Publications by authors named "Sajid Khan"

130 Publications

Discovery of a Novel BCL-X PROTAC Degrader with Enhanced BCL-2 Inhibition.

J Med Chem 2021 Sep 17. Epub 2021 Sep 17.

Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, Florida 32610, United States.

BCL-X and BCL-2 are important targets for cancer treatment. BCL-X specific proteolysis-targeting chimeras (PROTACs) have been developed to circumvent the on-target platelet toxicity associated with BCL-X inhibition. However, they have minimal effects on cancer cells that are dependent on BCL-2 or both BCL-X and BCL-2. Here we report a new series of BCL-PROTACs. The lead PZ703b exhibits high potency in inducing BCL-X degradation and in inhibiting but not degrading BCL-2, showing a hybrid dual-targeting mechanism of action that is unprecedented in a PROTAC molecule. As a result, PZ703b is highly potent in killing BCL-X dependent, BCL-2 dependent, and BCL-X/BCL-2 dual-dependent cells in an E3 ligase (VHL)-dependent fashion. We further found that PZ703b forms stable {BCL-2:PROTAC:VCB} ternary complexes in live cells that likely contribute to the enhanced BCL-2 inhibition by PZ703b. With further optimization, analogues of PZ703b could potentially be developed as effective antitumor agents by co-targeting BCL-X and BCL-2.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00517DOI Listing
September 2021

Epigenetic signatures differentiate uterine and soft tissue leiomyosarcoma.

Oncotarget 2021 Aug 3;12(16):1566-1579. Epub 2021 Aug 3.

Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.

Leiomyosarcomas (LMS) are diverse, rare, and aggressive mesenchymal soft tissue sarcomas. Epigenetic alterations influence multiple aspects of cancer, however epigenetic profiling of LMS has been limited. The goal of this study was to delineate the molecular landscape of LMS for subtype-specific differences (uterine LMS (ULMS) vs soft tissue LMS (STLMS)) based on integrated analysis of DNA methylation and gene expression to identify potential targets for therapeutic intervention and diagnosis. We identified differentially methylated and differentially expressed genes associated with ULMS and STLMS using DNA methylation and RNA-seq data from primary tumors. Two main clusters were identified through unsupervised hierarchical clustering: ULMS-enriched cluster and STLMS-enriched cluster. The integrated analysis demonstrated 34 genes associated with hypermethylation of the promoter CpG islands and downregulation of gene expression in ULMS or STLMS. In summary, these results indicate that differential DNA methylation and gene expression patterns are associated with ULMS and STLMS. Further studies are needed to delineate the contribution of epigenetic regulation to LMS subtype-specific gene expression and determine the roles of the differentially methylated and differentially expressed genes as potential therapeutic targets or biomarkers.
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http://dx.doi.org/10.18632/oncotarget.28032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351604PMC
August 2021

Identification of differentially expressed genes and pathways crosstalk analysis in Rheumatoid and Osteoarthritis using next-generation sequencing and protein-protein networks.

Saudi J Biol Sci 2021 Aug 1;28(8):4656-4663. Epub 2021 May 1.

Department of Biotechnology, COMSATS University Islamabad, Abbottabad Campus, 22010 Abbottabad, Pakistan.

Osteoarthritis occurs when protective cartilage of bones worn out. Similarlty, cartilage damage occurs mainly in the pannus cartilage in rheumatoid arthritis. It is a potentially debilitating condition, affecting women two to three times more often than men. The cause and prognosis of rheumatoid and osteoarthritis are still poorly known. However, advances in the study of disease pathogenesis have encouraged the creation of new therapeutics with improved outcomes. The purpose of this study is to investigate the differentially expressed genes potentially involved in dysregulated rheumatoid arthritis (RA) and their association to other types of arthritis, including osteoarthritis (OA). Complete RNAs were isolated for RNA expression profiling using next-generation sequencing from human primary cultured normal and RA chondrocytes. From RNA sequencing results 250 differentially expressed genes were identified using bioinformatics analysis, of which 32 were found to be significantly playing role in RA pathogenesis and its associated diseases. Molecular ontologies of the identified genes showed they are connected to Innate immune response, Protein phosphorylation, Transcription initiation from RNA polymerase II promoter, Immune response, Neoplasms of bones, as well as osteorthritis, and Rheumatoid arthritis. Among the identified genes, TRAF1, TRAF2, BAMP, STX11, MEOX2, AES, REL, FHL3, PNMA1, SGTA, LZTS2, SIAH2, PNMA1, and TFCP2 were found to be highly enriched in the protein-protein interaction network. The significant cross talks were found in Hypertrophic cardiomyopathy, Small cell lung cancer, Proteasome, p53 signaling pathway, Arrhythmogenic right ventricular cardiomyopathy, Small cell lung cancer, SNARE interactions in vesicular transport, RIG-I-like receptor signaling pathway, and Hypertrophic cardiomyopathy pathways. The results offer new opportunities for target gene control in RA and OA cartilage destruction.
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http://dx.doi.org/10.1016/j.sjbs.2021.04.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325051PMC
August 2021

Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2021 07 28;19(7):839-868. Epub 2021 Jul 28.

Vanderbilt-Ingram Cancer Center.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.
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http://dx.doi.org/10.6004/jnccn.2021.0032DOI Listing
July 2021

Kynurenic acid may underlie sex-specific immune responses to COVID-19.

Sci Signal 2021 07 6;14(690). Epub 2021 Jul 6.

Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06510, USA.

