Crystal Engineering: A Powerful Tool towards Designing Pharmaceutical Solids with Desirable Physicochemical Properties

Nowadays various techniques have been applied for the improvement of physicochemical properties such as solubility, bioavailability, stability and hygroscopic nature of pharmaceutical solids without effecting the biochemical composition of the active pharmaceutical ingredients (API). Supramolecular approach specially the crystal engineering technique is one of the best techniques which play an important role to improve the physico-chemical, thermal and mechanical properties of drug molecules. Crystal engineering approach offers a number of routes such as co-crystallization, polymorphism, hydrate and salt formation with the help of which drug molecules with good physico-chemical behavior can be prepared. This article covers the concept of supramolecular chemistry and crystal engineering approach for the preparation of co-crystals and their application in pharmaceutical industries

Resensitization of Akt induced docetaxel resistance in breast cancer by ‘Iturin A’ a lipopeptide molecule from marine bacteria bacillus megaterium

Development of the resistance is the major problem in cancer therapy. Docetaxel is a taxol alkaloid that is frequently used in metastatic breast cancer. However, resistance often limits the usefulness of this drug in many breast cancer patients. Manipulation of resistant cells to re-sensitize to the therapeutic effect of docetaxel is current strategy to overcome this problem. Here, we have introduced ‘Iturin A’ as a potent chemosensitizer in docetaxel resistant breast cancer cells. Combination of Iturin A and docetaxel treatment significantly hampered the proliferation of docetaxel resistant MDA-MB-231 and MDA-MB-468 breast cancer cells. Cell cycle analysis also showed massive amount of apoptotic population (Sub G0G1) in combination therapy. A number of apoptotic and anti-apoptotic proteins were significantly altered in dual drug treated groups. Caspase 3 dependent cell death was observed in dual treatment. Molecular mechanism study showed that over-expression of Akt and its downstream signaling pathway was associated with docetaxel resistance. Iturin A significantly reduced Akt signaling pathway in resistant cells. This mechanistic action might be the reason behind the chemo-sensitization effect of Iturin A in docetaxel resistant breast cancer cells. In conclusion, Iturin A resensitized the resistant breast cancer cells to docetaxel therapy by inhibiting Akt activity

Cross-Corpora Language Recognition: A Preliminary Investigation with Indian Languages

International audienceIn this paper, we conduct one of the very first studies for cross-corpora performance evaluation in the spoken language identification (LID) problem. Cross-corpora evaluation was not explored much in LID research, especially for the Indian languages. We have selected three Indian spoken language corpora: IIITH-ILSC, LDC South Asian, and IITKGP-MLILSC. For each of the corpus, LID systems are trained on the state-of-the-art time-delay neural network (TDNN) based architecture with MFCC features. We observe that the LID performance degrades drastically for cross-corpora evaluation. For example, the system trained on the IIITH-ILSC corpus shows an average EER of 11.80% and 43.34% when evaluated with the same corpora and LDC South Asian corpora, respectively. Our preliminary analysis shows the significant differences among these corpora in terms of mismatch in the long-term average spectrum (LTAS) and signal-to-noise ratio (SNR). Subsequently, we apply different feature level compensation methods to reduce the cross-corpora acoustic mismatch. Our results indicate that these feature normalization schemes can help to achieve promising LID performance on cross-corpora experiments

An Overview of Indian Spoken Language Recognition from Machine Learning Perspective

International audienceAutomatic spoken language identification (LID) is a very important research field in the era of multilingual voice-command-based human-computer interaction (HCI). A front-end LID module helps to improve the performance of many speech-based applications in the multilingual scenario. India is a populous country with diverse cultures and languages. The majority of the Indian population needs to use their respective native languages for verbal interaction with machines. Therefore, the development of efficient Indian spoken language recognition systems is useful for adapting smart technologies in every section of Indian society. The field of Indian LID has started gaining momentum in the last two decades, mainly due to the development of several standard multilingual speech corpora for the Indian languages. Even though significant research progress has already been made in this field, to the best of our knowledge, there are not many attempts to analytically review them collectively. In this work, we have conducted one of the very first attempts to present a comprehensive review of the Indian spoken language recognition research field. In-depth analysis has been presented to emphasize the unique challenges of low-resource and mutual influences for developing LID systems in the Indian contexts. Several essential aspects of the Indian LID research, such as the detailed description of the available speech corpora, the major research contributions, including the earlier attempts based on statistical modeling to the recent approaches based on different neural network architectures, and the future research trends are discussed. This review work will help assess the state of the present Indian LID research by any active researcher or any research enthusiasts from related fields

