Chemically modified mRNA beyond COVID-19: Potential preventive and therapeutic applications for targeting chronic diseases

Chemically modified mRNA represents a unique, efficient, and straightforward approach to produce a class of biopharmaceutical agents. It has been already approved as a vaccination-based method for targeting SARS-CoV-2 virus. The COVID-19 pandemic has highlighted the prospect of synthetic modified mRNA to efficiently and safely combat various diseases. Recently, various optimization advances have been adopted to overcome the limitations associated with conventional gene therapeutics leading to wide-ranging applications in different disease conditions. This review sheds light on emerging directions of chemically modified mRNAs to prevent and treat widespread chronic diseases, including metabolic disorders, cancer vaccination and immunotherapy, musculoskeletal disorders, respiratory conditions, cardiovascular diseases, and liver diseases.Qatar University (Grant # QUCG-CPH-20/21-4 and QUCG-CPH-21/22-1

A comprehensive review on the antiviral activities of chalcones

Some viral outbreaks have plagued the world since antiquity, including the most recent COVID-19 pandemic. The continuous spread and emergence of new viral diseases have urged the discovery of novel treatment options that can overcome the limitations of currently marketed antiviral drugs. Chalcones are natural open chain flavonoids that are found in various plants and can be synthesised in labs. Several studies have shown that these small organic molecules exert a number of pharmacological activities, including antiviral, anti-inflammatory, antimicrobial and anticancer. The purpose of this review is to provide a summary of the antiviral activities of chalcones and their derivatives on a set of human viral infections and their potential for targeting the most recent COVID-19 disease. Accordingly, we herein review chalcones activities on the following human viruses: Middle East respiratory syndrome coronavirus, severe acute respiratory syndrome coronavirus, human immunodeficiency, influenza, human rhinovirus, herpes simplex, dengue, human cytomegalovirus, hepatitis B and C, Rift Valley fever and Venezuelan equine encephalitis. We hope that this review will pave the way for the design and development of potentially potent and broad-spectrum chalcone based antiviral drugs.Open Access funding provided by the Qatar National Library. Our lab is supported by grants from Qatar University: # QUCG-CPH-20/21-4, QUHI-CMED-19/20-1, QUCG-CMED-20/21-2.Scopu

Characteristics and quality of adverse drug reaction reporting among healthcare providers at Rumailah Hospital in Qatar

Introduction: Under-reporting of adverse drug reactions (ADRs) and low-quality reporting are a widespread phenomenon globally.1 There is a need for more insight on the role of pharmacists and other healthcare professionals in ADR reporting. This study primarily aimed to compare the rates, quality, and characteristics of ADR reports received from different healthcare providers in Rumailah Hospital (RH) in Qatar. Methods: A retrospective descriptive analysis of ADR reports submitted by healthcare providers in RH between 1 January 2012 and 1 October 2014 was conducted. Outcome measures included rate of ADR reporting, quality, causality scores as well as characteristics of the reported ADRs. Results: A total of 92 ADR reports were submitted by different healthcare providers, of which 42% were submitted by pharmacists, 38% by physicians, and 9% by nurses. Most of the ADR reports by physicians (66%), nurses (63%) and pharmacists (41%) were judged to be of high quality (grade 2) based on WHO scheme (p>0.05%).2 Sixty percent of the submitted ADR reports were for medications considered 'possibly' causing the event according to Naranjo causality score, while 30% were considered probable (p < 0.05%). Most of the ADR reports were type B (54%) and were unpreventable (64%) according to the Medication Appropriateness Index (MAI).3 One hundred percent and 91% of nurses and physicians' ADR reports were for unpreventable events, respectively, while 41% of pharmacists' reports were definitely preventable ADRs (p < 0.05%). Conclusion: ADR reporting in RH was undertaken by different healthcare professionals and was generally of high quality. ADRs reported were often unpreventable. There were differences between characteristics and causality scores of ADR reports between different healthcare professionals.qscienc

Efficacy and tolerability of sulforaphane in the therapeutic management of cancers: a systematic review of randomized controlled trials

