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Objective: To evaluate the roles of thiopurine methyltransferase (TPMT), inosine triphosphatase (ITPA), and Nudix hydrolase 15 (NUDT15) in 6-mercaptopurine (6-MP) sensitivity during treatment of pediatric patients with acute lymphoblastic leukemia (ALL).Study Design: The study included 102 pediatric patients with ALL subject to the Nordic society Of Paediatric Haematology and Oncology (NOPHO) ALL-2000 and ALL-2008 protocols. Episodes of neutropenia and febrile neutropenia, TPMT sequence variants, as well as 6-MP end doses, were collected retrospectively from medical records. TPMT, ITPA, and NUDT15 sequence variants were analyzed using pyrosequencing.Results: TPMT variants were associated with a reduced risk of neutropenia and febrile neutropenia during the maintenance II period (P = .019 and P < .0001, respectively). In addition, a NUDT15 variant was associated with a lower end dose of 6-MP (P = .0097), but not with neutropenia and febrile neutropenia. ITPA variants were not associated with an increased risk of neutropenia, febrile neutropenia, nor lower end dose of 6-MP. However, when analyzing the entire treatment period, ITPA variants were associated with a decreased risk of febrile neutropenia.Conclusions: White blood cell count-based dose adjustments are regularly performed for known TPMT- deficient patients and results in a reduced risk of neutropenia and febrile neutropenia. Also in NUDT15-deficient patients dose adjustments are performed as indicated by low end dose of 6-MP. ITPA-deficient patients had a decreased risk of febrile neutropenia when analyzing the entire treatment period. Our data suggest that NUDT15 plays an important role in 6-MP treatment and the results should be confirmed in larger cohorts. Future studies should also follow up whether white blood cell count-based dose adjustments affect the risk of relapse. [ABSTRACT FROM AUTHOR]

To date, the definition that the off-label usage of drugs refers to the unapproved use of approved drugs, which covers unapproved indications, patient populations, doses, and/or routes of administration, has been in existence for many years. Currently, there is a limited frequency and prevalence of research on the off-label use of antineoplastic drugs, mainly due to incomplete definition and classification issues. It is time to embrace new categories for the off-label usage of anticancer drugs. This review provided an insight into an updated overview of the concept and categories of the off-label use of anticancer drugs, along with illustrating specific examples to establish the next studies about the extent of the off-label usage of anticancer drugs in the oncology setting. The scope of the offlabel use of current anticancer drugs beyond the previous definitions not only includes off-label uses in terms of indications, patient populations, doses, and/or routes of administration but also off-label use in terms of medication course, combination, sequence of medication, clinical purpose, contraindications scenarios, etc. In addition, the definition of the off-label usage of anticancer drugs should be added to the condition at a given time, and it varies from approval authorities. We presented a new and relatively comprehensive classification, providing extensive analysis and illustrative examples of the off-label usage of antineoplastic drugs for the first time. Such a classification has the potential to promote practical adoption and enhance management strategies for the offlabel use of antitumor drugs. [ABSTRACT FROM AUTHOR]

An abstract of the article "Expression of MAIT Cells in Blood and Genital Mucosa of HIV Infected and Uninfected Women" by Edwin Leeansyah, Andrea Introini and colleagues is presented.

A cure for HIV-1 (HIV) remains unrealized due to a reservoir of latently infected cells that persist during antiretroviral therapy (ART), with reservoir size associated with adverse health outcomes and inversely with time to viral rebound upon ART cessation. Once established during ART, the HIV reservoir decays minimally over time; thus, understanding factors that impact the size of the HIV reservoir near its establishment is key to improving the health of people living with HIV and for the development of novel cure strategies. Yet, to date, few correlates of HIV reservoir size have been identified, particularly in pediatric populations. Here, we employed a cross-subtype intact proviral DNA assay (CS-IPDA) to quantify HIV provirus between one- and two-years post-ART initiation in a cohort of Kenyan children (n = 72), which had a median of 99 intact (range: 0–2469), 1340 defective (range: 172–3.84 × 104), and 1729 total (range: 178–5.11 × 104) HIV proviral copies per one million T cells. Additionally, pre-ART plasma was tested for HIV Env-specific antibody-dependent cellular cytotoxicity (ADCC) activity. We found that pre-ART gp120-specific ADCC activity inversely correlated with defective provirus levels (n = 68, r = −0.285, p = 0.0214) but not the intact reservoir (n = 68, r = −0.0321, p-value = 0.800). Pre-ART gp41-specific ADCC did not significantly correlate with either proviral population (n = 68; intact: r = −0.0512, p-value = 0.686; defective: r = −0.109, p-value = 0.389). This suggests specific host immune factors prior to ART initiation can impact proviruses that persist during ART. [ABSTRACT FROM AUTHOR]

