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991.

Background

While Eustachian tube dysfunction (ETD) is a known comorbidity of chronic rhinosinusitis (CRS), the prevalence of ETD symptoms in the CRS population is poorly understood. We sought to determine the cross‐sectional prevalence of ETD in patients with CRS using the validated Eustachian Tube Dysfunction Questionnaire (ETDQ‐7) and to correlate ETDQ‐7 scores with 22‐item Sino‐Nasal Outcome Test (SNOT‐22) scores, endoscopy scores, and computed tomography (CT) scores.

Methods

A total of 101 patients with confirmed CRS completed the ETDQ‐7 and SNOT‐22 at their initial visit to our rhinology clinic. Lund‐Mackay CT and Lund‐Kennedy endoscopy scores were also obtained. Spearman's correlation coefficient (ρ) was calculated.

Results

Among the 101 patients, 49 patients (48.5%) had an ETDQ‐7 score of ≥14.5, signifying clinically significant ETD. The mean ± standard deviation (SD) ETDQ‐7 score of the entire cohort was 17.8 ± 10.1. There was a moderately strong correlation between ETDQ‐7 and the SNOT‐22 ear subdomain (ρ = 0.691, p < 0.001). The correlation coefficient between ETDQ‐7 and total SNOT‐22 scores was ρ = 0.491 (p < 0.001), indicating moderate correlation. ETDQ‐7 scores were poorly correlated to objective measures of sinonasal disease, including Lund‐Mackay CT score (ρ = ?0.055, p = 0.594) and Lund‐Kennedy endoscopy score (ρ = ?0.099, p = 0.334).

Conclusion

Symptoms of ETD are highly prevalent among patients with CRS as documented by patient‐reported outcome measures. The correlation between ETDQ‐7 scores and SNOT‐22 ear subdomain scores is moderately strong, while the correlation between ETDQ‐7 scores and SNOT‐22 scores is moderate. ETD severity does not correlate with CT score or nasal endoscopy score.
  相似文献   
992.

Objectives

To determine whether long‐term behavioral intervention targeting weight loss through increased physical activity and reduced caloric intake would alter cerebral blood flow (CBF ) in individuals with type 2 diabetes mellitus.

Design

Postrandomization assessment of CBF.

Setting

Action for Health in Diabetes multicenter randomized controlled clinical trial.

Participants

Individuals with type 2 diabetes mellitus who were overweight or obese and aged 45 to 76 (N = 310).

Interventions

A multidomain intensive lifestyle intervention (ILI ) to induce weight loss and increase physical activity for 8 to 11 years or diabetes support and education (DSE ), a control condition.

Measurements

Participants underwent cognitive assessment and standardized brain magnetic resonance imaging (MRI ) (3.0 Tesla) to assess CBF an average of 10.4 years after randomization.

Results

Weight changes from baseline to time of MRI averaged ?6.2% for ILI and ?2.8% for DSE (P < .001), and increases in self‐reported moderate or intense physical activity averaged 444.3 kcal/wk for ILI and 114.8 kcal/wk for DSE (P = .03). Overall mean CBF was 6% greater for ILI than DSE (P = .04), with the largest mean differences between ILI and DSE in the limbic region (3.39 mL /100 g per minute, 95% confidence interval (CI ) = 0.07–6.70 mL /100 g per minute) and occipital lobes (3.52 mL /100 g per minute, 95% CI = 0.20–6.84 mL /100 g per minute). In ILI , greater CBF was associated with greater decreases in weight and greater increases in physical activity. The relationship between CBF and scores on a composite measure of cognitive function varied between intervention groups (P = .02).

Conclusions

Long‐term weight loss intervention in overweight and obese adults with type 2 diabetes mellitus is associated with greater CBF .
  相似文献   
993.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Although activating mutations of the KRAS GTPase are the predominant dependency present in >90% of PDAC patients, targeting KRAS mutants directly has been challenging in PDAC. Similarly, strategies targeting known KRAS downstream effectors have had limited clinical success due to feedback mechanisms, alternate pathways, and dose-limiting toxicities in normal tissues. Therefore, identifying additional functionally relevant KRAS interactions in PDAC may allow for a better understanding of feedback mechanisms and unveil potential therapeutic targets. Here, we used proximity labeling to identify protein interactors of active KRAS in PDAC cells. We expressed fusions of wild-type (WT) (BirA-KRAS4B), mutant (BirA-KRAS4BG12D), and nontransforming cytosolic double mutant (BirA-KRAS4BG12D/C185S) KRAS with the BirA biotin ligase in murine PDAC cells. Mass spectrometry analysis revealed that RSK1 selectively interacts with membrane-bound KRASG12D, and we demonstrate that this interaction requires NF1 and SPRED2. We find that membrane RSK1 mediates negative feedback on WT RAS signaling and impedes the proliferation of pancreatic cancer cells upon the ablation of mutant KRAS. Our findings link NF1 to the membrane-localized functions of RSK1 and highlight a role for WT RAS signaling in promoting adaptive resistance to mutant KRAS-specific inhibitors in PDAC.

