Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydroxychloroquine (HCQ) enhances the anti-cancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in pre-clinical models and early phase clinical studies of metastatic colorectal cancer (mCRC). Mechanisms could include autophagy inhibition, accumulation of ubiquitinated proteins, and subsequent tumor cell apoptosis. There is growing evidence that autophagy inhibition could lead to improved anti-cancer immunity. To date, effects of autophagy on immunity have not been reported in cancer patients. To address this, we expanded an ongoing clinical study to include patients with advanced, refractory mCRC to evaluate further the clinical efficacy and immune effects of VOR plus HCQ. Refractory mCRC patients received VOR 400 milligrams orally with HCQ 600 milligrams orally daily, in a 3-week cycle. The primary endpoint was median progression-free survival (mPFS). Secondary endpoints include median overall survival (mOS), adverse events (AE), pharmacodynamic of inhibition of autophagy in primary tumors, immune cell analyses, and cytokine levels. Twenty patients were enrolled (19 evaluable for survival) with a mPFS of 2.8 months and mOS of 6.7 months. Treatment-related grade 3-4 AEs occurred in 8 patients (40%), with fatigue, nausea/vomiting, and anemia being the most common. Treatment significantly reduced CD4+CD25hiFoxp3+ regulatory and PD-1+ (exhausted) CD4+ and CD8+ T cells and decreased CD45RO-CD62L+ (naive) T cells, consistent with improved anti-tumor immunity. On-study tumor biopsies showed increases in lysosomal protease cathepsin D and p62 accumulation, consistent with autophagy inhibition. Taken together, VOR plus HCQ is active, safe and well tolerated in refractory CRC patients, resulting in potentially improved anti-tumor immunity and inhibition of autophagy.
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PMID:Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer. 2746 16

Porcine deltacoronavirus (PDCoV) causes severe diarrhea and vomiting in affected piglets. The aim of this study was to establish the basic, in vitro characteristics of the life cycle such as replication kinetics, cellular ultrastructure, virion morphology, and induction of autophagy of PDCoV. Time-course analysis of viral subgenomic and genomic RNA loads and infectious titers indicated that one replication cycle of PDCoV takes 5 to 6 h. Electron microscopy showed that PDCoV infection induced the membrane rearrangements with double-membrane vesicles and large virion-containing vacuoles. The convoluted membranes structures described in alpha- and beta-coronavirus were not observed. PDCoV infection also increased the number of autophagosome-like vesicles in the cytoplasm of cells, and the autophagy response was detected by LC3 I/II and p62 Western blot analysis. For the first time, this study presents the picture of the PDCoV infection cycle, which is crucial to help elucidate the molecular mechanism of deltacoronavirus replication.
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PMID:Characteristics of the Life Cycle of Porcine Deltacoronavirus (PDCoV) In Vitro: Replication Kinetics, Cellular Ultrastructure and Virion Morphology, and Evidence of Inducing Autophagy. 3110 68

Neuronal intranuclear inclusion disease (NIID) is a rare, neurodegenerative disorder characterized by the presence of eosinophilic hyaline intranuclear inclusions, which are ubiquitin-positive and p62-positive, in neuronal and somatic cells; this can be observed on skin biopsy. Although patients with NIID present with a variety of symptoms that often make the diagnosis difficult, characteristic high-signal intensity of the corticomedullary junction on diffusion-weighted imaging (DWI) often provides a clue to the diagnosis of NIID. We present a case of NIID in a 57-year-old woman who only had recurrent vomiting for four years, which is uncommon as the presenting symptom; moreover, DWI showed no apparent abnormality until a slightly abnormal intensity lesion appeared at the right frontal corticomedullary junction seven years after the first episode of recurrent vomiting. Skin biopsies revealed multiple p62-positive nuclear inclusions, and genetic test showed GGC repeat expansion in NOTCH2NLC; this may form the genetic basis for NIID. Retrospectively, we found that abnormal cerebellar signals besides the vermis in the fluid attenuation inversion recovery (FLAIR) images were detected early-on in the disease. Periodic vomiting may be the only symptom of NIID in the early stages of the disease, and cerebellar abnormalities in FLAIR may serve as an important finding in the diagnosis of NIID, even in the absence of characteristic clinical symptoms or abnormal DWI signals at the cerebral corticomedullary junction.
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PMID:A case of neuronal intranuclear inclusion disease with recurrent vomiting and without apparent DWI abnormality for the first seven years. 3281 96