Advances over the last decades have made renal transplantation an important therapy for patients with end-stage renal disease, as the incidences of acute rejection and short-term transplant loss have been significantly reduced. However, long-term transplant survival remains a challenge in the renal transplantation community. The main causes of long-term graft loss are acute and chronic rejection, as well as the complications related to immunosuppression therapy. In spite of the breakthroughs achieved in recent years, histology is the gold standard technique to confirm the activation of the immune system against the graft with all the ensuing problems that taking biopsies brings to immunosuppressed patients. For this reason, several assays have been developed to try to monitor the immune function, but they show serious constraints owing to the fact that they require substantial laboratory work, they are not clinically available and they provide controversial results, so the combination of multiple assays is often needed to obtain a reliable diagnosis. Thus, the aim of this review is to perform a retrospective study of the immune system in renal transplantation, with special emphasis on the cutting-edge technological developments for monitoring, classification and early detection of rejection episodes in order to contribute to a better adjustment of immunosuppressive therapies and, hence, to a more personalized medicine that improves the quality of life of patients. [ABSTRACT FROM AUTHOR]

HIV-2, compared to HIV-1, elicits potent and broadly neutralizing antibodies, and uses a broad range of co-receptors. However, both sensitivity to neutralization and breadth of co-receptor use varies between HIV-2 isolates, and the molecular background is still not fully understood. Thus, in the current study, we have deciphered relationships between HIV-2 neutralization sensitivity, co-receptor use and viral envelope glycoprotein (Env) molecular motifs. A panel of primary HIV-2 isolates, with predefined use of co-receptors, was assessed for neutralization sensitivity using a set of HIV-2 Env-directed monoclonal antibodies and co-receptor indicator cell lines. Neutralization sensitivity of the isolates was analysed in relation target cell co-receptor expression, in addition to amino acid motifs and predicted structures of Env regions. Results showed that HIV-2 isolates were more resistant to neutralizing antibodies when entering target cells via the alternative co-receptor GPR15, as compared to CCR5. A similar pattern was noted for isolates using the alternative co-receptor CXCR6. Sensitivity to neutralizing antibodies appeared also to be linked to specific Env motifs in V1/V2 and C3 regions. Our findings suggest that HIV-2 sensitivity to neutralization depends both on which co-receptor is used for cell entry and on specific Env motifs. This study highlights the multifactorial mechanisms behind HIV-2 neutralization sensitivity. [ABSTRACT FROM AUTHOR]

The article presents a list of authors who have contributed to the August 1991 issue of the journal "Immunology." Some of these authors are L. Akerblom, C. Ardavin, P.W. Andrew, R. Barclay, S. Briggs. F. Brown, A. Bryant, P.L. Cohen, M.J. Covas, F.Q. Cunsha, G. Dixon, R. A. Eisenberg, T.H. Ermak, A. Ferrante. A.M. Fontecha, K. Franklin, A. Franz, R. Gerli, A.A. Gerli, A.L. Givan, J. Hadua, P. Hauser, K.T. HayGlass, A. Hernanz, R.A. Hilger, M. Holscher, S.K. Huang, P. Hutchings, N. Hunter and G. Jung.