Coronavirus disease 2019 (COVID-19) has poorer clinical outcomes in males than in females, and immune responses underlie these sex-related differences. Because immune responses are, in part, regulated by metabolites, we examined the serum metabolomes of COVID-19 patients. In male patients, kynurenic acid (KA) and a high KA-to-kynurenine (K) ratio (KA:K) positively correlated with age and with inflammatory cytokines and chemokines and negatively correlated with T cell responses. Males that clinically deteriorated had a higher KA:K than those that stabilized. KA inhibits glutamate release, and glutamate abundance was lower in patients that clinically deteriorated and correlated with immune responses. Analysis of data from the Genotype-Tissue Expression (GTEx) project revealed that the expression of the gene encoding the enzyme that produces KA, kynurenine aminotransferase, correlated with cytokine abundance and activation of immune responses in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes in COVID-19, suggesting a positive feedback between metabolites and immune responses in males.
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http://dx.doi.org/10.1126/scisignal.abf8483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432948PMC
July 2021

Tailoring the bandgap of MnO for visible light driven photocatalysis.

J Environ Manage 2021 Sep 29;293:112854. Epub 2021 May 29.

School of Science, Minzu University of China, Beijing, 100081, China; Optoelectronics Research Centre, Minzu University of China, Beijing, 100081, China. Electronic address:

The photocatalytic activity of pure MnO and silver (Ag) modified MnO nanoparticles have been investigated. The nanoparticles were prepared by using co-precipitation technique. The structural analysis showed that the Ag modified MnO was successfully synthesized. For instance, a slight shift to lower angle of XRD pattern was observed after Ag doping. Morphological analysis revealed that the particles have an average size of 274 nm, 287 nm and 321 nm for pure, 1% and 3% Ag modified MnO respectively. The UV-Visible analysis indicated that the bandgap of MnO decreased with increased Ag content and the band gap is 1.4 eV with the 3% of Ag content. The spectra obtained from DRS were also evaluated through inverse logarithmic derivative method (ILD) to counter check the bandgap values. 3% Ag-modified photocatalysts exhibited the enhanced decolorization efficiency compared to pure MnO nanoparticles. The pseudo first order kinetic model is used to explain the photocatalytic kinetics of the photocatalyst. The rate constant values are 0.01/min, 0.017/min and 0.024/min for pure MnO, 1% Ag and 3% Ag modified MnO nanoparticles, respectively.
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http://dx.doi.org/10.1016/j.jenvman.2021.112854DOI Listing
September 2021

First report of post-harvest Fusarium rot of mandarin Citrus reticulata cv. 'Kinnow' caused by Fusarium equiseti in Pakistan.

Plant Dis 2021 May 24. Epub 2021 May 24.

University of Agriculture Faisalabad Pakistan Sub Campus Burewala-Vehari, Faisalabad, Punjab, Pakistan;

Citrus reticulata cv. 'Kinnow' mandarin is the most popular and widely grown fruit crop in Pakistan. During 2017, a survey was conducted to the local citrus fruit markets of Faisalabad, Pakistan. Citrus fruits (n=50) exhibiting stem end rot and fruit rot were collected with 15% disease incidence. The stem end region showed light to dark brown lesions and white fungal growth was also observed in the severely infected fruit. Infected fruit were excised into 2mm2 segments, surface disinfected with 1% NaClO, rinsed with sterilized water and dried. Later, these tissues were placed on potato dextrose agar (PDA) medium and subsequently incubated at 25 °C. Purified isolates produced white colonies with beige pigmentation. The frequency of fungal isolation was 47%. Microscopic observations revealed that macroconidia (n=50) had 5 to 6 septations, with a prominent dorsiventral curvature, tapered and elongated apical cell, and a foot shape basal cell. The macroconidia were measuring 22 to 45 × 2.9 to 4.3 µm with an average of 31 × 3.6 µm. However, microconidia were not observed. Chlamydospores were globose, intercalary, solitary, or in pairs, appearing in chains (Leslie and Summerell 2006). For molecular identification, DNA was extracted from all isolates. The internal transcribed spacer region (ITS) ITS1/4 (White et al. 1990), translation elongation factor-1 alpha (TEF) EF1/2 (O'Donnell et al. 1998), and RNA polymerase II subunit 1 (RPB1) (O'Donnell et al. 2013) were amplified using PCR and the product was subsequently sequenced. Based on BLAST analysis, the isolate was identified as Fusarium equiseti (FUS-21). The sequences of the representative isolate FUS-21 were deposited in the GenBank with accession numbers (ITS, MH581300), (TEF, MK203749), and (RPB1, MW596599) showing more than 99% similarity with ITS accession GQ505683, TEF accession GQ505594, and 100% to RPB1 accession JX171481. To determine the pathogenicity, 40 healthy surface disinfested citrus fruit were taken. The fruit were inoculated by creating artificial wounds on the surface with a sterilized needle and 10 μL of 105 spores/mL was deposited in the wounds. In case of control fruit were inoculated with 10 μL sterilized distilled water only, and incubated at 25 °C. All fruit inoculated with the putative pathogen, developed symptoms like the original fruit from which they were isolated. The pathogenicity test was repeated twice. Visible white mycelium appeared at the stem end region and the fruits became dried as the infection progressed. However, the control fruit remained asymptomatic. The pathogen was re-isolated from infected fruit and identified based on morphometric and molecular analysis. Previously we have reported F. oxysporum causing citrus fruit rot in Pakistan (Moosa et al. 2020). This is the first report of F. equiseti causing post-harvest rot of citrus fruits in Pakistan. Kinnow is an important fruit crop of Pakistan with huge export value the management of Fusarium rot is quite important to save the loss of fresh produce.
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http://dx.doi.org/10.1094/PDIS-03-21-0513-PDNDOI Listing
May 2021

Intratumour microbiome associated with the infiltration of cytotoxic CD8+ T cells and patient survival in cutaneous melanoma.

Eur J Cancer 2021 Jul 4;151:25-34. Epub 2021 May 4.

Department of Chronic Disease Epidemiology, Yale School of Public Health, School of Medicine, Yale Cancer Center, Yale University, New Haven, CT, USA. Electronic address:

Objective: The gut microbiome plays an important role in systemic inflammation and immune response. Microbes can translocate and reside in tumour niches. However, it is unclear how the intratumour microbiome affects immunity in human cancer. The purpose of this study was to investigate the association between intratumour bacteria, infiltrating CD8+ T cells and patient survival in cutaneous melanoma.

