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Extranodal natural killer (NK)/T-cell lymphoma is an aggressive malignancy of putative NK-cell origin, with a minority deriving from the T-cell lineage. Pathologically, the malignancy occurs in two forms, extranodal NK/T-cell lymphoma, nasal type; and aggressive NK-cell leukaemia. Lymphoma occur most commonly (80%) in the nose and upper aerodigestive tract, less commonly (20%) in non-nasal areas (skin, gastrointestinal tract, testis, salivary gland), and rarely as disseminated disease with a leukemic phase. Genetic analysis showed mutations of genes involved in the JAK/STAT pathway, RNA assembly, epigenetic regulation, and tumor suppression. In initial clinical evaluation, positron emission tomography computed tomography, and quantification of plasma EBV DNA are mandatory as they are useful for response monitoring and prognostication. In stage I/II diseases, combined chemotherapy and radiotherapy (sequentially or concurrently) is the best approach. Conventional anthracycline-containing regimens are ineffective and should be replaced by non-anthracycline-containing regimens, preferably including L-asparaginase. Radiotherapy alone is associated with high systemic relapse rates and should be avoided. In stage III/IV diseases, non-anthracycline-regimens-containing L-asparaginase are the standard. In relapsed/refractory cases, blockade of the programmed death protein 1 has recently shown promising results with high response rates. In the era of effective non-anthracycline-containing regimens, autologous haematopoietic stem cell transplantation (HSCT) has not been shown to be beneficial. However, allogeneic HSCT may be considered for high-risk or advanced-stage patients in remission or relapsed/refractory patients responding to salvage therapy. Prognostic models taking into account presentation, interim, and end-of-treatment parameters are useful in triaging patients to different treatment strategies.

Natural killer (NK)/T-cell lymphomas are aggressive malignancies with a predilection for Asian and South American populations. Epstein–Barr virus (EBV) infection in lymphoma cells is universal. Predominantly extranodal, NK/T-cell lymphomas are divided clinically into nasal (involving the nose and upper aerodigestive tract), non-nasal (involving the skin, gastrointestinal tract, testes, and other organs), and aggressive leukaemia/lymphoma (involving the marrow and multiple organs) subtypes. Initial assessment should include imaging with positron emission tomography computed tomography (PET/CT), quantification of plasma EBV DNA as a surrogate marker of lymphoma load, and bone marrow examination with in situ hybridization for EBV-encoded small RNA. Prognostication can be based on presentation parameters (age, stage, lymph node involvement, clinical subtypes, and EBV DNA), which represent patient factors and lymphoma load; and dynamic parameters during treatment (serial plasma EBV DNA and interim/end-of-treatment PET/CT), which reflect response to therapy. Therapeutic goals are to achieve undetectable plasma EBV DNA and normal PET/CT (Deauville score ≤ 3). NK/T-cell lymphomas express the multidrug resistance phenotype, rendering anthracycline-containing regimens ineffective. Stage I/II nasal cases are treated with non-anthracycline asparaginase-based regimens plus sequential/concurrent radiotherapy. Stage III/IV nasal, and non-nasal and aggressive leukaemia/lymphoma cases are treated with asparaginase-containing regimens and consolidated by allogeneic haematopoietic stem cell transplantation (HSCT) in suitable patients. Autologous HSCT does not improve outcome. In relapsed/refractory cases, novel approaches comprise immune checkpoint blockade of PD1/PD-L1, EBV-specific cytotoxic T-cells, monoclonal antibodies, and histone deacetylase inhibitors. Future strategies may include inhibition of signalling pathways and driver mutations, and immunotherapy targeting the lymphoma and its microenvironment.

Cell cycle progression is tightly controlled by many cell cycle-regulatory proteins that are in turn regulated by a family of cyclin-dependent kinases (CDKs) through protein phosphorylation. The peptidyl-prolyl / isomerase PIN1 provides a further post-phosphorylation modification and functional regulation of these CDK-phosphorylated proteins. PIN1 specifically binds the phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) motif of its target proteins and catalyzes the / isomerization on the pSer/Thr-Pro peptide bonds. Through this phosphorylation-dependent prolyl isomerization, PIN1 fine-tunes the functions of various cell cycle-regulatory proteins including retinoblastoma protein (Rb), cyclin D1, cyclin E, p27, Cdc25C, and Wee1. In this review, we discussed the essential roles of PIN1 in regulating cell cycle progression through modulating the functions of these cell cycle-regulatory proteins. Furthermore, the mechanisms underlying PIN1 overexpression in cancers were also explored. Finally, we examined and summarized the therapeutic potential of PIN1 inhibitors in cancer therapy.

Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer’s disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease-specific cross-β amyloid conformations that self-propagate and are implicated in neuronal loss. Development of molecular diagnostics and therapeutics is of critical importance. However, mechanisms of small molecule binding to the amyloid core is poorly understood. We used cryo–electron microscopy to determine a 2.7 Å structure of AD patient-derived tau paired-helical filaments bound to the PET ligand GTP-1. The compound is bound stoichiometrically at a single site along an exposed cleft of each protofilament in a stacked arrangement matching the fibril symmetry. Multiscale modeling reveals pi-pi aromatic interactions that pair favorably with the small molecule–protein contacts, supporting high specificity and affinity for the AD tau conformation. This binding mode offers critical insight into designing compounds to target different amyloid folds found across neurodegenerative diseases. Understanding the mode of small-molecule binding to amyloid filaments is critical for diagnosing and treating neurodegeneration. The authors use cryo-EM to reveal a stacked binding motif which may hasten design of diagnostics and therapeutics.

Bacterial ClpB and yeast Hsp104 are homologous Hsp100 protein disaggregases that serve critical functions in proteostasis by solubilizing protein aggregates. Two AAA+ nucleotide binding domains (NBDs) power polypeptide translocation through a central channel comprised of a hexameric spiral of protomers that contact substrate via conserved pore-loop interactions. Here we report cryo-EM structures of a hyperactive ClpB variant bound to the model substrate, casein in the presence of slowly hydrolysable ATPγS, which reveal the translocation mechanism. Distinct substrate-gripping interactions are identified for NBD1 and NBD2 pore loops. A trimer of N-terminal domains define a channel entrance that binds the polypeptide substrate adjacent to the topmost NBD1 contact. NBD conformations at the seam interface reveal how ATP hydrolysis-driven substrate disengagement and re-binding are precisely tuned to drive a directional, stepwise translocation cycle. Bacterial ClpB is a disaggregase that solubilizes protein aggregates. Here the authors present the 2.9 Å cryo-EM structure of a hyperactive variant of ClpB bound to the substrate casein in active translocation states and discuss its polypeptide translocation mechanism.

Small heat shock proteins (sHSPs) are a class of oligomeric molecular chaperones that limit protein aggregation. However, it is often not clear where sHSPs bind on their client proteins or how these protein-protein interactions (PPIs) are regulated. Here, we map the PPIs between human Hsp27 and the microtubule-associated protein tau (MAPT/tau). We find that Hsp27 selectively recognizes two aggregation-prone regions of tau, using the conserved β4-β8 cleft of its alpha-crystallin domain. The β4-β8 region is also the site of Hsp27–Hsp27 interactions, suggesting that competitive PPIs may be an important regulatory paradigm. Indeed, we find that each of the individual PPIs are relatively weak and that competition for shared sites seems to control both client binding and Hsp27 oligomerization. These findings highlight the importance of multiple, competitive PPIs in the function of Hsp27 and suggest that the β4-β8 groove acts as a tunable sensor for clients. Small heat shock proteins (sHSPs) limit the aggregation of proteins, such as tau. Here the authors show that Hsp27 recognizes two aggregation-prone regions of tau and that this interaction competes with Hsp27 oligomerization.

Aberrant aggregation of α-Synuclein is the pathological hallmark of a set of neurodegenerative diseases termed synucleinopathies. Recent advances in cryo-electron microscopy have led to the structural determination of the first synucleinopathy-derived α-Synuclein fibrils, which contain a non-proteinaceous, “mystery density” at the core of the protofilaments, hypothesized to be highly negatively charged. Guided by previous studies that demonstrated that polyphosphate (polyP), a universally conserved polyanion, significantly accelerates α-Synuclein fibril formation, we conducted blind docking and molecular dynamics simulation experiments to model the polyP binding site in α-Synuclein fibrils. Here, we demonstrate that our models uniformly place polyP into the lysine-rich pocket, which coordinates the mystery density in patient-derived fibrils. Subsequent in vitro studies and experiments in cells revealed that substitution of the 2 critical lysine residues K43 and K45 with alanine residues leads to a loss of all previously reported effects of polyP binding on α-Synuclein, including stimulation of fibril formation, change in filament conformation and stability as well as alleviation of cytotoxicity. In summary, our study demonstrates that polyP fits the unknown electron density present in in vivo α-Synuclein fibrils and suggests that polyP exerts its functions by neutralizing charge repulsion between neighboring lysine residues.

