SARS-CoV-2-associated lymphopenia: possible mechanisms and the role of CD147.

T lymphocytes play a primary role in the adaptive antiviral immunity. Both lymphocytosis and lymphopenia were found to be associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While lymphocytosis indicates an active anti-viral response, lymphopenia is a sign of poor prognosis. T-cells, in essence, rarely express ACE2 receptors, making the cause of cell depletion enigmatic. Moreover, emerging strains posed an immunological challenge, potentially alarming for the next pandemic. Herein, we review how possible indirect and direct key mechanisms could contribute to SARS-CoV-2-associated-lymphopenia. The fundamental mechanism is the inflammatory cytokine storm elicited by viral infection, which alters the host cell metabolism into a more acidic state. This "hyperlactic acidemia" together with the cytokine storm suppresses T-cell proliferation and triggers intrinsic/extrinsic apoptosis. SARS-CoV-2 infection also results in a shift from steady-state hematopoiesis to stress hematopoiesis. Even with low ACE2 expression, the presence of cholesterol-rich lipid rafts on activated T-cells may enhance viral entry and syncytia formation. Finally, direct viral infection of lymphocytes may indicate the participation of other receptors or auxiliary proteins on T-cells, that can work alone or in concert with other mechanisms. Therefore, we address the role of CD147-a novel route-for SARS-CoV-2 and its new variants. CD147 is not only expressed on T-cells, but it also interacts with other co-partners to orchestrate various biological processes. Given these features, CD147 is an appealing candidate for viral pathogenicity. Understanding the molecular and cellular mechanisms behind SARS-CoV-2-associated-lymphopenia will aid in the discovery of potential therapeutic targets to improve the resilience of our immune system against this rapidly evolving virus.

Stroke as a cause of death in patients with cancer: a SEER-based study.

BACKGROUND: Death from stroke is linked to cancer due to its pathogenesis and side effects of treatment. Despite this, guidelines regarding identifying cancer patients at the highest risk of mortality from stroke are unclear. AIMS: To determine which cancer subtypes are associated with higher risk of death from stroke. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program was used to obtain data regarding patients with cancer who died of a stroke. We calculated standardized mortality ratios (SMRs) using SEER*Stat software, version 8.4.0.1. RESULTS: Out of 6,136,803 patients with cancer, 57,523 (0.9%) died from stroke, and this rate was higher than general population (SMR= 1.05, 95%CI [1.04-1.06]). Deaths due to stroke decreased across years, from 24,280 deaths between 2000-2004 to 4,903 deaths between 2015-2019. Of the 57,523 stroke deaths, greatest numbers were observed in cancers of the prostate (n=11,761, 20.4%), breast (n=8,946, 15.5%), colon and rectum (n=7,401, 12.8%), and lung and bronchus (n=4,376, 7.6%). Patients with colon and rectum cancers (SMR= 1.08 95%CI [1.06-1.11]), lung and bronchus cancers (SMR=1.70 95%CI [1.65-1.75]) had a greater rate of death from stroke compared to the general population. CONCLUSION: The risk of death from stroke in cancer patients is significantly higher than in the general population. Patients with colorectal cancer and lung and bronchus cancer are at higher risk of death by stroke compared to the general population.

Primary and Secondary Breast Sarcoma: Clinical and Pathological Characteristics, Prognostic Factors, and Nomograms for Predicting Survival.

BACKGROUND: Breast sarcoma is one of the rare types of breast tumors with different features and outcomes compared to carcinoma. Our study aims to describe the clinical and pathological characteristics of primary breast sarcoma (PBS) and secondary breast sarcoma (SBS) along with determining prognostic factors and developing nomograms for predicting survival. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) Program, female patients diagnosed with breast sarcoma between 1975 and 2016 were identified. Cox regression was used to evaluate the association between survival and clinical features. RESULTS: Out of 1334 included patients, 816 had PBS and 518 had SBS. PBS had a significantly better overall survival than SBS with median survival months of 107 for PBS and 45 for SBS. The primary tumor site did not have a significant impact on the survival of SBS. Cox regression showed worse survival of PBS patients who were > 60 years (HR 3.04, 95% CI 2.46-3.74) and had tumor size > 50 mm (HR 2.01, 95% CI 1.61-2.51). Being not married was associated with worse survival of PBS (HR 1.29, 95% CI 1.06-1.56) and SBS (HR 1.50, 95% CI 1.19-1.90). Surgery was associated with better survival of PBS (HR 0.60, 95% CI 0.42-0.85) and SBS (HR 0.46, 95% CI 0.31-0.68). The C-indexes of created nomograms were 0.73 for PBS and 0.69 for SBS. CONCLUSION: Age and size were the most important prognostic factors for the survival. Surgery was associated with better survival. However, radiation and chemotherapy did not show significant improvement in survival.

