BIRC8 (baculoviral IAP repeat containing 8)

BIRC8, also known as ILP-2, is a homologous protein of BIRC4, however, its function has seldom been addressed. Despite the similarity with other Inhibitory Apoptosis Proteins (IAPs), there is evidence that BIRC8 acts in a peculiar manner, by impeding apoptosis induced by BAX without directly inhibiting the activity of caspases. BIRC8 expression has been detected in testis and lymphoblastic normal cells and, furthermore, it has been reported in different cancers, including breast carcinoma, hematological neoplasms, hepatocellular carcinoma, nasopharyngeal carcinoma, and neuroblastoma. However, the specific implications of such protein for treatment and prognosis must be further evaluated. In this review, current data on RNA, DNA, protein and the association of BIRC8 in cancer are presented

BIRC5 (baculoviral IAP repeat containing 5)

BIRC5, also known as survivin, has been implicated in cell cycle progression and apoptosis avoidance. BIRC5 is highly expressed in embryonic tissues, however very low or absent in adult tissues. BIRC5 overexpression has been frequently associated to cancer development, a poor prognosis and chemoresistance. Besides that, different BIRC5 isoforms has been characterized and related to better or worse chemotherapy responses depending on the isoform and the cancer type. So far, many efforts have been conducted in order to deplete BIRC5 in cancer cells, including gene therapy, pharmacological and nanotechnological approaches. In this review, we will discuss the role of BIRC5 in cancer cell biology and its clinical significance, demonstrating its DNA/RNA and protein aspects, also its relevance for diagnosis and prognosis, and advances as a target for the treatment of different cancer types

Insulin Substrate Receptor (IRS) proteins in normal and malignant hematopoiesis

The insulin receptor substrate (IRS) proteins are a family of cytoplasmic proteins that integrate and coordinate the transmission of signals from the extracellular to the intracellular environment via transmembrane receptors, thus regulating cell growth, metabolism, survival and proliferation. The PI3K/AKT/mTOR and MAPK signaling pathways are the best-characterized downstream signaling pathways activated by IRS signaling (canonical pathways). However, novel signaling axes involving IRS proteins (noncanonical pathways) have recently been identified in solid tumor and hematologic neoplasm models. Insulin receptor substrate-1 (IRS1) and insulin receptor substrate-2 (IRS2) are the best-characterized IRS proteins in hematologic-related processes. IRS2 binds to important cellular receptors involved in normal hematopoiesis (EPOR, MPL and IGF1R). Moreover, the identification of IRS1/ABL1 and IRS2/JAK2V617F interactions and their functional consequences has opened a new frontier for investigating the roles of the IRS protein family in malignant hematopoiesis. Insulin receptor substrate-4 (IRS4) is absent in normal hematopoietic tissues but may be expressed under abnormal conditions. Moreover, insulin receptor substrate-5 (DOK4) and insulin receptor substrate-6 (DOK5) are linked to lymphocyte regulation. An improved understanding of the signaling pathways mediated by IRS proteins in hematopoiesis-related processes, along with the increased development of agonists and antagonists of these signaling axes, may generate new therapeutic approaches for hematological diseases. The scope of this review is to recapitulate and review the evidence for the functions of IRS proteins in normal and malignant hematopoiesis

Embelin potentiates venetoclax-induced apoptosis in acute myeloid leukemia cells

Acute myeloid leukemia (AML) belongs to a group of hematological cancer whose relapse cases are often associated with chemoresistance that impairs treatment success and contributes to a poor outcome. For this reason, there is an urgent need for the development of new therapeutic strategies. Herein, we explore the combination of venetoclax, a BCL2 inhibitor, and embelin, an XIAP inhibitor, in the AML cell lines. Combinatory treatment of venetoclax and embelin potentiated cytotoxic effects of these drugs, demonstrating that both in combination present lower IC50 values than single treatment of either venetoclax or embelin alone in both cell lines analyzed. The combinatory treatment further increased the apoptosis-inducing properties of both compounds. Computer simulations suggest that embelin binds to both BIR2 and BIR3 domains of XIAP, reinforcing this inhibitory apoptosis protein as an embelin target. Although all AML cell lines presented similar basal levels of XIAP, the combinatory treatment effectively inhibited XIAP expression in OCI-AML3 cells. In conclusion, the inhibition of both apoptosis inhibitory players, BCL2 and XIAP, by venetoclax and embelin, respectively, potentiated their cytotoxic effects in AML cell lines.The authors want to express their acknowledgements to Prof. Dr. Eduardo Magalhaes Rego (University of Sao Paulo, Ribeirao Preto, Brazil) for providing leukemia cell lines. We are also grateful for the embelin HPLC analysis by Prof. Marcelo Jose Pena Ferreira (IB-USP). This work was supported by Fundaçao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), Brazil, under processes 2019/23864-7, 2018/ 06522-2, 2017/09022–8, and 2015/17177–6. This study was financed in part by the Coordenaçao de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.Postprint (author's final draft

Stathmin 1 Inhibition Amplifies Ruxolitinib-induced Apoptosis In Jak2v617f Cells.

The JAK/STAT pathway is constitutively activated in myeloproliferative neoplasms and can be inhibited by ruxolitinib, a selective JAK1/2 inhibitor. The JAK2(V617F) mutation leads to constitutive STAT3 phosphorylation and potentially leads to inhibition of Stathmin 1 activity via STAT3. In support of this hypothesis, we found that, in HEL JAK2(V617F) cells, ruxolitinib treatment decreased STAT3 and Stathmin 1 association, induced Stathmin 1 activation and microtubule instability. Silencing of Stathmin 1 significantly reduced cell proliferation and clonal growth, and increased apoptosis induced by ruxolitinib. Stathmin 1 silencing also prevented ruxolitinib-induced microtubule instability. To phenocopy the effect of Stathmin 1 inhibition, cells were treated with paclitaxel, a microtubule-stabilizing drug, in association or not with ruxolitinib; combined treatment significantly increased apoptosis, when compared to monotherapy. Notably, Stathmin 1 mRNA levels were highly expressed in CD34(+) cells from primary myelofibrosis patients. We then proposed that an undesired effect of ruxolitinib treatment may constitute Stathmin 1 activation and microtubule instability in JAK2(V617F) cells. Induction of microtubule stability, through Stathmin 1 silencing or paclitaxel treatment, combined with ruxolitinib could be an effective strategy for promoting apoptosis in JAK2(V617F) cells.629573-2958

XIAP (X-linked inhibitor of apoptosis)

X-linked inhibitor of apoptosis (XIAP), also referred to as BIRC4 or IAP3, is one of the most studied members among the proteins known as Inhibitors of Apoptosis Proteins (IAPs). This protein family portrays its main role by preventing apoptotic cell death through direct or indirect inhibition of caspase activity. All members of the IAPs carry at least one BIR domain in their structure, which are generally responsible for caspase interaction. XIAP has three BIR domains, enabling interaction with both initiation and effector caspases. Moreover, it is also structured with a RING finger domain, which functions as a ubiquitin ligase (E3), and one UBA domain, for binding to ubiquitin, further rendering XIAP a central role in the ubiquitination process and, thus, implicating such IAP in multiple signaling pathways, including cell death, autophagy, immunity, inflammation, cell cycle, and cell migration. XIAP overexpression is found in a variety of cancer types and is frequently associated with chemoresistance and increased risk of relapse. Furthermore, there are many evidences that XIAP inhibition may sensitize tumor cells to chemotherapy agents, which make this protein a potential target in cancer

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men