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NK/T-cell lymphomas are extranodal EBV-related malignancies, mostly of NK-cell and occasionally of T-cell lineage. They are divided into nasal, non-nasal, and disseminated subtypes. Nasal NK/T-cell lymphomas involve the nose, nasopharynx and the upper aerodigestive tract. Non-nasal NK/T-cell lymphomas involve the skin, gastrointestinal tract, testis and other sites. Disseminated NK/T-cell lymphoma involves multiple organs, and may present with a leukemic phase. Initial evaluation requires positron emission tomography computed tomography (PET/CT) and quantification of circulating EBV DNA. Radiotherapy alone is inadequate with frequent relapses. Anthracycline-containing regimens are ineffective. Regimens incorporating asparaginase are currently the standard. For stage I/II disease, combined chemotherapy and radiotherapy is recommended. For stage III/IV disease, asparaginase-containing regimens are needed. Autologous hematopoietic stem cell transplantation (HSCT) is of limited efficacy, whereas allogeneic HSCT may be useful in patients with stage III/IV and relapsed diseases. Immunotherapy with antibodies against CD30, programmed cell death protein 1 and CD38 is promising. [ABSTRACT FROM AUTHOR]

The AAA+ protein, Skd3 (human CLPB), solubilizes proteins in the mitochondrial intermembrane space, which is critical for human health. Skd3 variants with defective protein-disaggregase activity cause severe congenital neutropenia (SCN) and 3-methylglutaconic aciduria type 7 (MGCA7). How Skd3 disaggregates proteins remains poorly understood. Here, we report a high-resolution structure of a Skd3-substrate complex. Skd3 adopts a spiral hexameric arrangement that engages substrate via pore-loop interactions in the nucleotide-binding domain (NBD). Substrate-bound Skd3 hexamers stack head-to-head via unique, adaptable ankyrin-repeat domain (ANK)-mediated interactions to form dodecamers. Deleting the ANK linker region reduces dodecamerization and disaggregase activity. We elucidate apomorphic features of the Skd3 NBD and C-terminal domain that regulate disaggregase activity. We also define how Skd3 subunits collaborate to disaggregate proteins. Importantly, SCN-linked subunits sharply inhibit disaggregase activity, whereas MGCA7-linked subunits do not. These advances illuminate Skd3 structure and mechanism, explain SCN and MGCA7 inheritance patterns, and suggest therapeutic strategies. [Display omitted] • High-resolution structure of a PARL Skd3-substrate complex • Substrate-bound PARL Skd3 hexamers stack head-to-head to form dodecamers • Mechanisms by which PARL Skd3 subunits collaborate to disaggregate proteins • Mechanisms by which Skd3 mutations cause dominant and recessive forms of disease Cupo et al. reveal the structure and mechanism of Skd3, a protein disaggregase found in mitochondria, which is critical for human health. These advances explain the inheritance patterns and suggest therapeutic strategies for debilitating diseases caused by mutations in Skd3. [ABSTRACT FROM AUTHOR]

Background & Aims: The peptidyl prolyl isomerase Pin1 frequently is overexpressed in hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) is the most common etiologic agent in HCC, and its encoded X-protein (HBx) is oncogenic and possesses a serine-proline motif that may bind Pin1. The role of Pin1 in hepatocarcinogenesis, particularly in HBV-related HCC, was investigated. Methods: Immunohistochemical staining was performed to evaluate the prevalence of Pin1 overexpression in HCCs of different etiologies. Glutathione S-transferase pull-down and co-immunoprecipitation experiments were used to validate the physical interaction between Pin1 and HBx. Reporter assay, cell proliferation assay, and xenotransplantation experiments were used to show the functional consequence and importance of Pin1-HBx interaction in hepatocarcinogenesis. Results: We showed preferential Pin1 overexpression in HBV-related tumors and confirmed the interaction between Pin1 and HBx at the specific serine-proline motif. Pin1 overexpression increased the protein stability of HBx. Furthermore, HBx-mediated transactivation was enhanced by co-expression of Pin1. HepG2 expressing Pin1 and HBx showed a synergistic increase in cellular proliferation, as compared with cells expressing Pin1 or HBx alone. Furthermore, concomitant expression of Pin1 and HBx in the nontumorigenic human hepatocyte cell line MIHA led to a synergistic increase in tumor growth. Finally, in Hep3B cells with suppressed Pin1 expression, HBx-enhanced tumor growth in nude mice was abrogated. Conclusions: Pin1 binds HBx to enhance hepatocarcinogenesis in HBV-infected hepatocytes. The discovery of an interaction between Pin1 and HBx will further our understanding of the molecular pathogenic mechanism of HBV-related HCC in human beings. [Copyright &y& Elsevier]

