Integrins have a critical role in thrombosis and haemostasis. Antagonists of the platelet integrin αIIbβ3 are potent anti-thrombotic drugs, but also have the life-threatening adverse effect of ...causing bleeding. It is therefore desirable to develop new antagonists that do not cause bleeding. Integrins transmit signals bidirectionally. Inside-out signalling activates integrins through a talin-dependent mechanism. Integrin ligation mediates thrombus formation and outside-in signalling, which requires Gα13 and greatly expands thrombi. Here we show that Gα13 and talin bind to mutually exclusive but distinct sites within the integrin β3 cytoplasmic domain in opposing waves. The first talin-binding wave mediates inside-out signalling and also ligand-induced integrin activation, but is not required for outside-in signalling. Integrin ligation induces transient talin dissociation and Gα13 binding to an EXE motif (in which X denotes any residue), which selectively mediates outside-in signalling and platelet spreading. The second talin-binding wave is associated with clot retraction. An EXE-motif-based inhibitor of Gα13-integrin interaction selectively abolishes outside-in signalling without affecting integrin ligation, and suppresses occlusive arterial thrombosis without affecting bleeding time. Thus, we have discovered a new mechanism for the directional switch of integrin signalling and, on the basis of this mechanism, designed a potent new anti-thrombotic drug that does not cause bleeding.
•Consider two small business enterprises with heterogeneous product quality.•The product quality can be disclosed by selling through a retailer.•Study that if small business enterprises should ...disclose their quality.•The equilibrium depends on customers’ prior belief of the quality.•Both small business enterprises may or may not disclose their quality.
In this paper, we use a game-theoretic approach to investigate quality disclosure strategies for small business enterprises (SBEs). There are two SBEs with heterogeneous product quality competing in a competitive marketplace. In the first stage of the game, each SBE decides whether to disclose its quality information to customers through the retailer. In the second stage of the game, depending on the quality disclosure strategies chosen, the SBEs decide the selling prices, or they decide the wholesale prices and the retailer decides the selling prices. We derive the optimal disclosure and pricing strategies for the SBEs. We show that in equilibrium the high-quality SBE may choose not to disclose its quality and the low-quality SBE may choose to disclose its quality to customers through the retailer, which depends on the customers’ common prior belief regarding the quality of the product in the market. Besides, the high-quality SBE has a higher selling price and will obtain a higher profit than the low-quality SBE, even for the case where the customers only know the true quality of one SBE. However, when only one SBE discloses its quality to customers, the selling price of the high-quality product with disclosed quality information may be lower than that without quality information, due to the competition and information discourse mechanism. Moreover, we derive the results on how the optimal selling prices, wholesale prices, retailer’s profit and SBEs’ profits change when the customers’ common prior belief changes, and generate managerial insights of the research findings.
Advanced ovarian cancer usually spreads to the omentum. However, the omental cell-derived molecular determinants modulating its progression have not been thoroughly characterized. Here, we show that ...circulating ITLN1 has prognostic significance in patients with advanced ovarian cancer. Further studies demonstrate that ITLN1 suppresses lactotransferrin's effect on ovarian cancer cell invasion potential and proliferation by decreasing MMP1 expression and inducing a metabolic shift in metastatic ovarian cancer cells. Additionally, ovarian cancer-bearing mice treated with ITLN1 demonstrate marked decrease in tumor growth rates. These data suggest that downregulation of mesothelial cell-derived ITLN1 in the omental tumor microenvironment facilitates ovarian cancer progression.
Aggression and violence by patient (and their relatives/friends) is widely acknowledged as a serious occupational hazard, with physicians being particularly susceptible to witnessing and experiencing ...such incidents within hospitals. Research has shown that the negative consequences of such aggression and violence are not only felt at the individual level, but also at the team and organizational levels. Understanding how to prevent and manage this behavior towards physicians in hospitals is urgent and not fully researched. While there are many potentially effective interventions, it is unclear which ones would be valuable and feasible for Chinese hospitals. Because patient aggression and violence may occur more frequently in Chinese hospitals than in other countries, this suggests that cultural differences play a role and that tailored interventions may be needed.
We conducted a Delphi study to reach a consensus on the importance and feasibility of hospital interventions to prevent and manage patient (and their relatives/friends) aggression and violence against physicians in Chinese hospitals. Seventeen experts in China were invited to complete online questionnaires over three rounds.
After three rounds, consensus was achieved concerning 44 interventions, five other interventions were rejected, and no consensus was reached on another two. These interventions were clustered into eight categories: environment design, access and entrance, staffing and working practices, leadership and culture, training and education, support, during/after-the-event actions, and hospital policy. Each category is considered important in preventing and managing patient (and their relatives/friends) aggression and violence towards physicians in Chinese hospitals. This study also investigated the feasibility of the suggested interventions and found that 36 of the 44 interventions were considered not only relevant, but also feasible for implementation in Chinese hospitals.
This study provides an overview of interventions that can be implemented in Chinese hospitals to prevent and manage patient (and their relatives/friends) aggression and violence before, during, and after a violent incident occurs.