Methods: Using The Cancer Genome Altas's cutaneous melanoma RNA sequencing data, levels of intratumour bacteria and infiltrating CD8+ T cells were determined. Correlation between intratumour bacteria and infiltrating CD8+ T cells or chemokine gene expression and survival analysis of infiltrating CD8+ T cells and Lachnoclostridium in cutaneous melanoma were performed.

Results: Patients with low levels of CD8+ T cells have significantly shorter survival than those with high levels. The adjusted hazard ratio was 1.57 (low vs high) (95% confidence interval: 1.17-2.10, p = 0.002). Intratumour bacteria of the Lachnoclostridium genus ranked top in a positive association with infiltrating CD8+ T cells (correlation coefficient = 0.38, p = 9.4 × 10), followed by Gelidibacter (0.31, p = 1.13 × 10), Flammeovirga (0.29, p = 1.96 × 10) and Acinetobacter (0.28, p = 8.94 × 10). These intratumour genera positively correlated with chemokine CXCL9, CXCL10 and CCL5 expression. The high Lachnoclostridium load significantly reduced the mortality risk (p = 0.0003). However, no statistically significant correlation was observed between intratumour Lachnoclostridium abundance and the levels of either NK, B or CD4+ T cells.

Conclusion: Intratumour-residing gut microbiota could modulate chemokine levels and affect CD8+ T-cell infiltration, consequently influencing patient survival in cutaneous melanoma. Manipulating the intratumour gut microbiome may benefit patient outcomes for those undergoing immunotherapy.
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http://dx.doi.org/10.1016/j.ejca.2021.03.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184628PMC
July 2021

Occurrence and molecular characterization of on rice in Central Punjab, Pakistan.

J Nematol 2020 16;52. Epub 2021 Jan 16.

Department of Plant Pathology, University of Agriculture Faisalabad, P.O. Box 38040, Pakistan.

threatens global rice production, yet is understudied for many areas where it is cultivated. To better understand the prevalence and incidence of in central Punjab, Pakistan, we carried out field surveys of rice fields in the districts of Faisalabad and Chiniot. isolates were recovered from soil and root samples and identified on the basis of perineal patterns and rDNA ITS-based sequencing. The severity of nematode attack on rice roots and infested fields at various locations was based on galling index, root-knot nematode juveniles per root system, juveniles per 100 ml of soil, and prevalence of stylet-bearing nematodes and non-stylet-bearing nematodes. Maximum prevalence (22.5 and 27.5%) and minimum prevalence (17.5 and 20%) of was observed in Chiniot and Faisalabad, respectively. Eleven alternate host-plant species were examined in this study revealing varying degrees of infestation. ITS sequencing and phylogenetic analysis indicated that isolates from this study form a well-resolved clade with others from Asia, while another isolate falls outside of this clade in an unresolved polytomy with those from Europe and South America. Though monophyletic with the other , the isolates from Pakistan are distinguished by their high genetic variability and long branch lengths relative to the other isolates of , suggesting Pakistan as a possible ancestral area. Our results indicate that rice is severely attacked by a genetically diverse and aggressive , necessitating the development of appropriate control measures for its management in rice and other graminaceous crops.
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http://dx.doi.org/10.21307/jofnem-2020-123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015280PMC
January 2021

In silico analysis of quranic and prophetic medicinals plants for the treatment of infectious viral diseases including corona virus.

Saudi J Biol Sci 2021 May 23;28(5):3137-3151. Epub 2021 Feb 23.

The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Coronavirus disease (COVID-19) is an infection of the respiratory system caused by single standard RNA viruses named as Severe Acute Respiratory Syndrome 2 (SARS-CoV-2). The disease appeared as a serious problem and the leading cause of death in human beings throughout the world. The main source of different phytochemicals are plants, which helps in the development of new drugs against various ailments. Islam is comprehensive religion and a complete code of life for Muslims. The teaching of Islam, according to the Holy Quran and Hadith are universal for the benefit of humanity. Islam believes that every ailment is from God and who made the disease definitely made its medication. There is a complete guideline with regard to taking measures against infectious diseases such as quarantine and seeking medicinal treatment. The research objective is to gather the knowledge of medicinal plants described in the Holy Quran or utilized by the Prophet (SAW) for the treatment of different ailments or advised to use them to boost immunity and strengthen the body. Scientists across the globe have found these plants beneficial for many diseases and have antiviral potential. In present study, the six plant species including and were selected which contain phytochemicals like Calcium Elenolate, Thymoquinone, S-Allylcysteine, Dipropyl Disulfide, Sesquiterpene, Monoterpene, Pelargonidin 3-Galactoside ion and Kaempferol. The phytochemicals monoterpene (from ) shows best interaction with target proteins RdRP, 3CLPro, ACE2. Calcium Elonate (from olive) bonds with 3CLPro, ACE2 and Kemoferol and Pelargomidine (from Senna Makki) bonds with RdRP, ACE2. The ligands show a unique set of intersections i.e. hydrogen bonding, and alkyl interaction. These medicinal plants can be utilized immediately for the treatment of COVID-19 as their safety is already established. This treatment can enhance recovery when combined with other treatments. Furthermore, the screening of bioactive compounds or phytochemicals found in these plants can be utilized to design new therapeutic drug to treat COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.sjbs.2021.02.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899931PMC
May 2021

Proteolysis-targeting chimera against BCL-X destroys tumor-infiltrating regulatory T cells.

Nat Commun 2021 02 24;12(1):1281. Epub 2021 Feb 24.

Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.

