Identification of chalcone derivatives as putative non-steroidal aromatase inhibitors potentially useful against breast cancer by molecular docking and ADME prediction

283-293Aromatase is an influential target to overcome estrogen receptor positive breast cancer, as the enzyme is responsible for conversion of androstenedione to estrone, a promising drug target for therapeutic management of breast cancer. Chalcones are prominent biosynthetic compounds and parent candidate for the synthesis of heterocycles with diversified biological activities. The prime objective of the present study is to evaluate the binding interaction of 2-hydroxyphenyl- prop-2-en-1-one (1A-1X), 2-hydroxy-4-methoxyphenyl- prop-2-en-1-one (3A-3X), 2,4-dihydroxyphenyl- prop-2-en-1-one (9A-9X) and 1-hydroxynaphthalen-2-yl-prop-2-en-1-one (5A-5X) derivatives with aromatase enzyme by molecular docking study and also check their ADME properties by maestro suit. The designed chalcones derivatives have been docked against our target protein with PDB id 3S7S retrieved from the protein data bank, whereas exemestane has been taken as the positive control. As docking data revealed that docking score of 1K, 1U, 1B 3K 3N, 5K, 5U, 9S, 9K, 9N and 9F compounds found less than exemestane and all of these compounds with appropriate ADME properties have proven their excellent absorption as well as solubility characteristics. The present findings provided valuable information about binding interactions of chalcones derivatives to the active site of aromatase. These compounds may serve as potential lead compound for developing new aromatase inhibitors in breast cancer treatment

Identification of chalcone derivatives as putative non-steroidal aromatase inhibitors potentially useful against breast cancer by molecular docking and ADME prediction

Aromatase is an influential target to overcome estrogen receptor positive breast cancer, as the enzyme is responsible for conversion of androstenedione to estrone, a promising drug target for therapeutic management of breast cancer. Chalcones are prominent biosynthetic compounds and parent candidate for the synthesis of heterocycles with diversified biological activities. The prime objective of the present study is to evaluate the binding interaction of 2-hydroxyphenyl- prop-2-en-1-one (1A-1X), 2-hydroxy-4-methoxyphenyl- prop-2-en-1-one (3A-3X), 2,4-dihydroxyphenyl- prop-2-en-1-one (9A-9X) and 1-hydroxynaphthalen-2-yl-prop-2-en-1-one (5A-5X) derivatives with aromatase enzyme by molecular docking study and also check their ADME properties by maestro suit. The designed chalcones derivatives have been docked against our target protein with PDB id 3S7S retrieved from the protein data bank, whereas exemestane has been taken as the positive control. As docking data revealed that docking score of 1K, 1U, 1B 3K 3N, 5K, 5U, 9S, 9K, 9N and 9F compounds found less than exemestane and all of these compounds with appropriate ADME properties have proven their excellent absorption as well as solubility characteristics. The present findings provided valuable information about binding interactions of chalcones derivatives to the active site of aromatase. These compounds may serve as potential lead compound for developing new aromatase inhibitors in breast cancer treatment

Trans-arterial therapy for Fibrolamellar carcinoma: A case report and literature review

Introduction: Fibrolamellar carcinoma (FLC) is a rare pathologically distinct primary liver cancer. Surgical resection is the only treatment associated with prolonged survival. Trans-arterial embolization (TAE), which is a recognised treatment for hepatocellular carcinoma has been used to treat FLC. We present a case and performed a literature review of patients with FLC treated with TAE. Case presentation: We present a 19-year old female with a large potentially resectable FLC which was initially treated with trans-arterial chemo-embolization (TACE) with drug eluting beads. The TACE was followed by surgical resection. Histology confirmed tumour necrosis related to the previous TACE. Discussion & literature review: We identified seven case reports and one case series of TAE for FLC. TAE was either used as a neo-adjuvant therapy to facilitate subsequent tumour resection or as a palliative treatment modality. We propose an algorithm for the treatment of FLC that includes TAE. Conclusion: The rarity of FLC and the paucity of data precludes establishing clear evidence-based standards of care. We propose an algorithm for the treatment of FLC. The establishment of an international registry may facilitate the collection of better quality evidence

Cervicofacial Actinomycosis in the Pediatric Population: Presentation and Management

Background: Infection caused by Actinomyces species is a rare cause of head and neck infection in children. This chronic cervicofacial infection can present with localized swelling, abscess formation, sinus drainage and can be complicated by osteomyelitis. Methods: Presented are 2 pediatric cases of secondary actinomycosis in the context of congenital lesions: 1 patient with a previously excised preauricular sinus and another with a persistent sublingual mass. A comprehensive literature search was conducted for reported cases of pediatric actinomycosis in the cervicofacial region. Results: Both cases presented were successfully treated with a combination of complete surgical excision of the lesions and prolonged antibiotic therapy. Thirty-four pediatric cases of cervicofacial actinomycosis are reviewed, 2 presented herein, and 32 from the published literature. There was equal gender distribution and the median age was 7.5 years. The most common site for infection was the submandibular area. Four (12%) of cases arose in pre-existing congenital lesions. Most patients were treated with penicillin-based antibiotics for a median duration of 6 months following surgical excision or debridement. Conclusions: Actinomycosis is a rare infection of the cervicofacial region; secondary infections arising from congenital lesions of the head and neck are even more rare. A previously excised pre-auricular sinus and a sublingual dermoid cyst are not previously reported sites of infection. Actinomycosis should be suspected in chronically draining sinuses of the head and neck region and confirmed through anaerobic culture. Osteomyelitis is a potential complication and magnetic resonance (MR) imaging is warranted. Long-term antibiotic therapy with a penicillin-based antibiotic and surgical excision should be considered

The management and outcomes of hepatocellular carcinoma in sub-Saharan Africa: A systematic review.