Marine lipopeptide Iturin A inhibits Akt mediated GSK3β and FoxO3a signaling and triggers apoptosis in breast cancer

Akt kinase is a critical component of the PI3K/Akt signaling pathway, which is frequently over expressed in human cancers including breast. Therapeutic regimens for inhibiting breast cancer with aberrant Akt activity are essential. Here, we evaluated antitumor effect of a marine bacteria derived lipopeptide ‘Iturin A’ on human breast cancer in vitro and in vivo through disrupting Akt pathway. Proliferation of MDA-MB-231 and MCF-7 breast cancer cells were significantly inhibited by Iturin A and it induced apoptosis as confirmed by increased Sub G1 populations, DNA fragmentation, morphological changes and western blot analysis. Furthermore, Iturin A inhibited EGF induced Akt phosphorylation (Ser473 and Thr308) and its downstream targets GSK3β and FoxO3a. Iturin A inactivated MAPK as well as Akt kinase leading to the translocation of FoxO3a to the nucleus. Gene silencing of Akt in MDA-MB-231 and MCF-7 cells reduced the sensitivity of cancer cells to Iturin A. Interestingly, overexpression of Akt with Akt plasmid in cancer cells caused highly susceptible to induce apoptosis by Iturin A treatment. In a xenograft model, Iturin A inhibited tumor growth with reduced expressions of Ki-67, CD-31, P-Akt, P-GSK3β, P-FoxO3a and P-MAPK. Collectively, these findings imply that Iturin A has potential anticancer effect on breast cancer

Enterotoxin production, DNA repair and alkaline phosphatase of Vibrio cholerae before and after animal passage

Summary: Three strains of Vibrio cholerae differing in biotype, serotype and/or toxinogenicity were studied. The capability for dark repair of DNA and stability of alkaline phosphatase decreased concomitantly with toxinogenicity on laboratory passage of highly enterotoxinogenic strain 569B. These properties could be restored by passaging strain 569B once through a guinea-pig

Pre-clinical risk assessment and therapeutic potential of antitumor lipopeptide ‘Iturin A’ in an in vivo and in vitro model

Lipopeptides are versatile bio-active weapons having antifungal, antibacterial, antimycoplasma and anticancer properties. In this study, the therapeutic potential and safety assessment of a lipopeptide molecule ‘Iturin A’ were evaluated. Iturin A was found to inhibit in vivo tumor growth in a sarcoma 180 mouse xenograft model. The antitumor efficacy of Iturin A was correlated with increased DNA fragmentation and modulation of CD-31, Ki-67, P-Akt, P-MAPK, apoptotic and anti-apoptotic proteins. Further, safety assessment was carried out in Sprague Dawley rats by 28 days repeated dose (28 days) toxicity and a bio-distribution study. In the toxicity study, Iturin A (10, 20 and 50 mg per kg per day) was administered to the animals for 28 days. Another group was kept for another 14 days without drug exposure after 28 days of treatment to access the reversibility of the toxicity. At the end of the treatment, body weight, food and water intake, organ weight, motility, hematology, serum biochemistry and histopathology of the major organs were evaluated. The bio-distribution of Iturin A was also performed in plasma as well as in different major organs by a well-developed and validated administration of Iturin A radiolabeled with 99mTc. The in vitro cytotoxic effect of Iturin A was also evaluated in BRL-3A rat liver cells. In the treated groups, various toxicities were found in the liver and spleen. However, these adverse effects were transient and reversible after discontinuation of Iturin A treatment. In conclusion, this pre-clinical study offered a preliminary investigation regarding the efficacy and safety assessment of Iturin A

