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Synthesis and Antitumor Evaluation of Glutathione Responsive Self-Immolative Disulphide Linked Camptothecin-Biotin Conjugate

Kaur A, Dhiman S, Lee HB, Sharma M

Anticancer Agents Med Chem, 2022;22(18):3182-3192.
PMID: 35469577 DOI: 10.2174/1871520622666220425114553

BACKGROUND: Camptothecin is a naturally occurring alkaloid obtained from the stem wood of the Chinese tree, Camptotheca acuminata. It exerts pharmacological effects due to its ability to selectively inhibit the type-I topoisomerase DNA nuclear enzyme. Several semisynthetic analogs of camptothecin have been synthesized to date possessing antitumor activity.
OBJECTIVE: Camptothecin (CPT) is one of the most promising anticancer drugs but it produces various side effects because of its non-selectivity towards cancer cells. To overcome these adverse effects, we synthesized biotin conjugate of camptothecin, which was linked via a self-immolative disulfide linker (CPT-SS-Biotin).
METHODS: Biotin conjugated camptothecin linked through a disulfide bond was synthesized following schemes, and the structural characterization was carried out. The stability and drug release studies were performed in the presence of glutathione (GSH) while in vitro studies were performed on 4T1 tumor cell lines. In vivo pharmacological investigation was done using an antitumor Wistar rat model.
RESULTS: The stability and drug release studies were performed in the presence of glutathione (GSH), and CPT-SSBiotin was found to be physiologically stable moiety and can only be cleaved in the presence of GSH to release free CPT. The CPT-SS-Biotin showed higher toxicity in the biotin-overexpressing 4T1 tumor cell line with a lower IC50 value (8.44 μM) compared to camptothecin alone (IC50 > 30 μM). CPT-SS-Biotin also showed 10.6% higher cellular uptake by cells in comparison to free camptothecin. The CPT-SS-Biotin was delivered to cells by binding to the biotin receptors on the cell surface, followed by energy-dependent endocytosis and internalization to cause cellular toxicity.
CONCLUSION: In-vivo tumor suppression studies and in vitro cell line studies along with serological parameters and histopathological studies showed that conjugate produced a high therapeutic effect and remarkably reduced toxic effects in comparison to free CPT. The results suggested that biotinylation of camptothecin via disulfide linker can be a safe and efficacious method in cancer therapeutics.
Role of Yes-associated protein and transcriptional coactivator with PDZ-binding motif in the malignant transformation of oral submucous fibrosis

Sharma M, Hunter KD, Fonseca FP, Shetty SS, Radhakrishnan R

Arch Oral Biol, 2021 Aug;128:105164.
PMID: 34044344 DOI: 10.1016/j.archoralbio.2021.105164

OBJECTIVE(S): The objective of the present manuscript is to elucidate the role of matrix stiffness in the malignant transformation of oral submucous fibrosis.
DESIGN: The role of matrix stiffness in several cancers including oral cancer was reviewed with a tailored search strategy using relevant keywords as per the Medline format. The role of molecular mediators, Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) was weighed in the context of OSF along two distinct pathways.
RESULTS: Increased matrix stiffness activates the transcriptional coactivators, YAP and TAZ shuttling between the nucleus and cytoplasm. YAP and TAZ, serve as mechanical transducers in promoting cell migration, invasion and epithelial-mesenchymal transition (EMT). The hypoxic microenvironment in the advanced stage of OSF promotes the migratory phenotype through mechanical memory.
CONCLUSIONS: Reprogramming of a stiff matrix has the potential to restore the Hippo-YAP/TAZ tumor suppressor pathway and reverse fibrosis-associated tumor development.
Fulltext Mapping quantitative trait loci (QTLs) for fatty acid composition in an interspecific cross of oil palm

Singh R, Tan SG, Panandam JM, Rahman RA, Ooi LC, Low ET, et al.

