Exploring molecular fragments for fraction unbound in human plasma of chemicals: a fragment-based cheminformatics approach.

Fraction unbound in plasma (fu,p) of drugs is an significant factor for drug delivery and other biological incidences related to the pharmacokinetic behaviours of drugs. Exploration of different molecular fragments for fu,p of different small molecules/agents can facilitate in identification of suitable candidates in the preliminary stage of drug discovery. Different researchers have implemented strategies to build several prediction models for fu,p of different drugs. However, these studies did not focus on the identification of responsible molecular fragments to determine the fraction unbound in plasma. In the current work, we tried to focus on the development of robust classification-based QSAR models and evaluated these models with multiple statistical metrics to identify essential molecular fragments/structural attributes for fractions unbound in plasma. The study unequivocally suggests various N-containing aromatic rings and aliphatic groups have positive influences and sulphur-containing thiadiazole rings have negative influences for the fu,p values. The molecular fragments may help for the assessment of the fu,p values of different small molecules/drugs in a speedy way in comparison to experiment-based in vivo and in vitro studies.

Relation of Serum Magnesium Level in Adult Patients with Idiopathic Generalized Epilepsy in a Tertiary Care Hospital.

Magnesium plays a vast role in the nervous system. In particular, high magnesium in cerebrospinal fluid appears to enhance the neural functions, while low magnesium induces neuronal diseases. The aim of the study was to find out the relation of serum magnesium with idiopathic generalized epilepsy attending in a tertiary care hospital. This cross-sectional comparative study was conducted in the department of Neurology at Mymensingh Medical College and Hospital, Bangladesh from January 2019 to June 2020 following ethical approval. Total 110 purposively selected participants (55 with idiopathic generalized epilepsy and 55 non epileptic apparently healthy individuals) were enrolled in this study. Serum total Mg was measured by EMP-168 Biochemical Analyzer. Average age of epileptic individuals was 33.13±9.5 years and majority was female (60.0%). Mean serum magnesium level was lower in epileptic patients than controls (1.80±0.041 vs. 2.02±0.19 mg/dl; p<0.001). Patients with higher seizure attack (>3 per month) had significantly lower mean serum magnesium level than the patients with seizure attack three or less per month. Serum magnesium levels are reduced in epileptic patients compared to healthy age and gender matched controls. Studies involving larger numbers of patients are needed to confirm these results.

ESMO Resilience Task Force recommendations to manage psychosocial risks, optimise well-being, and reduce burnout in oncology.

BACKGROUND: Burnout in health care professionals (HCPs) results from exposure to psychosocial risks at work. Left unaddressed, burnout can lead to chronic health problems, increased staff turnover, reduced work hours, absenteeism, and early retirement from clinical practice, thus impacting patient care. The European Society for Medical Oncology (ESMO) Resilience Task Force (RTF) was established in December 2019 to support the well-being of oncology HCPs globally. This ESMO RTF position paper aims to provide a set of recommendations to optimise well-being and mitigate burnout in oncology, and to help individuals and institutions maintain the delivery of optimal cancer care. DESIGN: Recommendations were developed by a diverse multinational panel of interprofessional experts based on the key findings from three previously reported ESMO RTF surveys. RESULTS: Several recurrent work-related psychosocial risks in oncology were identified; in particular, concerns about workload and professional development. The need for flexible work patterns, continued use of virtual resources, well-being resources, and targeted support for at-risk groups were highlighted as key considerations to safeguard HCPs' health and prevent burnout. In total, 11 recommendations relating to three priority themes were developed: (i) information and training; (ii) resources; (iii) activism and advocacy. CONCLUSION: Optimising the well-being of oncology HCPs is essential for the provision of high-quality, sustainable care for patients globally. The ESMO RTF will continue its mission and is rolling out several initiatives and activities to support the implementation of these recommendations.

Weak antilocalization in the topological semimetal candidate YbAuSb.

