cancers. We have investigated Notch signaling receptor and its ligand expressions in TSCC cell lines, tissues and its significance. We clarified Notch signaling pathway in TSCC and its mechanism. We regulated Notch signaling pathway of tumor cells, thereby inhibiting tumor cell proliferation and differentiation. METHODS: We detected Jagged1 protein and mRNA expression levels in specimens (tongue cancer and adjacent tissues) from 74 patients with tongue cancer and in TSCC cell line. The Jagged1-targeted lentiviral vector RNAi system was constructed, and its suppressive effects on the proliferation and invasion of tongue carcinoma cells in in vivo and ex vivo were determined. RESULTS: Jagged1 was expressed in tongue squamous cell cancer tissues and cell line, but there were differences in its expression. Jagged1 was knocked down and the tumor growth was inhibited accompanying cell cycle changes. Animal studies also showed that the tumor growth was inhibited. CONCLUSIONS: Jagged1 may be involved in the differentiation and proliferation of tongue cancer. Targeting Jagged1 RNA interference lentiviral vector can effectively lower Jagged1 mRNA and protein expression levels of Tca8113 cells, thereby preventing the proliferation of TSCC cells. Jagged1 is expected to be a promising new target for curing tongue cancer. In-depth study of the interaction between Jagged1 and other molecules of Notch signaling pathway in the process of carcinogenesis has important theoretical guidance and clinical significance in revealing the mechanism of Jagged1 and its application in the therapy for tongue cancer.

Disruption of mediator complex subunit 19 (Med19) inhibits cell growth and migration in tongue cancer.

BACKGROUND: Mediator complex subunit 19 (Med19) is a critical subunit of the mediator complex that forms a bridge between the transcription factors and RNA polymerase II. Although it has been reported that Med19 plays an important role in stabilizing the whole mediator complex, its biological importance in tongue cancer cell proliferation and migration has not been addressed. METHODS: By using MTT, BrdU incorporation, colony formation, flow cytometric, tumorigenesis and transwell assays, We tested the Med19 role on tongue cancer cell growth and migration. RESULTS: We demonstrated that lentivirus-mediated Med19 knockdown could arrest tongue cancer cells at G1 phase, inhibit tongue cancer cell proliferation and migration in vitro. The tumorigenicity of Med19 short hairpin RNA (shRNA)-expressing lentivirus infected tongue cancer cells were decreased after inoculating into nude mice. CONCLUSIONS: These results indicate that Med19 plays an important role in tongue cancer proliferation and migration, and suggest possible applications for tongue cancer therapy.

Brain Insulin Signaling is Associated with Late-Life Cognitive Decline.

Type-2 diabetes is associated with an increased risk of dementia, and the underlying mechanism might involve abnormal insulin signaling in the brain. The objective of this study was to examine the association of postmortem brain insulin signaling with late-life cognitive decline. Among participants of Religious Orders Study, a community-based clinical-pathological cohort, 150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had postmortem brain insulin signaling measurements collected in the prefrontal cortex using ELISA and immunohistochemistry. By using adjusted linear mixed-effects models, we examined the association of postmortem brain insulin signaling with late-life cognitive function assessed longitudinally (mean follow-up duration = 9.4 years) using a battery of neuropsychological tests. We found that a higher level of serine/threonine-protein kinase (AKT) phosphorylation (pT308AKT1/total AKT1) was associated with a faster decline in global cognition (estimate = -0.023, p = 0.030), and three domains: episodic memory (estimate = -0.024, p = 0.032), working memory (estimate = -0.018, p = 0.012), and visuospatial abilities (estimate = -0.013, p = 0.027). The level of insulin receptor substrate-1 (IRS1) phosphorylation (pS307IRS1/total IRS1) was not associated with decline in global cognition or most cognitive domains, except for perceptual speed (estimate = 0.020, p = 0.020). The density of pS616IRS1-stained cells was not associated with decline in global cognition or any of the domains. In conclusion, these findings provide novel evidence for an association between brain insulin signaling and late-life cognitive decline. AKT phosphorylation is associated with a decline in global cognition and memory in particular, whereas IRS1 phosphorylation is associated with a decline in perceptual speed.

State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer's Disease.

Type 2 diabetes mellitus (T2DM) is common and increasing in prevalence worldwide, with devastating public health consequences. While peripheral insulin resistance is a key feature of most forms of T2DM and has been investigated for over a century, research on brain insulin resistance (BIR) has more recently been developed, including in the context of T2DM and non-diabetes states. Recent data support the presence of BIR in the aging brain, even in non-diabetes states, and found that BIR may be a feature in Alzheimer's disease (AD) and contributes to cognitive impairment. Further, therapies used to treat T2DM are now being investigated in the context of AD treatment and prevention, including insulin. In this review, we offer a definition of BIR, and present evidence for BIR in AD; we discuss the expression, function, and activation of the insulin receptor (INSR) in the brain; how BIR could develop; tools to study BIR; how BIR correlates with current AD hallmarks; and regional/cellular involvement of BIR. We close with a discussion on resilience to both BIR and AD, how current tools can be improved to better understand BIR, and future avenues for research. Overall, this review and position paper highlights BIR as a plausible therapeutic target for the prevention of cognitive decline and dementia due to AD.