ObjectivesThis paper presents a systematic review aimed at assessing the therapeutic potential of sulforaphane (SFN) in the treatment of diverse cancer types.MethodsFollowing Cochrane guidelines for systematic reviews, we conducted an exhaustive search of electronic databases up to May 12, 2023, encompassing PubMed, Cochrane, Embase, Web of Science, Google Scholar, Natural Medicines, ProQuest, ClinicalTrials.gov, and ICTRP. Studies were included if they were human-based RCTs involving cancer patients where SFN was the primary experimental treatment. The Cochrane Risk of Bias tool for RCTs (RoB2) was used for quality assessment.ResultsEight studies investigating the efficacy and safety of SFN in prostate cancer (PCa), breast cancer, pancreatic cancer, and melanoma were identified and included in the review. The dosing regimens were variable and inconsistent across the studies. SFN treatment led to statistically significant alterations in several vital genes and histological biomarkers across the studies. However, it did not impact some other key genes. Although not statistically significant, SFN improved overall survival in pancreatic cancer patients. The results on prostate-specific antigen (PSA) were inconsistent in PCa. None of the studies reported significant differences between SFN and comparative controls in terms of adverse events.ConclusionSFN has emerged as a promising and safe therapeutic agent for diverse cancer types. Nevertheless, the high levels of methodological and clinical heterogeneity across the included studies precluded the possibility of conducting meta-analyses. Further robust clinical investigations to conclusively ascertain the chemotherapeutic potential of SFN in the management of various cancer forms are needed.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022323788, identifier CRD42022323788

Novel nitrogen-based chalcone analogs provoke substantial apoptosis in HER2-positive human breast cancer cells via JNK and ERK1/ERK2 signaling pathways

Natural chalcones possess antitumor properties and play a role as inducers of apoptosis, antioxidants and cytotoxic compounds. We recently reported that novel nitrogen chalcone-based compounds, which were generated in our lab, have specific effects on triple-negative breast cancer cells. However, the outcome of these two new compounds on human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains nascent. Thus, we herein investigated the effects of these compounds (DK-13 and DK-14) on two HER2-positive breast cancer cell lines, SKBR3 and ZR75. Our data revealed that these compounds inhibit cell proliferation, deregulate cell-cycle progression and significantly induce cell apoptosis in both cell lines. Furthermore, the two chalcone compounds cause a significant reduction in the cell invasion ability of SKBR3 and ZR75 cancer cells. In parallel, we found that DK-13 and DK-14 inhibit colony formation of both cell lines in comparison to their matched controls. On the other hand, we noticed that these two compounds can inhibit angiogenesis in the chorioallantoic membrane model. The molecular pathway analysis of chalcone compounds exposed cells revealed that these compounds inhibit the expression of both JNK1/2/3 and ERK1/2, the major plausible molecular pathways behind these events. Our findings implicate that DK-13 and DK-14 possess effective chemotherapeutic outcomes against HER2-positive breast cancer via the ERK1/2 and JNK1/2/3 signaling pathways.Funding: This research was funded by the following Qatar University Grants: (QUCG-CPH-20/21-4), (QUCP-CMED-2019-1) and (QUHI-CMED-19/20-1).Scopu

Targeting triple negative breast cancer heterogeneity with chalcones: a molecular insight.

Triple negative breast cancers (TNBCs) are aggressive heterogeneous cancers with not yet determined conventional targeted medication. Therefore, identification of new alternatives or improved treatment options to combat this deadly disease is highly needed. On the other hand, various derived products with chalcone scaffold were historically considered excellent candidates for the development of anticancer drugs. Chalcones unique chemical structure and their substantial biological activities in cancer cells make them an extremely attractive target for the treatment of several human carcinomas including TNBCs. This review highlights the promising therapeutic role of chalcones in TNBC management

Characteristics and quality of adverse drug reaction reporting: a comparison of pharmacists with other healthcare providers at a multi-specialty hospital in Qatar