We report a study of the magnetic and magnetotransport properties of YbAuSb single crystals, which were grown using the bismuth flux. The x-ray diffraction data indicate that YbAuSb crystallizes in LiGaGe-type hexagonal structure with space groupP63mc. Our magnetic measurements revealed that YbAuSb is nonmagnetic with a divalent state of ytterbium ion. The temperature-dependent electrical resistivity exhibits a metallic behavior. A cusp-like feature in transverse and longitudinal magnetoresistance is observed at the low field regime. This cusp-like feature is attributed to the weak antilocalization (WAL) effect, which is more prominent at low temperatures. The transverse magnetoconductivity in low field region follows semiclassical model∼B, which is consistent with the presence of WAL phenomena. The WAL effect in transverse and longitudinal magnetoconductance is well explained using the modified Hikami-Larkin-Nagaoka and generalized Altshuler-Aronov model, respectively. The Hall resistivity shows a linear field dependence with a positive slope, suggesting hole charge carriers dominate in electrical transport. The calculated carrier density and mobility are in the order of 1020 cm-3and 102 cm2 V-1 s-1, respectively.

An Exploration of the Peri-Diagnostic Experiences of Lesbian, Gay and Bisexual People With Dementia Using the Candidacy Framework.

OBJECTIVES: How dementia affects lesbian, gay, bisexual, trans, queer people or those with other minoritised sexual/gender identities (LGBTQ+) is not well understood. Furthermore, existing research often excludes the voices of LGBTQ+ people living with dementia and focuses instead on their care partners. This study addresses this evidence gap by drawing on the ESRC/NIHR funded DETERMIND cohort, consisting of 940 newly diagnosed people with dementia, to explore the peri-diagnostic experiences of people living with dementia who identify as LGBTQ+. METHODS: We recruited five people (who identified as lesbian, gay or bisexual [LGB]) and completed semi-structured interviews with them and their partner caregivers (n = 3) discussing their experiences of (1) engaging with dementia health care services, (2) receiving a dementia diagnosis, and (3) the support they were offered after diagnosis. Interviews were shaped by the Candidacy Framework, a theoretical model for understanding accessibility of health services, and an inductive thematic analysis was employed to develop common themes. FINDINGS: Participants did not routinely disclose their LGBTQ+ identities to health service professionals, despite feeling this was an essential aspect of who they are. They relied on their resilience of overcoming previous experiences of lifetime discrimination to navigate complicated dementia care systems. The importance of 'chosen families' as informal support networks for LGBTQ+ people living with dementia was highlighted, particularly given the lack of formal care services they felt comfortable accessing. All participants were concerned about their future care needs and whether they would receive home-based or community-based support that respected their LGBTQ+ identities. CONCLUSIONS: This study adds to the limited evidence base that can be used to inform future research, policy and practice seeking to address inequalities across the dementia care pathway. We only interviewed people who identified as LGB so generalizability to the whole LGBTQ+ population is limited, however our data suggest dementia health care professionals should encourage and support disclosures of LGBTQ+ identities so that inclusive care and support planning can be provided to LGBTQ+ people at every stage of dementia.

Pinpointing prime structural attributes of potential MMP-2 inhibitors comprising alkyl/arylsulfonyl pyrrolidine scaffold: a ligand-based molecular modelling approach validated by molecular dynamics simulation analysis.

MMP-2 overexpression is strongly related to several diseases including cancer. However, none of the MMP-2 inhibitors have been marketed as drug candidates due to various adverse effects. Here, a set of sulphonyl pyrrolidines was subjected to validation of molecular modelling followed by binding mode analysis to explore the crucial structural features required for the discovery of promising MMP-2 inhibitors. This study revealed the importance of hydroxamate as a potential zinc-binding group compared to the esters. Importantly, hydrophobic and sterical substituents were found favourable at the terminal aryl moiety attached to the sulphonyl group. The binding interaction study revealed that the S1' pocket of MMP-2 similar to 'a basketball passing through a hoop' allows the aryl moiety for proper fitting and interaction at the active site to execute potential MMP-2 inhibition. Again, the sulphonyl pyrrolidine moiety can be a good fragment necessary for MMP-2 inhibition. Moreover, some novel MMP-2 inhibitors were also reported. They showed the significance of the 3rd position substitution of the pyrrolidine ring to produce interaction inside S2' pocket. The current study can assist in the design and development of potential MMP-2 inhibitors as effective drug candidates for the management of several diseases including cancers in the future.