Background: Hepatocellular carcinoma (HCC) is a leading cause of mortality in sub-Saharan Africa (SSA). This systematic review aimed to appraise all population-based studies describing the management and outcomes of HCC in SSA. Methods: A systematic review based on a search in PubMed, PubMed Central, Scopus, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), AfricaWide and Cochrane up to June 2023 was performed. PRISMA guidelines for systematic reviews were followed. The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (registration no: CRD42022363955). Results: Thirty-nine publications from 15 of 48 SSA countries were identified; 3989 patients were studied. The majority (74%) were male, with median ages ranging from 28 to 54 years. Chronic Hepatitis B infection was a leading aetiology and non-cirrhotic HCC was frequently reported. Curative treatment (liver resection, transplantation and ablation) was offered to 6% of the cohort. Most patients (84%) received only best supportive care (BSC), with few survivors at one year. Conclusion: The majority of SSA countries do not have data reporting outcomes for HCC. Most patients receive only BSC, and curative treatment is seldom available in the region. Outcomes are poor compared to high-income countries

Molecular modeling and ADMET predictions of flavonoids as prospective aromatase inhibitors

192-200With the advent of a myriad of treatment possibilities for breast cancer, enzyme inhibition turns out to be the prevailing strategy for inhibiting estrogen biosynthesis. Aromatization of ring A of androstenedione, testosterone and 16-hydroxytestosterone results in increased estrogen level, which embraces the risk for breast cancer. In this present research, we have targeted human placental aromatase complexed with HDDG046 (PDB ID: 4GL7) for its inhibition by several inhibitors of flavonoid derivatives and further screening those molecules for ADMET properties for assessing its credibility for acceptance in successive steps of drug discovery. Novel flavonoid derivative molecules have been designed using Maestro 10.4, based on the literature review. Further, their molecular modeling studies have been performed against the imported target PDB ID: 4GL7 using the GLIDE platform and have been subjected to ADMET assessment using the QikProp and pkCSM program. From all the series exposed to molecular modeling; 2K, 4K, 6K, 8W and 10K molecules have been subjected to ADMET study based on their interaction profile. Successively screening of these molecules led to selection of 8W molecule for further validation by pkCSM. The results obtained have been compared with the reported molecule HDDG046 which presents substantially positive outcomes for 8W in terms of CaCo2 permeability, water solubility, P- glycoprotein; hERG I, II and CYP interactions, hepatotoxicity, LD50 value and so forth. Juxtaposing the results of all the designed molecules under study, we have established that these prospective molecules especially 8W of flavonoid derivatives have the potency to inhibit the target under study, which can be useful in the treatment of breast cancer. This has been estimated based on the in silico approaches performed using Molecular Modeling which utilizes the integral function of Molecular Mechanics and Quantum Mechanics. In addition, the ADMET predictions validate their integrity for being the lead molecules in drug discovery stages in the near future

Better Outcomes for Older people with Spinal Trouble (BOOST) Trial: a randomised controlled trial of a combined physical and psychological intervention for older adults with neurogenic claudication, a protocol

Introduction Neurogenic claudication due to spinal stenosis is common in older adults. The effectiveness of conservative interventions is not known. The aim of the study is to estimate the clinical and cost-effectiveness of a physiotherapist-delivered, combined physical and psychological intervention. Methods and analysis This is a pragmatic, multicentred, randomised controlled trial. Participants are randomised to a combined physical and psychological intervention (Better Outcomes for Older people with Spinal Trouble (BOOST) programme) or best practice advice (control). Community-dwelling adults, 65 years and over, with neurogenic claudication are identified from community and secondary care services. Recruitment is supplemented using a primary care-based cohort. Participants are registered prospectively and randomised in a 2:1 ratio (intervention:control) using a web-based service to ensure allocation concealment. The target sample size is a minimum of 402. The BOOST programme consists of an individual assessment and twelve 90 min classes, including education and discussion underpinned by cognitive behavioural techniques, exercises and walking circuit. During and after the classes, participants undertake home exercises and there are two support telephone calls to promote adherence with the exercises. Best practice advice is delivered in one to three individual sessions with a physiotherapist. The primary outcome is the Oswestry Disability Index at 12 months. Secondary outcomes include the 6 Minute Walk Test, Short Physical Performance Battery, Fear Avoidance Beliefs Questionnaire and Gait Self-Efficacy Scale. Outcomes are measured at 6 and 12 months by researchers who are masked to treatment allocation. The primary statistical analysis will be by ‘intention to treat’. There is a parallel health economic evaluation and qualitative study

