Browsing by Author "Hachim, Mahmood Yaseen"

Now showing 1 - 20 of 55

ACE2 polymorphisms impact COVID-19 severity in obese patients
(2022-12) Jalaleddine, Nour; Hachim, Mahmood Yaseen; Senok, Abiola; Al Heialy, Saba
Abstract: A strong association between obesity and COVID-19 complications and a lack of prognostic factors that explain the unpredictable severity among these patients still exist despite the various vaccination programs. The expression of angiotensin converting enzyme 2 (ACE2), the main receptor for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is enhanced in obese individuals. The occurrence of frequent genetic single nucleotide polymorphisms (SNPs) in ACE2 is suggested to increase COVID-19 severity. Accordingly, we hypothesize that obesity-associated ACE2 polymorphisms increase the severity of COVID-19. In this study, we profiled eight frequently reported ACE2 SNPs in a cohort of lean and obese COVID-19 patients (n = 82). We highlight the significant association of rs2285666, rs2048683, rs879922, and rs4240157 with increased severity in obese COVID-19 patients as compared to lean counterparts. These co-morbid-associated SNPs tend to positively correlate, hence proposing possible functional cooperation to ACE2 regulation. In obese COVID-19 patients, rs2285666, rs879922, and rs4240157 are significantly associated with increased blood nitrogen urea and creatinine levels. In conclusion, we highlight the contribution of ACE2 SNPs in enhancing COVID-19 severity in obese individuals. The results from this study provide a basis for further investigations required to shed light on the underlying mechanisms of COVID-19 associated SNPs in COVID-19 obese patients.
Acute cardiac injury is associated with adverse outcomes, including mortality in COVID-19 patients
(2020) Hachim, Mahmood Yaseen
Abstract: Objectives: To evaluate acute cardiac injury in COVID-19 patients and its association with adverse outcomes including mortality in the United Arab Emirates (UAE) population. Methods: A retrospective study conducted between February and June 2020 in Dubai, UAE, for all laboratory-confirmed Coronavirus disease-19 patients. Demographic, clinical, laboratory, radiological, and clinical outcomes were compared between patients with and without acute cardiac injury. Results: During the study period, 203 patients were included, of which, 44 (21.7%) had evidence of acute cardiac injury. Compared with patients without acute cardiac injury, patients with acute cardiac injury were: older, had more shortness of breath, diabetes, hypertension, and more bilateral airspace shadowing on admission chest radiography. These patients also had a higher neutrophil count, C-reactive protein, procalcitonin, ferritin, D-dimers and lactate dehydrogenase but lower lymphocyte count. Regarding outcomes, these patients had higher intensive care admissions; a higher rate of complications including acute kidney and liver injury, acidosis, septic shock, acute respiratory distress syndrome, needed more mechanical ventilation, and had a significantly higher risk of death. Conclusion: Acute cardiac injury is common among Coronavirus disease-19 patients. These patients present with higher comorbidities, have high inflammatory markers and have greater risk for in-hospital multiorgan damage, need for mechanical ventilation, and death. Prompt full assessment and intervention are recommended.
Analyzing single cell transcriptome data from severe COVID-19 patients
(2022) Nassir, Nasna; Tambi, Richa; Bankapur, Asma; Karuvantevida, Noushad; Zehra, Binte; Begum, Ghausia; Hameid, Reem Abdel; Ahmed, Awab; Shabestari, Seyed Ali Safizadeh; Hachim, Mahmood Yaseen; Alsheikh-Ali, Alawi; Berdiev, Bakhrom; Al Heialy, Saba; Uddin, Mohammed
SUMMARY: We describe the protocol for identifying COVID-19 severity specific cell types and their regulatory marker genes using single-cell transcriptomics data. We construct COVID-19 comorbid disease-associated gene list using multiple databases and literature resources. Next, we identify specific cell type where comorbid genes are upregulated. We further characterize the identified cell type using gene enrichment analysis. We detect upregulation of marker gene restricted to severe COVID-19 cell type and validate our findings using in silico, in vivo, and in vitro cellular models.