Abstract: Research over the past decade has unraveled important molecular pathways involved in hepatocellular carcinoma (HCC), and several chromosomal and genetic aberrations have been identified to be responsible for initiation of the carcinogenic process. HBx protein and HCV core protein appear to play a pivotal role in hepatocarcinogenesis related to hepatitis B virus and hepatitis C virus, respectively. These viral oncoproteins allow cells to bypass some of the multi-steps in hepatocarcinogenesis, accounting for the etiological role of the two viruses in HCC. Understanding of the molecular pathways of HCC facilitates the development of novel molecular strategies for chemoprevention and therapy of HCC. [Copyright &y& Elsevier]

• Isolated distal DVT (IDDVT), which comprise 1/3rd of all lower extremity DVTs is sparsely studied • Prandoni P et.al., 2023, assessed the development of PTS in 745 patients with IDDVT • PTS patients had a higher rate of previous VTE • They were more likely to have chronic heart failure (CHF) and had a lower prevalence of recent surgery • CHF, immobilization and prior DVT and/or PE were associated with increased risk of PTS in IDDVT • Results suggest long-term sequelae are to be expected in 1/5 patients with isolated below-knee DVT • This real-world study allowed the identification of a promising prediction score [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality worldwide. GARFIELD-VTE is a prospective, non-interventional observational study of real-world treatment practices. We aimed to capture the 36-month clinical outcomes of 10,679 patients with objectively confirmed VTE enrolled between May 2014 and January 2017 from 415 sites in 28 countries. A total of 6582 (61.6 %) patients had DVT alone, 4097 (38.4 %) had PE ± DVT. At baseline, 98.1 % of patients received anticoagulation (AC) with or without other modalities of therapy. The proportion of patients on AC therapy decreased over time: 87.6 % at 3 months, 73.0 % at 6 months, 54.2 % at 12 months and 42.0 % at 36 months. At 12-months follow-up, the incidences (95 % confidence interval [CI]) of all-cause mortality, recurrent VTE and major bleeding were 6.5 (7.0–8.1), 5.4 (4.9–5.9) and 2.7 (2.4–3.0) per 100 person-years, respectively. At 36-months, these decreased to 4.4 (4.2–4.7), 3.5 (3.2–2.7) and 1.4 (1.3–1.6) per 100 person-years, respectively. Over 36-months, the rate of all-cause mortality and major bleeds were highest in patients treated with parenteral therapy (PAR) versus oral anti-coagulants (OAC) and no OAC, and the rate of recurrent VTE was highest in patients on no OAC versus those on PAR and OAC. The most frequent cause of death after 36-month follow-up was cancer (n = 565, 48.6 %), followed by cardiac (n = 94, 8.1 %), and VTE (n = 38, 3.2 %). Most recurrent VTE events were DVT alone (n = 564, 63.3 %), with the remainder PE, (n = 236, 27.3 %), or PE in combination with DVT (n = 63, 7.3 %). GARFIELD-VTE provides a global perspective of anticoagulation patterns and highlights the accumulation of events within the first 12 months after diagnosis. These findings may help identify treatment gaps for subsequent interventions to improve patient outcomes in this patient population. [ABSTRACT FROM AUTHOR]

