Opinion statement
Adenoid cystic carcinoma (ACC) is a heterogeneous cancer that commonly develops in the salivary glands. Approximately 40 to 50% of patients with ACC develop recurrence and/or ...metastasis. Although most patients with ACC have slow-growing disease, a subset experiences aggressive disease with early visceral and/or bone metastasis. Thus far, there is no consensus on the best time to start palliative treatment in patients with indolent disease. The only systemic therapies available for recurrent or metastatic ACC are cytotoxic agents and multikinase inhibitors targeting vascular endothelial growth factor receptor, and both types of therapy have modest activity. Studies integrating proteomics, genomics, and clinical data have revealed distinct molecular ACC subtypes, ACC-I and ACC-II, with ACC-I generally associated with more aggressive disease biology. ACC-I tumors were enriched for
NOTCH1
-activating mutation and upregulation of MYC and MYC targets, while ACC-II tumors exhibited upregulation of TP63 and receptor tyrosine kinases. These findings highlight the importance of patient selection for surveillance and targeted therapy development in ACC. In recent clinical trials of targeted therapy in ACC, patients are being selected according to tumor molecular profile (e.g., presence of
NOTCH
-activating mutations), which represents a major advance in the field. Ongoing collaborative research focusing on the development of novel therapeutic strategies for ACC patients based on disease biology will increase the drug armamentarium and improve survival outcomes for these patients in dire need.
Leber congenital amaurosis (LCA) is an inherited retinal dystrophy that causes childhood blindness. Photoreceptors are especially sensitive to an intronic mutation in the cilia-related gene CEP290, ...which causes missplicing and premature termination, but the basis of this sensitivity is unclear. Here, we generated differentiated photoreceptors in three-dimensional optic cups and retinal pigment epithelium (RPE) from iPSCs with this common CEP290 mutation to investigate disease mechanisms and evaluate candidate therapies. iPSCs differentiated normally into RPE and optic cups, despite abnormal CEP290 splicing and cilia defects. The highest levels of aberrant splicing and cilia defects were observed in optic cups, explaining the retinal-specific manifestation of this CEP290 mutation. Treating optic cups with an antisense morpholino effectively blocked aberrant splicing and restored expression of full-length CEP290, restoring normal cilia-based protein trafficking. These results provide a mechanistic understanding of the retina-specific phenotypes in CEP290 LCA patients and potential strategies for therapeutic intervention.
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•Generation of 3D optic cups with opsin-expressing photoreceptors and outer segments•A CEP290-LCA intronic mutation creates a cryptic exon that impairs ciliogenesis•Aberrant splicing is increased in photoreceptors compared to other cell types•Antisense oligonucleotide can block the cryptic exon and restore CEP290 function
Parfitt et al. derived human 3D optic cup organoids to model LCA, a retinal dystrophy associated with aberrant CEP290 splicing leading to cilia defects. Retinal-specific defects result from higher aberrant CEP290 splicing in photoreceptors versus other cells, and treating cups with an antisense oligonucleotide restored CEP290 protein, function, and ciliation.
RP2 mutations cause a severe form of X-linked retinitis pigmentosa (XLRP). The mechanism of RP2-associated retinal degeneration in humans is unclear, and animal models of RP2 XLRP do not recapitulate ...this severe phenotype. Here, we developed gene-edited isogenic RP2 knockout (RP2 KO) induced pluripotent stem cells (iPSCs) and RP2 patient-derived iPSC to produce 3D retinal organoids as a human retinal disease model. Strikingly, the RP2 KO and RP2 patient-derived organoids showed a peak in rod photoreceptor cell death at day 150 (D150) with subsequent thinning of the organoid outer nuclear layer (ONL) by D180 of culture. Adeno-associated virus-mediated gene augmentation with human RP2 rescued the degeneration phenotype of the RP2 KO organoids, to prevent ONL thinning and restore rhodopsin expression. Notably, these data show that 3D retinal organoids can be used to model photoreceptor degeneration and test potential therapies to prevent photoreceptor cell death.