Regulatory T cells (Tregs) play an important role in maintaining immune homeostasis and, within tumors, their upregulation is common and promotes an immunosuppressive microenvironment. Therapeutic strategies that can eliminate Tregs in the tumor (i.e., therapies that do not run the risk of affecting normal tissues), are urgently needed for the development of cancer immunotherapies. Here we report our discovery of B-cell lymphoma extra-large (BCL-X) as a potential molecular target of tumor-infiltrating (TI) Tregs. We show that pharmacological degradation of BCL-X using a newly developed platelet-sparing BCL-X Proteolysis-targeting chimera (PROTAC) induces the apoptosis of TI-Tregs and the activation of TI-CD8 T cells. Moreover, these activities result in an effective suppression of syngeneic tumor growth in immunocompetent, but not in immunodeficient or CD8 T cell-depleted mice. Notably, treatment with BCL-X PROTAC does not cause detectable damage within several normal tissues or thrombocytopenia. These findings identify BCL-X as a target in the elimination of TI-Tregs as a component of cancer immunotherapies, and that the BCL-X-specific PROTAC has the potential to be developed as a therapeutic for cancer immunotherapy.
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http://dx.doi.org/10.1038/s41467-021-21573-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904819PMC
February 2021

5-Fluorouracil efficacy requires anti-tumor immunity triggered by cancer-cell-intrinsic STING.

EMBO J 2021 Apr 22;40(7):e106065. Epub 2021 Feb 22.

Yale Stem Cell Center, New Haven, CT, USA.

5-Fluorouracil (5-FU) is a widely used chemotherapeutic drug, but the mechanisms underlying 5-FU efficacy in immunocompetent hosts in vivo remain largely elusive. Through modeling 5-FU response of murine colon and melanoma tumors, we report that effective reduction of tumor burden by 5-FU is dependent on anti-tumor immunity triggered by the activation of cancer-cell-intrinsic STING. While the loss of STING does not induce 5-FU resistance in vitro, effective 5-FU responsiveness in vivo requires cancer-cell-intrinsic cGAS, STING, and subsequent type I interferon (IFN) production, as well as IFN-sensing by bone-marrow-derived cells. In the absence of cancer-cell-intrinsic STING, a much higher dose of 5-FU is needed to reduce tumor burden. 5-FU treatment leads to increased intratumoral T cells, and T-cell depletion significantly reduces the efficacy of 5-FU in vivo. In human colorectal specimens, higher STING expression is associated with better survival and responsiveness to chemotherapy. Our results support a model in which 5-FU triggers cancer-cell-initiated anti-tumor immunity to reduce tumor burden, and our findings could be harnessed to improve therapeutic effectiveness and toxicity for colon and other cancers.
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http://dx.doi.org/10.15252/embj.2020106065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013832PMC
April 2021

network-based analysis of drugs used against COVID-19: Human well-being study.

Saudi J Biol Sci 2021 Mar 21;28(3):2029-2039. Epub 2021 Jan 21.

Department of Zoology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia.

Introduction: Researchers worldwide with great endeavor searching and repurpose drugs might be potentially useful in fighting newly emerged coronavirus. These drugs show inhibition but also show side effects and complications too. On December 27, 2020, 80,926,235 cases have been reported worldwide. Specifically, in Pakistan, 471,335 has been reported with inconsiderable deaths.

Problem Statement: Identification of COVID-19 drugs pathway through drug-gene and gene-gene interaction to find out the most important genes involved in the pathway to deal with the actual cause of side effects beyond the beneficent effects of the drugs.

Methodology: The medicines used to treat COVID-19 are retrieved from the Drug Bank. The drug-gene interaction was performed using the Drug Gene Interaction Database to check the relation between the genes and the drugs. The networks of genes are developed by Gene MANIA, while Cytoscape is used to check the active functional association of the targeted gene. The developed systems cross-validated using the EnrichNet tool and identify drug genes' concerned pathways using Reactome and STRING.

Results: Five drugs Azithromycin, Bevacizumab, CQ, HCQ, and Lopinavir, are retrieved. The drug-gene interaction shows several genes that are targeted by the drug. Gene MANIA interaction network shows the functional association of the genes like co-expression, physical interaction, predicted, genetic interaction, co-localization, and shared protein domains.

Conclusion: Our study suggests the pathways for each drug in which targeted genes and medicines play a crucial role, which will help experts o overcome and deal with the side effects of these drugs, as we find out the gene analysis for the COVID-19 drugs.
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http://dx.doi.org/10.1016/j.sjbs.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825994PMC
March 2021

Gene Alterations of N6-Methyladenosine (mA) Regulators in Colorectal Cancer: A TCGA Database Study.

Biomed Res Int 2020 19;2020:8826456. Epub 2020 Dec 19.

Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, CT 06520-8034, USA.

N6-methyladenosine (mA) plays an important role in many cancers. However, few studies have examined the role of m6A in colorectal CRC. To examine the effect of m6A on CRC, we studied the genome of 591 CRC cases from The Cancer Genome Atlas (TCGA). The relationship between the messenger RNA (mRNA) expression, copy number variation (CNVs), and mutations of m6A "Writers," "Readers," and "Erasers," prognosis, immune cell infiltration, and genetic mutations in CRC cases were analyzed. CNVs and mutations were found in thirteen m6A regulators. As expected, gain and amplification of m6A regulators increased the mRNA expression of these regulators, while deletion led to reduction in the mRNA expression. Moreover, CNVs and mutation of these regulators were significantly associated with APC, TP53, and microsatellite instability (MSI) status ( < 0.001, < 0.001, and = 0.029, respectively). CNVs of m6A regulators also correlated with inferred immune cell infiltration in CRC tissues, especially in colon tissues. Additionally, alterations of RBM15, YTHDF2, YTHDC1, YTHDC2, and METTL14 genes were related to the worse overall survival and disease-free survival (DFS) of CRC patients. Specifically, the deletion status of "Writers" was also correlated to the DFS of CRC patients ( = 0.02). Gene set enrichment analysis found that FTO was involved in mRNA 3' end processing, polyubiquitin binding, and RNA polymerase promoter elongation, while YTHDC1 was related to interferon-alpha and gamma response. In conclusion, a novel relationship was identified between CNVs and mutations of m6A regulators with prognosis and inferred immune function of CRC. These findings will improve the understanding of the relationship of m6A in CRC.
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http://dx.doi.org/10.1155/2020/8826456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769650PMC
September 2021

Margin negative resection and pathologic downstaging with multiagent chemotherapy with or without radiotherapy in patients with localized pancreas cancer: A national cancer database analysis.