Asthma Associated Cytokines Regulate the Expression of SARS-CoV-2 Receptor ACE2 in the Lung ‎Tissue of Asthmatic Patients
(2022) Heialy, Saba Al; Hachim, Mahmood Yaseen
Abstract:‎ It is still controversial whether chronic lung inflammation increases the risk for COVID-19. One of the ‎risk factors for acquiring COVID-19 is the level of expression of SARS-CoV-2 entry receptors, ACE2 and ‎TMPRSS2, in lung tissue. It is, however, not clear how lung tissue inflammation affects expression ‎levels of these receptors. We hence aimed to determine the level of SARS-CoV-2 receptors in lung ‎tissue of asthmatic relative to age, gender, and asthma severity, and to investigate the factors ‎regulating that. Therefore, gene expression data sets of well-known asthmatic cohorts (SARP and U-‎BIOPRED) were used to evaluate the association of ACE2 and TMPRSS2 with age, gender of the ‎asthmatic patients, and also the type of the underlying lung tissue inflammatory cytokines. Notably, ‎ACE2 and to less extent TMPRSS2 expression were upregulated in the lung tissue of asthmatics ‎compared to healthy controls. Although a differential expression of ACE2, but not TMPRSS2 was ‎observed relative to age within the moderate and severe asthma groups, our data suggest that age ‎may not be a key regulatory factor of its expression. The type of tissue inflammation, however, ‎associated significantly with ACE2 and TMPRSS2 expression levels following adjusting with age, gender ‎and oral corticosteroids use of the patient. Type I cytokine (IFN-g), IL-8, and IL-19 were associated with ‎increased expression, while Type II cytokines (IL-4 and IL-13) with lower expression of ACE2 in lung ‎tissue (airway epithelium and/or lung biopsies) of moderate and severe asthmatic patients. Of note, ‎IL-19 was associated with ACE2 expression while IL-17 was associated with TMPRSS2 expression in ‎sputum of asthmatic subjects. In vitro treatment of bronchial fibroblasts with IL-17 and IL-19 cytokines ‎confirmed the regulatory effect of these cytokines on SARS-CoV-2 entry receptors. Our results ‎suggest that the type of inflammation may regulate ACE2 and TMPRSS2 expression in the lung tissue ‎of asthmatics and may hence affect susceptibility to SARS-CoV-2 infection.‎
Author Correction: Derangement of cell cycle markers in peripheral blood mononuclear cells of asthmatic patients as a reliable biomarker for asthma control
(2021) Hachim, Mahmood Yaseen; Al Heialy, Saba
Author Correction: Derangement of cell cycle markers in peripheral blood mononuclear cells of asthmatic patients as a reliable biomarker for asthma control
Bcl10 Regulates Lipopolysaccharide-Induced Pro-Fibrotic Signaling in Bronchial Fibroblasts from Severe Asthma Patients
(2022) Rawat, Surendra Singh; Hachim, Mahmood Yaseen
Abstract: Subepithelial fibrosis is a characteristic hallmark of airway remodeling in asthma. Current asthma medications have limited efficacy in treating fibrosis, particularly in patients with severe asthma, necessitating a deeper understanding of the fibrotic mechanisms. The NF-κB pathway is key to airway inflammation in asthma, as it regulates the activity of multiple pro-inflammatory mediators that contribute to airway pathology. Bcl10 is a well-known upstream mediator of the NF-κB pathway that has been linked to fibrosis in other disease models. Therefore, we investigated Bcl10- mediated NF-κB activation as a potential pathway regulating fibrotic signaling in severe asthmatic fibroblasts. We demonstrate here the elevated protein expression of Bcl10 in bronchial fibroblasts and bronchial biopsies from severe asthmatic patients when compared to non-asthmatic individuals. Lipopolysaccharide (LPS) induced the increased expression of the pro-fibrotic cytokines IL-6, IL-8 and TGF-β1 in bronchial fibroblasts, and this induction was associated with the activation of Bcl10. Inhibition of the Bcl10-mediated NF-κB pathway using an IRAK1/4 selective inhibitor abrogated the pro-fibrotic signaling induced by LPS. Thus, our study indicates that Bcl10-mediated NF-κB activation signals increased pro-fibrotic cytokine expression in severe asthmatic airways. This reveals the therapeutic potential of targeting Bcl10 signaling in ameliorating inflammation and fibrosis, particularly in severe asthmatic individuals.
