Lactose drives Enterococcus expansion to promote graft-versus-host disease.

Disruption of intestinal microbial communities appears to underlie many human illnesses, but the mechanisms that promote this dysbiosis and its adverse consequences are poorly understood. In patients who received allogeneic hematopoietic cell transplantation (allo-HCT), we describe a high incidence of enterococcal expansion, which was associated with graft-versus-host disease (GVHD) and mortality. We found that Enterococcus also expands in the mouse gastrointestinal tract after allo-HCT and exacerbates disease severity in gnotobiotic models. Enterococcus growth is dependent on the disaccharide lactose, and dietary lactose depletion attenuates Enterococcus outgrowth and reduces the severity of GVHD in mice. Allo-HCT patients carrying lactose-nonabsorber genotypes showed compromised clearance of postantibiotic Enterococcus domination. We report lactose as a common nutrient that drives expansion of a commensal bacterium that exacerbates an intestinal and systemic inflammatory disease.

Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial.

INTRODUCTION: The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I-III BC. MATERIALS AND METHODS: Two doses of weekly oral MK2206 were administered at days - 9 and - 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls. RESULTS: Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06). CONCLUSION: While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.

Postmortem evaluation of 435 cases of intracranial neoplasia in dogs and relationship of neoplasm with breed, age, and body weight.

BACKGROUND: Intracranial neoplasia of dogs is frequently encountered in veterinary medicine, but large-scale studies on prevalence are lacking. OBJECTIVES: To determine the prevalence of intracranial neoplasia in a large population of dogs examined postmortem and the relationship between breed, age, and weight with the presence of primary intracranial neoplasms. ANIMALS: All dogs that underwent postmortem examination from 1986 through 2010 (n = 9,574), including dogs with a histopathologic diagnosis of primary (n = 227) and secondary (n = 208) intracranial neoplasia. METHODS: Retrospective evaluation of medical records from 1986 through 2010. RESULTS: Overall prevalence of intracranial neoplasia in this study's population of dogs was 4.5%. A statistically significant higher prevalence of primary intracranial neoplasms was found in dogs with increasing age and body weights. Dogs ≥15 kg had an increased risk of meningioma (odds ratio 2.3) when compared to dogs <15 kg. The Boxer, Boston Terrier, Golden Retriever, French Bulldog, and Rat Terrier had a significantly increased risk of primary intracranial neoplasms while the Cocker Spaniel and Doberman Pinscher showed a significantly decreased risk of primary intracranial neoplasms. CONCLUSIONS AND CLINICAL IMPORTANCE: Intracranial neoplasia in dogs might be more common than previous estimates. The study suggests that primary intracranial neoplasia should be a strong differential in older and larger breed dogs presenting with signs of nontraumatic intracranial disease. Specific breeds have been identified with an increased risk, and others with a decreased risk of primary intracranial neoplasms. The results warrant future investigations into the role of age, size, genetics, and breed on the development of intracranial neoplasms.

Identification of additional IDH mutations associated with oncometabolite R(-)-2-hydroxyglutarate production.

Mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) or its mitochondrial homolog IDH2 can lead to R(-)-2-hydroxyglutarate (2HG) production. To date, mutations in three active site arginine residues, IDH1 R132, IDH2 R172 and IDH2 R140, have been shown to result in the neomorphic production of 2HG. Here we report on three additional 2HG-producing IDH1 mutations: IDH1 R100, which is affected in adult glioma, IDH1 G97, which is mutated in colon cancer cell lines and pediatric glioblastoma, and IDH1 Y139. All these new mutants stereospecifically produced 2HG's (R) enantiomer. In contrast, we find that the IDH1 SNPs V71I and V178I, as well as a number of other single-sample reports of IDH non-synonymous mutation, did not elevate cellular 2HG levels in cells and retained the wild-type ability for isocitrate-dependent NADPH production. Finally, we report the existence of additional rare, but recurring mutations found in lymphoma and thyroid cancer, which while failing to elevate 2HG nonetheless displayed loss of function, indicating a possible tumorigenic mechanism for a non-2HG-producing subset of IDH mutations in some malignancies. These data broaden our understanding of how IDH mutations may contribute to cancer through either neomorphic R(-)-2HG production or reduced wild-type enzymatic activity, and highlight the potential value of metabolite screening in identifying IDH-mutated tumors associated with elevated oncometabolite levels.

Viral pro-survival proteins block separate stages in Bax activation but changes in mitochondrial ultrastructure still occur.

Mitochondrial dysfunction mediated by Bax and Bak is a critical step in mammalian cell apoptosis. However, the molecular mechanism of Bax activation remains unknown and has been difficult to investigate due to its rapid and stochastic nature. It is currently unclear whether mitochondria play a passive role in the initiation of apoptosis, remaining unaffected by cell stresses until Bax and Bak are active, or whether they actively participate in Bax/Bak activation. Here, two viral proteins, E1B19K and BHRF1, are examined for their ability to block Bax activation at different steps and thereby reveal the timing of mitochondrial changes during apoptosis. We demonstrate that BHRF1 strongly inhibits Bax activation but not upstream apoptotic signaling events, while E1B19K permits initial stages of Bax activation but prevents the subsequent oligomerization of Bax that is required for mitochondrial dysfunction. In this defined system we show that changes in mitochondrial ultrastructure, characteristic of cells undergoing apoptosis, precede Bax activation and are not blocked by E1B19K and BHRF1. We suggest that the ability of mitochondria to respond to apoptotic stress prior to Bax activation indicates that these organelles may play a direct role in activating Bax.

Interaction of F1L with the BH3 domain of Bak is responsible for inhibiting vaccinia-induced apoptosis.

Apoptosis represents an important cellular defence mechanism against viral pathogens by virtue of its ability to remove infected cells. Consequently, many viruses have developed numerous strategies to prevent or delay host cell apoptosis in order to achieve productive replication. Here we report that deletion of the F1L gene from the vaccinia genome results in increased apoptosis during infection. We demonstrate that F1L, which has no sequence homology to Bcl-2 family members, inhibits apoptosis at the level of mitochondria by binding to Bak. As a consequence, F1L prevents Bak activation, oligomerization and interaction with active Bax, all critical steps in the induction of apoptosis. We demonstrate that residues 64-84 of F1L interact directly with the Bcl-2 homology domain 3 (BH3) domain of Bak. This region of F1L has limited sequence similarity to known Bak-interacting BH3 domains. We also find that such additional BH3-like domains exist in the vaccinia genome. We conclude that F1L uses this specific, BH3-like domain to bind and inhibit Bak at the mitochondria.

The infection connection. Rules & regs.

Gone are the days of ED personnel telling EMTs/paramedics to "wipe some disinfectant" on an abrasion that's been exposed to the hepatitis-B virus.

Spirituality: integral to quality care.

Caring is the medium through which nursing knowledge, skill, and touch are operationalized. Caring is a profound act of hope (White T. 1986. Unpublished data) that contributes to the spiritual well-being of others. In order to assure quality care, the impact of identifying and meeting patient spiritual needs must be taken into account.