BMC Plant Biol, 2009;9:114.
PMID: 19706196 DOI: 10.1186/1471-2229-9-114

Marker Assisted Selection (MAS) is well suited to a perennial crop like oil palm, in which the economic products are not produced until several years after planting. The use of DNA markers for selection in such crops can greatly reduce the number of breeding cycles needed. With the use of DNA markers, informed decisions can be made at the nursery stage, regarding which individuals should be retained as breeding stock, which are satisfactory for agricultural production, and which should be culled. The trait associated with oil quality, measured in terms of its fatty acid composition, is an important agronomic trait that can eventually be tracked using molecular markers. This will speed up the production of new and improved oil palm planting materials.
Fulltext Rationale and design for the detection and neurological impact of cerebrovascular events in non-cardiac surgery patients cohort evaluation (NeuroVISION) study: a prospective international cohort study

Mrkobrada M, Chan MTV, Cowan D, Spence J, Campbell D, Wang CY, et al.

BMJ Open, 2018 07 06;8(7):e021521.
PMID: 29982215 DOI: 10.1136/bmjopen-2018-021521

OBJECTIVES: Covert stroke after non-cardiac surgery may have substantial impact on duration and quality of life. In non-surgical patients, covert stroke is more common than overt stroke and is associated with an increased risk of cognitive decline and dementia. Little is known about covert stroke after non-cardiac surgery.NeuroVISION is a multicentre, international, prospective cohort study that will characterise the association between perioperative acute covert stroke and postoperative cognitive function.
SETTING AND PARTICIPANTS: We are recruiting study participants from 12 tertiary care hospitals in 10 countries on 5 continents.
PARTICIPANTS: We are enrolling patients ≥65 years of age, requiring hospital admission after non-cardiac surgery, who have an anticipated length of hospital stay of at least 2 days after elective non-cardiac surgery that occurs under general or neuraxial anaesthesia.
PRIMARY AND SECONDARY OUTCOME MEASURES: Patients are recruited before elective non-cardiac surgery, and their cognitive function is measured using the Montreal Cognitive Assessment (MoCA) instrument. After surgery, a brain MRI study is performed between postoperative days 2 and 9 to determine the presence of acute brain infarction. One year after surgery, the MoCA is used to assess postoperative cognitive function. Physicians and patients are blinded to the MRI study results until after the last patient follow-up visit to reduce outcome ascertainment bias.We will undertake a multivariable logistic regression analysis in which the dependent variable is the change in cognitive function 1 year after surgery, and the independent variables are acute perioperative covert stroke as well as other clinical variables that are associated with cognitive dysfunction.
CONCLUSIONS: The NeuroVISION study will characterise the epidemiology of covert stroke and its clinical consequences. This will be the largest and the most comprehensive study of perioperative stroke after non-cardiac surgery.
TRIAL REGISTRATION NUMBER: NCT01980511; Pre-results.
Synthesis of lantadene analogs with marked in vitro inhibition of lung adenocarcinoma and TNF-α induced nuclear factor-kappa B (NF-κB) activation

Monika, Sharma A, Suthar SK, Aggarwal V, Lee HB, Sharma M

Bioorg Med Chem Lett, 2014 Aug 15;24(16):3814-8.
PMID: 25027934 DOI: 10.1016/j.bmcl.2014.06.068

The new series of pentacyclic triterpenoids reduced lantadene A (3), B (4), and 22β-hydroxy-3-oxo-olean-12-en-28-oic acid (5) analogs were synthesized and tested in vitro for their NF-κB and IKKβ inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead analog (11) showed sub-micromolar activity against TNF-α induced activation of NF-κB and exhibited inhibition of IKKβ in a single-digit micromolar dose. At the same time, 11 showed promising cytotoxicity against A549 lung cancer cells with IC50 of 0.98 μM. The Western blot analysis further showed that the suppression of NF-κB activity by the lead analog 11 was due to the inhibition of IκBα degradation, a natural inhibitor of NF-κB. The physicochemical evaluation demonstrated that the lead analog 11 was stable in the simulated gastric fluid of pH 2, while hydrolyzed at a relatively higher rate in the human blood plasma to release the active parent moieties. Molecular docking analysis showed that 11 was hydrogen bonded with the Arg-31 and Gln-110 residues of the IKKβ.
Luteolin: a flavonoid with a multifaceted anticancer potential

Prasher P, Sharma M, Singh SK, Gulati M, Chellappan DK, Zacconi F, et al.