Comparative Study on Clinical and Echocardiographic Findings in Ischemic Heart Disease Patients with or without Mitral Annular Calcification in a Tertiary Hospital.

The presence of bright resonance of more than 1 mm or more cusps of the aortic valve, mitral valve or mitral annulus is termed as cardiac valve calcification. If an intense echo producing structure located at the junction of the atrioventricular groove and posterior mitral valve leaflet on Echocardiography that is Mitral annular calcification (MAC). This study was conducted to observe the association of MAC with clinical and echocardiographic findings of ischemic heart disease (IHD) and the role of trans-thoracic echocardiography to detect MAC which is a marker IHD. In this prospective, observational, case-control study, total of 100 IHD patients, 50 patients with MAC were assigned as case group and 50 patients without MAC were control group after fulfilling inclusion criteria. All the detailed history, clinical examination and relevant investigation reports of each patient were recorded in pre designed data collection sheet. MAC was detected with transthorasic echocardiography. Analysis was done to observe the association and correlation of MAC with clinical findings of IHD. Mean age of the case control was 55.16±10.73 years and control was 49.80±8.84 years. MAC was noted highest about 56.0% in between age 45 to 60 years. Eighty two percent (82.0%) of cases and 84.0% of controls were male, 18.0% of cases and 16.0% of controls were female. BMI among the MAC group 2.0% were underweight, 72.0% normal, 24.0% over weight and 2.0% were obese and among non MAC controls group 10.0% were underweight, 68.0% normal, 20.0% over weight and 2.0% were obese. Clinically among cases 14(28.0%) had Stable angina, 8(16.0%) had UA, 3(6.0%) had Non STEMI, 2(4.0%) had AMI, 2(4.0%) had Recent myocardial infarction and 21(42.0%) had OMI. Diabetes mellitus was significantly higher in the case groups (p=0.006). Significant p-value was noted in hyper-triyglyceridemia and low HDL in case group than control. Echocardiographic studies showed 52.0% of cases and 32.0% of controls had regional wall motion abnormality (RWMA). Transthorasic echocardiographically detected MAC is an independent predictor of Ischemic heart disease. The low cost, portable and radiation free nature of the ultrasound approach make MAC an attractive parameter in the ongoing search for IHD.

Association of Serum Homocysteine Level with Parkinson's Disease.

Parkinson's disease (PD) is a chronic, progressive neurodegenerative disease with unknown etiology. Some previous studies suggest that elevated serum homocysteine level is a risk factor for stroke, ischemic heart disease; atherosclerosis and neurodegenerative diseases like Parkinson's disease. Serum homocysteine level relates with Parkinson's disease through various mechanisms including gene defect, apoptosis, oxidative stress and DNA damage. Some recent studies reveal that serum homocysteine level is elevated in Parkinson's disease patient compared to healthy individuals. This study was aimed to compare the serum homocysteine level in Parkinson's disease patients and age and sex matched apparently healthy individuals. This was a case control study which was conducted in Department of Neurology and Medicine, Mymensingh Medical College Hospital, Mymensingh during November 2019 to April 2021. Total 55 cases of Parkinson's disease patients and age and sex matched 55 apparently healthy controls were enrolled in this study. Demographics and clinical data were collected using structured case record form and adopting purposive type of sampling method. Serum homocysteine level was measured in both case and control groups. The study reveals that, average age of the patients and control group was in sixth decade. Male predominance was found with male to female ratio was 1.5:1 in case group. Both groups showed almost similar demographic profiles. Twenty-nine (52.72%) patients of Parkinson's disease observed higher serum homocysteine level in contrast to only 8(14.54%) in control group. The mean serum homocysteine ±SD was 15.43±6.04µmol/L in case group and 10.04±5.31µmol/L in control group; the difference was statistically significant (p=0.001). Mean serum homocysteine levels were measured progressively higher with increased duration and advanced stages of disease. It was concluded that, serum homocysteine level is higher in Parkinson's disease patients than normal healthy individuals. In addition, there was significant positive correlation of elevated serum homocysteine with increased duration of Parkinson's disease and advanced stages of the disease.

Fragment-based QSAR study to explore the structural requirements of DPP-4 inhibitors: a stepping stone towards better type 2 diabetes mellitus management.