Abstract Background The effect of ovarian ablation or suppression (OAS) in premenopausal women with breast cancer is controversial. The overall survival (OS), disease-free survival (DFS) and adverse ...event of OAS versus no OAS were compared. Methods A literature review of EMBASE, Web of Science, PUBMED, and Cochrane Library was conducted. The hazard ratio (HR) and 95% confidence interval (CI) for OS and DFS, as well as risk ratio (RR) and 95% CI for adverse events were evaluated. I-squared statistic ( I2 ) represents heterogeneity. Results Twenty-nine studies with a total of 21,249 women were included. In premenopausal women aged 40 years or younger, there were significant differences in OS (HR 0.78, 95% CI: 0.66–0.94, P = 0.008, I2 = 0%) and DFS (HR 0.84, 95% CI: 0.73–0.97, P = 0.02, I2 = 0%) between OAS and no OAS. In advanced stage breast cancer, a significant difference was found in OS (HR 0.76, 95% CI: 0.60–0.96, P = 0.02, I2 = 0%). Patients treated with OAS had more chances to have hot flushes (RR 1.91, 95% CI: 1.62–2.26, P < 0.01, I2 = 0%) and vaginal dryness (RR 1.19, 95% CI: 1.08–1.31, P = 0.0003, I2 = 0%). No significant difference in depression (RR 1.28, 95% CI: 0.94–1.74, P = 0.12, I2 = 0%). Conclusions The study shows that OAS plays a beneficial role in premenopausal women aged 40 years or younger and advanced stage breast cancer. However, OAS is associated with increase in hot flushes and vaginal dryness.
Irinotecan (CPT-11) induced diarrhea occurs frequently in patients with cancer and limits its usage. Bacteria β-glucuronidase (GUS) enzymes in intestines convert the nontoxic metabolite of CPT-11, ...SN-38G, to toxic SN-38, and finally lead to damage of intestinal epithelial cells and diarrhea. We previously reported amoxapine as a potent GUS inhibitor in vitro. To further understand the molecular mechanism of amoxapine and its potential for treatment of CPT-11-induced diarrhea, we studied the binding modes of amoxapine and its metabolites by docking and molecular dynamics simulation, and tested the in vivo efficacy on mice in combination with CPT-11.
The binding of amoxapine, its metabolites, 7-hydroxyamoxapine and 8-hydroxyamoxapine, and a control drug loxapine with GUS was explored by computational protocols. The in vitro potencies of metabolites were measured by Escherichia coli GUS enzyme and cell-based assay. Low-dosage daily oral administration was designed to use along with CPT-11 to treat tumor-bearing mice.
Computational modeling results indicated that amoxapine and its metabolites bound in the active site of GUS and satisfied critical pharmacophore features: aromatic features near bacterial loop residue F365' and hydrogen bond toward E413. Amoxapine and its metabolites were demonstrated as potent in vitro. Administration of low dosages of amoxapine with CPT-11 in mice achieved significant suppression of diarrhea and reduced tumor growth.
Amoxapine has great clinical potential to be rapidly translated to human subjects for irinotecan-induced diarrhea.
We study the formation of exceptional points (EPs) in a photonic medium with a complex time-periodic permittivity, i.e., ɛ(t)=ɛo+ɛrsin(Ωt). We formulate Maxwell's equations in the form of a ...first-order non-Hermitian Floquet Hamiltonian matrix and solve it analytically for the Floquet band structures. In the case when ɛr is real, to the first order in ɛr, the band structures show a phase transition from an exact phase with real quasienergies to a broken phase with complex quasienergies inside a region of wave-vector space, the so-called k gap. We show that the two EPs at the upper and lower edges of the k gap have opposite chiralities in the stroboscopic sense. By picking up the mode with a positive imaginary quasienergy, the wave propagation inside the k gap can grow exponentially. In three dimensions, such pairs of EPs span two concentric spherical surfaces in the k⃗ space and repeat themselves periodically in the quasienergy space with Ω as the period. However, in the case when ɛr is purely imaginary, the k gap disappears and gaps in the quasienergy space are opened. Our analytical results agree well with finite-difference time domain simulations. To second order in ɛr, additional EP pairs are found for both the cases of real and imaginary ɛr. We also extend our theory to the case where the permittivity is simultaneously modulated in both space and time, i.e., ɛ(x,t)=ɛo+ɛrsin(Ωt−βx+ϕ). For a real ɛr, we find that EPs also exist when the modulation speed cm=Ω/β is faster than the speed of the wave travelling inside the medium.
Summary
Guidelines for doctors managing osteoporosis in the Asia-Pacific region vary widely. We compared 18 guidelines for similarities and differences in five key areas. We then used a structured ...consensus process to develop clinical standards of care for the diagnosis and management of osteoporosis and for improving the quality of care.
Purpose
Minimum clinical standards for assessment and management of osteoporosis are needed in the Asia-Pacific (AP) region to inform clinical practice guidelines (CPGs) and to improve osteoporosis care. We present the framework of these clinical standards and describe its development.
Methods
We conducted a structured comparative analysis of existing CPGs in the AP region using a “5IQ” model (identification, investigation, information, intervention, integration, and quality). One-hundred data elements were extracted from each guideline. We then employed a four-round Delphi consensus process to structure the framework, identify key components of guidance, and develop clinical care standards.
Results
Eighteen guidelines were included. The 5IQ analysis demonstrated marked heterogeneity, notably in guidance on risk factors, the use of biochemical markers, self-care information for patients, indications for osteoporosis treatment, use of fracture risk assessment tools, and protocols for monitoring treatment. There was minimal guidance on long-term management plans or on strategies and systems for clinical quality improvement. Twenty-nine APCO members participated in the Delphi process, resulting in consensus on 16 clinical standards, with levels of attainment defined for those on identification and investigation of fragility fractures, vertebral fracture assessment, and inclusion of quality metrics in guidelines.
Conclusion
The 5IQ analysis confirmed previous anecdotal observations of marked heterogeneity of osteoporosis clinical guidelines in the AP region. The Framework provides practical, clear, and feasible recommendations for osteoporosis care and can be adapted for use in other such vastly diverse regions. Implementation of the standards is expected to significantly lessen the global burden of osteoporosis.
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