Cancer Cell Int, 2022 Dec 08;22(1):386.
PMID: 36482329 DOI: 10.1186/s12935-022-02808-3

Therapeutic effect of phytochemicals has been emphasized in the traditional medicine owing to the presence of bioactive molecules, such as polyphenols. Luteolin is a flavone belonging to the flavonoid class of polyphenolic phytochemicals with healing effect on hypertension, inflammatory disorders, and cancer due to its action as pro-oxidants and antioxidants. The anticancer profile of luteolin is of interest due to the toxic effect of contemporary chemotherapy paradigm, leading to the pressing need for the development and identification of physiologically benevolent anticancer agents and molecules. Luteolin exerts anticancer activity by downregulation of key regulatory pathways associated with oncogenesis, in addition to the induction of oxidative stress, cell cycle arrest, upregulation of apoptotic genes, and inhibition of cell proliferation and angiogenesis in cancer cells. In this review, we discuss about the anticancer profile of luteolin.
Fulltext Plants derived therapeutic strategies targeting chronic respiratory diseases: Chemical and immunological perspective

Prasher P, Sharma M, Mehta M, Paudel KR, Satija S, Chellappan DK, et al.

Chem Biol Interact, 2020 Jul 01;325:109125.
PMID: 32376238 DOI: 10.1016/j.cbi.2020.109125

The apparent predicament of the representative chemotherapy for managing respiratory distress calls for an obligatory deliberation for identifying the pharmaceuticals that effectively counter the contemporary intricacies associated with target disease. Multiple, complex regulatory pathways manifest chronic pulmonary disorders, which require chemotherapeutics that produce composite inhibitory effect. The cost effective natural product based molecules hold a high fervor to meet the prospects posed by current respiratory-distress therapy by sparing the tedious drug design and development archetypes, present a robust standing for the possible replacement of the fading practice of poly-pharmacology, and ensure the subversion of a potential disease relapse. This study summarizes the experimental evidences on natural products moieties and their components that illustrates therapeutic efficacy on respiratory disorders.
Cationic cycloamylose based nucleic acid nanocarriers

Prasher P, Sharma M, Agarwal V, Singh SK, Gupta G, Dureja H, et al.

Chem Biol Interact, 2024 Apr 12;395:111000.
PMID: 38614318 DOI: 10.1016/j.cbi.2024.111000

Nucleic acid delivery by viral and non-viral methods has been a cornerstone for the contemporary gene therapy aimed at correcting the defective genes, replacing of the missing genes, or downregulating the expression of anomalous genes is highly desirable for the management of various diseases. Ostensibly, it becomes paramount for the delivery vectors to intersect the biological barriers for accessing their destined site within the cellular environment. However, the lipophilic nature of biological membranes and their potential to limit the entry of large sized, charged, hydrophilic molecules thus presenting a sizeable challenge for the cellular integration of negatively charged nucleic acids. Furthermore, the susceptibility of nucleic acids towards the degrading enzymes (nucleases) in the lysosomes present in cytoplasm is another matter of concern for their cellular and nuclear delivery. Hence, there is a pressing need for the identification and development of cationic delivery systems which encapsulate the cargo nucleic acids where the charge facilitates their cellular entry by evading the membrane barriers, and the encapsulation shields them from the enzymatic attack in cytoplasm. Cycloamylose bearing a closed loop conformation presents a robust candidature in this regard owing to its remarkable encapsulating tendency towards nucleic acids including siRNA, CpG DNA, and siRNA. The presence of numerous hydroxyl groups on the cycloamylose periphery provides sites for its chemical modification for the introduction of cationic groups, including spermine, (3-Chloro-2 hydroxypropyl) trimethylammonium chloride (Q188), and diethyl aminoethane (DEAE). The resulting cationic cycloamylose possesses a remarkable transfection efficiency and provides stability to cargo oligonucleotides against endonucleases, in addition to modulating the undesirable side effects such as unwanted immune stimulation. Cycloamylose is known to interact with the cell membranes where they release certain membrane components such as phospholipids and cholesterol thereby resulting in membrane destabilization and permeabilization. Furthermore, cycloamylose derivatives also serve as formulation excipients for improving the efficiency of other gene delivery systems. This review delves into the various vector and non-vector-based gene delivery systems, their advantages, and limitations, eventually leading to the identification of cycloamylose as an ideal candidate for nucleic acid delivery. The synthesis of cationic cycloamylose is briefly discussed in each section followed by its application for specific delivery/transfection of a particular nucleic acid.
Fulltext Review of global neurosurgery education: Horizon of Neurosurgery in the Developing Countries

Kato Y, Liew BS, Sufianov AA, Rasulic L, Arnautovic KI, Dong VH, et al.