Chronic graft-versus-host disease (cGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation that affects various organs leading to a reduced quality of life. The condition often requires enduring immunosuppressive therapy, which can also lead to the development of severe side effects. Several approaches including small molecule inhibitors, antibodies, cytokines, and cellular therapies are now being developed for the treatment of cGvHD, and some of these therapies have been or are currently tested in clinical trials. In this review, we discuss these emerging therapies with particular emphasis on tyrosine kinase inhibitors (TKIs). TKIs are a class of compounds that inhibits tyrosine kinases, thereby preventing the dissemination of growth signals and activation of key cellular proteins that are involved in cell growth and division. Because they have been shown to inhibit key kinases in both B cells and T cells that are involved in the pathophysiology of cGvHD, TKIs present new promising therapeutic approaches. Ibrutinib, a Bruton tyrosine kinase (Btk) inhibitor, has recently been approved by the Food and Drug Administration (FDA) in the United States for the treatment of adult patients with cGvHD after failure of first-line of systemic therapy. Also, Janus Associated Kinases (JAK1 and JAK2) inhibitors, such as itacitinib (JAK1) and ruxolitinib (JAK1 and 2), are promising in the treatment of cGvHD. Herein, we present the current status and future directions of the use of these new drugs with particular spotlight on their targeting of specific intracellular signal transduction cascades important for cGvHD, in order to shed some light on their possible mode of actions. [ABSTRACT FROM AUTHOR]

The majority of anti-cancer drugs show poor water solubility and produce adverse effects in healthy tissue. The combination of polymer technology and targeted drug delivery system may overlay the way for more effective yet safer therapeutic options for cancer therapy. Polymer drug conjugate are the polymer based prodrugs designed to increase the aqueous solubility of anti-cancers drugs, subsequently enhance the bioavailability. This update introduced basic concept of polymer drug conjugates (PDC) (prodrug) and provided an overview on currently used synthetic strategies for PDCs. In addition, brief overview on various polymer-drug conjugates updating their clinical status and highlights with major anticipated clinical application in cancer therapy. [ABSTRACT FROM AUTHOR]

The oncology clinic is changing, with an increasing number of cancer therapies becoming available as formulations for subcutaneous (SC) injection. Using targeted therapies, such as alemtuzumab, bortezomib, rituximab or trastuzumab, via SC injection can be advantageous for patients, healthcare professionals, and healthcare systems. However, their use can also present challenges, and nurses have a unique opportunity to positively influence the integration of SC agents in the clinic. This article summarizes practical suggestions for optimal administration of SC targeted therapies, and provides pragmatic considerations for managing the change process related to their adoption. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by ineffective hematopoiesis and a wide spectrum of manifestations ranging from indolent and asymptomatic cytopenias to acute myeloid leukemia (AML). MDS result from genetic and epigenetic derangements in clonal cells and their surrounding microenvironments. Studies have shown associations between MDS and other autoimmune diseases. Several immune mechanisms have been identified in MDS, suggesting that immune dysregulation might be at least partially implicated in its pathogenesis. This has led to rigorous investigations on the role of immunomodulatory drugs as potential treatment options. Epigenetic modification via immune check point inhibition, while well established as a treatment method for advanced solid tumors, is a new approach being considered in hematologic malignancies including high risk MDS. Several trials are looking at the efficacy of these agents in MDS, as frontline therapy and in relapse, both as monotherapy and in combination with other drugs. In this review, we explore the utility of immune checkpoint inhibitors in MDS and current research evaluating their efficacy. [ABSTRACT FROM AUTHOR]

Dengue is the most prevalent mosquito‐borne disease in Southeast Asia, where the incidence of systemic lupus erythematosus (SLE) is approximately 30 to 53 per 100,000. Severe dengue, however, is rarely reported among individuals with SLE. Here, whether sera of patients with SLE cross‐neutralize dengue virus (DENV) was investigated. Serum samples were obtained from individuals with SLE who were dengue IgG and IgM serology negative. Neutralization assays were performed against the three major DENV serotypes. Of the dengue serology negative sera of individuals with SLE, 60%, 61% and 52% of the sera at 1/320 dilution showed more than 50% inhibition against dengue type‐1 virus (DENV‐1), DENV‐2 and DENV‐3, respectively. The neutralizing capacity of the sera was significantly greater against DENV‐1 (P < 0.001) and DENV‐3 (P < 0.01) than against DENV‐2 (P < 0.05). Neutralization against the DENV correlated with dengue‐specific IgG serum titers below the cut‐off point for dengue positivity. Depletion of total IgG from the sera of patients with SLE resulted in significant decreases of up to 80% in DENV inhibition, suggesting that IgG plays an important role. However, some of the SLE sera was still able to neutralize DENV, even with IgG titers <0.1 OD absorbance. Our findings suggest that sera of patients with SLE contain IgG, and possibly other type of antibodies, that can cross‐neutralize DENV, which may explain the rarity of severe dengue in individuals with SLE. Further studies, are needed to further substantiate this finding and to elucidate the specific neutralizing epitopes recognized by the sera of individuals with SLE. [ABSTRACT FROM AUTHOR]

The article provides information on a study which observed the link between different blood count parameters at baseline with response and progression-free survival (PFS) in relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL) patients treated with the anti-PD1 antibody, nivolumab. Topics discussed include role of eosinophils as co-effectors of the immune response, and results of the study.