Regulation of mitochondrial temperature in health and disease.

Mitochondrial temperature is produced by various metabolic processes inside the mitochondria, particularly oxidative phosphorylation. It was recently reported that mitochondria could normally operate at high temperatures that can reach 50℃. The aim of this review is to identify mitochondrial temperature differences between normal cells and cancer cells. Herein, we discussed the different types of mitochondrial thermosensors and their advantages and disadvantages. We reviewed the studies assessing the mitochondrial temperature in cancer cells and normal cells. We shed the light on the factors involved in maintaining the mitochondrial temperature of normal cells compared to cancer cells.

Immunoinformatics approach of epitope prediction for SARS-CoV-2.

BACKGROUND: The novel coronavirus (SARS-CoV-2) caused lethal infections worldwide during an unprecedented pandemic. Identification of the candidate viral epitopes is the first step in the design of vaccines against the viral infection. Several immunoinformatic approaches were employed to identify the SARS-CoV-2 epitopes that bind specifically with the major histocompatibility molecules class I (MHC-I). We utilized immunoinformatic tools to analyze the whole viral protein sequences, to identify the SARS-CoV-2 epitopes responsible for binding to the most frequent human leukocyte antigen (HLA) alleles in the Egyptian population. These alleles were also found with high frequency in other populations worldwide. RESULTS: Molecular docking approach showed that using the co-crystallized MHC-I and T cell receptor (TCR) instead of using MHC-I structure only, significantly enhanced docking scores and stabilized the conformation, as well as the binding affinity of the identified SARS-CoV-2 epitopes. Our approach directly predicts 7 potential vaccine subunits from the available SARS-CoV-2 spike and ORF1ab protein sequence. This prediction has been confirmed by published experimentally validated and in silico predicted spike epitope. On the other hand, we predicted novel epitopes (RDLPQGFSA and FCLEASFNY) showing high docking scores and antigenicity response with both MHC-I and TCR. Moreover, antigenicity, allergenicity, toxicity, and physicochemical properties of the predicted SARS-CoV-2 epitopes were evaluated via state-of-the-art bioinformatic approaches, showing high efficacy of the proposed epitopes as a vaccine candidate. CONCLUSION: Our predicted SARS-CoV-2 epitopes can facilitate vaccine development to enhance the immunogenicity against SARS-CoV-2 and provide supportive data for further experimental validation. Our proposed molecular docking approach of exploiting both MHC and TCR structures can be used to identify potential epitopes for most microbial pathogens, provided the crystal structure of MHC co-crystallized with TCR.

Molecular basis of the potential interaction of SARS-CoV-2 spike protein to CD147 in COVID-19 associated-lymphopenia.

Lymphopenia is considered one of the most characteristic clinical features of the coronavirus disease 2019 (COVID-19). SARS-CoV-2 infects host cells via the interaction of its spike protein with the human angiotensin-converting enzyme 2 (hACE2) receptor. Since T lymphocytes display a very low expression level of hACE2, a novel receptor might be involved in the entry of SARS-CoV-2 into T cells. The transmembrane glycoprotein CD147 is highly expressed by activated T lymphocytes, and was recently proposed as a probable route for SARS-CoV-2 invasion. To understand the molecular basis of the potential interaction of SARS-CoV-2 to CD147, we have investigated the binding of the viral spike protein to this receptor in-silico. The results showed that this binding is dominated by electrostatic interactions involving residues Arg403, Asn481, and the backbone of Gly502. The overall binding arrangement shows the CD147 C-terminal domain interacting with the spike external subdomain in the grove between the short antiparallel ß strands, ß1' and ß2', and the small helix α1'. This proposed interaction was further confirmed using MD simulation and binding free energy calculation. These data contribute to a better understanding of the mechanism of infection of SARS-CoV-2 to T lymphocytes and could provide valuable insights for the rational design of adjuvant treatment for COVID-19. Communicated by Ramaswamy H. Sarma.

Causes of Death Among Patients With Metastatic Prostate Cancer in the US From 2000 to 2016.