Chinese neurosurgical journal, 2020;6:19.
PMID: 32922948 DOI: 10.1186/s41016-020-00194-1

Globally, the discipline of neurosurgery has evolved remarkably fast. Despite being one of the latest medical specialties, which appeared only around hundred years ago, it has witnessed innovations in the aspects of diagnostics methods, macro and micro surgical techniques, and treatment modalities. Unfortunately, this development is not evenly distributed between developed and developing countries. The same is the case with neurosurgical education and training, which developed from only traditional apprentice programs in the past to more structured, competence-based programs with various teaching methods being utilized, in recent times. A similar gap can be observed between developed and developing counties when it comes to neurosurgical education. Fortunately, most of the scholars working in this field do understand the coherent relationship between neurosurgical education and neurosurgical practice. In context to this understanding, a symposium was organized during the World Federation of Neurological Surgeons (WFNS) Special World Congress Beijing 2019. This symposium was the brain child of Prof. Yoko Kato-one of the eminent leaders in neurosurgery and an inspiration for female neurosurgeons. Invited speakers from different continents presented the stages of development of neurosurgical education in their respective countries. This paper summarizes the outcome of these presentations, with particular emphasis on and the challenges faced by developing countries in terms of neurosurgical education and strategies to cope with these challenges.
Fulltext Correction to: Review of global neurosurgery education: Horizon of Neurosurgery in the Developing Countries

Kato Y, Liew BS, Sufianov AA, Rasulic L, Arnautovic KI, Dong VH, et al.

Chinese neurosurgical journal, 2020;6:30.
PMID: 32925985 DOI: 10.1186/s41016-020-00209-x

[This corrects the article DOI: 10.1186/s41016-020-00194-1.].
An accurate sleep stages classification system using a new class of optimally time-frequency localized three-band wavelet filter bank

Sharma M, Goyal D, Achuth PV, Acharya UR

Comput Biol Med, 2018 07 01;98:58-75.
PMID: 29775912 DOI: 10.1016/j.compbiomed.2018.04.025

Sleep related disorder causes diminished quality of lives in human beings. Sleep scoring or sleep staging is the process of classifying various sleep stages which helps to detect the quality of sleep. The identification of sleep-stages using electroencephalogram (EEG) signals is an arduous task. Just by looking at an EEG signal, one cannot determine the sleep stages precisely. Sleep specialists may make errors in identifying sleep stages by visual inspection. To mitigate the erroneous identification and to reduce the burden on doctors, a computer-aided EEG based system can be deployed in the hospitals, which can help identify the sleep stages, correctly. Several automated systems based on the analysis of polysomnographic (PSG) signals have been proposed. A few sleep stage scoring systems using EEG signals have also been proposed. But, still there is a need for a robust and accurate portable system developed using huge dataset. In this study, we have developed a new single-channel EEG based sleep-stages identification system using a novel set of wavelet-based features extracted from a large EEG dataset. We employed a novel three-band time-frequency localized (TBTFL) wavelet filter bank (FB). The EEG signals are decomposed using three-level wavelet decomposition, yielding seven sub-bands (SBs). This is followed by the computation of discriminating features namely, log-energy (LE), signal-fractal-dimensions (SFD), and signal-sample-entropy (SSE) from all seven SBs. The extracted features are ranked and fed to the support vector machine (SVM) and other supervised learning classifiers. In this study, we have considered five different classification problems (CPs), (two-class (CP-1), three-class (CP-2), four-class (CP-3), five-class (CP-4) and six-class (CP-5)). The proposed system yielded accuracies of 98.3%, 93.9%, 92.1%, 91.7%, and 91.5% for CP-1 to CP-5, respectively, using 10-fold cross validation (CV) technique.
Application of an optimal class of antisymmetric wavelet filter banks for obstructive sleep apnea diagnosis using ECG signals