Abstract: Twenty-seven patients received the anti-CD52 monoclonal antibody alemtuzumab for hematologic malignancies and autoimmune cytopenias in a tuberculosis-endemic area. Seven patients developed mycobacterium tuberculosis (TB) infections (median: 4, 1–24, months from alemtuzumab). The actuarial 1- and 2-year incidence of TB was 31% and 45%. All patients had severe depression of lymphocyte counts subsequent to alemtuzumab treatment, and tuberculosis was extra-pulmonary in three cases. All seven patients had received prior chemotherapy/immunosuppression and tuberculosis had not occurred until alemtuzumab was administered. Patients receiving alemtuzumab in areas endemic for tuberculosis should have careful initial evaluation of TB exposure, so that prophylactic antibiotics might be administered. Tuberculosis reactivation should be considered for unexplained fever and symptoms after alemtuzumab treatment. [Copyright &y& Elsevier]

Although epidemiological studies report a lower risk of venous thromboembolism (VTE) than in the Western world, VTE rates in Asia may be underestimated. Furthermore, it is uncertain whether VTE outcomes differ in Asia and the rest of the world (ROW). GARFIELD-VTE is a global, prospective, non-interventional study of real-world treatment practices. In this study, we compared baseline characteristics, treatment patterns, and 12-month outcomes in Asia and ROW. Of the 10,684 enrolled patients, 1822 (17.1%) were Asian (China n = 420, Hong Kong n = 98, Japan n = 148, Malaysia n = 244, South Korea n = 343, Taiwan n = 232, Thailand n = 337). Compared with ROW patients, those from Asia were more often female (57.4% vs. 48.0%), non-smokers (74.0% vs. 58.9%) and had a lower BMI (24.8 kg/m2 vs. 29.1 kg/m2). Asian patients were more likely to be managed in the hospital (86.9% vs. 70.4%) and to have active cancer (19.8% vs. 8.1%) or a history of cancer (19.1% vs. 12.0%). Asian patients received no anticoagulation more frequently than ROW patients (6.5% vs. 2.1%). Over 12-months follow-up, the rate of all-cause mortality (per 100 person-years [95% confidence interval]) was higher in Asians (15.2 [13.4–17.3] vs. 5.9 [5.4–6.5]). Adjusted hazard ratios indicated a higher risk of all-cause mortality in Asian patients than the ROW (1.32 [1.08–1.62]). The frequencies of major bleeding and recurrent VTE were similar. Asian patients have different risk profiles, treatment patterns and a higher risk of mortality compared with the ROW. • GARFIELD-VTE compared VTE practices among Asian and non-Asian patients • Asian patients with VTE were more likely to have active or history of cancer • Asian patients with VTE were less likely to receive anticoagulation therapy • After adjustment, the risk of mortality was higher in Asians than non-Asians [ABSTRACT FROM AUTHOR]

Intercellular propagation of protein aggregation is emerging as a key mechanism in the progression of several neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia (FTD). However, we lack a systematic understanding of the cellular pathways controlling prion-like propagation of aggregation. To uncover such pathways, here we performed CRISPR interference (CRISPRi) screens in a human cell-based model of propagation of tau aggregation monitored by FRET. Our screens uncovered that knockdown of several components of the endosomal sorting complexes required for transport (ESCRT) machinery, including charged multivesicular body protein 6 (CHMP6), or CHMP2A in combination with CHMP2B (whose gene is linked to familial FTD), promote propagation of tau aggregation. We found that knocking down the genes encoding these proteins also causes damage to endolysosomal membranes, consistent with a role for the ESCRT pathway in endolysosomal membrane repair. Leakiness of the endolysosomal compartment significantly enhanced prion-like propagation of tau aggregation, likely by making tau seeds more available to pools of cytoplasmic tau. Together, these findings suggest that endolysosomal escape is a critical step in tau propagation in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Heat shock protein 70 (Hsp70) and Hsp90 are molecular chaperones that play essential roles in tumor growth by stabilizing pro-survival client proteins. However, although the development of Hsp90 inhibitors has benefited from the identification of clients, such as Raf-1 proto-oncogene, Ser/Thr kinase (RAF1), that are particularly dependent on this chaperone, no equivalent clients for Hsp70 have been reported. Using chemical probes and MDA-MB-231 breast cancer cells, we found here that the inhibitors of apoptosis proteins, including c-IAP1 and X-linked inhibitor of apoptosis protein (XIAP), are obligate Hsp70 clients that are rapidly (within ~3-12 h) lost after inhibition of Hsp70 but not of Hsp90. Mutagenesis and pulldown experiments revealed multiple Hsp70-binding sites on XIAP, suggesting that it is a direct, physical Hsp70 client. Interestingly, this interaction was unusually tight (~260 nM) for an Hsp70-client interaction and involved non-canonical regions of the chaperone. Finally, we also found that Hsp70 inhibitor treatments caused loss of c-IAP1 and XIAP in multiple cancer cell lines and in tumor xenografts, but not in healthy cells. These results are expected to significantly accelerate Hsp70 drug discovery by providing XIAP as a pharmacodynamic biomarker. More broadly, our findings further suggest that Hsp70 and Hsp90 have partially non-overlapping sets of obligate protein clients in cancer cells. [ABSTRACT FROM AUTHOR]