A total of 60,430 new cases of pancreatic cancer were estimated for 2021, and the 5-y relative survival rate has consistently remained below 11% (1). About 85% of these pancreatic cancer tumors are pancreatic ductal adenocarcinoma (PDAC) (2). Poor outcomes of PDAC cases result from late diagnoses leading to unresectable and heterogeneous tumors as well as ineffective therapies, which only prolong survival on the order of months (35). Mutations in the KRAS proto-oncogene are present in over 90% of PDAC cases and are associated with a poor prognosis (6). Furthermore, mice expressing mutant KRAS in the pancreas develop precursor lesions, which sporadically progress into frank PDAC. This progression is accelerated when combined with other mutations or deletion of tumor suppressor genes (711). Additionally, independent studies have shown that the maintenance of murine PDAC cells require KRAS (1214).As a RAS GTPase, KRAS acts as a molecular switch at the plasma membrane that relays growth factor signaling from receptor tyrosine kinases to downstream pathways such as RAF/MEK and PI3K/AKT (15). GTP binding alters the conformation of the KRAS G domain, thereby creating binding sites for downstream effectors to trigger enzymatic cascades that promote cell transformation (1619). Intrinsically, KRAS slowly hydrolyzes GTP into GDP to halt signaling; however, GTPase activating proteins (GAPs) such as neurofibromin 1(NF1) catalyze this process (20). In contrast, guanine nucleotide exchange factors, such as son of sevenless homolog 1 (SOS1), catalyze the exchange of GTP for bound GDP. In most PDAC cases, KRAS is mutated at the 12th residue located in the G domain from glycine to either a valine (G12V), or more commonly, aspartate (G12D). These mutations sterically prevent the “arginine finger domain” of GAPs from entering the GTPase site, thereby blocking extrinsic allosteric GTPase activation and stabilizing RAS-GTP (21, 22). Activating mutations in KRAS constitutively trigger RAF/MEK and PI3K/AKT pathways leading to increased cell proliferation as well as other prooncogenic behaviors (15). KRAS signaling not only relies on the G domain but also the C-terminal hypervariable domain (HVR), which is required to stabilize KRAS on membranes where signaling is most efficient (2326). Independent studies suggest that specific biochemical and cellular consequences of KRAS activation are attributed to the unique properties of the HVR of the predominant splice form KRAS4B, namely the polybasic domain and the lipid anchor (2730). Localization of RAS proteins to the plasma membrane requires the prenylation of the CAAX motif (23). Additionally, for KRAS4B, the hypervariable region contains a highly polybasic domain consisting of several consecutive lysines, which can interact with the negative charges on the polar heads of phospholipids and stabilize protein interactions (31). Structural and biochemical characterization of the HVR and G domain has contributed to a better understanding of the signaling outputs of KRAS and led to KRAS-targeting strategies.Various approaches to inhibit KRAS include direct inhibition, expression interference, mislocalization, and targeting of downstream effectors (32). Thus far, direct inhibitors against KRAS have only successfully targeted the G12C mutant, which comprises 2.9% of KRAS mutant PDAC (21, 33). For other KRAS mutants, targeting downstream effectors of KRAS in pancreatic cancer remains an alternative approach. Unfortunately, dual inhibition of MEK and AKT pathways was ineffective in PDAC patients (34). Difficulty in targeting KRAS due to adaptive resistance and feedback regulation motivates a better understanding of KRAS biology (35). For example, although PDAC typically features a mutant KRAS, there may be a role for its wild-type (WT) counterpart as well as WT RAS paralogs (HRAS and NRAS), which are GAP sensitive and subject to signaling feedback. While oncogenic KRAS has been shown to activate WT HRAS and NRAS via allosteric stimulation of SOS1 (36), WT KRAS has been proposed to be a tumor suppressor in some KRAS mutant cancers based on the commonly observed mutant-specific allele imbalance that occurs throughout tumor progression (37). Additionally, the reintroduction of WT KRAS abolished tumor T cell acute lymphoblastic leukemia development and impaired tumor growth in KRAS mutant lung cancer cells in vivo (3739). The discovery of novel KRAS protein interactors involved in downstream signaling or feedback and compensatory pathways may elucidate why inhibition of downstream pathways have had limited clinical impact in PDAC. Here, we perform proximity labeling experiments by expressing a fusion of BirAR118G biotin ligase and KRAS in PDAC cells, which, in the presence of high concentrations of biotin, generates reactive biotinoyl-AMP that labels lysines of nearby proteins, such as interactors of its fusion partner KRAS (4042). The biotinylated interactor proteins can be isolated by streptavidin pulldown and analyzed by proteomics to identify novel protein interactors (4345). Because covalent