Sharma M, Agarwal S, Acharya UR

Comput Biol Med, 2018 09 01;100:100-113.
PMID: 29990643 DOI: 10.1016/j.compbiomed.2018.06.011

Obstructive sleep apnea (OSA) is a sleep disorder caused due to interruption of breathing resulting in insufficient oxygen to the human body and brain. If the OSA is detected and treated at an early stage the possibility of severe health impairment can be mitigated. Therefore, an accurate automated OSA detection system is indispensable. Generally, OSA based computer-aided diagnosis (CAD) system employs multi-channel, multi-signal physiological signals. However, there is a great need for single-channel bio-signal based low-power, a portable OSA-CAD system which can be used at home. In this study, we propose single-channel electrocardiogram (ECG) based OSA-CAD system using a new class of optimal biorthogonal antisymmetric wavelet filter bank (BAWFB). In this class of filter bank, all filters are of even length. The filter bank design problem is transformed into a constrained optimization problem wherein the objective is to minimize either frequency-spread for the given time-spread or time-spread for the given frequency-spread. The optimization problem is formulated as a semi-definite programming (SDP) problem. In the SDP problem, the objective function (time-spread or frequency-spread), constraints of perfect reconstruction (PR) and zero moment (ZM) are incorporated in their time domain matrix formulations. The global solution for SDP is obtained using interior point algorithm. The newly designed BAWFB is used for the classification of OSA using ECG signals taken from the physionet's Apnea-ECG database. The ECG segments of 1 min duration are decomposed into six wavelet subbands (WSBs) by employing the proposed BAWFB. Then, the fuzzy entropy (FE) and log-energy (LE) features are computed from all six WSBs. The FE and LE features are classified into normal and OSA groups using least squares support vector machine (LS-SVM) with 35-fold cross-validation strategy. The proposed OSA detection model achieved the average classification accuracy, sensitivity, specificity and F-score of 90.11%, 90.87% 88.88% and 0.92, respectively. The performance of the model is found to be better than the existing works in detecting OSA using the same database. Thus, the proposed automated OSA detection system is accurate, cost-effective and ready to be tested with a huge database.
A novel automated diagnostic system for classification of myocardial infarction ECG signals using an optimal biorthogonal filter bank

Sharma M, Tan RS, Acharya UR

Comput Biol Med, 2018 11 01;102:341-356.
PMID: 30049414 DOI: 10.1016/j.compbiomed.2018.07.005

Myocardial infarction (MI), also referred to as heart attack, occurs when there is an interruption of blood flow to parts of the heart, due to the acute rupture of atherosclerotic plaque, which leads to damage of heart muscle. The heart muscle damage produces changes in the recorded surface electrocardiogram (ECG). The identification of MI by visual inspection of the ECG requires expert interpretation, and is difficult as the ECG signal changes associated with MI can be short in duration and low in magnitude. Hence, errors in diagnosis can lead to delay the initiation of appropriate medical treatment. To lessen the burden on doctors, an automated ECG based system can be installed in hospitals to help identify MI changes on ECG. In the proposed study, we develop a single-channel single lead ECG based MI diagnostic system validated using noisy and clean datasets. The raw ECG signals are taken from the Physikalisch-Technische Bundesanstalt database. We design a novel two-band optimal biorthogonal filter bank (FB) for analysis of the ECG signals. We present a method to design a novel class of two-band optimal biorthogonal FB in which not only the product filter but the analysis lowpass filter is also a halfband filter. The filter design problem has been composed as a constrained convex optimization problem in which the objective function is a convex combination of multiple quadratic functions and the regularity and perfect reconstruction conditions are imposed in the form linear equalities. ECG signals are decomposed into six subbands (SBs) using the newly designed wavelet FB. Following to this, discriminating features namely, fuzzy entropy (FE), signal-fractal-dimensions (SFD), and renyi entropy (RE) are computed from all the six SBs. The features are fed to the k-nearest neighbor (KNN). The proposed system yields an accuracy of 99.62% for the noisy dataset and an accuracy of 99.74% for the clean dataset, using 10-fold cross validation (CV) technique. Our MI identification system is robust and highly accurate. It can thus be installed in clinics for detecting MI.
Development of solid dispersion systems of dapivirine to enhance its solubility

Gorajana A, Ying CC, Shuang Y, Fong P, Tan Z, Gupta J, et al.

