Endogenous TAP-independent MHC-I antigen presentation: not just the ER lumen.

Altered and infected cells are eliminated by CD8 cytotoxic T lymphocytes. This requires production of antigenic peptides mostly in the cytosol, transport to the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP), and cell surface presentation by major histocompatibility complex class I (MHC-I). Strikingly, antigen presentation occurs without TAP, although it is inefficient and associated to human pathology.

Mitophagy Failure in Fibroblasts and iPSC-Derived Neurons of Alzheimer's Disease-Associated Presenilin 1 Mutation.

Familial Alzheimer's disease (FAD) is clearly related with the accumulation of amyloid-beta (Aβ) and its deleterious effect on mitochondrial function is well established. Anomalies in autophagy have also been described in these patients. In the present work, functional analyses have been performed to study mitochondrial recycling process in patient-derived fibroblasts and neurons from induced pluripotent stem cells harboring the presenilin 1 mutation A246E.

Novel potential predictive markers of sunitinib outcomes in long-term responders versus primary refractory patients with metastatic clear-cell renal cell carcinoma.

Background: Several potential predictive markers of efficacy of targeted agents in patients with metastatic renal cell carcinoma (mRCC) have been identified. Interindividual heterogeneity warrants further investigation.

Patients And Methods: Multicenter, observational, retrospective study in patients with clear-cell mRCC treated with sunitinib.

Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors.

MHC class I molecules display oligopeptides on the cell surface to enable T cell immunosurveillance of intracellular pathogens and tumors. Speed is of the essence in detecting viruses, which can complete a full replication cycle in just hours, whereas tumor detection is typically a finding-the-needle-in-the-haystack exercise. We review current evidence supporting a nonrandom, compartmentalized selection of peptidogenic substrates that focuses on rapidly degraded translation products as a main source of peptide precursors to optimize immunosurveillance of pathogens and tumors.

Are membrane proteins favored over cytosolic proteins in TAP-independent processing pathways?

Recognition of infected or altered cells by CD8(+) cytotoxic T lymphocytes is mediated by direct interaction of their T-cell receptor with peptides presented by MHC class I molecules. Peptides are transferred for assembly with newly synthesized MHC molecules by the transporters associated with antigen processing (TAP). Yet, a fraction of described epitopes are presented independently of TAP.

Accumulation of polyubiquitylated proteins in response to Ala-Ala-Phe-chloromethylketone is independent of the inhibition of Tripeptidyl peptidase II.

In the present study we have addressed the issue of proteasome independent cytosolic protein degradation. Tripeptidyl peptidase II (TPPII) has been suggested to compensate for a reduced proteasome activity, partly based on evidence using the inhibitor Ala-Ala-Phe-chloromethylketone (AAF-cmk). Here we show that AAF-cmk induces the formation of polyubiquitin-containing accumulations in osteosarcoma and Burkitt's lymphoma cell lines.

Inhibition of the ubiquitin-proteasome system prevents vaccinia virus DNA replication and expression of intermediate and late genes.

The ubiquitin-proteasome system has a central role in the degradation of intracellular proteins and regulates a variety of functions. Viruses belonging to several different families utilize or modulate the system for their advantage. Here we showed that the proteasome inhibitors MG132 and epoxomicin blocked a postentry step in vaccinia virus (VACV) replication.

Is there an alternative to the proteasome in cytosolic protein degradation?

While it is clear that the proteasome is the major player in degradative proteolysis in the nucleus and cytosol, there is a lack of complete agreement on whether there are alternative proteolytic pathways or activities responsible for a significant degradation of cytosolic/nuclear substrates. Particularly relevant is the case of the aminopeptidase TPPII (tripeptidyl peptidase II), which has been suggested to be able to perform some of the proteasome functions. However, the current evidence seems to support only a limited role for these cytosolic alternatives.

Gemcitabine plus docetaxel as first-line chemotherapy in patients with advanced non-small cell lung cancer: a lung cancer Galician group phase II study.

Background: Numerous phase II and III clinical trials have demonstrated a higher activity of combined gemcitabine plus docetaxel schedules against non-small cell lung cancer (NSCLC) than that of both agents in monotherapy.

Methods: This phase II study evaluated a 3-week based schedule of docetaxel 85 mg/m(2) (1-h i.v.

Need for tripeptidyl-peptidase II in major histocompatibility complex class I viral antigen processing when proteasomes are detrimental.

CD8(+) T lymphocytes recognize infected cells that display virus-derived antigenic peptides complexed with major histocompatibility complex class I molecules. Peptides are mainly byproducts of cellular protein turnover by cytosolic proteasomes. Cytosolic tripeptidyl-peptidase II (TPPII) also participates in protein degradation.

Serous cystadenoma of the pancreas in a child.

Pancreatic tumors are very rare in children. Until now, approximately 150 cases have been reported in the English-language medical literature. Only 4 of them represented serous cystadenoma.