Dipeptidyl peptidase-4 (DPP-4) inhibitors belong to a prominent group of pharmaceutical agents that are used in the governance of type 2 diabetes mellitus (T2DM). They exert their antidiabetic effects by inhibiting the incretin hormones like glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide which, play a pivotal role in the regulation of blood glucose homoeostasis in our body. DPP-4 inhibitors have emerged as an important class of oral antidiabetic drugs for the treatment of T2DM. Surprisingly, only a few 2D-QSAR studies have been reported on DPP-4 inhibitors. Here, fragment-based QSAR (Laplacian-modified Bayesian modelling and Recursive partitioning (RP) approaches have been utilized on a dataset of 108 DPP-4 inhibitors to achieve a deeper understanding of the association among their molecular structures. The Bayesian analysis demonstrated satisfactory ROC values for the training as well as the test sets. Meanwhile, the RP analysis resulted in decision tree 3 with 2 leaves (Tree 3: 2 leaves). This present study is an effort to get an insight into the pivotal fragments modulating DPP-4 inhibition.

Exploring different classification-dependent QSAR modelling strategies for HDAC3 inhibitors in search of meaningful structural contributors.

Histone deacetylase 3 (HDAC3), a Zn2+-dependent class I HDACs, contributes to numerous disorders such as neurodegenerative disorders, diabetes, cardiovascular disease, kidney disease and several types of cancers. Therefore, the development of novel and selective HDAC3 inhibitors might be promising to combat such diseases. Here, different classification-based molecular modelling studies such as Bayesian classification, recursive partitioning (RP), SARpy and linear discriminant analysis (LDA) were conducted on a set of HDAC3 inhibitors to pinpoint essential structural requirements contributing to HDAC3 inhibition followed by molecular docking study and molecular dynamics (MD) simulation analyses. The current study revealed the importance of hydroxamate function for Zn2+ chelation as well as hydrogen bonding interaction with Tyr298 residue. The importance of hydroxamate function for higher HDAC3 inhibition was noticed in the case of Bayesian classification, recursive partitioning and SARpy models. Also, the importance of substituted thiazole ring was revealed, whereas the presence of linear alkyl groups with carboxylic acid function, any type of ester function, benzodiazepine moiety and methoxy group in the molecular structure can be detrimental to HDAC3 inhibition. Therefore, this study can aid in the design and discovery of effective novel HDAC3 inhibitors in the future.

Heterotypic Seeding Generates Mixed Amyloid Polymorphs.

Aggregation of the amyloid ß (Aß) peptide into fibrils represents one of the major biochemical pathways underlying the development of Alzheimer's disease (AD). Extensive studies have been carried out to understand the role of fibrillar seeds on the overall kinetics of amyloid aggregation. However, the precise effect of seeds that are structurally or sequentially different from Aß on the structure of the resulting amyloid aggregates is yet to be fully understood. In this work, we use nanoscale infrared spectroscopy to probe the spectral facets of individual aggregates formed by aggregating Aß42 with antiparallel fibrillar seeds of Aß (16-22) and E22Q Aß (1-40) Dutch mutant and demonstrate that Aß can form heterotypic or mixed polymorphs that deviate significantly from its expected parallel cross ß structure. We further show that formation of heterotypic aggregates is not limited to coaggregation of Aß and its isomers, and that the former can form heterotypic fibrils with alpha synuclein and brain protein lysates. These findings highlight the complexity of Aß aggregation in AD and underscore the need to explore how Aß interacts with other brain components, which is crucial for developing better therapeutic strategies for AD.

COVID-19 Stroke Apical Lung Examination Study 2: a national prospective CTA biomarker study of the lung apices, in patients presenting with suspected acute stroke (COVID SALES 2).

