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SARS-CoV Infections in Humans
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
ORF 6 is 63 amino acid residues in size and is found in the membranes of the rough endoplasmic reticulum. Its expression in the target cells of patients’ specimen has been detected.81 ORF 6 is considered to be one of the important virulent factors for SARS-CoV. ORF 6 might act as an antagonist to IFN, suppressing IFN induction and the IFN signaling pathways.98,99 ORF 6 binds to karyopherin a2 (KPNA2), inhibiting recruitment of KPNB1 (a component of classical nuclear import complex) and preventing translocation of ISGF3 (STAT1/STAT2/IRF-9) to the nuclei indirectly.98 ORF 6 appears to play an important role in assisting SARS-CoV to evade the host innate immune responses. When ORF 6 was expressed in the host cells, double-membrane structures were formed, recapturing features observed during viral replications.98,100 Together with the finding of colocalization of this protein with nonstructural protein nsp3, ORF 6 may also play a role in viral replication.99,100
Leukaemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Despite the significant improvement in the therapy of ALL, in particular in children, approximately 25% of children and 50%–60% of adults relapse. Second remissions (CR2) can be achieved in most of these patients, but in many cases they are not sustained. Factors associated with a poor outcome after relapse include a shorter length of first remission, bone marrow as the initial site of relapse, older age, T-ALL, BCR-ABL1 and male sex. For patients who relapse more than 2 years after achieving CR, remission may be re-induced with the same drugs that induced the first remission. For primary resistant disease, most specialists use high-dose cytarabine either alone or in combination with an anthracycline. Recent efforts are assessing novel approaches in targeting pathways. The karyopherin exportin1 (XPO1/CRM1) regulates cell proliferation and survival by facilitating nuclear export of several factors, including tumour suppressors, such as p53, p21, FOXO and IκB, and leukaemia-relevant proto-oncogenes, including hnRNP A1, ABL1 and SET. The observation that the expression and activity of XPO1/CRM1 is altered in BCR-ABL1 positive and other poor-risk ALLs, suggests its potential role in pathogenesis.82 Candidate drugs in clinical trials include KPT-330, nelarabine (506U78), immunotoxins/immuno-conjugates such as inotuzumab ozogamicin and a variety of antibody-based therapies, such as blinatumumab, epratuzumab, and alemtuzumab. Nelarabine, a prodrug that is rapidly demethylated to AraG, have substantial clinical activity in T-ALL in first relapse and is currently in clinical trials for newly diagnosed patients.83 Antigen-directed immune therapies, such as blinatumomab, a bi-specific monoclonal antibody designed to harness cytotoxic T-cells (CTL) responses to CD19-expressing target B cells, appear to accord some adults patients with MRD-positive B-ALL and relapsed ALL a CR. Patients who express the cytokine receptor CRLF2 appear to benefit from Janus kinase (JAK) and mammalian target of rapamycin (mTOR) inhibitors, probably by virtue of both JAK-STAT and mTOR pathways being involved. It is of some interest that approximately 60% children with DS-ALL, uniquely, express CRLF2 and should receive a trial of either JAK or mTOR inhibitors.84 Two new drugs, clofarabine, a purine analogue discussed earlier, and a liposomal formulation of vincristine sulfate, have recently been licensed in the United States for patients with Ph chromosome-negative ALL in second relapse.85
A drug profile on selinexor for the treatment of refractory diffuse large B-cell lymphoma
Published in Expert Review of Hematology, 2022
Macromolecules larger than 40 kDa, such as proteins and RNAs, require active transport to go from the nucleus to the cytoplasm [15]. This transport involves special pores called ‘nuclear pore complex,’ embedded in the nuclear membrane. To pass through these pores, the macromolecules carry specific transport signals that allow them to attach to transport receptors called karyopherins (hence the name ‘Karyopharm’ of the company that produces selinexor), also called ‘exportins,’ for export from nucleus toward the cytoplasm or ‘importins’ for the reentry from the cytoplasm toward the nucleus. There are approximately 20 different karyphorins. The direction of passage is regulated by the GTPase Ran in the nucleus. The RanGTP form binds to exportins and allows the passage toward the cytoplasm where the GTP is dephosphorylated into GDP by GTPase activating protein (GAP). This in turn allows the passage toward the nucleus, after fixation on importins, where RanGTP Exchange Factor (GEF) allows phosphorylation of GDP to GTP (see Figure 2).
Case-only analysis of gene–gene interactions in inflammatory bowel disease
Published in Scandinavian Journal of Gastroenterology, 2020
Milda Aleknonytė-Resch, Sandra Freitag-Wolf, Stefan Schreiber, Michael Krawczak, Astrid Dempfle
The IL27 gene on human chromosome 16, encoding Interleukin 27, is widely known to play an important role in IBD, and there is even evidence for an IL27 therapy being effective in IBD [29]. Interestingly, SNP rs26528 is also located in an enhancer (GH16J028503) that has seven target genes, including IL27. The other interacting SNP, rs9297145, is located in an intron of the KPNA7 gene on chromosome 7. This gene encodes Karyopherin Subunit Alpha 7, a member of the importin alpha family involved in nuclear protein import. As was highlighted by Pumroy and Cingolani [30], importin expression is an important regulator of NF-κB signaling, disruption of which is associated with various human conditions, including neurological and cardiovascular diseases. Most importantly, however, nucleocytoplasmic shuttling of NF-κB plays a key role in IBD pathophysiology [31]. In our current understanding, IBD is characterized by an overwhelming expression of pro-inflammatory cytokines that are expressed in signaling pathways in the gut that are controlled by NF-κB as a master regulator of gene transcription. In particular, NF-κB is targeting the IL27 gene promoter. Therefore, one plausible biological explanation of the statistical interaction observed here between SNPs rs26528 and rs9297145 could be genotype-dependent mutual tuning of the efficiency by which GH16J028503 and the NF-κB pathway control IL27 gene expression. This interpretation would raise interest in IL-27 both as a biomarker and as a therapeutic target.
Selinexor for the treatment of multiple myeloma
Published in Expert Opinion on Pharmacotherapy, 2020
Klaus Podar, Jatin Shah, Ajai Chari, Paul G Richardson, Sundar Jagannath
The nucleus is an organelle, which encapsulates the genetic material with a double membrane, the nuclear envelope, thereby separating transcription in the nucleus from the translational machinery in the cytoplasm. To allow adequate cell function this spatial compartmentalization in eukaryotic cells requires a finely tuned, selective and efficient bidirectional nuclear-cytoplasmic transport of specific proteins and mRNAs through the nuclear pore complex (NPC) of the nuclear envelope. The passage of macro-molecules (>40 kDa), cargo, through the NPC requires specific transport receptor proteins. The mammalian family of karyopherins, representing the main group of transport receptor proteins, consists of 20 members including karyopherin alpha (KPNA) 1–6, karyopherin beta (KPNB) 1, and exportin-1 (XPO-1), also termed chromosome region maintenance – 1 (CRM-1). Dependent on the presence of precise transport signs in cargo proteins, nuclear localization signals (NLS) or nuclear export signals (NES), karyopherins chaperone them into (importins) or out (exportins) of the nucleus using energy from the RanGTPase complex.