Objective: Rumailah Hospital (RH) is a multi-specialty hospital with a capacity of 605 beds that serves subacute and long-term patients in Qatar. Since under-reporting and low-quality reporting of adverse drug reactions (ADRs) are widespread phenomena globally, there is a need for greater insight into pharmacists' and other healthcare professionals' roles in ADR reporting in RH. Thus, this study primarily aimed to compare the number, quality, and characteristics of ADR reports received from pharmacists compared with other healthcare providers at RH in Qatar. Methods: A retrospective descriptive analysis of ADR reports submitted by healthcare providers at RH between January 1, 2012 and October 1, 2014 was conducted. Results: A total of 92 ADR reports were submitted by different healthcare providers, of which 42.8% were by pharmacists, 38.4% by physicians, and 8.8% by nurses. Most of the physicians' (65.7%), nurses' (62.5%), and pharmacists' (41.0%) ADR reports were judged to be of high quality (grade 2) based on the World Health Organization's quality scheme (p>0.05). A causality assessment using the Naranjo algorithm revealed that 62.2% of the reports were 'possibly' caused by the suspected medications, while 31.1% were considered to 'probably' have been caused by the suspected medications (p<0.05). Furthermore, most of the ADR reports were type B (54.9%) and unpreventable (64.8%) according to the Medication Appropriateness Index. One hundred percent and 91.2% of nurses' and physicians' ADR reports were for unpreventable events, respectively, while 41.0% of pharmacists' reports were for definitely preventable ADRs (p < 0.05). Conclusions: ADR reporting at RH was undertaken by different healthcare professionals, and a high proportion of the reports were judged to be of high quality. ADRs reported were often unpreventable. There were differences between the characteristics and causality scores of ADR reports between different healthcare professionals. There is a need to develop interventions that will further increase ADR reporting as well as the quality of the reports.This study was supported by Qatar University under a student grant (Grant No. QUST-CPH-FALL-14/15-17).Scopu

Novel polymethoxylated chalcones as potential compounds against kras-mutant colorectal cancers

Background/Objective: KRAS-mutant colorectal cancers (CRC) are tumors that are associated with poor prognosis. However, no effective treatments are available to target them. Therefore, we designed and synthesized novel chalcone analogs, small organic molecules, to investigate their effects on KRAS-mutant CRC cells. Methods: Fourteen new chalcone analogs were synthesized, optimized, characterized, and tested against two KRAS-mutant CRC cell lines (HCT-116 and LoVo), one p-53 and BRAF mutant CRC cell line (HT-29) and one normal immortalized colon cells (NCE-1 E6/E7). Effects on cell viability, apoptosis, cell cycle, migration, colony formation, EMT, and angiogenesis were investigated. Results: Compounds 3 and 14 were the most effective. Compound 3 showed potent activity against HCT-116 and LoVo cell lines (GI50 of 6.10 μM and 7.00 μM, respectively). While compound 14 showed GI50 of 8.60 μM and 8.80 μM on HCT-116 and LoVo cell lines, respectively. Both compounds were approximately 2-3 times more selective toward cancer cells rather than normal colon cells. Compound 3 was effective in inducing apoptosis in HCT-116 cells via Bax upregulation and Bcl-2 downregulation. Invasion and metastasis of KRAS-mutant cells were modulated by compounds 3 and 14 through significant inhibition of cell migration and the prevention of colony formation. In addition, they reversed EMT by downregulation of EMT markers (vimentin, fascin, and β- catenin) and upregulation of cell-cell adhesion marker, E-cadherin. Furthermore, compounds 3 and 14 had significantly inhibited angiogenesis in ovo. Conclusion: Compounds 3 and 14 represent potent and selective leads for KRAS-mutant CRC cells, thus, further in vitro and in vivo studies are necessary to confirm their effect on KRAS-mutant CRCs.This research work was supported by Grants no. QUST-1-CPH-2018-19, QUST-1-CPH-2019-2 and Grant no. GCC-2017-002 from Qatar University. The NMR and the elemental analyses were accomplished in the Central Laboratories Unit, Qatar University.Scopu