BACKGROUND: Apical ground-glass opacification (GGO) identified on CT angiography (CTA) performed for suspected acute stroke was developed in 2020 as a coronavirus-disease-2019 (COVID-19) diagnostic and prognostic biomarker in a retrospective study during the first wave of COVID-19. OBJECTIVE: To prospectively validate whether GGO on CTA performed for suspected acute stroke is a reliable COVID-19 diagnostic and prognostic biomarker and whether it is reliable for COVID-19 vaccinated patients. METHODS: In this prospective, pragmatic, national, multi-center validation study performed at 13 sites, we captured study data consecutively in patients undergoing CTA for suspected acute stroke from January-March 2021. Demographic and clinical features associated with stroke and COVID-19 were incorporated. The primary outcome was the likelihood of reverse-transcriptase-polymerase-chain-reaction swab-test-confirmed COVID-19 using the GGO biomarker. Secondary outcomes investigated were functional status at discharge and survival analyses at 30 and 90 days. Univariate and multivariable statistical analyses were employed. RESULTS: CTAs from 1,111 patients were analyzed, with apical GGO identified in 8.5 % during a period of high COVID-19 prevalence. GGO showed good inter-rater reliability (Fleiss κ = 0.77); and high COVID-19 specificity (93.7 %, 91.8-95.2) and negative predictive value (NPV; 97.8 %, 96.5-98.6). In subgroup analysis of vaccinated patients, GGO remained a good diagnostic biomarker (specificity 93.1 %, 89.8-95.5; NPV 99.7 %, 98.3-100.0). Patients with COVID-19 were more likely to have higher stroke score (NIHSS (mean +/- SD) 6.9 +/- 6.9, COVID-19 negative, 9.7 +/- 9.0, COVID-19 positive; p = 0.01), carotid occlusions (6.2 % negative, 14.9 % positive; p = 0.02), and larger infarcts on presentation CT (ASPECTS 9.4 +/- 1.5, COVID-19 negative, 8.6 +/- 2.4, COVID-19 positive; p = 0.00). After multivariable logistic regression, GGO (odds ratio 15.7, 6.2-40.1), myalgia (8.9, 2.1-38.2) and higher core body temperature (1.9, 1.1-3.2) were independent COVID-19 predictors. GGO was associated with worse functional outcome on discharge and worse survival after univariate analysis. However, after adjustment for factors including stroke severity, GGO was not independently predictive of functional outcome or mortality. CONCLUSION: Apical GGO on CTA performed for patients with suspected acute stroke is a reliable diagnostic biomarker for COVID-19, which in combination with clinical features may be useful in COVID-19 triage.

ESGO-ESMO-ESP consensus conference recommendations on ovarian cancer: pathology and molecular biology and early, advanced and recurrent disease.

The European Society of Gynaecological Oncology, the European Society for Medical Oncology (ESMO) and the European Society of Pathology held a consensus conference (CC) on ovarian cancer on 15-16 June 2022 in Valencia, Spain. The CC panel included 44 experts in the management of ovarian cancer and pathology, an ESMO scientific advisor and a methodologist. The aim was to discuss new or contentious topics and develop recommendations to improve and harmonise the management of patients with ovarian cancer. Eighteen questions were identified for discussion under four main topics: (i) pathology and molecular biology, (ii) early-stage disease and pelvic mass in pregnancy, (iii) advanced stage (including older/frail patients) and (iv) recurrent disease. The panel was divided into four working groups (WGs) to each address questions relating to one of the four topics outlined above, based on their expertise. Relevant scientific literature was reviewed in advance. Recommendations were developed by the WGs and then presented to the entire panel for further discussion and amendment before voting. This manuscript focuses on the recommendation statements that reached a consensus, their voting results and a summary of evidence supporting each recommendation.

Exploring crucial structural attributes of quinolinyl methoxyphenyl sulphonyl-based hydroxamate derivatives as ADAM17 inhibitors through classification-dependent molecular modelling approaches.