Epstein Barr virus (EBV)-associated lymphoproliferative diseases (LPDs) express all EBV latent antigens (type III latency) in immunodeficient patients and limited antigens (type I and II latencies) in immunocompetent patients. Post-transplantation lymphoproliferative disease (PTLD) is the prototype exhibiting type III EBV latency. Although EBV antigens are highly immunogenic, PTLD cell proliferation remains unchecked because of the underlying immunosuppression. The restoration of anti-EBV immunity by EBV-specific T cells of either autologous or allogeneic origin has been shown to be safe and effective in PTLDs. Cellular therapy can be improved by establishing a bank of human leukocyte antigen-characterized allogeneic EBV-specific T cells. In EBV+ LPDs exhibiting type I and II latencies, the use of EBV-specific T cells is more limited, although the safety and efficacy of this therapy have also been demonstrated. The therapeutic role of EBV-specific T cells in EBV+ LPDs needs to be critically reappraised with the advent of monoclonal antibodies and other targeted therapy. Another strategy involves the use of epigenetic approaches to induce EBV to undergo lytic proliferation when expression of the viral thymidine kinase renders host tumor cells susceptible to the cytotoxic effects of ganciclovir. Finally, the prophylactic use of antiviral drugs to prevent EBV reactivation may decrease the occurrence of EBV+ LPDs. Blood cancer: Fighting the Epstein-Barr virus Cellular therapies, which use living cells to treat disease, could be useful against cancers associated with Epstein-Barr virus (EBV). Best-known for causing glandular fever, EBV is also implicated in many malignant \"lymphoproliferative\" conditions, in which white blood cells multiply excessively. Yok-Lam Kwong and Eric Tse of Queen Mary Hospital in Hong Kong have reviewed the advantages and disadvantages of several forms of cellular therapy, which utilize healthy white blood cells from donors or from patients themselves to combat EBV. Such treatment has proven to be safe and effective, especially in patients with immunity suppressed by diseases or drugs. The availability of cellular therapy could be widened by establishing a bank of suitable cells. Its efficacy needs to be evaluated against emerging alternatives including antibodies and drugs.

The contribution of inflammation to neurodegenerative diseases is increasingly recognized, but the role of inflammation in sporadic amyotrophic lateral sclerosis (sALS) is not well understood and no animal model is available. We used enzyme-linked immunosorbent assays (ELISAs) to measure the cytokine interleukin-17A (IL-17A) in the serum of ALS patients (n = 32; 28 sporadic ALS (sALS) and 4 familial ALS (fALS)) and control subjects (n = 14; 10 healthy subjects and 4 with autoimmune disorders). IL-17A serum concentrations were 5767 ± 2700 pg/ml (mean ± SEM) in sALS patients and 937 ± 927 pg/ml in fALS patients in comparison to 7 ± 2 pg/ml in control subjects without autoimmune disorders (p = 0.008 ALS patients vs. control subjects by Mann-Whitney test). Sixty-four percent of patients and no control subjects had IL-17A serum concentrations > 50 pg/ml (p = 0.003 ALS patients vs. healthy subjects by Fisher's exact test). The spinal cords of sALS (n = 8), but not control subjects (n = 4), were infiltrated by interleukin-1β- (IL-1β-), and tumor necrosis factor-α-positive macrophages (co-localizing with neurons), IL-17A-positive CD8 cells, and IL-17A-positive mast cells. Mononuclear cells treated with aggregated forms of wild type superoxide dismutase-1 (SOD-1) showed induction of the cytokines IL-1β, interleukin-6 (IL-6), and interleukin-23 (IL-23) that may be responsible for induction of IL-17A. In a microarray analysis of 28,869 genes, stimulation of peripheral blood mononuclear cells by mutant superoxide dismutase-1 induced four-fold higher transcripts of interleukin-1α (IL-1α), IL-6, CCL20, matrix metallopeptidase 1, and tissue factor pathway inhibitor 2 in mononuclear cells of patients as compared to controls, whereas the anti-inflammatory cytokine interleukin-10 (IL-10) was increased in mononuclear cells of control subjects. Aggregated wild type SOD-1 in sALS neurons could induce in mononuclear cells the cytokines inducing chronic inflammation in sALS spinal cord, in particular IL-6 and IL-17A, damaging neurons. Immune modulation of chronic inflammation may be a new approach to sALS.

PIN1 is a peptidyl-prolyl isomerase that specifically binds and catalyzes the isomerization of the phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) motif of its interacting proteins. Through this phosphorylation-dependent prolyl isomerization, PIN1 is involved in the regulation of various important cellular processes including cell cycle progression, cell proliferation, apoptosis and microRNAs biogenesis; hence its dysregulation contributes to malignant transformation. PIN1 is highly expressed in hepatocellular carcinoma (HCC). By fine-tuning the functions of its interacting proteins such as cyclin D1, x-protein of hepatitis B virus and exportin 5, PIN1 plays an important role in hepatocarcinogenesis. Growing evidence supports that targeting PIN1 is a potential therapeutic approach for HCC by inhibiting cell proliferation, inducing cellular apoptosis, and restoring microRNAs biogenesis. Novel formulation of PIN1 inhibitors that increases bioavailability of PIN1 inhibitors represents a promising future direction for the therapeutic strategy of HCC treatment. In this review, the mechanisms underlying PIN1 over-expression in HCC are explored. Furthermore, we also discuss the roles of PIN1 in HCC tumorigenesis and metastasis through its interaction with various phosphoproteins. Finally, recent progress in the therapeutic options targeting PIN1 for HCC treatment is examined and summarized.