Bone marrow mammaglobin‑1 (SCGB2A2) immunohistochemistry expression as a breast cancer specific marker for early detection of bone marrow micrometastases
(2020) Hachim, Mahmood Yaseen
Abstract: Despite all the advances in the management of breast cancer (BC), patients with distance metastasis are still considered incurable with poor prognosis. For that reason, early detection of the metastatic lesions is crucial to improve patients’ life span as well as quality of life. Many markers were proposed to be used as biomarkers for metastatic BC lesions, however many of them lack organ specificity. This highlights the need for novel markers that are more specific in detecting disseminated BC lesions. Here, we investigated mammaglobin-1 expression as a potential and specific marker for metastatic BC lesions using our patient cohort consisting of 30 newly diagnosed BC patients. For all patients, bone marrow (BM) aspiration, BM biopsy stained by H&E and BM immunohistochemically stained for mammaglobin-1 were performed. In addition, the CA15-3 in both serum and bone marrow plasma was also evaluated for each patient. Indeed, mammaglobin-1 immuno-staining was able to detect BM micrometastases in 16/30 patients (53.3%) compared to only 5/30 patients (16.7%) in BM biopsy stained by H&E and no cases detected by BM aspirate (0%). In addition, our results showed a trend of association between mammaglobin-1 immunoreactivity and the serum and BM plasma CA15-3. Further validation was done using large publicly available databases. Our results showed that mammaglobin-1 gene expression to be specifically upregulated in BC patients’ samples compared to normal tissue as well as samples from other cancers. Moreover, our findings also showed mammaglobin-1 expression to be a marker of tumour progression presented as lymph nodes involvement and distant metastasis. These results provide an initial evidence for the use of mammaglobin-1 (SCGB2A2) immunostaining in bone marrow as a tool to investigate early BM micrometastases in breast cancer.
C-C chemokine receptor type 5 links COVID-19, rheumatoid arthritis, and Hydroxychloroquine: in silico analysis
(2020) Hachim, Mahmood Yaseen
Abstract: Patients with rheumatoid arthritis (RA) represent one of the fragile patient groups that might be susceptible to the critical form of the coronavirus disease − 19 (COVID-19). On the other side, RA patients have been found not to have an increased risk of COVID-19 infection. Moreover, some of the Disease-Modifying Anti-Rheumatic Drugs (DMA DS) commonly used to treat rheumatic diseases like Hydroxychloroquine (HCQ) were proposed as a potential therapy for COVID-19 with a lack of full understanding of their molecular mechanisms. This highlights the need for the discovery of common pathways that may link both diseases at the molecular side. In this research, we used the in silico approach to investigate the transcriptomic profile of RA synovium to identify shared molecular pathways with that of severe acute respiratory syndrome-corona virus-2 (SARS-COV-2) infected lung tissue. Our results showed upregulation of chemotactic factors, including CCL4, CCL8, and CCL11, that all shared CCR5 as their receptor, as a common derangement observed in both diseases; RA and COVID-19. Moreover, our results also highlighted a possible mechanism through which HCQ, which can be used as a monotherapy in mild RA or as one of the triple-DMARDs therapy (tDMARDs; methotrexate, sulphasalazine, and HCQ), might interfere with the COVID- 19 infection. This might be achieved through the ability of HCQ to upregulate specific immune cell populations like activated natural killer (NK) cells, which were found to be significantly reduced in COVID-19 infection. In addition to its ability to block CCR5 rich immune cell recruitment that also was upregulated in the SARS-COV-2 infected lungs. This might explain some of the reports that showed beneficial effects.
Clinical and Laboratory Profile of Hospitalized Symptomatic COVID-19 Patients: Case Series Study From the First COVID-19 Center in the UAE
(2021) Hachim, Mahmood Yaseen; Hannawi, Haifa
Introduction: COVID-19 is raising with a second wave threatening many countries. Therefore, it is important to understand COVID-19 characteristics across different countries. Methods: This is a cross-sectional descriptive study of 525 hospitalized symptomatic COVID-19 patients, from the central federal hospital in Dubai-UAE during period of March to August 2020. Results: UAE’s COVID-19 patients were relatively young; mean (SD) of the age 49(15) years, 130 (25%) were older than 60 and 4 (<1%) were younger than 18 years old. Majority were male(47; 78%). The mean (SD) BMI was 29 (6) kg/m2. While the source of contracting COVID-19 was not known in 369 (70%) of patients, 29 (6%) reported travel to overseas-country and 127 (24%) reported contact with another COVID-19 case/s. At least one comorbidity was present in 284 (54%) of patients and 241 (46%) had none. The most common comorbidities were diabetes (177; 34%) and hypertension (166; 32%). The mean (SD) of symptoms duration was 6 (3) days. The most common symptoms at hospitalization were fever (340; 65%), cough (296; 56%), and shortness of breath (SOB) (243; 46%). Most of the laboratory values were within normal range, but (184; 35%) of patients had lymphopenia, 43 (8%) had neutrophilia, and 116 (22%) had prolong international normalized ratio (INR), and 317 (60%) had high D-dimer. Chest x ray findings of consolidation was present in 334 (64%) of patients and CT scan ground glass appearance was present in 354 (68%). Acute cardiac injury occurred in 124 (24%), acute kidney injury in 111 (21%), liver injury in 101 (19%), ARDS in 155 (30%), acidosis in 118 (22%), and septic shock in 93 (18%). Consequently, 150 (29%) required ICU admission with 103 (20%) needed mechanical ventilation. Conclusions: The study demonstrated the special profile of COVID-19 in UAE. Patients were young with diabetes and/or hypertension and associated with severe infection as shown by various clinical and laboratory data necessitating ICU admission.