Recognizing the significant biological and clinical heterogeneity of mature T cell and natural killer (NK)/T cell lymphomas, the American Society for Blood and Marrow Transplantation invited experts to develop clinical practice recommendations related to the role of autologous hematopoietic cell transplantation (auto-HCT) and allogeneic HCT (allo-HCT) for specific histological subtypes. We used the GRADE methodology to aid in moving from evidence to decision making and ultimately to generating final recommendations. Auto-HCT in front-line consolidation is recommended in peripheral T cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T cell lymphoma (AITL), anaplastic large cell lymphoma–anaplastic lymphoma kinase (ALCL-ALK)-negative, NK/T cell (disseminated), enteropathy-associated T cell lymphoma (EATL), and hepatosplenic lymphomas. Auto-HCT in relapsed-sensitive disease is recommended for NK/T cell (localized and disseminated), EATL, subcutaneous panniculitis-like T cell, and ALCL-ALK–positive lymphomas. Auto-HCT is also recommended for PTCL-NOS, AITL, and ALCL-ALK–negative lymphomas if not performed as front-line therapy. Auto-HCT in refractory (primary or relapsed) disease is not recommended for any of the histological subtypes discussed. Allo-HCT in front-line consolidation is recommended for NK/T cell (disseminated), adult T cell leukemia/lymphoma (ATLL; acute and lymphoma type), and hepatosplenic lymphomas. Allo-HCT for relapsed-sensitive disease is recommended for PTCL-NOS, AITL, ALCL-ALK–negative, ALCL-ALK–positive, NK/T cell (localized and disseminated), ATLL (acute, lymphoma type, smoldering/chronic), mycosis fungoides/Sezary syndrome (advanced stage IIB-IVB or tumor stage/extracutaneous), EATL, subcutaneous panniculitis-like T cell, and hepatosplenic lymphoma. Allo-HCT in refractory (primary or relapsed refractory) disease is recommended for any aforementioned histological subtypes. Emerging novel therapies will likely be incorporated into the pretransplantation, peritransplantation, and post-transplantation algorithms (auto-HCT or allo-HCT) with the goals of optimizing efficacy and improving outcomes. We acknowledge that there are unique clinical scenarios not covered by these recommendations that may require individualized decisions. [ABSTRACT FROM AUTHOR]

Abstract: Background: Reactivation of latent herpes viruses occurs with immunosuppression. Alemtuzumab is an antibody targeting CD52, which is expressed on all B- and T-cells. Treatment with alemtuzumab leads to profound T-cell suppression, and reactivation of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) occurs. Valganciclovir is used as an anti-CMV prophylaxis during alemtuzumab therapy. Objective: To determine if EBV reactivation is decreased with valganciclovir prophylaxis. Study design: Plasma EBV DNA was serially quantified by quantitative polymerase chain reaction with a World Health Organization EBV standard in patients receiving alemtuzumab therapy with valganciclovir as anti-CMV prophylaxis. Results: Twenty-nine patients were studied. A total of 258 samples were quantified, at a median of 7 (3–25) specimens per patient. Twenty-four patients never had any quantifiable EBV DNA. Five patients (17%) developed EBV reactivation. Two patients had EBV reactivation at very low levels of about 103 IU/mL, 3–4 logs lower than those typically found in post-transplant lymphoproliferative diseases. Three patients had EBV reactivation at higher levels of 104 IU/mL, which only occurred after two courses of alemtuzumab were administered. EBV reactivation subsided spontaneously in four cases. One patient developed EBV-positive Hodgkin lymphoma, but he had also received previously another potent T-cell suppressing drug fludarabine. Conclusion: Valganciclovir suppressed EBV reactivation during alemtuzumab therapy. It might be a useful prophylaxis in immunocompromized patient populations at high risk of EBV reactivation. [Copyright &y& Elsevier]