VITAMIN D STATUS AND ITS EFFECT ON FUNCTIONAL OUTCOME IN PATIENTS WITH HIP FRACTURE: AN OBSERVATIONAL STUDY

Aims and Objectives: The study aimed to study the Vitamin D status of adult patients presenting with hip fractures and analyze potential impact of Vitamin D status on outcome of these patients. Methods: This was an observational study of Vitamin D status of patients presenting with hip fractures. It was conducted in the department of orthopedics of a tertiary care medical college. One hundred and twenty adult patients presenting with hip fractures were included in this study on the foundation of a predefined inclusion and exclusion criteria. Demographic details of all the patients such as age, gender, and socioeconomic status were noted. Vitamin D status of patients was determined and correlated with functional outcome at the time of final follow-up visit at 6 months. Results: Among the 120 studied with hip fractures, 64 cases (53.33%) involved females, while 56 cases (46.67%) involved males having a M: F ratio of 1:1.14. The mean age of male and female patients was found to be 45.85±10.12 and 46.74±9.86 years. Overall, 65 (54.17%) patients were Vitamin D sufficient and remaining 55 (45.83%) were either inefficient (26.67%) or deficient (19.17%). Seventy-three (60.83%) patients had excellent to good outcome whereas 31 (25.83%) patients had fair outcome. Out of remaining 16 patients, 11 (9.17%) patients had poor outcome and 5 (4.17%) patients had very poor outcome. The patients with sufficient Vitamin D status were found to have a better outcome as compared to those patients with inefficient or deficient Vitamin D status and the difference was found to be statistically significant (p=0.01). Conclusion: It is significant to treat Vitamin D deficiency in patients presenting with hip fractures as Vitamin D deficiency is associated with suboptimal functional outcome in cases with hip fractures

Case Report Clozapine Use Presenting with Pseudopheochromocytoma in a Schizophrenic Patient: A Case Report

Introduction. ere have been six previous cases that reported pseudopheochromocytoma in patients taking clozapine. Our case showed the direct link of clozapine to serum levels of certain markers. Case. is is a case of a 49-year-old obese Caucasian female who was referred to endocrinology for investigation of Cushing's syndrome, based on raised blood pressure and Cushingoid facies. e patient had underlying schizophrenia and was stable on clozapine. Her blood pressure was 150/99 mmHg on bendro�umethiazide and candesartan. We measured her 24-hour urinary-free cortisol, which was normal but 24-hour urinary-free noradrenaline was elevated at 835 nmol (76-561) with normal adrenaline 36 nmol (7-82) and dopamine 2679 nmol (366-2879), as the patient had history of palpitations and sweating. Two sets of 24-hour urinary-free cortisol measurements were normal and serum cortisol suppressed to <50 nmol/l aer a 1 mg overnight dexamethasone. Two further 24-hour urinary-free catecholamines showed a raised level of noradrenaline. MRI demonstrated normal adrenals and MIBG scan did not show any abnormal uptake at adrenal glands. Conclusion. Pseudopheochromocytoma has been reported in patients taking clozapine. A number of different mechanisms for raised plasma noradrenaline levels with clozapine have been postulated. e above case highlights an unusual but known side effect of clozapine

Molecular modeling and ADMET predictions of flavonoids as prospective aromatase inhibitors

With the advent of a myriad of treatment possibilities for breast cancer, enzyme inhibition turns out to be the prevailing strategy for inhibiting estrogen biosynthesis. Aromatization of ring A of androstenedione, testosterone and 16a-hydroxytestosterone results in increased estrogen level, which embraces the risk for breast cancer. In this present research, we have targeted human placental aromatase complexed with HDDG046 (PDB ID: 4GL7) for its inhibition by several inhibitors of flavonoid derivatives and further screening those molecules for ADMET properties for assessing its credibility for acceptance in successive steps of drug discovery. Novel flavonoid derivative molecules have been designed using Maestro 10.4, based on the literature review. Further, their molecular modeling studies have been performed against the imported target PDB ID: 4GL7 using the GLIDE platform and have been subjected to ADMET assessment using the QikProp and pkCSM program. From all the series exposed to molecular modeling; 2K, 4K, 6K, 8W and 10K molecules have been subjected to ADMET study based on their interaction profile. Successively screening of these molecules led to selection of 8W molecule for further validation by pkCSM. The results obtained have been compared with the reported molecule HDDG046 which presents substantially positive outcomes for 8W in terms of CaCo2 permeability, water solubility, P- glycoprotein; hERG I, II and CYP interactions, hepatotoxicity, LD50 value and so forth. Juxtaposing the results of all the designed molecules under study, we have established that these prospective molecules especially 8W of flavonoid derivatives have the potency to inhibit the target under study, which can be useful in the treatment of breast cancer. This has been estimated based on the in silico approaches performed using Molecular Modeling which utilizes the integral function of Molecular Mechanics and Quantum Mechanics. In addition, the ADMET predictions validate their integrity for being the lead molecules in drug discovery stages in the near future