Clin Transl Radiat Oncol 2021 Mar 16;27:15-23. Epub 2020 Dec 16.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA.

Purpose: Margin-negative (R0) resection is the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC). Pre-operative multi-agent chemotherapy alone (MAC) or MAC followed by pre-operative radiotherapy (MAC + RT) may be used to improve resectability and potentially survival. However, the optimal pre-operative regimen is unknown.

Methods: Patients with non-metastatic PDAC from 2006 to 2016 who received pre-operative MAC or MAC + RT before oncologic resection were identified in the National Cancer Database. Univariable and multivariable (MVA) associates with R0 resection were identified with logistic regression, and survival was analyzed secondarily with the Kaplan Meier method and Cox regression analysis.

Results: 4,599 patients were identified (MAC: 3,109, MAC + RT: 1,490). Compared to those receiving MAC, patients receiving MAC + RT were more likely to have cT3-4 disease (76% vs 64%, p < 0.001) and cN + disease (33% vs 29%, p = 0.010), but were less likely to have ypT3-4 disease (59% vs 74%, p < 0.001) and ypN + disease (32% vs 55%, p < 0.001) and more likely to have a pathologic complete response (5% vs 2%, p < 0.001) and R0 resection (86% vs 80%, p < 0.001). On MVA, MAC + RT (OR 1.58, 95% CI 1.33-1.89, p < 0.001), evaluation at an academic center (OR 1.33, 95% CI 1.14-1.56, p < 0.001), and female sex (OR 1.43, 95% CI 1.23-1.67, p < 0.001) were associated with higher odds of R0 resection, while cT3-4 disease (OR 0.81, 95% CI 0.68-0.96, p = 0.013) was associated with lower odds of R0 resection.

Conclusion: For patients with localized PDAC who receive pre-operative MAC, the addition of pre-operative RT was associated with improved rates of R0 resection and pathologic response.
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http://dx.doi.org/10.1016/j.ctro.2020.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772693PMC
March 2021

A Digital Image Confidentiality Scheme Based on Pseudo-Quantum Chaos and Lucas Sequence.

Entropy (Basel) 2020 Nov 11;22(11). Epub 2020 Nov 11.

School of Computer Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.

Several secure image encryption systems have been researched and formed by chaotic mechanisms in current decades. This work recommends an innovative quantum color image encryption method focused on the Lucas series-based substitution box to enhance the competence of encryption. The suggested encryption technique has more excellent key space and significant confidentiality. The chaotic system, along with the substitution box, exhibits additional complicated dynamical behavior, sufficient arbitrariness, and uncertainty than all others focused on just chaotic models. Theoretical and simulation assessments show that the offered image encryption performs admirably, its traditional equivalents in terms by efficiency in terms of statistical analysis.
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http://dx.doi.org/10.3390/e22111276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711479PMC
November 2020

Fast and Efficient Image Encryption Algorithm Based on Modular Addition and SPD.

Entropy (Basel) 2020 Jan 16;22(1). Epub 2020 Jan 16.

School of Electronic Information and Communications, Huazhong University of Science and Technology, Wuhan 430074, China.

Bit-level and pixel-level methods are two classifications for image encryption, which describe the smallest processing elements manipulated in diffusion and permutation respectively. Most pixel-level permutation methods merely alter the positions of pixels, resulting in similar histograms for the original and permuted images. Bit-level permutation methods, however, have the ability to change the histogram of the image, but are usually not preferred due to their time-consuming nature, which is owed to bit-level computation, unlike that of other permutation techniques. In this paper, we introduce a new image encryption algorithm which uses binary bit-plane scrambling and an SPD diffusion technique for the bit-planes of a plain image, based on a card game trick. Integer values of the hexadecimal key SHA-512 are also used, along with the adaptive block-based modular addition of pixels to encrypt the images. To prove the first-rate encryption performance of our proposed algorithm, security analyses are provided in this paper. Simulations and other results confirmed the robustness of the proposed image encryption algorithm against many well-known attacks; in particular, brute-force attacks, known/chosen plain text attacks, occlusion attacks, differential attacks, and gray value difference attacks, among others.
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http://dx.doi.org/10.3390/e22010112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516419PMC
January 2020

Treatment Selection and Survival Outcomes in Locally Advanced Proximal Gastric Cancer: A National Cancer Data Base Analysis.

Front Oncol 2020 25;10:537051. Epub 2020 Sep 25.

Department of Surgery, Yale School of Medicine, New Haven, CT, United States.

We aimed to assess long-term survival between locally advanced proximal gastric cancer (LAPGC) patients who underwent proximal gastrectomy (PG) and those who underwent total gastrectomy (TG) to evaluate the optimal extent of resection and adjuvant therapy. Patients diagnosed with locally advanced proximal gastric adenocarcinoma were selected from the National Cancer Data Base (2004-2015) in America. Survival analysis was performed via Kaplan-Meier and Cox proportional hazards models. A total of 4,381 eligible patients were identified, 1,243 underwent PG and 3,138 underwent TG. Patients in TG group had a poor prognosis (hazard ratio [HR] = 1.13, 95% confidence interval [CI]: 1.03-1.25) compared with those in PG group. Moreover, postoperative chemoradiation therapy was associated with improved overall survival compared to surgery alone (HR = 0.71, 95% CI: 0.53-0.97) in LAPGC patients who had PG, while preoperative chemotherapy (HR = 0.74, 95% CI: 0.59-0.92) was associated with improved survival among patients who had TG. Our study suggested that LAPGC patients underwent PG experienced better long-term outcomes than those underwent TG. It also suggested that multimodality treatment of LAPGC, including preoperative chemotherapy followed by TG or postoperative chemotherapy followed by PG, should be considered to achieve better long-term outcomes.
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http://dx.doi.org/10.3389/fonc.2020.537051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546198PMC
September 2020

Exploring Probabilistic Network-Based Modeling of Multidimensional Factors Associated with Country Risk.