Misuse of Cardiac Lipid upon Exposure to Toxic Trace Elements—A Focused Review

Funding Information: Ricardo Lagoa acknowledges research support by the Applied Molecular Biosciences Unit-UCIBIO which is financed by national funds from FCT–Foundation for Science and Technology (UIDP/04378/2020 and UIDB/04378/2020). Publisher Copyright: © 2022 by the authors.Heavy metals and metalloids like cadmium, arsenic, mercury, and lead are frequently found in the soil, water, food, and atmosphere; trace amounts can cause serious health issues to the human organism. These toxic trace elements (TTE) affect almost all the organs, mainly the heart, kidney, liver, lungs, and the nervous system, through increased free radical formation, DNA damage, lipid peroxidation, and protein sulfhydryl depletion. This work aims to advance our understanding of the mechanisms behind lipid accumulation via increased free fatty acid levels in circulation due to TTEs. The increased lipid level in the myocardium worsens the heart function. This dysregulation of the lipid metabolism leads to damage in the structure of the myocardium, inclusive fibrosis in cardiac tissue, myocyte apoptosis, and decreased contractility due to mitochondrial dysfunction. Additionally, it is discussed herein how exposure to cadmium decreases the heart rate, contractile tension, the conductivity of the atrioventricular node, and coronary flow rate. Arsenic may induce atherosclerosis by increasing platelet aggregation and reducing fibrinolysis, as exposure interferes with apolipoprotein (Apo) levels, resulting in the rise of the Apo-B/Apo-A1 ratio and an elevated risk of acute cardiovascular events. Concerning mercury and lead, these toxicants can cause hypertension, myocardial infarction, and carotid atherosclerosis, in association with the generation of free radicals and oxidative stress. This review offers a complete overview of the critical factors and biomarkers of lipid and TTE-induced cardiotoxicity useful for developing future protective interventions.publishersversionpublishe

Non-small cell lung carcinoma (NSCLC): Implications on molecular pathology and advances in early diagnostics and therapeutics.

Continuous revision of the histologic and stage-wise classification of lung cancer by the World Health Organization (WHO) provides the foundation for therapeutic advances by promoting molecular targeted and immunotherapies and ensuring accurate diagnosis. Cancer epidemiologic data provide helpful information for cancer prevention, diagnosis, and management, supporting health-care interventions. Global cancer mortality projections from 2016 to 2060 show that cancer will overtake ischemic heart diseases (IHD) as the leading cause of death (18.9 million) immediately after 2030, surpassing non-small cell lung cancer (NSCLC), which accounts for 85 percent of lung cancers. The clinical stage at the diagnosis is the main prognostic factor in NSCLC therapies. Advanced early diagnostic methods are essential as the initial stages of cancer show reduced mortality compared to the advanced stages. Sophisticated approaches to proper histological classification and NSCLC management have improved clinical efficiency. Although immune checkpoint inhibitors (ICIs) and targeted molecular therapies have refined the therapeutic management of late-stage NSCLC, the specificity and sensitivity of cancer biomarkers should be improved by focusing on prospective studies, followed by their use as therapeutic tools. The liquid biopsy candidates such as circulating tumor cells (CTCs), circulating cell-free tumor DNA (cfDNA), tumor educated platelets (TEP), and extracellular vesicles (EVs) possess cancer-derived biomolecules and aid in tracing: driver mutations leading to cancer, acquired resistance caused by various generations of therapeutic agents, refractory disease, prognosis, and surveillance. [Abstract copyright: © 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

Cross-corpora spoken language identification with domain diversification and generalization

International audienceThis work addresses the cross-corpora generalization issue for the low-resourced spoken language identification (LID) problem. We have conducted the experiments in the context of Indian LID and identified strikingly poor cross-corpora generalization due to corpora-dependent nonlingual biases. Our contribution to this work is twofold. First, we propose domain diversification, which diversifies the limited training data using different audio data augmentation methods. We then propose the concept of maximally diversity-aware cascaded augmentations and optimize the augmentation fold-factor for effective diversification of the training data. Second, we introduce the idea of domain generalization considering the augmentation methods as pseudo-domains. Towards this, we investigate both domain-invariant and domain-aware approaches. Our LID system is based on the state-of-the-art emphasized channel attention, propagation, and aggregation based time delay neural network (ECAPA-TDNN) architecture. We have conducted extensive experiments with three widely used corpora for Indian LID research. In addition, we conduct a final blind evaluation of our proposed methods on the Indian subset of VoxLingua107 corpus collected in the wild. Our experiments demonstrate that the proposed domain diversification is more promising over commonly used simple augmentation methods. The study also reveals that domain generalization is a more effective solution than domain diversification. We also notice that domain-aware learning performs better for same-corpora LID, whereas domain-invariant learning is more suitable for cross-corpora generalization. Compared to basic ECAPA-TDNN, its proposed domain-invariant extensions improve the cross-corpora EER up to 5.23%. In contrast, the proposed domain-aware extensions also improve performance for same-corpora test scenarios