With immunochemotherapy, remission duration and survival in patients with chronic lymphocytic leukaemia is dependent on the level of minimal residual disease ( MRD) after treatment. This phase II trial assessed alemtuzumab consolidation post-chemotherapy in patients who responded with persistent low levels of detectable disease. Blood was screened for MRD using multi-parameter flow cytometry, 6-24 months post-chemotherapy. MRD-positive participants received alemtuzumab 30 mg subcutaneously 3 times weekly for 6 weeks. Following a marrow assessment, MRD-negative participants or non-responders stopped therapy and MRD-positive participants with 1 + log reduction had 6 more weeks of alemtuzumab. Alemtuzumab consolidation was received by 47 participants. One death and 19 of 22 serious adverse events reported from 17 (36%) participants were alemtuzumab-related. MRD eradication from blood and bone marrow was achieved in 39 (83%) participants at the end of consolidation, with 18 (38%) remaining MRD-negative in the blood 6 months later. Of the 18 participants who were MRD-negative at 6 months, the median time to MRD relapse was 46 months, which was similar to patients who were MRD-negative at baseline and were followed up. The 5-year progression-free survival ( PFS) and overall survival ( OS) of participants who were MRD-negative at 6 months was significantly better than MRD-positive participants [ PFS: 78% vs. 39% ( P = 0·010), OS: 89% vs. 64% ( P = 0·029)]. [ABSTRACT FROM AUTHOR]

The role of antibodies in HIV-1 infection is investigated using a discrete-time mathematical model that considers cell-free and cell-associated transmission of the virus. Model analysis shows that the effect of each type of antibody is dependent on the stage of the infection. Neutralizing antibodies are efficient in controlling the viral levels in the early days after seroconversion and antibodies that coat HIV-1- infected cells and recruit effector cells to either kill the HIV-1-infected cells or inhibit viral replication are efficient when the infection becomes established. Model simulations show that antibodies that inhibit viral replication are more effective in controlling the infection than those that recruit Natural Killer T cells after infection establishment. The model was fitted to subjects of the Tsedimoso study conducted in Botswana and conclusions similar to elasticity analysis results were obtained. Model fitting results predicted that neutralizing antibodies are more efficient in controlling the viral levels than antibodies that coat HIV-1-infected cells and recruit effector cells to either kill the HIV-1-infected cells or inhibit viral replication in the early days after seroconversion. [ABSTRACT FROM AUTHOR]

Lectin-like oxidized low-density lipoprotein receptor-1 (SR-E1, LOX-1, OLR1) was first discovered as a vascular receptor for modified lipoprotein particles nearly 20 years ago. Since then, in vitro and in vivo studies have demonstrated an association between LOX-1, a soluble form (sLOX-1) and a number of diseases including atherosclerosis, arthritis, hypertension and pre-eclampsia. However, converting such discoveries into tools and drugs for routine clinical use is dependent on translational preclinical and clinical studies but such studies have only begun to emerge in the past decade. In this review, we identify the key clinical applications and corresponding criteria that need to be addressed for the effective use of LOX-1-related probes and molecules for patient benefit in different disease states. [ABSTRACT FROM AUTHOR]

