Structure-based virtual screening towards the discovery of usnic acid derivatives as novel mTOR inhibitor to treat breast cancer

In this study, mTOR is chosen as the main target for breast cancer treatment. While the existing drugs still pose severe side effects, research on finding new anti-cancer drug should be done continuously. Usnic acid (UA) has been studied for its wide range of biological properties and potential in pharmaceutical research. A structure-based virtual screening approach is applied since it could reduce production time, cost and environmental issues. This study comprises molecular docking simulation, ADMET filtration and drug-likeness prediction. 340 UA derivatives were retrieved from literature and used to build an in-house database. The resulting compounds from docking were then filtered using ADMET prediction which comprises human intestine absorption, aqueous solubility, plasma protein binding, cytochrome P450 2D6 (CYP2D6) and hepatotoxicity parameters to identify the most potent UA derivatives with favourable physicochemical characteristics. After all, the hit compound, 118, was further stimulated in order to forecast its drug-like features. The chalcone-based scaffold of 118 resembled the reported breast cancer compound’s chemical structure strengthening the results obtained from this study. Thus, it is concluded that the structure-based virtual screening was an efficient and effective approach in the discovery of UA derivative, 118, as a potential novel mTOR inhibitor to treat breast cancer

Socio-economic development for happier households: the residents’ perspectives / Vloreen Nity Mathew ... [et al.]

The government plays a very important role in providing for its people in terms of developing opportunities to improve the household’s socioeconomic development. But how far has the local government developments made the people happy? Finding a balance between the socio-economic development and the happiness of the household concern is important to sustain the development well. This paper discusses the government initiatives and perspectives from the residents of Batu Kawa on household happiness are also reported. Data were analysed using pictography and focus group discussions. The findings show that the local government is responsible for doing their part quite well in providing the basic needs of the residents, though some improvements and addition to amenities would be essential to contribute to happiness among the households in the studied area

A mini-review on the insight into the effect of natural and Synthetic α,β-unsaturated carbonyl-containing compounds on PI3K/AKT/mTOR signaling pathways to treat breast cancer

Breast cancer, which has been one of the most frequently diagnosed cancers worldwide for decades, continues to defy treatment. While researching a remedy to this problem, it was discovered that mTOR has a strong association with breast cancer. Uncontrolled activation of mTOR is shown in a variety of different cancer, making it a critical target for cancer treatment. Inhibition of the mTOR protein kinase can cause autophagic cell death. It is known that covalent inhibitors have become a prominent issue in drug discovery, with covalent inhibitors focusing on �; �-unsaturated carbonyl molecules. Structural modifications to �; �-unsaturated carbonyl may be one of the finest avenues for developing the best breast cancer medication. This review article discusses recent research on natural and synthetic �; �-unsaturated carbonyls and their anti-cancer properties targeting on mTOR, with SAR to showcase the efficacy of synthetic natural products compared to parental compounds using both biological assays and in silico studies

A Mini-Review on the Insight into the Effect of Natural and Synthetic α,β-Unsaturated Carbonyl-Containing Compounds on PI3K/AKT/mTOR Signaling Pathways to Treat Breast Cancer

Breast cancer, which has been one of the most frequently diagnosed cancers worldwide for decades, continues to defy treatment. While researching a remedy to this problem, it was discovered that mTOR has a strong association with breast cancer. Uncontrolled activation of mTOR is shown in a variety of different cancer, making it a critical target for cancer treatment. Inhibition of the mTOR protein kinase can cause autophagic cell death. It is known that covalent inhibitors have become a prominent issue in drug discovery, with covalent inhibitors focusing on α,β-unsaturated carbonyl molecules. Structural modifications to α,β-unsaturated carbonyl may be one of the finest avenues for developing the best breast cancer medication. This review article discusses recent research on natural and synthetic α,β-unsaturated carbonyls and their anti-cancer properties targeting on mTOR, with SAR to showcase the efficacy of synthetic natural products compared to parental compounds using both biological assays and in silico studies

Pharmacophore-based molecular docking of usnic acid derivatives to discover anti-viral drugs against influenza A virus