Coinfections in Patients Hospitalized with COVID-19: A Descriptive Study from the United Arab Emirates
(2021) Senok, Abiola; Nassar, Rania; Hachim, Mahmood Yaseen; Al Suwaidi, Hanan; Alsheikh-Ali, Alawi
Purpose: Microbial coinfections in COVID-19 patients carry a risk of poor outcomes. This study aimed to characterize the clinical and microbiological profiles of coinfections in patients with COVID-19. Methods: A retrospective review of the clinical and laboratory records of COVID-19 patients with laboratory-confirmed infections with bacteria, fungi, and viruses was conducted. Only adult COVID-19 patients hospitalized at participating health-care facilities between February 1 and July 31, 2020 were included. Data were collected from the centralized electronic system of Dubai Health Authority hospitals and Sheikh Khalifa General Hospital Umm Al Quwain. Results: Of 29,802 patients hospitalized with COVID-19, 392 (1.3%) had laboratory-confirmed coinfections. The mean age of patients with coinfections was 49.3±12.5 years, and a majority were male (n=330 of 392, 84.2%). Mean interval to commencement of empirical antibiotics was 1.2±3.6) days postadmission, with ceftriaxone, azithromycin, and piperacillin–tazobactam the most commonly used. Median interval between admission and first positive culture (mostly from blood, endotracheal aspirates, and urine specimens) was 15 (IQR 8–25) days. Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli were predominant in first positive cultures, with increased occurrence of Stenotrophomonas maltophilia, methicillin-resistant Staphylococcus aureus, Acinetobacter baumannii, Candida auris, and Candida parapsilosis in subsequent cultures. The top three Gram-positive organisms were Staphylococcus epidermidis, Enterococcus faecalis, and Staphylococcus aureus. There was variability in levels of sensitivity to antibiotics and isolates harboring mecA, ESBL, AmpC, and carbapenemase-resistance genes were prevalent. A total of 130 (33.2%) patients died, predominantly those in the intensive-care unit undergoing mechanical ventilation or extracorporeal membrane oxygenation. Conclusion: Despite the low occurrence of coinfections among patients with COVID-19 in our setting, clinical outcomes remained poor. Predominance of Gram-negative pathogens, emergence of Candida species, and prevalence of isolates harboring drug-resistance genes are of concern.
Combination of obesity and co-morbidities leads to unfavorable outcomes in COVID-19 patients
(2020) Heialy, Saba Al; Hachim, Mahmood Yaseen
Objective: Obesity has been described as a significant independent risk factors of COVID-19. We aimed to study the association between obesity, co-morbidities and clinical outcomes of COVID-19. Methods: Clinical data from 417 patients were collected retrospectively from the Al Kuwait Hospital, Ministry of Health and Prevention (MOHAP), Dubai, United Arab Emirates, who were admitted between March and June 2020. Patients were divided according to their body mass index (BMI). Various clinical outcomes were examined: presenting symptoms, severity, major co-morbidities, ICU admission, death, ventilation, ARDS, septic shock and laboratory parameters. Results: The average BMI was 29 ± 6.2 kg/m2. BMI alone was not associated with the outcomes examined. However, class II obese patients had more co-morbidities compared to other groups. Hypertension was the most significant co-morbidity associated with obesity. Patients with BMI above the average BMI (29 kg/m2) and presence of underlying co-morbidities showed significant increase in admission to ICU compared to patients below 29 kg/m2 and underlying co-morbidities (21.7% Vs. 9.2%), ARDS development (21.7% Vs. 10.53%), need for ventilation (8.3% Vs. 1.3%), and mortality (10% Vs. 1.3%). Conclusions: Our data suggests that presence of underlying co-morbidities and high BMI work synergistically to affect the clinical outcomes of COVID-19.
