A Plausible Prebiotic One-Pot Synthesis of Orotate and Pyruvate Suggestive of Common Protometabolic Pathways.

A reaction between two prebiotically plausible building blocks, hydantoin and glyoxylate, generates both the nucleobase orotate, a precursor of biological pyrimidines, and pyruvate, a core metabolite in the citric acid cycle and amino acid biosynthesis. The reaction proceeds in water to provide significant yields of the two widely divergent chemical motifs. Additionally, the reaction of thiohydantoin and glyoxylate produces thioorotate in high yield under neutral aqueous conditions. The use of an open-chain thiohydantoin derivative also enables the potential pre-positioning of a nucleosidic bond prior to the synthesis of an orotate nucleoside. The observation that diverse building blocks of modern metabolism can be produced in a single reaction pot, from common reactants under mild conditions, supports the plausibility of orthogonal chemistries operating at the origins of chemical evolution.

Phase II trial of single-agent panobinostat consolidation improves responses after sub-optimal transplant outcomes in multiple myeloma.

Panobinostat is a pan-deacetylase inhibitor that modulates the expression of oncogenic and immune-mediating genes involved in tumour cell growth and survival. We evaluated panobinostat-induced post-transplant responses and identified correlative biomarkers in patients with multiple myeloma who had failed to achieve a complete response after autologous transplantation. Patients received panobinostat 45 mg administered three-times weekly (TIW) on alternate weeks of 28-day cycles commencing 8-12 weeks post-transplant. Twelve of 25 patients (48%) improved their depth of response after a median (range) of 4·3 (1·9-9·7) months of panobinostat. In responders, T-lymphocyte histone acetylation increased after both three cycles (P < 0·05) and six cycles (P < 0·01) of panobinostat when compared to baseline, with no differences in non-responders. The reduction in the proportion of CD127+ CD8+ T cells and CD4:CD8 ratio was significantly greater, after three and six cycles of panobinostat compared to pre-transplant, in non-responders when compared to responders. Whole marrow RNA-seq revealed widespread transcriptional changes only in responders with baseline differences in genes involved in ribosome biogenesis, oxidative phosphorylation and metabolic pathways. This study confirmed the efficacy of panobinostat as a single agent in multiple myeloma and established acetylation of lymphocyte histones, modulation of immune subsets and transcriptional changes as pharmacodynamic biomarkers of clinical benefit.

Impact of age-, cancer-, and treatment-driven inflammation on T cell function and immunotherapy.

Many cancers are predominantly diagnosed in older individuals and chronic inflammation has a major impact on the overall health and immune function of older cancer patients. Chronic inflammation is a feature of aging, it can accelerate disease in many cancers and it is often exacerbated during conventional treatments for cancer. This review will provide an overview of the factors that lead to increased inflammation in older individuals and/or individuals with cancer, as well as those that result from conventional treatments for cancer, using ovarian cancer (OC) and multiple myeloma (MM) as key examples. We will also consider the impact of chronic inflammation on immune function, with a particular focus on T cells as they are key targets for novel cancer immunotherapies. Overall, this review aims to highlight specific pathways for potential interventions that may be able to mitigate the impact of chronic inflammation in older cancer patients.

Immunotherapeutics in Multiple Myeloma: How Can Translational Mouse Models Help?

Multiple myeloma (MM) is usually diagnosed in older adults at the time of immunosenescence, a collection of age-related changes in the immune system that contribute to increased susceptibility to infection and cancer. The MM tumor microenvironment and cumulative chemotherapies also add to defects in immunity over the course of disease. In this review we discuss how mouse models have furthered our understanding of the immune defects caused by MM and enabled immunotherapeutics to progress to clinical trials, but also question the validity of using immunodeficient models for these purposes. Immunocompetent models, in particular the 5T series and Vk⁎MYC models, are increasingly being utilized in preclinical studies and are adding to our knowledge of not only the adaptive immune system but also how the innate system might be enhanced in anti-MM activity. Finally we discuss the concept of immune profiling to target patients who might benefit the most from immunotherapeutics, and the use of humanized mice and 3D culture systems for personalized medicine.

Spontaneous onset and transplant models of the Vk*MYC mouse show immunological sequelae comparable to human multiple myeloma.

BACKGROUND: The Vk*MYC transgenic and transplant mouse models of multiple myeloma (MM) are well established as a research tool for anti-myeloma drug discovery. However, little is known of the immune response in these models. Understanding the immunological relevance of these models is of increasing importance as immunotherapeutic drugs are developed against MM. METHODS: We set out to examine how cellular immunity is affected in Vk*MYC mouse models and compare that to the immunology of patients with newly diagnosed and relapsed/refractory MM. RESULTS: We found that there were significant immunological responses in mice developing either spontaneous (transgenic) or transplanted MM as a consequence of the degree of tumor burden. Particularly striking were the profound B cell lymphopenia and the expansion of CD8(+) effector memory T cells within the lymphocyte population that progressively developed with advancing disease burden, mirroring changes seen in human MM. High disease burden was also associated with increased inflammatory cytokine production by T lymphocytes, which is more fitting with relapsed/refractory MM in humans. CONCLUSIONS: These findings have important implications for the application of this mouse model in the development of MM immunotherapies. Trial registration LitVacc ANZCTR trial ID ACTRN12613000344796; RevLite ANZCTR trial ID NCT00482261.

Fertility in premenopausal women post autologous stem cell transplant with BEAM conditioning.

There is currently minimal data on fertility outcomes in premenopausal women undergoing autologous stem cell transplant (ASCT) with carmustine, etoposide, cytarabine and melphalan (BEAM) conditioning. A retrospective analysis of fertility outcomes in premenopausal females aged between 18 and 40 yr who underwent BEAM/ASCT for lymphoma between 1995 and 2011 was performed at four transplant centres. Of 41 premenopausal women who underwent BEAM conditioning, 25 met the inclusion criteria with the main exclusion criterion being inadequate documentation. Eighteen had Hodgkin lymphoma, and seven had non-Hodgkin lymphoma. Median number of chemotherapy regimens pretransplant was 2 (1-3). Seventeen women (68%) with a median age at transplant of 25 yr (range 17-33) recovered their menses. The comparative group without recovery was older with a median age of 34 yr (range 20-40) (P = 0.007). Ten patients, with a median age at transplant of 22 yr (range 17-30), had 15 naturally conceived pregnancies. Chemotherapy regimens and lymphoma type did not obviously influence the incidence of menses recovery or conception. The incidence of recovery of menses and fertility in premenopausal women undergoing BEAM/ASCT for lymphoma is substantial. Younger age at transplant correlates with superior fertility outcomes.

PTRAMP; a conserved Plasmodium thrombospondin-related apical merozoite protein.

A gene encoding a 352 amino acid protein with a putative signal sequence, transmembrane domain and thrombospondin structural homology repeat was identified in the genome of the human malaria parasite, Plasmodium falciparum and the rodent malaria parasite, Plasmodium berghei. The protein localises in the apical organelles of P. falciparum and P. berghei merozoites within intraerythrocytic schizonts and has, therefore, been termed the Plasmodium thrombospondin-related apical merozoite protein (PTRAMP). PTRAMP co-localises with the Apical Merozoite Antigen-1 (AMA-1) in developing micronemes and subsequently relocates onto the merozoite surface. Although the gene appears to be specific to the Plasmodium genus, orthologues are present in the genomes of all malaria parasite species examined suggesting a conserved function in host-cell invasion. PTRAMP, therefore, has all the features to merit further evaluation as a malaria vaccine candidate.