A Randomized Trial Comparing the Effect of Fiberoptic Selection and Guidance Versus Random Selection, Blind Insertion, and Direct Laryngoscopy, on the Incidence and Severity of Epistaxis After Nasotracheal Intubation.

BACKGROUND: Epistaxis, or nasal bleeding, is a common complication after nasotracheal intubation (NTI). Because such bleeding is likely related to trauma during intubation, use of fiberoptic visualization and guidance rather than direct laryngoscopy may affect the incidence and severity of epistaxis. We compared the incidence of epistaxis after NTI using a fiberoptic versus a direct laryngoscopy approach. METHODS: Seventy patients who were able to breathe easily through unobstructed nostrils and required NTI as part of their anesthetic management were recruited. Exclusion criteria included unequal nasal airflow, nostril obstruction, previous nasal trauma or surgery, and coagulation abnormalities as determined by history. Patients were randomly assigned to undergo NTI with thermosoftened Mallinckrodt nasal Ring-Adair-Elwyn (RAE) tubes via either traditional direct laryngoscopy using a Macintosh blade or fiberoptic nasal intubation. All patients first underwent anesthetic induction and were randomized to blind or fiberoptic groups. Patients in the blind insertion/direct laryngoscopy group were then intubated via a randomly selected nostril. Patients in the fiberoptic group underwent an asleep nasal fiberoptic examination to determine the most patent nostril, followed by tube insertion under fiberoptic guidance. Ten minutes after NTI, the incidence and severity of epistaxis were evaluated and graded by the surgeon, who was blinded to the intubation method. RESULTS: Initial nasal fiberoptic endoscopy identified asymptomatic nasal pathology in 51% of patients: inferior turbinate hypertrophy (28.6%) and deviation of the nasal septum in (22.8%). The incidence of epistaxis was higher in the blind insertion/direct laryngoscopy group (88%) than in the fiberoptic group (51%; relative risk, 0.55; 95% confidence interval, 0.38-0.79; P = .0011). The severity of bleeding was also greater in the blind tube insertion/direct laryngoscopy cohort (Wilcoxon Mann-Whitney odds, 3.5; 95% confidence interval, 1.8-11.1). CONCLUSIONS: Fiberoptic nostril selection and guidance during NTI reduced the incidence and severity of epistaxis when compared with NTI performed via blind insertion and direct laryngoscopy.

AI and climate resilience governance.

While artificial intelligence (AI) offers promising solutions to address climate change impacts, it also raises many application limitations and challenges. A risk governance perspective is used to analyze the role of AI in supporting decision-making for climate adaptation, spanning risk assessment, policy analysis, and implementation. This comprehensive review combines expert insights and systematic literature review. The study's findings indicate a large emphasis on applying AI to climate "risk assessments," particularly regarding hazard and exposure assessment, but a lack of innovative approaches and tools to evaluate resilience and vulnerability as well as prioritization and implementation process, all of which involve subjective, qualitative, and context-specific elements. Additionally, the study points out challenges such as difficulty of simulating complex long-term changes, and evolving policies and human behavior, reliance on data quality and computational resources, and the need for improved interpretability of results as areas requiring further development.

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer.

Targeting Hsp90 is an attractive strategy for anticancer therapy because the diversity and relevance of biological processes are regulated by these proteins in most cancers. However, the role and mode of action of Hsp90 inhibitors in pancreatic cancer has not been studied. This study aimed to assess the antitumor activity of the Hsp90 inhibitor, IPI-504, in pancreatic cancer and to determine the biological effects of the agent. In vitro, we show that pharmacologic inhibition of Hsp90 by IPI-504 exerts antiproliferative effects in a panel of pancreatic cancer cells in a dose- and time-dependent manner. In pancreatic cancer xenografts obtained directly from patients with pancreas cancer, the agent resulted in a marked suppression of tumor growth. Although known Hsp90 client proteins were significantly modulated in IPI-504-treated cell line, no consistent alteration of these proteins was observed in vivo other than induction of Hsp70 expression in the treated xenografted tumors. Using a proteomic profiling analysis with isotope tags for relative and absolute quantitation labeling technique, we have identified 20 down-regulated proteins and 42 up-regulated proteins on IPI-504 treatment.tumor growth Identical changes were observed in the expression of the genes coding for these proteins in a subset of proteins including HSPA1B, LGALS3, CALM1, FAM84B, FDPS, GOLPH2, HBA1, HIST1H1C, HLA-B, and MARCKS. The majority of these proteins belong to the functional class of intracellular signal transduction, immune response, cell growth and maintenance, transport, and metabolism. In summary, we show that IPI-504 has potent antitumor activity in pancreatic cancer and identify potential pharmacologic targets using a proteomics and gene expression profiling.

Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90.

17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.

Dissecting histone deacetylase function.

Recent research describes the use of chromatin immunoprecipitation and intergenic chromosomal-DNA microarrays to analyze HDAC function genome-wide. The next step in realizing the full potential of these analyses will be to develop specific and temporal control over HDAC perturbation.

Endothelial function, carotid-femoral stiffness, and plasma matrix metalloproteinase-2 in men with bicuspid aortic valve and dilated aorta.

OBJECTIVES: This study sought to examine the relationship between proximal aortic dilation and systemic vascular function in men with bicuspid aortic valve (BAV). BACKGROUND: Proximal aortic dilation in subjects with BAV is associated with structural and functional abnormalities in the ascending aorta. METHODS: We studied 32 men (median age 31 years [range 28 to 32 years]) with nonstenotic BAV categorized into 2 subgroups according to proximal ascending aorta dimensions (nondilated or=40 mm, respectively). Sixteen healthy men were studied as control subjects. Flow-mediated dilation in response to hyperemia (a marker of endothelial dysfunction) and carotid-femoral pulse wave velocity (an index of aortic stiffness) were assessed, and peripheral blood was sampled for matrix metalloproteinases (MMP-2 and -9) and their tissue inhibitors (TIMP-1 and -2), respectively. Cardiac chamber and aortic dimensions were assessed by echocardiography and cardiac magnetic resonance imaging, respectively. RESULTS: Despite the similar severity of aortic stenosis, left ventricular mass, and function, men with dilated aortas had blunted brachial flow-mediated vasodilation to hyperemia (5% [interquartile range (IQR) 4% to 6%] vs. 8% [IQR 7% to 9%] change, p = 0.001), higher carotid-femoral pulse wave velocity (9.3 cm/s [IQR 9 to 10 cm/s] vs. 7 cm/s [IQR 6.9 to 7.4 cm/s], p = 0.001), and significantly higher plasma levels of MMP-2 (1,523 [IQR 1,460 to 1,674] vs. 1,036 [IQR 962 to 1,167], p = 0.001) compared with men with BAV and nondilated aorta. Values for MMP-9, TIMP-1 and -2 levels, and nitroglycerin-induced (endothelium-independent) vasodilation were similar in all 3 groups. CONCLUSIONS: Young men with BAV and dilated proximal aortas manifest systemic endothelial dysfunction, increased carotid-femoral pulse wave velocity, and higher plasma levels of MMP-2. These observations could introduce new targets for screening and perhaps for therapeutic intervention.

Semisynthetic cyclopamine analogues as potent and orally bioavailable hedgehog pathway antagonists.

Herein is reported the synthesis of a novel class of hedgehog antagonists derived from cyclopamine. The acid sensitive D-ring of cyclopamine was homologated utilizing a sequence of chemoselective cyclopropanation and stereoselective acid-catalyzed rearrangement. Further modification of the A/B-ring homoallylic alcohol to the conjugated ketone led to the discovery of new cyclopamine analogues with improved pharmaceutical properties and in vitro potency (EC 50) ranging from 10 to 1000 nM.

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90.

Heat shock protein 90 (Hsp90) is an emerging therapeutic target of interest for the treatment of cancer. Its role in protein homeostasis and the selective chaperoning of key signaling proteins in cancer survival and proliferation pathways has made it an attractive target of small molecule therapeutic intervention. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), the most studied agent directed against Hsp90, suffers from poor physical-chemical properties that limit its clinical potential. Therefore, there exists a need for novel, patient-friendly Hsp90-directed agents for clinical investigation. IPI-504, the highly soluble hydroquinone hydrochloride derivative of 17-AAG, was synthesized as an Hsp90 inhibitor with favorable pharmaceutical properties. Its biochemical and biological activity was profiled in an Hsp90-binding assay, as well as in cancer-cell assays. Furthermore, the metabolic profile of IPI-504 was compared with that of 17-AAG, a geldanamycin analog currently in clinical trials. The anti-tumor activity of IPI-504 was tested as both a single agent as well as in combination with bortezomib in myeloma cell lines and in vivo xenograft models, and the retention of IPI-504 in tumor tissue was determined. In conclusion, IPI-504, a potent inhibitor of Hsp90, is efficacious in cellular and animal models of myeloma. It is synergistically efficacious with the proteasome inhibitor bortezomib and is preferentially retained in tumor tissues relative to plasma. Importantly, it was observed that IPI-504 interconverts with the known agent 17-AAG in vitro and in vivo via an oxidation-reduction equilibrium, and we demonstrate that IPI-504 is the slightly more potent inhibitor of Hsp90.