Importance: Owing to improved survival among US patients with prostate cancer (PC), patients tend to live long enough after a PC diagnosis for non-cancer-related comorbidities to be associated with their overall survival. Although studies have investigated causes of death among patients with localized PC, data are lacking regarding causes of death among patients with metastatic PC. Objective: To assess causes of death among US patients with metastatic PC from 2000 to 2016. Design, Setting, and Participants: This retrospective cohort study used data from the Surveillance, Epidemiology, and End Results Program database to analyze a sample of 26 168 US men who received a diagnosis of metastatic PC from January 1, 2000, to December 31, 2016. Data were analyzed from February 2 to July 28, 2020. Exposure: Diagnosis of metastatic PC. Main Outcomes and Measures: Standardized mortality ratios (SMRs) for different causes of death were calculated by dividing the observed number of deaths from each cause of death by the expected number of deaths in the age-matched US male population for the same period, adjusting for age and race/ethnicity. Results: Of 26 168 patients with metastatic PC included in the analysis, 48.9% were aged 50 to 70 years (mean age at diagnosis, 70.83 years); 74.5% were White individuals, and 72.7% received a diagnosis of stage M1b metastatic PC. A total of 16 732 patients (63.9%) died during the follow-up period. The mean age at death was 74.13 years. Most deaths (59.0%) occurred within the latency period of 2 years after diagnosis of metastatic PC, whereas 31.6% occurred 2 to 5 years after diagnosis and 9.4% occurred more than 5 years after diagnosis. Of the total deaths, 13 011 (77.8%) were from PC, 924 (5.5%) were from other cancers, and 2797 (16.7%) were from noncancer causes. During all latency periods, the most common noncancer causes of death were cardiovascular diseases (SMR, 1.34; 95% CI, 1.26-1.42), chronic obstructive pulmonary disease (SMR, 1.19; 95% CI, 1.03-1.36), and cerebrovascular diseases (SMR, 1.31; 95% CI, 1.13-1.50). Conclusions and Relevance: In this cohort study, deaths from noncancer causes, including cardiovascular disease, constituted a substantial number of deaths among men with metastatic PC. Therapy and follow-up should be tailored to the needs of each patient with metastatic PC, and counseling regarding future health risks should be provided.

Protein networks linking Warburg and reverse Warburg effects to cancer cell metabolism.

It was 80 years after the Otto Warburg discovery of aerobic glycolysis, a major hallmark in the understanding of cancer. The Warburg effect is the preference of cancer cell for glycolysis that produces lactate even when sufficient oxygen is provided. "reverse Warburg effect" refers to the interstitial tissue communications with adjacent epithelium, that in the process of carcinogenesis, is needed to be explored. Among these cell-cell communications, the contact between epithelial cells; between epithelial cells and matrix; and between fibroblasts and inflammatory cells in the underlying matrix. Cancer involves dysregulation of Warburg and reverse Warburg cellular metabolic pathways. How these gene and protein-based regulatory mechanisms have functioned has been the basis for this review. The importance of the Warburg in oxidative phosphorylation suppression, with increased glycolysis in cancer growth and proliferation is emphasized. Studies that are directed at pathways that would be expected to shift cell metabolism to an increased oxidation and to a decrease in glycolysis are emphasized. Key enzymes required for oxidative phosphorylation, and affect the inhibition of fatty acid metabolism and glutamine dependence are conferred. The findings are of special interest to cancer pharmacotherapy. Studies described in this review are concerned with the effects of therapeutic modalities that are intimately related to the Warburg effect. These interactions described may be helpful as adjuvant therapy in controlling the process of proliferation and metastasis.

Causes of Death Following Nonmetastatic Colorectal Cancer Diagnosis in the U.S.: A Population-Based Analysis.