Risk Anal 2021 06 23;41(6):911-928. Epub 2020 Sep 23.

School of Business Administration, American University of Sharjah, Sharjah, United Arab Emirates.

Assessment of country risk provides a vital source of information to organizations for expanding and globalizing their operations. Various rating agencies are involved in developing models for assessing country risk, which utilize different statistical techniques for establishing the overall impact of individual factors on country risk. The main limitation of existing studies on country risk is their limited focus on exploring the relative contribution of individual factors to country risk in a probabilistic network setting. Utilizing real data, we develop a probabilistic network model that captures dependencies among multidimensional factors associated with country risk. Further, we assess the network-wide vulnerability and resilience potential of individual factors to identify critical factors. The findings of this study provide policy-makers with some unique insights into prioritizing strategies to mitigate country risk. Further, this study provides the context for multinational enterprises to utilize the proposed methodology for prioritizing key factors associated with the relative variables of interest such as regional stability and business environment among others.
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http://dx.doi.org/10.1111/risa.13589DOI Listing
June 2021

Kynurenic acid underlies sex-specific immune responses to COVID-19.

medRxiv 2020 Sep 8. Epub 2020 Sep 8.

Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06510, USA.

Coronavirus disease-2019 (COVID-19) has poorer clinical outcomes in males compared to females, and immune responses underlie these sex-related differences in disease trajectory. As immune responses are in part regulated by metabolites, we examined whether the serum metabolome has sex-specificity for immune responses in COVID-19. In males with COVID- 19, kynurenic acid (KA) and a high KA to kynurenine (K) ratio was positively correlated with age, inflammatory cytokines, and chemokines and was negatively correlated with T cell responses, revealing that KA production is linked to immune responses in males. Males that clinically deteriorated had a higher KA:K ratio than those that stabilized. In females with COVID-19, this ratio positively correlated with T cell responses and did not correlate with age or clinical severity. KA is known to inhibit glutamate release, and we observed that serum glutamate is lower in patients that deteriorate from COVID-19 compared to those that stabilize, and correlates with immune responses. Analysis of Genotype-Tissue Expression (GTEx) data revealed that expression of kynurenine aminotransferase, which regulates KA production, correlates most strongly with cytokine levels and aryl hydrocarbon receptor activation in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes, in COVID-19 infection.
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http://dx.doi.org/10.1101/2020.09.06.20189159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491534PMC
September 2020

In silico authentication of amygdalin as a potent anticancer compound in the bitter kernels of family Rosaceae.

Saudi J Biol Sci 2020 Sep 30;27(9):2444-2451. Epub 2020 Jun 30.

Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia.

Amygdalin a naturally occurring compound, predominantly in the bitter kernels of apricot, almond, apple and other members of Rosaceae family. Though, amygdalin is used as an alternative therapy to treat various types of cancer but its role in cancer pathways has rarely been explored yet. Therefore, present study was intended with the aim to investigate the alleged anti-cancerous effects of amygdalin specifically on PI3K-AKT-mTOR and Ras pathways of cancer in human body. Computational modelling and simulation techniques were used to assess the effect of amygdalin on PI3K-AKT-mTOR and Ras pathways using different level of dosage. It was observed that amygdalin had direct and substantial contribution to regulate PI3K-mTOR activities on threshold levels while the other caner pathways were effected indirectly. Consequently, amygdalin is a down-regulator of a cancer within a specified amount and contribute considerably to reduce various types of cancer in human. Furthermore, and analyses of amygdalin could be of helpful to authenticate its pharmacological effects.
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http://dx.doi.org/10.1016/j.sjbs.2020.06.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451698PMC
September 2020

In-silico elucidation of phytochemicals against diabetes mellitus.

Saudi J Biol Sci 2020 Sep 13;27(9):2299-2307. Epub 2020 Apr 13.

Department of Environmental Sciences, COMSATS University Islamabad, Abbottabad Campus 22060, Pakistan.

is also known as "Miracle tree", due to its multiple uses and adaptability. Because of nutritive and pharmacological values, it is widely cultivated across the world. leaves are rich source of minerals, vitamins and many health beneficial secondary metabolites, and possess significant anti-diabetic potential. Consequently, study could be noteworthy to expand effective anti-diabetic drugs from this plant. Present study was designed to find out the best bioactive compounds of as a potential therapeutic agent against diabetes mellitus through method. For this, structures of phytochemicals were extracted from PubChem and docked to mutated protein from PBD. Afterwards, datasets were prepared for ligand based pharmacophore and their pharmacophoric features were generated from LigandScout. Finally five phytochemicals viz. anthraquinone, 2-phenylchromenylium (Anthocyanins), hemlock tannin, sitogluside (glycoside) and A-phenolic steroid were selected, which exhibited effective binding within the active binding pocket of the targeted protein. Ligand based pharmacophore model showed the key features i.e. HBD, HBA, aromatic ring, hydrophobic, positively ionizable surface essential for receptor binding. Our findings suggest that screened phytochemicals present in can be used as potential therapeutic drug candidates to treat diabetes mellitus.
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http://dx.doi.org/10.1016/j.sjbs.2020.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451590PMC
September 2020

Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies.

J Hematol Oncol 2020 07 27;13(1):103. Epub 2020 Jul 27.

Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that utilize the ubiquitin proteasome system (UPS) to degrade proteins of interest (POI). PROTACs are potentially superior to conventional small molecule inhibitors (SMIs) because of their unique mechanism of action (MOA, i.e., degrading POI in a sub-stoichiometric manner), ability to target "undruggable" and mutant proteins, and improved target selectivity. Therefore, PROTACs have become an emerging technology for the development of novel targeted anticancer therapeutics. In fact, some of these reported PROTACs exhibit unprecedented efficacy and specificity in degrading various oncogenic proteins and have advanced to various stages of preclinical and clinical development for the treatment of cancer and hematologic malignancy. In this review, we systematically summarize the known PROTACs that have the potential to be used to treat various hematologic malignancies and discuss strategies to improve the safety of PROTACs for clinical application. Particularly, we propose to use the latest human pan-tissue single-cell RNA sequencing data to identify hematopoietic cell type-specific/selective E3 ligases to generate tumor-specific/selective PROTACs. These PROTACs have the potential to become safer therapeutics for hematologic malignancies because they can overcome some of the on-target toxicities of SMIs and PROTACs.
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http://dx.doi.org/10.1186/s13045-020-00924-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384229PMC
July 2020

DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas.