DataSheet_1_Efficacy and tolerability of sulforaphane in the therapeutic management of cancers: a systematic review of randomized controlled trials.pdf

ObjectivesThis paper presents a systematic review aimed at assessing the therapeutic potential of sulforaphane (SFN) in the treatment of diverse cancer types.MethodsFollowing Cochrane guidelines for systematic reviews, we conducted an exhaustive search of electronic databases up to May 12, 2023, encompassing PubMed, Cochrane, Embase, Web of Science, Google Scholar, Natural Medicines, ProQuest, ClinicalTrials.gov, and ICTRP. Studies were included if they were human-based RCTs involving cancer patients where SFN was the primary experimental treatment. The Cochrane Risk of Bias tool for RCTs (RoB2) was used for quality assessment.ResultsEight studies investigating the efficacy and safety of SFN in prostate cancer (PCa), breast cancer, pancreatic cancer, and melanoma were identified and included in the review. The dosing regimens were variable and inconsistent across the studies. SFN treatment led to statistically significant alterations in several vital genes and histological biomarkers across the studies. However, it did not impact some other key genes. Although not statistically significant, SFN improved overall survival in pancreatic cancer patients. The results on prostate-specific antigen (PSA) were inconsistent in PCa. None of the studies reported significant differences between SFN and comparative controls in terms of adverse events.ConclusionSFN has emerged as a promising and safe therapeutic agent for diverse cancer types. Nevertheless, the high levels of methodological and clinical heterogeneity across the included studies precluded the possibility of conducting meta-analyses. Further robust clinical investigations to conclusively ascertain the chemotherapeutic potential of SFN in the management of various cancer forms are needed.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022323788, identifier CRD42022323788.</p

Utilization of evidence-based secondary prevention medications at the time of discharge in patients with acute coronary syndrome (ACS) in Qatar

Background and Objectives: In Qatar, ACS (Acute Coronary Syndrome) has become the leading cause of morbidity and mortality. Guidelines recommend that ACS patients should receive indefinite treatment with antiplatelets, β-blockers, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and statins. The study objectives were to assess the use of evidence-based secondary prevention medication at discharge among ACS patients in Qatar and to determine the clinical and demographic characteristics associated with the use of these medications. Setting and Methods: A retrospective medical record review was conducted at the Heart Hospital in Qatar. A random sample of 1068 ACS patients was selected. Patient characteristics were summarized. Prevalence of medications at discharge were computed for each medication as well as for medication combinations. Multiple logistic regression was used to detect patient variables that were associated with the outcomes. A p≤0.05 was considered significant. Main Outcome Measures: -Percentage of ACS patients discharged on each of the following medications: antiplatelets (aspirin, clopidogrel), β-blockers, ACEI or ARBs and statins and on the combination of these medications-Association between the use of these medications and patient characteristics. Results: In total, 1064 records were reviewed. The majority were males (85.3%) and about 1 in 5 (18.7%) were Qatari. At discharge, patients were prescribed the following: aspirin (96.0%), clopidogrel (92.0%), -blockers (90.6%) and statins (97.7%). ACEI and ARBs were prescribed to 63.5 and 11.3%, respectively. The concurrent 4 medications (aspirin or clopidogrel, statins or other lowering cholesterol medication, β-blockers and ACEI or ARB) were prescribed to 773 patients (77.8%; 95% confidence interval: 75.2-80.4%). Being overweight or obese, and having PCI (percutaneous coronary intervention) or hypertension were associated with higher prescription of the concurrent medications. Those with diabetes had a 52% increase in the odds of prescribing the 4 medications. Those with kidney disease had a 67% reduction in the odds of prescribing. Conclusion: Most ACS patients were prescribed antiplatelets, β-blockers and statins, but the use of ACEIs or ARBs was suboptimal. Strategies are needed to enhance ACEI or ARB prescribing, especially for high risk patients who would have the greatest therapeutic benefit from these drugs.Scopu