COVID-19 Transcriptomic Atlas: A Comprehensive Analysis of COVID-19 Related Transcriptomics ‎Datasets
(2021) Alqutami, Fatma; Senok, Abiola; Hachim, Mahmood Yaseen
Background:‎ To develop anti-viral drugs and vaccines, it is crucial to understand the molecular basis and pathology of ‎COVID-19. An increase in research output is required to generate data and results at a faster rate, ‎therefore bioinformatics plays a crucial role in COVID- 19 research. There is an abundance of ‎transcriptomic data from studies carried out on COVID- 19, however, their use is limited by the ‎confounding factors pertaining to each study. The reanalysis of all these datasets in a unified approach ‎should help in understanding the molecular basis of COVID-19. This should allow for the identification of ‎COVID-19 biomarkers expressed in patients and the presence of markers specific to disease severity ‎and condition.‎ Aim: In this study, we aim to use the multiple publicly available transcriptomic datasets retrieved from the ‎Gene Expression Omnibus (GEO) database to identify consistently differential expressed genes in ‎different tissues and clinical settings.‎ Materials and Methods: A list of datasets was generated from NCBI’s GEO using the GEOmetadb package through R software. ‎Search keywords included SARS-COV-2 and COVID-19. Datasets in human tissues containing more than ‎ten samples were selected for this study. Differentially expressed genes (DEGs) in each dataset were ‎identified. Then the common DEGs between different datasets, conditions, tissues and clinical settings ‎were shortlisted.‎ Results: Using a unified approach, we were able to identify common DEGs based on the disease conditions, ‎samples source and clinical settings. For each indication, a different set of genes have been identified, ‎revealing that a multitude of factors play a role in the level of gene expression.‎ Conclusion: Unified reanalysis of publically available transcriptomic data showed promising potential in identifying ‎core targets that can explain the molecular pathology.
D-dimer, Troponin, and Urea Level at Presentation With COVID-19 can Predict ICU Admission: A Single Centered Study
(2020) Hachim, Mahmood Yaseen
Background: Identifying clinical-features or a scoring-system to predict a benefit from hospital admission for patients with COVID-19 can be of great value for the decision-makers in the health sector. We aimed to identify differences in patients’ demographic, clinical, laboratory, and radiological findings of COVID-19 positive cases to develop and validate a diagnostic-model predicting who will develop severe-form and who will need critical-care in the future. Methods: In this observational retrospective study, COVID-19 positive cases (total 417) diagnosed in Al Kuwait Hospital, Dubai, UAE were recruited, and their prognosis in terms of admission to the hospital and the need for intensive care was reviewed until their tests turned negative. Patients were classified according to their clinical state into mild, moderate, severe, and critical. We retrieved all the baseline clinical data, laboratory, and radiological results and used them to identify parameters that can predict admission to the intensive care unit (ICU). Results: Patients with ICU admission showed a distinct clinical, demographic as well as laboratory features when compared to patients who did not need ICU admission. This includes the elder age group, male gender, and presence of comorbidities like diabetes and history of hypertension. ROC and Precision-Recall curves showed that among all variables, D dimers (>1.5 mg/dl), Urea (>6.5 mmol/L), and Troponin (>13.5 ng/ml) could positively predict the admission to ICU in patients with COVID-19. On the other hand, decreased Lymphocyte count and albumin can predict admission to ICU in patients with COVID-19 with acceptable sensitivity (59.32, 95% CI [49.89–68.27]) and specificity (79.31, 95% CI [72.53–85.07]). Conclusion: Using these three predictors with their cut of values can identify patients who are at risk of developing critical COVID-19 and might need aggressive intervention earlier in the course of the disease.