Curr Drug Deliv, 2013 Jun;10(3):309-16.
PMID: 23360246

Dapivirine, formerly known as TMC 120, is a poorly-water soluble anti-HIV drug, currently being developed as a vaginal microbicide. The clinical use of this drug has been limited due to its poor solubility. The aim of this study was to design solid dispersion systems of Dapivirine to improve its solubility. Solid dispersions were prepared by solvent and fusion methods. Dapivirine release from the solid dispersion system was determined by conducting in-vitro dissolution studies. The physicochemical characteristics of the drug and its formulation were studied using Differential Scanning Calorimetry (DSC), powder X-ray Diffraction (XRD), Fourier-transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). A significant improvement in drug dissolution rate was observed with the solid dispersion systems. XRD, SEM and DSC results indicated the transformation of pure Dapivirine which exists in crystalline form into an amorphous form in selected solid dispersion formulations. FTIR and HPLC analysis confirmed the absence of drug-excipient interactions. Solid dispersion systems can be used to improve the dissolution rate of Dapivirine. This improvement could be attributed to the reduction or absence of drug crystallinity, existence of drug particles in an amorphous form and improved wettability of the drug.
Recent Trends in Rationally Designed Molecules as Kinase Inhibitors

Prasher P, Sharma M, Chan Y, Singh SK, Anand K, Dureja H, et al.

Curr Med Chem, 2023;30(13):1529-1567.
PMID: 34766883 DOI: 10.2174/0929867328666211111161811

Protein kinases modulate the structure and function of proteins by adding phosphate groups to threonine, tyrosine, and serine residues. The phosphorylation process mediated by the kinases regulates several physiological processes, while their overexpression results in the development of chronic diseases, including cancer. Targeting of receptor tyrosine kinase pathways results in the inhibition of angiogenesis and cell proliferation that validates kinases as a key target in the management of aggressive cancers. As such, the identification of protein kinase inhibitors revolutionized the contemporary anticancer therapy by inducing a paradigm shift in the management of disease pathogenesis. Contemporary drug design programs focus on a broad range of kinase targets for the development of novel pharmacophores to manage the overexpression of kinases and their pathophysiology in cancer pathogenesis. In this review, we present the emerging trends in the development of rationally designed molecular inhibitors of kinases over the last five years (2016-2021) and their incipient role in the development of impending anticancer pharmaceuticals.
Probing 3CL protease: Rationally designed chemical moieties for COVID-19

Sharma M, Prasher P, Mehta M, Zacconi FC, Singh Y, Kapoor DN, et al.

Drug Dev Res, 2020 Jul 30.
PMID: 32729640 DOI: 10.1002/ddr.21724
Hybrid molecules based on 1,3,5-triazine as potential therapeutics: A focused review

Prasher P, Sharma M, Aljabali AAA, Gupta G, Negi P, Kapoor DN, et al.

Drug Dev Res, 2020 11;81(7):837-858.
PMID: 32579723 DOI: 10.1002/ddr.21704

Majority of the representative drugs customarily interact with multiple targets manifesting unintended side effects. In addition, drug resistance and over expression of the cellular efflux-pumps render certain classes of drugs ineffective. With only a few innovative formulations in development, it is necessary to identify pharmacophores and novel strategies for creating new drugs. The conjugation of dissimilar pharmacophoric moieties to design hybrid molecules with an attractive therapeutic profile is an emerging paradigm in the contemporary drug development regime. The recent decade witnessed the remarkable biological potential of 1,3,5-triazine framework in the development of various chemotherapeutics. The appending of the 1,3,5-triazine nucleus to biologically relevant moieties has delivered exciting results. The present review focuses on 1,3,5-triazine based hybrid molecules in the development of pharmaceuticals.
Fulltext An international, multi-institution survey of the use of EUS in the diagnosis of pancreatic cystic lesions

Ge N, Brugge WR, Saxena P, Sahai A, Adler DG, Giovannini M, et al.