CD8+ T cells are important for immunity against human cytomegalovirus (HCMV). The HCMV-specific CD8+ T-cell response is characterized by the accumulation of terminally differentiated effector cells that have downregulated the costimulatory molecules CD27 and CD28. These HCMV-specific CD8+ T cells maintain high levels of cytotoxic molecules such as granzyme B and rapidly produce the inflammatory cytokine IFN-γ upon activation. Remarkably, HCMV-specific CD8+ T cells are able to persist long term as fully functional effector cells, suggesting a unique differentiation pathway that is distinct from the formation of memory CD8+ T cells after infection with acute viruses. In this review, we aim to highlight the most recent developments in HCMV-specific CD8+ T-cell differentiation, maintenance, tissue distribution, metabolism and function. HCMV also induces the differentiation of effector CD4+ T cells and NK cells, which share characteristics with HCMV-specific CD8+ T cells. We propose that the overlap in differentiation of NK cells, CD4+ and CD8+ T cells after HCMV infection may be regulated by a shared transcriptional machinery. A better understanding of the molecular framework of HCMV-specific CD8+ T-cell responses may benefit vaccine design, as these cells uniquely combine the capacity to rapidly respond to infection with long-term survival. [ABSTRACT FROM AUTHOR]

Multi-HIV, a multiepitopic protein derived from both gp120 and gp41 envelope proteins of the human immunodeficiency virus (HIV), has been proposed as a vaccine prototype capable of inducing broad immune responses, as it carries various B and T cell epitopes from several HIV strains. In this study, the immunogenic properties of a Multi-HIV expressed in tobacco chloroplasts are evaluated in test mice. BALB/c mice orally immunized with tobacco-derived Multi-HIV have elicited antibody responses, including both the V3 loop of gp120 and the ELDKWA epitope of gp41. Based on splenocyte proliferation assays, stimulation with epitopes of the C4, V3 domain of gp120, and the ELDKWA domain of gp41 elicits positive cellular responses. Furthermore, specific interferon gamma production is observed in both CD4+ and CD8+ T cells stimulated with HIV peptides. These results demonstrate that plant-derived Multi-HIV induces T helper-specific responses. Altogether, these findings illustrate the immunogenic potential of plant-derived Multi-HIV in an oral immunization scheme. The potential of this low-cost immunization approach and its implications on HIV/AIDS vaccine development are discussed. [ABSTRACT FROM AUTHOR]

An abstract of the article "Low Immune Activation in the Ectocervix of HIV-exposed Seronegative Commercial Sex Workers" by Kristina Broliden and colleagues is presented.

Although pretransplant alemtuzumab can reduce GVHD following allogeneic transplantation, it may also increase the risk of mixed donor T-cell chimerism and infections. We hypothesized that the early use of DLI without withdrawal of immunosuppressive drugs in patients with mixed T-cell chimerism would lower the risk of relapse without significantly increasing the risk of GVHD post DLI. Thirty-six patients (median age 59 years) were treated in this phase II trial using reduced-intensity conditioning including s.c. alemtuzumab (total dose 43 mg) and a PBSC graft from a matched unrelated donor (UD). DLI without withdrawal of immunosuppressive drugs was administered to all 25 patients with <50% donor T-cell chimerism on day +60. The cumulative risks of acute and chronic GVHD were 42% and 59%, respectively. Estimated probabilities of non-relapse mortality (NRM) at day 100 and 1 year were 3% and 14%, respectively. With a median follow up 2.4 years, estimated survivals at day 100, 1 and 2 years were 97%, 71% and 57%, respectively. In multivariate analysis, the occurrence of acute GVHD was associated with an increased risk of mortality, whereas the occurrence of chronic GVHD had a protective effect, associated with decreased relapse and improved disease-free survival. Low-dose alemtuzumab and preemptive DLI provides favorable transplant outcomes including low NRM in an older patient population with high-risk malignancies undergoing UD transplantation. [ABSTRACT FROM AUTHOR]

As front line therapy has improved, the treatment of relapsed chronic lymphocytic leukaemia has become more difficult as the disease becomes resistant and the patient accumulates comorbidities. The outcome for those who relapse after immunochemotherapy with fludarabine, cyclophosphamide and rituximab is strongly influenced by the duration of initial response. Patients who relapse within the first year or with a TP53 abnormality have very high-risk disease and will not respond to chemotherapy. High dose glucocorticoid and ale-mtuzumab followed by an allogeneic stem cell transplant is probably the best approach for younger, fitter patients in this category. Those who relapse after 2-3 years without TP53 abnormality will probably respond to their initial therapy again. Relapse within 12-24 months carries an intermediate outlook. Additional options include bendamustine and ritux-imab, of at umumab and lenalidomide. New therapies are on the horizon and patients should be discussed with a specialist centre and entered into a clinical trial whenever possible. [ABSTRACT FROM AUTHOR]