Derangement of cell cycle markers in peripheral blood mononuclear cells of asthmatic patients as a reliable biomarker for asthma control
(2021) Hachim, Mahmood Yaseen; Al Heialy, Saba
Abstract: In asthma, most of the identifed biomarkers pertain to the Th2 phenotype and no known biomarkers have been verifed for severe asthmatics. Therefore, identifying biomarkers using the integrative phenotype-genotype approach in severe asthma is needed. The study aims to identify novel biomarkers as genes or pathways representing the core drivers in asthma development, progression to the severe form, resistance to therapy, and tissue remodeling regardless of the sample cells or tissues examined. Comprehensive reanalysis of publicly available transcriptomic data that later was validated in vitro, and locally recruited patients were used to decipher the molecular basis of asthma. Our in-silicoanalysis revealed a total of 10 genes (GPRC5A, SFN, ABCA1, KRT8, TOP2A, SERPINE1, ANLN, MKI67, NEK2, and RRM2) related to cell cycle and proliferation to be deranged in the severe asthmatic bronchial epithelium and fbroblasts compared to their healthy counterparts. In vitro, RT qPCR results showed that (SERPINE1 and RRM2) were upregulated in severe asthmatic bronchial epithelium and fbroblasts, (SFN, ABCA1, TOP2A, SERPINE1, MKI67, and NEK2) were upregulated in asthmatic bronchial epithelium while (GPRC5A and KRT8) were upregulated only in asthmatic bronchial fbroblasts. Furthermore, MKI76, RRM2, and TOP2A were upregulated in Th2 high epithelium while GPRC5A, SFN, ABCA1 were upregulated in the blood of asthmatic patients. SFN, ABCA1 were higher, while MKI67 was lower in severe asthmatic with wheeze compared to nonasthmatics with wheezes. SERPINE1 and GPRC5A were downregulated in the blood of eosinophilic asthmatics, while RRM2 was upregulated in an acute attack of asthma. Validation of the gene expression in PBMC of locally recruited asthma patients showed that SERPINE1, GPRC5A, SFN, ABCA1, MKI67, and RRM2 were downregulated in severe uncontrolled asthma. We have identifed a set of biologically crucial genes to the homeostasis of the lung and in asthma development and progression. This study can help us further understand the complex interplay between the transcriptomic data and the external factors which may deviate our understanding of asthma heterogeneity.
Differential expression of pyruvate dehydrogenase E1A and its inactive phosphorylated form among breast cancer subtypes
(2021) Hachim, Mahmood Yaseen
Aims: Pyruvate dehydrogenase E1A (PDH-E1A) is one of the key regulators of metabolic pathways that determines pyruvate entry into the citric acid cycle or glycolysis. When PDH-E1A is phosphorylated (P-PDH-E1A), it loses its activity, shifting the metabolism towards glycolysis. Breast cancer (BC) is a highly heterogeneous disease by which different breast cancer subtypes acquire distinct metabolic profiles. Assessing PDH-E1A and PPDH-E1A expressions among BC subtypes might reveal their association with the distinct molecular profiles of BCs. Methods: The expressions of PDH-E1A and P-PDH-E1A were investigated in BC cell lines and 115 BC tissues using Western blot and immunohistochemistry, respectively. Besides, PDHE1A mRNA expression was assessed in 1084 BCE patients’ transcriptomics data retrieved from Cancer Genome Atlas database. Statistical analyses were performed to assess the correlation of PDH-E1A and P-PDH-E1A expressions with patients’ clinicopathological characteristics. Kaplan-Meier method was used to evaluate their prognostic value. Key findings: Multivariate analysis revealed a significant association between PDH-E1A/P-PDH-E1A expressions and the molecular subtype, histological type, and tumor size of breast cancer tissues. The hormonal receptors (ER and PR), HER-2, and Ki67 protein expressions were significantly associated with PDH-E1A and P-PDH-E1A protein expressions. Similar findings were observed when PDHA1 mRNA expression was assessed. The increased protein expression of PDH-E1A could be an independent prognostic factor for unfavorable overall survival (OS). In contrast, high PDHA1 mRNA expression had better OS. Significance: This study revealed the differential expression of PDH-E1A and P-PDH-E1A among breast cancer subtypes and suggested PDH-E1A expression as a prognostic factor for BC patients’ OS.
