Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation.

Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers

Polycationic Glycosides

Cationic lipids have long been known to serve as antibacterial and antifungal agents. Prior efforts with attachment of cationic lipids to carbohydrate-based surfaces have suggested the possibility that carbohydrate-attached cationic lipids might serve as antibacterial and antifungal pharmaceutical agents. Toward the understanding of this possibility, we have synthesized several series of cationic lipids attached to a variety of glycosides with the intent of generating antimicrobial agents that would meet the requirement for serving as a pharmaceutical agent, specifically that the agent be effective at a very low concentration as well as being biodegradable within the organism being treated. The initial results of our approach to this goal are presented

Evolving case of emphysematous pyelonephritis in a second renal allograft

Emphysematous pyelonephritis is an acute necrotizing infection with gas in the kidney that portends a poor prognosis. Patients present with sepsis, requiring fluid resuscitation, glucose control, and broad-spectrum antibiotics. Surgical intervention ranges from relief of urinary obstruction (nephrostomy tube or stent), percutaneous drainage or nephrectomy. We present a 51-year-old second kidney transplant recipient diabetic male, suffering from sepsis of unknown etiology which was subsequently revealed to be due to emphysematous pyelonephritis. Percutaneous drainage was performed initially followed by renal transplant nephrectomy after no improvement of his clinical status. Herein, we describe the clinical course and escalation in management

Small Capsid Protein pORF65 Is Essential for Assembly of Kaposi's Sarcoma-Associated Herpesvirus Capsids▿

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent for KS tumors, multicentric Castleman's disease, and primary effusion lymphomas. Like other herpesvirus capsids, the KSHV capsid is an icosahedral structure composed of six proteins. The capsid shell is made up of the major capsid protein, two triplex proteins, and the small capsid protein. The scaffold protein and the protease occupy the internal space. The assembly of KSHV capsids is thought to occur in a manner similar to that determined for herpes simplex virus type 1 (HSV-1). Our goal was to assemble KSHV capsids in insect cells using the baculovirus expression vector system. Six KSHV capsid open reading frames were cloned and the proteins expressed in Sf9 cells: pORF25 (major capsid protein), pORF62 (triplex 1), pORF26 (triplex 2), pORF17 (protease), pORF17.5 (scaffold protein), and also pORF65 (small capsid protein). When insect cells were coinfected with these baculoviruses, angular capsids that contained internal core structures were readily observed by conventional electron microscopy of the infected cells. Capsids were also readily isolated from infected cells by using rate velocity sedimentation. With immuno-electron microscopy methods, these capsids were seen to be reactive to antisera to pORF65 as well as to KSHV-positive human sera, indicating the correct conformation of pORF65 in these capsids. When either virus expressing the triplex proteins was omitted from the coinfection, capsids did not assemble; similar to observations made in HSV-1-infected cells. If the virus expressing the scaffold protein was excluded, large open shells that did not attain icosahedral structure were seen in the nuclei of infected cells. The presence of pORF65 was required for capsid assembly, in that capsids did not form if this protein was absent as judged by both by ultrastructural analysis of infected cells and rate velocity sedimentation experiments. Thus, a novel outcome of this study is the finding that the small capsid protein of KSHV, like the major capsid and triplex proteins, is essential for capsid shell assembly

Socioeconomic constraints to effective management of Burkitt's lymphoma in south-eastern Nigeria

This paper presents health outcomes and associated socioeconomic factors of 41 children admitted to a tertiary care institution in south-east Nigeria with Burkitt's lymphoma (BL) between 1987 and 2004. BL responds well to chemotherapy and does not pose a significant threat to health in industrialized nations. However, in resource-poor settings where it is endemic, socioeconomic factors significantly affect access to care for affected children, making this readily treatable condition a cause of considerable distress and early death in affected children. Half of the children reported in this paper presented with late stage disease. Although laboratory facilities were available, they were not accessible to all the children. Nearly a quarter of parents of these children could not afford the cost of confirmatory tests, and about a fifth (n = 8; 19.5%) of the children received no chemotherapy because of their parents' inability to pay. Only 21 of 41 children (51.2%) remained on treatment long enough (at least 12 weeks) to enable them to be confirmed either as short-term cure (n = 9; 64.3%), or as early relapse (n = 2; 4.9%). Owing to financial constraint, 13 of the parents (31.7%) withdrew their children against medical advice (n = 7; 17.1%) or left the hospital (n = 6; 14.6%). To address the challenge posed by these factors, we call for the establishment of a regional BL programme in Africa to help establish a critical mass of resources (human and material) to facilitate the development of an effective and accessible control programme in the region

Predictive Value of Cytokines and Immune Activation Biomarkers in AIDS-Related Non-Hodgkin Lymphoma Treated with Rituximab plus Infusional EPOCH (AMC-034 trial).

PurposeThe aims of this study were to determine whether pretreatment plasma levels of cytokines and immune activation-associated molecules changed following treatment for AIDS-NHL with rituximab plus infusional EPOCH, and to determine whether pretreatment levels of these molecules were associated with response to treatment and/or survival.Experimental designWe quantified plasma levels of B-cell activation-associated molecules (sCD27, sCD30, and sCD23) and cytokines (IL6, IL10, and CXCL13) before and after the initiation of treatment in persons with AIDS-NHL (n = 69) in the AIDS Malignancies Consortium (AMC) 034 study, which evaluated treatment of AIDS-NHL with EPOCH chemotherapy and rituximab.ResultsTreatment resulted in decreased plasma levels of some of these molecules (CXCL13, sCD27, and sCD30), with decreased levels persisting for one year following the completion of treatment. Lower levels of CXCL13 before treatment were associated with complete responses following lymphoma therapy. Elevated levels of IL6 pretreatment were associated with decreased overall survival, whereas higher IL10 levels were associated with shorter progression-free survival (PFS), in multivariate analyses. Furthermore, patients with CXCL13 or IL6 levels higher than the median levels for the NHL group, as well as those who had detectable IL10, had lower overall survival and PFS, in Kaplan-Meier analyses.ConclusionsThese results indicate that CXCL13, IL6, and IL10 have significant potential as prognostic biomarkers for AIDS-NHL