labeling occurs in living cells, enzymatic labeling may potentially identify transient interactors and protein complexes.Two recent studies used proximity-dependent biotin identification (BioID) labeling methods to identify KRAS interactors in 293T and colon cancer cells (46, 47). These studies uncovered and validated the functional relevance of PIP5KA1 and mTORC2 in PDAC cells. However, BirA-KRAS screens in PDAC models have not yet been performed. Since the tumor context may determine protein expression and relevant interactions, we sought to perform a BirA-KRAS screen in PDAC cells. We hypothesize that proximity labeling with BioID presents a means for identifying new mutant KRAS-specific interactions in PDAC, which may unveil new insights into therapeutic design for this malignancy.  相似文献   
994.
HbA1c values are heavily relied on to assess glycemic control. Hemoglobin variants may interfere with measurements of HbA1c resulting in falsely low values. We present the first report of a rare variant of Hb in a patient with type 2 diabetes, which lead to a falsely low HbA1c.  相似文献   
995.
Biochemical Markers for Alcoholism   总被引:2,自引:0,他引:2  
A panel of blood tests, purportedly markers for alcohol abuse, were examined in 543 relatively healthy alcoholics entering ambulatory rehabilitation treatment. Individual tests were too low in sensitivity: gamma-glutamyl transpeptidase was abnormally high in only 49%, then mean corpuscular volume (45%), high density lipoprotein cholesterol (HDLC) (25%), serum glutamic oxaloacetic transaminase (SGOT) (28%), and blood alcohol (21%). HDLC was of low sensitivity, generally unaffected by liver disease, and related to quantitation of recent alcohol consumed. Combining seven markers, 82% of males and 71% females had at least one abnormally high value. Histories of heavy recent drinking, positive blood alcohol levels on admission, and manifest liver disease on physical examination or by hyperbilirubinemia were associated with high sensitivities of individual and pooled markers. The biochemical markers studied can be useful to suggest alcohol abuse, especially in some populations of drivers. In other populations of alcoholics, especially with intermittent alcohol or recent abstinence, their sensitivities were so low as to discourage extensive reliance on their use. The diagnosis of alcoholism continues to depend on clinical history of alcohol-related problems, including social, familial, legal, medical, psychological, and economic.  相似文献   
996.
The use of HSCT is the only potentially curative treatment for CAMT, but access is limited by the availability of suitable donors. We report five consecutive patients with CAMT who received MAC and partially HLA‐mismatched, UCBT (unrelated, n = 4). Median times to neutrophil (>500/μL) and platelet (≥20 000 and ≥50 000/μL) engraftment were 19, 57, and 70 days, respectively. Acute GvHD, grade II, developed in one patient, who subsequently developed limited chronic GvHD. At median follow‐up of 14 yr, all patients are alive with sustained donor cell engraftment. To our knowledge, this is the largest single‐center series of UCBT for patients with this disease and suggests that UCBT is a successful curative option for patients with CAMT.  相似文献   
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We examined the influences of aging on gastric damage and gastric mucosal blood flow (GMBF) responses induced by acid back-diffusion, following the barrier disruption, and investigated the relation of capsaicin-sensitive sensory nerves to these changes. Male Fischer rats 3, 13, and 24 months old were used. Under urethane anesthesia, a rat stomach was mounted on a chamber, and gastric potential difference (PD), luminal H+ loss, and GMBF were measured before, during, and after exposure to 20 mM sodium taurocholate (TC) for 30 min, in the presence of 50 mM HCl. Mucosal exposure to TC caused surface cell damage, PD reduction, and acid back-diffusion (luminal H+ loss) in all groups of rats; PD reduction and the amount of H+ loss were not significantly different between young and aged rats. In young rats, a marked increase of GMBF was observed with luminal acid loss following TC treatment, yet it resulted in less damage in the gastric mucosa. In aged rats, however, such GMBF responses were apparently mitigated, leading to a significant worsening of gastric mucosal lesions induced by TC. Mucosal application of capsaicin (0.1 mg/ml) caused an increase of GMBF in young rats, but this response was significantly attenuated in aged rats. In addition, the amount of calcitonin gene-related peptide (CGRP) released in the isolated stomach in response to capsaicin (1 × 10–5 M) was significantly lower in aged animals when compared to young rats. These findings suggest that the gastric mucosa of aged rats is more vulnerable to acid back-diffusion following the barrier disruption, partly because of dysfunction of GMBF responses mediated by capsaicin-sensitive sensory neurons in the acidic conditions.  相似文献   
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