Divulging a Pleiotropic Role of Succinate Receptor SUCNR1 in Renal Cell Carcinoma Microenvironment
(2022-12) Najm, Rania; Hachim, Mahmood Yaseen
Abstract: The succinate receptor, SUCNR1, has been attributed to tumor progression, metastasis, and immune response modulation upon its activation via the oncometabolite succinate. Nonetheless, little is known about the prognostic relevance of SUCNR1 and its association with tumor immune infiltrates and microbiota in renal cell carcinoma (RCC). Herein, publicly available platforms including Human Protein Atlas, cBioPortal, TIMER2.0, and TISIDB were utilized to depict a divergent implication of SUCNR1 in the immune microenvironment of clear cell RCC (KIRC) and papillary RCC (KIRP); the two major subtypes of RCC. Our results showed that the SUCNR1 expression level was augmented in RCC compared to other solid cancers, yet with opposite survival rate predictions in RCC subtypes. Consequently, a higher expression level of SUCNR1 was associated with a good disease-specific survival rate (p = 5.797 × 10-5) in KIRC patients albeit a poor prognostic prediction in KIRP patients (p = 1.9282 × 10-3). Intriguingly, SUCNR1 was mainly correlated to immunomodulators and diverse immune infiltrates in KIRP. Additionally, the SUCNR1 was mostly associated with a repertoire of microbes including beneficial bacteria that likely influenced a better disease-specific survival rate in KIRC. Our findings illustrate a significant novel subtype-specific role of SUCNR1 in RCC which potentially modulates tumor immune infiltration and microbiome signature, hence altering the prognosis of cancer patients.
DKK3’s protective role in prostate cancer is partly due to the modulation of immune-related pathways
(2023) Hachim, Mahmood Yaseen
Introduction: While it is considered one of the most common cancers and the leading cause of death in men worldwide, prognostic stratification and treatment modalities are still limited for patients with prostate cancer (PCa). Recently, the introduction of genomic profiling and the use of new techniques like next-generation sequencing (NGS) in many cancers provide novel tools for the discovery of new molecular targets that might improve our understanding of the genomic aberrations in PCa and the discovery of novel prognostic and therapeutic targets. In this study, we investigated the possible mechanisms through which Dickkopf-3 (DKK3) produces its possible protective role in PCa using NGS in both the DKK3 overexpression PCa cell line (PC3) model and our patient cohort consisting of nine PCa and five benign prostatic hyperplasia. Interestingly, our results have shown that DKK3 transfection-modulated genes are involved in the regulation of cell motility, senescence-associated secretory phenotype (SASP), and cytokine signaling in the immune system, as well as in the regulation of adaptive immune response. Further analysis of our NGS using our in vitro model revealed the presence of 36 differentially expressed genes (DEGs) between DKK3 transfected cells and PC3 empty vector. In addition, both CP and ACE2 genes were differentially expressed not only between the transfected and empty groups but also between the transfected and Mock cells. The top common DEGs between the DKK3 overexpression cell line and our patient cohort are the following: IL32, IRAK1, RIOK1, HIST1H2BB, SNORA31, AKR1B1, ACE2, and CP. The upregulated genes including IL32, HIST1H2BB, and SNORA31 showed tumor suppressor functions in various cancers including PCa. On the other hand, both IRAK1 and RIOK1 were downregulated and involved in tumor initiation, tumor progression, poor outcome, and radiotherapy resistance. Together, our results highlighted the possible role of the DKK3-related genes in protecting against PCa initiation and progression.
Enhanced mitophagy in bronchial fibroblasts from severe asthmatic patients
(2020) Hachim, Mahmood Yaseen
Background: Sub-epithelial fibrosis is a characteristic feature of airway remodeling in asthma which correlates with disease severity. Current asthma medications are ineffective in treating fibrosis. In this study, we aimed to investigate the mitochondrial phenotype in fibroblasts isolated from airway biopsies of non-asthmatic and severe asthmatic subjects by examining mitophagy as a mechanism contributing to fibroblast persistence and thereby, fibrosis in severe asthma. Methods: Bioinformatics analysis of publicly available transcriptomic data was performed to identify the top enriched pathways in asthmatic fibroblasts. Endogenous expression of mitophagy markers in severe asthmatic and non-asthmatic fibroblasts was determined using qRTPCR, western blot and immunofluorescence. Mitophagy flux was examined by using lysosomal protease inhibitors, E64d and pepstatin A. Mitochondrial membrane potential and metabolic activity were also evaluated using JC-1 assay and MTT assay, respectively. Results: Bioinformatics analysis revealed the enrichment of Pink/Parkin-mediated mitophagy in asthmatic fibroblasts compared to healthy controls. In severe asthmatic fibroblasts, the differential expression of mitophagy genes, PINK1 and PRKN, was accompanied by the accumulation of PINK1, Parkin and other mitophagy proteins at baseline. The further accumulation of endogenous LC3BII, p62 and PINK1 in the presence of E64d and pepstatin A in severe asthmatic fibroblasts reinforced their enhanced mitophagy flux. Significantly reduced mitochondrial membrane potential and metabolic activity were also demonstrated at baseline confirming the impairment in mitochondrial function in severe asthmatic fibroblasts. Interestingly, these fibroblasts displayed neither an apoptotic nor senescent phenotype but a pro-fibrotic phenotype with an adaptive survival mechanism triggered by increased AMPKα phosphorylation and mitochondrial biogenesis. Conclusions : Our results demonstrated a role for mitophagy in the pathogenesis of severe asthma where the enhanced turnover of damaged mitochondria may contribute to fibrosis in severe asthma by promoting the persistence and pro-fibrotic phenotype of fibroblasts.