J Hematol Oncol 2020 07 16;13(1):95. Epub 2020 Jul 16.

Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Background: Patients with advanced T cell lymphomas (TCLs) have limited therapeutic options and poor outcomes in part because their TCLs evade apoptosis through upregulation of anti-apoptotic Bcl-2 proteins. Subsets of TCL cell lines, patient-derived xenografts (PDXs), and primary patient samples depend on Bcl-xL for survival. However, small molecule Bcl-xL inhibitors such as ABT263 have failed during clinical development due to on-target and dose-limiting thrombocytopenia.

Methods: We have developed DT2216, a proteolysis targeting chimera (PROTAC) targeting Bcl-xL for degradation via Von Hippel-Lindau (VHL) E3 ligase, and shown that it has better anti-tumor activity but is less toxic to platelets compared to ABT263. Here, we examined the therapeutic potential of DT2216 for TCLs via testing its anti-TCL activity in vitro using MTS assay, immunoblotting, and flow cytometry and anti-TCL activity in vivo using TCL cell xenograft and PDX model in mice.

Results: The results showed that DT2216 selectively killed various Bcl-xL-dependent TCL cells including MyLa cells in vitro. In vivo, DT2216 alone was highly effective against MyLa TCL xenografts in mice without causing significant thrombocytopenia or other toxicity. Furthermore, DT2216 combined with ABT199 (a selective Bcl-2 inhibitor) synergistically reduced disease burden and improved survival in a TCL PDX mouse model dependent on both Bcl-2 and Bcl-xL.

Conclusions: These findings support the clinical testing of DT2216 in patients with Bcl-xL-dependent TCLs, both as a single agent and in rational combinations.
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http://dx.doi.org/10.1186/s13045-020-00928-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364785PMC
July 2020

Tumor Tissue-Specific Biomarkers of Colorectal Cancer by Anatomic Location and Stage.

Metabolites 2020 Jun 19;10(6). Epub 2020 Jun 19.

Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA.

The progress in the discovery and validation of metabolite biomarkers for the detection of colorectal cancer (CRC) has been hampered by the lack of reproducibility between study cohorts. The majority of discovery-phase biomarker studies have used patient blood samples to identify disease-related metabolites, but this pre-validation phase is confounded by non-specific disease influences on the metabolome. We therefore propose that metabolite biomarker discovery would have greater success and higher reproducibility for CRC if the discovery phase was conducted in tumor tissues, to find metabolites that have higher specificity to the metabolic consequences of the disease, that are then validated in blood samples. This would thereby eliminate any non-tumor and/or body response effects to the disease. In this study, we performed comprehensive untargeted metabolomics analyses on normal (adjacent) colon and tumor tissues from CRC patients, revealing tumor tissue-specific biomarkers ( = 39/group). We identified 28 highly discriminatory tumor tissue metabolite biomarkers of CRC by orthogonal partial least-squares discriminant analysis (OPLS-DA) and univariate analyses (VIP > 1.5, < 0.05). A stepwise selection procedure was used to identify nine metabolites that were the most predictive of CRC with areas under the curve (AUCs) of >0.96, using various models. We further identified five biomarkers that were specific to the anatomic location of tumors in the colon ( = 236). The combination of these five metabolites (S-adenosyl-L-homocysteine, formylmethionine, fucose 1-phosphate, lactate, and phenylalanine) demonstrated high differentiative capability for left- and right-sided colon cancers at stage I by internal cross-validation (AUC = 0.804, 95% confidence interval, CI 0.670-0.940). This study thus revealed nine discriminatory biomarkers of CRC that are now poised for external validation in a future independent cohort of samples. We also discovered a discrete metabolic signature to determine the anatomic location of the tumor at the earliest stage, thus potentially providing clinicians a means to identify individuals that could be triaged for additional screening regimens.
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http://dx.doi.org/10.3390/metabo10060257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345993PMC
June 2020

nCOV-19 peptides mass fingerprinting identification, binding, and blocking of inhibitors flavonoids and anthraquinone of and hydroxychloroquine.

J Biomol Struct Dyn 2021 07 22;39(11):4089-4099. Epub 2020 Jun 22.

Department of Bioinformatics, Govt. Postgraduate College Mandian Abbottabad, Abbottabad, KPK, Pakistan.

An rare pandemic of viral pneumonia occurs in December 2019 in Wuhan, China, which is now recognized internationally as Corona Virus Disease 2019 (COVID-19), the etiological agent classified as Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2). According to the World Health Organization (WHO), it has so far expanded to more than 213 countries/territories worldwide. Our study aims to find the viral peptides of SARS-COV-2 by peptide mass fingerprinting (PMF) in order to predict its novel structure and find an inhibitor for each viral peptide. For this reason, we calculated the mass of amino acid sequences translated from the SARS-CoV2 whole genome and identify the peptides that may be a target for inhibition. Molecular peptide docking with phytochemicals (aqueous and ethanolic) leaf extracts of flavonoids (3.56 ± 0.03), (3.83 ± 0.02), anthraquinone (11.68 ± 0.04), (10.86 ± 0.06) and hydroxychloroquine present therapy of COVID-19 in Pakistan for comparative study. Results indicate that 15 peptides of SARS-CoV2 have been identified from PMF, which is then used as a selective inhibitor. The maximum energy obtained from AutoDock Vina for hydroxychloroquine is -5.1 kcal/mol, kaempferol (flavonoid) is -6.2 kcal/mol, and for anthraquinone -6 kcal/mol. Visualization of docking complex, important effects are observed regarding the binding of peptides to drug compounds. In conclusion, it is proposed that these compounds are effective antiviral agents against COVID-19 and can be used in clinical trials.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1778534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332867PMC
July 2021

Centchroman prevents metastatic colonization of breast cancer cells and disrupts angiogenesis via inhibition of RAC1/PAK1/β-catenin signaling axis.