INTRODUCTION: Because of the improved colorectal cancer (CRC) survival in the U.S., patients may live long enough after CRC diagnosis to the point where non-cancer-related comorbidities may considerably impact their overall survival. In this study, we perform a long-term analysis of causes of death (CODs) following nonmetastatic CRC with respect to different demographic and tumor-related criteria. MATERIALS AND METHODS: We gained access to the Surveillance, Epidemiology, and End Results data to review patients diagnosed with nonmetastatic CRC during 2000-2015. We calculated standardized mortality ratios (SMRs) for each COD following CRC. SMRs represented the change of risk of a specific COD following CRC diagnoses when compared with the risk in the general U.S. RESULTS: We reviewed 302,345 patients, of whom 112,008 died during the study period. More deaths (68.3%) occurred within 5 years following nonmetastatic CRC diagnosis, with 76,486 deaths. CRC was the most common COD (51.4%) within 5 years of diagnosis followed by heart disease (15.2%) and other cancers (8.4%). As time passed after diagnosis, the number of CRC deaths decreased, and other noncancer causes increased to the point that after 10 years only 10.4% of deaths were attributed to CRC, 15.3% were attributed to other cancers, and 34.2% were secondary to heart disease. CONCLUSION: Following nonmetastatic CRC diagnosis, most deaths remain secondary to CRC. Other causes, including other cancers and cardiovascular disease, represent a significant number of deaths, especially in the 5 years following initial CRC diagnosis. Our findings help guide counseling patients with CRC regarding future health risks. IMPLICATIONS FOR PRACTICE: Most common causes of death following nonmetastatic colorectal cancer (CRC) are heart diseases, other cancers, chronic obstructive pulmonary disease, and cerebrovascular diseases. Physicians should counsel patients regarding survivorship with cancer screening and focus on prevention of noncancer deaths. These findings should be considered by physicians who give care for survivors of nonmetastatic CRC.

Quality Assessment of Published Systematic Reviews in High Impact Cardiology Journals: Revisiting the Evidence Pyramid.

Objective: Systematic reviews are increasingly used as sources of evidence in clinical cardiology guidelines. In the present study, we aimed to assess the quality of published systematic reviews in high impact cardiology journals. Methods: We searched PubMed for systematic reviews published between 2010 and 2019 in five general cardiology journals with the highest impact factor (according to Clarivate Analytics 2019). We extracted data on eligibility criteria, methodological characteristics, bias assessments, and sources of funding. Further, we assessed the quality of retrieved reviews using the AMSTAR tool. Results: A total of 352 systematic reviews were assessed. The AMSTAR quality score was low or critically low in 71% (95% CI: 65.7-75.4) of the assessed reviews. Sixty-four reviews (18.2%, 95% CI: 14.5-22.6) registered/published their protocol. Only 221 reviews (62.8%, 95% CI: 57.6-67.7) reported adherence to the EQUATOR checklists, 208 reviews (58.4%, 95% CI: 53.9-64.1) assessed the risk of bias in the included studies, and 177 reviews (52.3%, 95% CI: 45.1-55.5) assessed the risk of publication bias in their primary outcome analysis. The primary outcome was statistically significant in 274 (79.6%, 95% CI: 75.1-83.6) and had statistical heterogeneity in 167 (48.5%, 95% CI: 43.3-53.8) reviews. The use and sources of external funding was not disclosed in 87 reviews (24.7%, 95% CI: 20.5-29.5). Data analysis showed that the existence of publication bias was significantly associated with statistical heterogeneity of the primary outcome and that complex design, larger sample size, and higher AMSTAR quality score were associated with higher citation metrics. Conclusion: Our analysis uncovered widespread gaps in conducting and reporting systematic reviews in cardiology. These findings highlight the importance of rigorous editorial and peer review policies in systematic review publishing, as well as education of the investigators and clinicians on the synthesis and interpretation of evidence.

Non-cancer death causes after ovarian cancer diagnosis: A population-based cohort.

BACKGROUND: Research on non-cancer death causes in ovarian cancer (OC) patients remains limited. We aim to focus on and evaluate the non-cancer death causes after OC diagnosis. METHODS: We studied 82 590 OC patients diagnosed between 2000 and 2016, using the Surveillance, Epidemiology, and End Results (SEER) Program. Risks of death causes were calculated as standardized mortality ratios. RESULTS: Of included patients, 48 125 (58.3%) died during the follow-up period. The highest number of deaths, 21 722 (45.1%), occurred within 1-5 years after OC diagnosis. On the other hand, 19 992 (41.5%) of deaths occurred within a year from ovary cancer diagnosis, 5255 (10.9%) occurred within 5-10 years, and 1156 (2.4%) deaths occurred after more than 10 years following OC diagnosis. Non-cancer death causes comprise a significant percentage of deaths in OC patients, increasing with time after diagnosis. CONCLUSIONS: Cardiac diseases, cerebrovascular diseases, and COPD were among the most common non-cancer death causes after OC diagnosis. Other critical non-cancer death causes include septicemia and benign neoplasms. Mortality risk differences based on race and age were also highlighted. These findings provide critical insights into how OC survivors should be followed-up and counseled for relevant future health risks.