EXOC6 (Exocyst Complex Component 6) Is Associated with the Risk of Type 2 Diabetes and Pancreatic β-Cell Dysfunction
(2022) Hachim, Mahmood Yaseen; Al Heialy, Saba
Abstract: EXOC6 and EXOC6B (EXOC6/6B) components of the exocyst complex are involved in the secretory granule docking. Recently, EXOC6/6B were anticipated as a molecular link between dysfunctional pancreatic islets and ciliated lung epithelium, making diabetic patients more prone to severe SARS-CoV-2 complications. However, the exact role of EXOC6/6B in pancreatic β-cell function and risk of T2D is not fully understood. Herein, microarray and RNA-sequencing (RNA-seq) expression data demonstrated the expression of EXOC6/6B in human pancreatic islets. Expression of EXOC6/6B was not affected by diabetes status. Exploration of the using the translational human pancreatic islet genotype tissue-expression resource portal (TIGER) revealed three genetic variants (rs947591, rs2488071 and rs2488073) in the EXOC6 gene that were associated (p < 2.5 × 10−20) with the risk of T2D. Exoc6/6b silencing in rat pancreatic β-cells (INS1-832/13) impaired insulin secretion, insulin content, exocytosis machinery and glucose uptake without cytotoxic effect. A significant decrease in the expression Ins1, Ins1, Pdx1, Glut2 and Vamp2 was observed in Exoc6/6b-silenced cells at the mRNA and protein levels. However, NeuroD1, Gck and InsR were not influenced compared to the negative control. In conclusion, our data propose that EXOC6/6B are crucial regulators for insulin secretion and exocytosis machinery in β-cells. This study identified several genetic variants in EXOC6 associated with the risk of T2D. Therefore, EXOC6/6B could provide a new potential target for therapy development or early biomarkers for T2D.
Expression Profile of SARS-CoV-2 Host Receptors in Human Pancreatic Islets Revealed Upregulation of ACE2 in Diabetic Donors
(2020) Hachim, Mahmood Yaseen
Abstract: Cellular entry of SARS-CoV-2 is thought to occur through the binding of viral spike S1 protein to ACE2. The entry process involves priming of the S protein by TMPRSS2 and ADAM17, which collectively mediate the binding and promote ACE2 shedding. In this study, microarray and RNA sequencing (RNA-seq) expression data were utilized to profile the expression pattern of ACE2, ADAM17, and TMPRSS2 in type 2 diabetic (T2D) and non-diabetic human pancreatic islets. Our data show that pancreatic islets express all three receptors irrespective of diabetes status. The expression of ACE2 was significantly increased in diabetic/hyperglycemic islets compared to non-diabetic/normoglycemic. Islets from female donors showed higher ACE2 expression compared to males; the expression of ADAM17 and TMPRSS2 was not a_ected by gender. The expression of the three receptors was statistically similar in young (_40 years old) versus old (_60 years old) donors. Obese (BMI > 30) donors have significantly higher expression levels of ADAM17 and TMPRSS2 relative to those from non-obese donors (BMI < 25). TMPRSS2 expression correlated positively with HbA1c and negatively with age, while ADAM17 and TMPRSS2 correlated positively with BMI. The expression of the three receptors was statistically similar in muscle and subcutaneous adipose tissues obtained from diabetic and nondiabetic donors. Lastly, ACE2 expression was higher in sorted pancreatic _-cell relative to other endocrine cells. In conclusion, ACE2 expression is increased in diabetic human islets. More studies are required to investigate whether variations of ACE2 expression could explain the severity of COVID-19 infection-related symptoms between diabetics and non-diabetic patients.