Endosc Ultrasound, 2019 9 26;8(6):418-427.
PMID: 31552915 DOI: 10.4103/eus.eus_61_19

Background and Objectives: Currently, pancreatic cystic lesions (PCLs) are recognized with increasing frequency and have become a more common finding in clinical practice. EUS is challenging in the diagnosis of PCLs and evidence-based decisions are lacking in its application. This study aimed to develop strong recommendations for the use of EUS in the diagnosis of PCLs, based on the experience of experts in the field.
Methods: A survey regarding the practice of EUS in the evaluation of PCLs was drafted by the committee member of the International Society of EUS Task Force (ISEUS-TF). It was disseminated to experts of EUS who were also members of the ISEUS-TF. In some cases, percentage agreement with some statements was calculated; in others, the options with the greatest numbers of responses were summarized.
Results: Fifteen questions were extracted and disseminated among 60 experts for the survey. Fifty-three experts completed the survey within the specified time frame. The average volume of EUS cases at the experts' institutions is 988.5 cases per year.
Conclusion: Despite the limitations of EUS alone in the morphologic diagnosis of PCLs, the results of the survey indicate that EUS-guided fine-needle aspiration is widely expected to become a more valuable method.
Long-Term Treatment with the Combination of Rivaroxaban and Aspirin in Patients with Chronic Coronary or Peripheral Artery Disease: Outcomes During the Open Label Extension of the COMPASS trial

Eikelboom JW, Bosch J, Connolly SJ, Tyrwitt J, Fox KAA, Muehlhofer E, et al.

Eur Heart J Cardiovasc Pharmacother, 2022 Dec 02;8(8):786-795.
PMID: 35383832 DOI: 10.1093/ehjcvp/pvac023

AIMS: To describe outcomes of patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial who were treated with the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily during long-term open-label extension (LTOLE).
METHODS AND RESULTS: Of the 27 395 patients enrolled in COMPASS, 12 964 (mean age at baseline 67.2 years) from 455 sites in 32 countries were enrolled in LTOLE and treated with the combination of rivaroxaban and aspirin for a median of 374 additional days (range 1-1191 days). During LTOLE, the incident events per 100 patient years were as follows: for the primary outcome [cardiovascular death, stroke, or myocardial infarction (MI)] 2.35 [95% confidence interval (CI) 2.11-2.61], mortality 1.87 (1.65-2.10), stroke 0.62 (0.50-0.76), and MI 1.02 (0.86-1.19), with CIs that overlapped those seen during the randomized treatment phase with the combination of rivaroxaban and aspirin. The incidence rates for major and minor bleeding were 1.01 (0.86-1.19) and 2.49 (2.24-2.75), compared with 1.67 (1.48-1.87) and 5.11 (95% CI 4.77-5.47), respectively, during the randomized treatment phase with the combination.
CONCLUSION: In patients with chronic CAD and/or PAD, extended combination treatment for a median of 1 year and a maximum of 3 years was associated with incidence rates for efficacy and bleeding that were similar to or lower than those seen during the randomized treatment phase, without any new safety signals.
Novel lung adenocarcinoma and nuclear factor-kappa B (NF-κB) inhibitors: synthesis and evaluation of lantadene congeners

Suthar SK, Boon HL, Sharma M

Eur J Med Chem, 2014 Mar 3;74:135-44.
PMID: 24457265 DOI: 10.1016/j.ejmech.2013.12.052

The C-3, C-17 and C-22 congeners of pentacyclic triterpenoids reduced lantadene A (3), B (4) and 22β-hydroxyoleanolic acid (5) were synthesized and were tested in vitro for their NF-κB and IKKβ inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead congeners 12 and 13 showed IC50 of 0.56 and 0.42 μmol, respectively against TNF-α induced activation of NF-κB. The congeners 12 and 13 exhibited inhibition of IKKβ in a single-digit micromolar dose and at the same time, 12 and 13 showed marked cytotoxicity against A549 lung cancer cells with IC50 of 0.12 and 0.08 μmol, respectively. The lead ester congeners were stable in the acidic pH, while hydrolyzed readily in the human blood plasma to release the active parent moieties.

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