Protein phosphatase 5 (PP5) is auto-inhibited by intramolecular interactions with its tetratricopeptide repeat (TPR) domain.Hsp90 has been shown to bind PP5 to activate its phosphatase activity. However, the functional implications of binding Hsp70 to PP5 are not yet clear. In this study, we find that both Hsp90 and Hsp70 bind to PP5 using a luciferase fragment complementation assay. A fluorescence polarization assay shows that Hsp90 (MEEVD motif) binds to the TPR domain of PP5 almost 3-fold higher affinity than Hsp70 (IEEVD motif). However, Hsp70 binding to PP5 stimulates higher phosphatase activity of PP5 than the binding of Hsp90. We find that PP5 forms a stable 1:1 complex with Hsp70, but the interaction appears asymmetric with Hsp90, with one PP5 binding the dimer. Solution NMR studies reveal that Hsc70 and PP5 proteins are dynamically independent in complex, tethered by a disordered region that connects the Hsc70 core and the IEEVD-TPR contact area. This tethered binding is expected to allow PP5 to carry out multi-site dephosphorylation of Hsp70-bound clients with a range of sizes and shapes. Together, these results demonstrate that Hsp70 recruits PP5 and activates its phosphatase activity which suggests dual roles for PP5 that might link chaperone systems with signaling pathways in cancer and development. [ABSTRACT FROM AUTHOR]

Summary: CKS proteins are evolutionarily conserved cyclin-dependent kinase (CDK) subunits whose functions are incompletely understood. Mammals have two CKS proteins. CKS1 acts as a cofactor to the ubiquitin ligase complex SCFSKP2 to promote degradation of CDK inhibitors, such as p27. Little is known about the role of the closely related CKS2. Using a Cks2 −/− knockout mouse model, we show that CKS2 counteracts CKS1 and stabilizes p27. Unopposed CKS1 activity in Cks2 −/− cells leads to loss of p27. The resulting unrestricted cyclin A/CDK2 activity is accompanied by shortening of the cell cycle, increased replication fork velocity, and DNA damage. In vivo, Cks2 −/− cortical progenitor cells are limited in their capacity to differentiate into mature neurons, a phenotype akin to animals lacking p27. We propose that the balance between CKS2 and CKS1 modulates p27 degradation, and with it cyclin A/CDK2 activity, to safeguard replicative fidelity and control neuronal differentiation. [ABSTRACT FROM AUTHOR]

Summary: Survival for adults and children with acute lymphoblastic leukaemia has risen substantially in recent years because use of improved risk-directed treatments and supportive care has widened. In nearly all developed countries, multidisciplinary panels of leukaemia experts have formulated clinical practice guidelines in which standard treatment approaches are recommended on the basis of current evidence. However, those guidelines do not take into account resource limitations in low-income countries, including financial and technical challenges. In Asia, huge disparities in economy and infrastructure exist between countries, and even among different regions in some large countries. At a consensus session held as part of the 2013 Asian Oncology Summit in Bangkok, Thailand, a panel of experts summarised recommendations for management of adult and paediatric acute lymphoblastic leukaemia. Strategies were developed for Asian countries on the basis of available financial, skill, and logistical resources and were stratified in a four-tier system according to the resources available in a particular country or region (basic, limited, enhanced, and maximum). [Copyright &y& Elsevier]