Life Sci 2020 Sep 16;256:117976. Epub 2020 Jun 16.

Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India; Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, India. Electronic address:

Aims: We have previously reported that Centchroman (CC), an oral contraceptive drug, inhibits breast cancer progression and metastasis. In this study, we investigated whether CC inhibits local invasion of tumor cells and/or their metastatic colonization with detailed underlying mechanisms.

Main Methods: The effect of CC on the experimental metastasis and spontaneous metastasis was demonstrated by using tail-vein and orthotopic 4T1-syngeneic mouse tumor models, respectively. The anti-angiogenic potential of CC was evaluated using well established in vitro and in vivo models. The role of RAC1/PAK1/β-catenin signaling axis in the metastasis was investigated and validated using siRNA-mediated knockdown of PAK1 as well as by pharmacological PAK1-inhibitor.

Key Findings: The oral administration of CC significantly suppressed the formation of metastatic lung nodules in the 4T1-syngeneic orthotopic as well as experimental metastatic models. More importantly, CC treatment suppressed the tube formation and migration capacities of human umbilical vein endothelial cells (HUVEC) and inhibited pre-existing vasculature as well as the formation of neovasculature. The suppression of migration and invasion capacities of metastatic breast cancer cells upon CC treatment was associated with the inhibition of small GTPases (Rac1 and Cdc42) concomitant with the downregulation of PAK1 and downstream β-catenin signaling. In addition, CC upregulated the expression of miR-145, which is known to target PAK1.

Significance: This study warrants the repurposing of CC as a potential therapeutic agent against metastatic breast cancer.
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http://dx.doi.org/10.1016/j.lfs.2020.117976DOI Listing
September 2020

PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics.

Oncogene 2020 06 31;39(26):4909-4924. Epub 2020 May 31.

Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Using PROteolysis TArgeting Chimeras (PROTACs) to degrade proteins that are important for tumorigenesis has emerged as a potential therapeutic strategy for cancer. PROTACs are heterobifunctional molecules consisting of one ligand for binding to a protein of interest (POI) and another to an E3 ubiquitin (E3) ligase, connected via a linker. PROTACs recruit the E3 ligase to the POI and cause proximity-induced ubiquitination and degradation of the POI by the ubiquitin-proteasome system (UPS). PROTACs have been developed to degrade a variety of cancer targets with unprecedented efficacy against a multitude of tumor types. To date, most of the PROTACs developed have utilized ligands to recruit E3 ligases that are ubiquitously expressed in both tumor and normal tissues. These PROTACs can cause on-target toxicities if the POIs are not tumor-specific. Therefore, identifying and recruiting the E3 ligases that are enriched in tumors with minimal expression in normal tissues holds the potential to develop tumor-specific/selective PROTACs. In this review, we will discuss the potential of PROTACs to become anticancer therapeutics, chemical and bioinformatics approaches for PROTAC design, and safety concerns with a special focus on the development of tumor-specific/selective PROTACs. In addition, the identification of tumor types in terms of solid versus hematological malignancies that can be best targeted with PROTAC approach will be briefly discussed.
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http://dx.doi.org/10.1038/s41388-020-1336-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319888PMC
June 2020

A review of airport dual energy X-ray baggage inspection techniques: Image enhancement and noise reduction.

J Xray Sci Technol 2020 ;28(3):481-505

Department of Education & Research, The University of Lakki Marwat, KPK, Pakistan.

In this paper, we present a review of the research literature regarding applying X-ray imaging of baggage scrutiny at airport. It discusses multiple X-ray imaging inspection systems used in airports for detecting dangerous objects inside the baggage. Moreover, it also explains the dual energy X-ray image fusion and image enhancement factors. Different types of noises in digital images and noise models are explained in length. Diagrammatical representations for different noise models are presented and illustrated to clearly show the effect of Poisson and Impulse noise on intensity values. Overall, this review discusses in detail of Poisson and Impulse noise, as well as its causes and effect on the X-ray images, which create un-certainty for the X-ray inspection imaging system while discriminating objects and for the screeners as well. The review then focuses on image processing techniques used by different research studies for X-ray image enhancement, de-noising, and their limitations. Furthermore, the most related approaches for noise reduction and its drawbacks are presented. The methods that may be useful to overcome the drawbacks are also discussed in subsequent sections of this paper. In summary, this review paper highlights the key theories and technical methods used for X-ray image enhancement and de-noising effect on X-ray images generated by the airport baggage inspection system.
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http://dx.doi.org/10.3233/XST-200663DOI Listing
January 2020

Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity.

Nat Commun 2020 04 24;11(1):1996. Epub 2020 Apr 24.

Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Small molecules that selectively kill senescent cells (SCs), termed senolytics, have the potential to prevent and treat various age-related diseases and extend healthspan. The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity. Here, we report the use of proteolysis-targeting chimera (PROTAC) technology to reduce the platelet toxicity of navitoclax (also known as ABT263), a Bcl-2 and Bcl-xl dual inhibitor, by converting it into PZ15227 (PZ), a Bcl-xl PROTAC, which targets Bcl-xl to the cereblon (CRBN) E3 ligase for degradation. Compared to ABT263, PZ is less toxic to platelets, but equally or slightly more potent against SCs because CRBN is poorly expressed in platelets. PZ effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia. With further improvement, Bcl-xl PROTACs have the potential to become safer and more potent senolytic agents than Bcl-xl inhibitors.
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http://dx.doi.org/10.1038/s41467-020-15838-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181703PMC
April 2020
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