A Disintegrin and Metalloproteinase 17 (ADAM17), a Zn2+-dependent metalloenzyme of the adamalysin family of the metzincin superfamily, is associated with various pathophysiological conditions including rheumatoid arthritis and cancer. However, no specific inhibitors have been marketed yet for ADAM17-related disorders. In this study, 94 quinolinyl methoxyphenyl sulphonyl-based hydroxamates as ADAM17 inhibitors were subjected to classification-based molecular modelling and binding pattern analysis to identify the significant structural attributes contributing to ADAM17 inhibition. The statistically validated classification-based models identified the importance of the P1' substituents such as the quinolinyl methoxyphenyl sulphonyl group of these compounds for occupying the S1' - S3' pocket of the enzyme. The quinolinyl function of these compounds was found to explore stable binding of the P1' substituents at the S1' - S3' pocket whereas the importance of the sulphonyl and the orientation of the P1' moiety also revealed stable binding. Based on the outcomes of the current study, four novel compounds of different classes were designed as promising ADAM17 inhibitors. These findings regarding the crucial structural aspects and binding patterns of ADAM17 inhibitors will aid the design and discovery of novel and effective ADAM17 inhibitors for therapeutic advancements of related diseases.

Association of Serum Magnesium Level with Severity of Neurological Disability in Patients with Acute Ischemic Stroke.

Magnesium (Mg) has important effects on vascular system and deficiency of this cation is thought to be a risk factor for cerebrovascular atherosclerosis and complications. The study was planned to find out the association of serum magnesium level with severity of neurological disability in patient with acute ischemic stroke. This cross-sectional descriptive study was conducted in the department of Neurology and Medicine at Mymensingh Medical College & Hospital, Mymensingh from June, 2018 to October, 2019. Patients with acute ischemic stroke were evaluated following informed written consent. Diagnosis was confirmed by neuroimaging of brain. Moreover, serum magnesium assay was done for each patient. Data were collected by interview, clinical examination and laboratory investigations of patients using a case record form and analysis was carried out by using the SPSS 22.0 (IBM Inc., Armonk, NY, USA). Mean age of acute ischemic stroke patients was 63.94±13.93 years with male predominance (58.30%). Majority of the respondents (70.2%) had NIH Stroke Scale (NIHSS) score 5-15 (moderate stroke), 13.1% had score 1-5 (minor stroke), 13.1% had score15-20 (Moderate to severe stroke) and 3.6% had score 21-42 (severe stroke). Mean serum magnesium level was 1.83±0.283mg/dl. Hypomagnesaemia was present in 28(33.3%) patients and it was related with higher NIHSS scoring (p<0.05). Multiple regression showed that among the risk factors, serum magnesium level was independently associated with severity of neurological disability of the acute ischemic stroke (p<0.001). In this study, the correlation coefficient between serum magnesium level and NIHSS score was found as r= - 0.667 which showed negative relationship between serum magnesium and NIHSS score. Lower serum magnesium level is associated with the severity of neurological disability of acute ischemic stroke patient. Further case-control studies are required to validate this finding.

The inclusion of adults with intellectual disabilities in health research - challenges, barriers and opportunities: a mixed-method study among stakeholders in England.

BACKGROUND: The study aims to understand system barriers to research participation for people with intellectual disabilities. METHODS: A mixed-methods approach examined the inclusivity of people with intellectual disabilities (IDs) in a random sample of National Institute for Health and Care Research (NIHR) studies conducted in 2019-2020. An online questionnaire (stage 1) was sent to the selected studies lead investigators. An expert by experience panel of 25 people with intellectual disabilities (IDs, stage 2), discussed the stage 1 feedback. Descriptive statistics for quantitative data and thematic analysis for qualitative data was conducted. RESULTS: Of 180 studies reviewed, 131 studies (78%) excluded people with IDs. Of these, 45 (34.3%) study researchers provided feedback. Seven (20%) of the 34 studies which included people with IDs gave feedback. Of all respondents over half felt their study had some relevance to people with IDs. A minority (7.6%) stated their study had no relevance. For a quarter of respondents (23.5%), resource issues were a challenge. Qualitative analysis of both stages produced four overarching themes of Research design and delivery, Informed consent, Resource allocation, and Knowledge and skills. CONCLUSION: Health research continues to exclude people with IDs. Researchers and experts by experience identified non-accessible research design, lack of confidence with capacity and consent processes, limited resources such as time and a need for training as barriers. Ethics committees appear reluctant to include people with cognitive deficits to 'protect' them. People with IDs want to be included in research, not only as participants but also through coproduction.

Probing the strongly correlated magnetic state of Co2C nanoparticles at low temperatures usingµSR.