For decades, influenza virus infection has been a serious health concern due to seasonal epidemics and pandemics, and it is continuing on the rise today, yet there is no gold-standard medication available for treating influenza viral infection. As a result, better influenza medicine is necessary to prevent illness. The purpose of this work was to investigate how effective usnic acid derivatives were as antiviral medications against the influenza virus in a computational approach. To discover the prospective medication as an anti-influenza agent, we employed pharmacophore-based molecular docking, ADMET, and drug-likeness studies, CYP isoform analysis and MD simulation approaches. Using pharmacophore filtering processes, twenty-three (23) usnic acid derivatives were acquired from an in-house database of 340 usnic acid derivatives. A docking simulation on the Influenza A H1N1 polymerase resulted in four molecules with a high affinity for the protein. The pharmacokinetics and drug-likeness predictions yielded two hit compounds, which were then subjected to cytochrome P450 enzyme screening to provide the lead molecule, denoted as compound-4. In addition, MD simulation of lead compound (Compound-4) was performed to verify the stability of the docked complex and the binding posture acquired in docking experiments. The findings revealed that compound-4 is a promising option for antiviral treatment of influenza illness in the future

Pharmacophore-based molecular docking and in-silico study of novel usnic acid derivatives as avian influenza A (H7N9) inhibitor

The Avian Influenza virus is not only dangerous to birds, but it is also dangerous to people and other animals. It is a serious danger to poultry worldwide with the capacity to spread to other species, including people; consequently, more efficient medicines are required to treat this virus. This study examined the binding effectiveness of twentyone (21) Usnic acid derivatives out of 340 generated via pharmacophore filtering with AIV A (H7N9) utilising an in-silico technique. The docking simulation to AIV A obtained five compounds with a high affinity to the target protein. The ADMET and druggability prediction produced two lead molecules that were then submitted to Cytochrome (CYP) P450 enzyme screening to generate the best molecule, labelled as compound 5. According to the findings, compound 5 might be employed as a lead inhibitor in developing an anti-AIV medicatio

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Evolving trends in the management of acute appendicitis during COVID-19 waves. The ACIE appy II study

Background: In 2020, ACIE Appy study showed that COVID-19 pandemic heavily affected the management of patients with acute appendicitis (AA) worldwide, with an increased rate of non-operative management (NOM) strategies and a trend toward open surgery due to concern of virus transmission by laparoscopy and controversial recommendations on this issue. The aim of this study was to survey again the same group of surgeons to assess if any difference in management attitudes of AA had occurred in the later stages of the outbreak. Methods: From August 15 to September 30, 2021, an online questionnaire was sent to all 709 participants of the ACIE Appy study. The questionnaire included questions on personal protective equipment (PPE), local policies and screening for SARS-CoV-2 infection, NOM, surgical approach and disease presentations in 2021. The results were compared with the results from the previous study. Results: A total of 476 answers were collected (response rate 67.1%). Screening policies were significatively improved with most patients screened regardless of symptoms (89.5% vs. 37.4%) with PCR and antigenic test as the preferred test (74.1% vs. 26.3%). More patients tested positive before surgery and commercial systems were the preferred ones to filter smoke plumes during laparoscopy. Laparoscopic appendicectomy was the first option in the treatment of AA, with a declined use of NOM. Conclusion: Management of AA has improved in the last waves of pandemic. Increased evidence regarding SARS-COV-2 infection along with a timely healthcare systems response has been translated into tailored attitudes and a better care for patients with AA worldwide

Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

753 SCARLESS APPROACH FOR KILLIAN JAMIESON DIVERTICULUM: TRANSORAL ENDOSCOPIC ASSISTED ESOPHAGODIVERTICULOSTOMY

Abstract   Killian-Jamieson Diverticulum (KJD) is a rare variant of proximal esophageal diverticulum that arises from the Killian-Jamieson area (antero-lateral). It differs from the more common Zenkers diverticulum which usually arise from the posterior aspect of the proximal esophagus. The choice of surgical intervention for symptomatic KJD is still unclear due its rare incidence and surgeons still prefer the transcutaneous cervical approach. Here we present the transoral endoscopic assisted esophagodiverticulostomy approach and the relevant literature. Methods 26 year old male presented with progressive dysphagia for the past two years. A Killian-Jamieson Diverticulum was diagnosed after an Oesophagogastroduodenoscopy and Barium swallow. Patient underwent a transoral endoscopic assisted esophagodiverticulostomy. Results The surgery was uneventful and no complications were observed post-operatively. A year after the surgery patient is asymptomatic and no sign of recurrence. Conclusion Transoral endoscopic assisted esophagodiverticulostomy is a safe approach for treatment of symptomatic KJD. In this era of minimally invasive surgery it should be considered when formulating a treatment approach based on its obvious advantages. </jats:sec