Co2C nanoparticles (NPs) are amongst transition metal carbides whose magnetic properties have not been well explored. An earlier study (Royet al2021J. Phys.: Condens. Matter33375804) showed that a pellet made from Co2C NPs exhibits exchange bias (EB) effect below a temperature,TEB= 50 K and a spin glass (SG) feature emerges belowTSG= 5 K. In the current study we use magnetic, electrical transport, specific heat, and muon spin rotation (µSR) measurements to explore further the magnetic properties of a pellet made with 40 nm diameter pure Co2C NPs. We uncover the onset of Kondo localization at Kondo temperatureTK(= 40.1 K), which is close to the onset temperature (TEB) of the EB effect. A crossover from the Kondo-screened scenario to the Ruderman-Kittel-Kasuya-Yosida interaction-dominated regime is also observed forT

Assessing structural insights into in-house arylsulfonyl L-(+) glutamine MMP-2 inhibitors as promising anticancer agents through structure-based computational modelling approaches.

MMP-2 is potentially contributing to several cancer progressions including leukaemias. Therefore, considering MMP-2 as a promising target, novel anticancer compounds may be designed. Here, 32 in-house arylsulfonyl L-(+) glutamines were subjected to various structure-based computational modelling approaches to recognize crucial structural attributes along with the spatial orientation for higher MMP-2 inhibition. Again, the docking-based 2D-QSAR study revealed that the Coulomb energy conferred by Tyr142 and total interaction energy conferred by Ala84 was crucial for MMP-2 inhibition. Importantly, the docking-dependent CoMFA and CoMSIA study revealed the importance of favourable steric, electrostatic, and hydrophobic substituents at the terminal phenyl ring. The MD simulation study revealed a lower fluctuation in the RMSD, RMSF, and Rg values indicating stable binding interactions of MMP-2 and these molecules. Moreover, the residual hydrogen bond and their interaction analysis disclosed crucial amino acid residues responsible for forming potential hydrogen bonding for higher MMP-2 inhibition. The results can effectively aid in the design and discovery of promising small-molecule drug-like MMP-2 inhibitors with greater anticancer potential in the future.

Relation of Neutrophil-Lymphocyte Ratio with Clinical Severity in Patients with Guillain-Barre Syndrome.

Guillain-Barre syndrome (GBS) is an acute autoimmune polyradiculoneuropathy. Neutrophil-lymphocyte ratio (NLR) is a novel prognostic and inflammatory marker in patients with neurological diseases. The study was designed to observe the relation between neutrophil lymphocyte ratio and the clinical severity in patients with Guillain-Barre Syndrome (GBS). This cross-sectional descriptive study was conducted at the department of Neurology and Medicine, Mymensingh Medical College and Hospital from April 2019 to September 2020. Total 58 patients with GBS were enrolled according to the inclusion and exclusion criteria within 7 days of development of symptoms. The clinical diagnosis of GBS was done according to Ausbury and Cornblath's diagnostic criteria; moreover clinical severity was done according to Hughes and Rees scale, Medical Research Council (MRC) grade, cranial nerve involvement and autonomic involvement. After measuring complete blood count, NLR was calculated by dividing neutrophil count to lymphocyte count. Data analysis was done on SPSS 23.0. Mean age of the GBS patients was 36.21±11.55 years. Among 58 respondents 70.69% (41) were male and 29.31% (17) were female. Most of the patients had a GBS severity score of 4(62.07%) followed by 3(27.59%) and 5(10.34%). The mean NLR of the respondents was 3.22±2.25. Acute motor axonal neuropathy (AMAN) was in 48.28% respondents and their mean NLR was 3.89±0.31, 31.03% had AIDP and mean NLR was 3.28±0.46 and 20.69% had Acute motor sensory axonal neuropathy (AMSAN) and mean NLR was 4.5±0.52. The mean NLR of the MRC grade 0, 1, 2, 3 patients was 6.61±1.78, 3.39±0.92, 2.71±1.39 and 1.45±0.40 respectively. Hughes score had a positive correlation (r=0.5333 and p<0.01) and MRC grade had a negative correlation (r= - 0.76805 and p<0.01) with NLR. Severity of GBS was significantly associated with raised NLR. Increase Hughes and Rees scale and decrease MRC grade also related to increased NLR.