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•Isogenic RP2 knockouts match the phenotype of RP2 patient-derived organoids•Retinal organoids from RP2 nulls undergo rod photoreceptor cell death•Cell death correlates with rod photoreceptor differentiation•AAV gene therapy improved photoreceptor viability and increased rhodopsin expression
Cheetham and colleagues show that 3D retinal organoids lacking the RP2 protein develop rod photoreceptor degeneration that can be prevented with AAV gene augmentation for RP2.
Ciliary trafficking defects are the underlying cause of many ciliopathies, including Retinitis Pigmentosa (RP). Anterograde intraflagellar transport (IFT) is mediated by kinesin motor proteins; ...however, the function of the homodimeric Kif17 motor in cilia is poorly understood, whereas Kif7 is known to play an important role in stabilizing cilia tips. Here we identified the ciliary tip kinesins Kif7 and Kif17 as novel interaction partners of the small GTPase Arl3 and its regulatory GTPase activating protein (GAP) Retinitis Pigmentosa 2 (RP2). We show that Arl3 and RP2 mediate the localization of GFP-Kif17 to the cilia tip and competitive binding of RP2 and Arl3 with Kif17 complexes. RP2 and Arl3 also interact with another ciliary tip kinesin, Kif7, which is a conserved regulator of Hedgehog (Hh) signaling. siRNA-mediated loss of RP2 or Arl3 reduced the level of Kif7 at the cilia tip. This was further validated by reduced levels of Kif7 at cilia tips detected in fibroblasts and induced pluripotent stem cell (iPSC) 3D optic cups derived from a patient carrying an RP2 nonsense mutation c.519C > T (p.R120X), which lack detectable RP2 protein. Translational read-through inducing drugs (TRIDs), such as PTC124, were able to restore Kif7 levels at the ciliary tip of RP2 null cells. Collectively, our findings suggest that RP2 and Arl3 regulate the trafficking of specific kinesins to cilia tips and provide additional evidence that TRIDs could be clinically beneficial for patients with this retinal degeneration.
This review covers the 2003-2012 literature data published for natural products originating from marine red algae. The focus is on new antitumour substances, together with details related to the ...organism sourced. It emphasises 14 promising compounds (isolated from 13 species) whose chemical structures are briefly discussed.
Leber congenital amaurosis type 10 (LCA10) is a severe inherited retinal dystrophy associated with mutations in CEP290. The deep intronic c.2991+1655A>G mutation in CEP290 is the most common mutation ...in LCA10 individuals and represents an ideal target for oligonucleotide therapeutics. Here, a panel of antisense oligonucleotides was designed to correct the splicing defect associated with the mutation and screened for efficacy and safety. This identified QR-110 as the best-performing molecule. QR-110 restored wild-type CEP290 mRNA and protein expression levels in CEP290 c.2991+1655A>G homozygous and compound heterozygous LCA10 primary fibroblasts. Furthermore, in homozygous three-dimensional iPSC-derived retinal organoids, QR-110 showed a dose-dependent restoration of mRNA and protein function, as measured by percentage and length of photoreceptor cilia, without off-target effects. Localization studies in wild-type mice and rabbits showed that QR-110 readily reached all retinal layers, with an estimated half-life of 58 days. It was well tolerated following intravitreal injection in monkeys. In conclusion, the pharmacodynamic, pharmacokinetic, and safety properties make QR-110 a promising candidate for treating LCA10, and clinical development is currently ongoing.
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This review covers the 2003-2012 literature data published for antitumor natural products from marine-derived fungi. The focus is on new and highly potent cytotoxic compounds, together with details ...related to the relevant fungal species. It describes 22 promising bioactives, originating mainly from symbiotic fungi. The chemical structures of all highlighted organic molecules are briefly discussed.
Extraosseous Ewing’s sarcoma is extremely rare in the soft tissues of the neck, especially in the sternocleidomastoid muscle. It usually manifests clinically as a rapidly growing mass that shows ...great potential for local spread. The aim of this paper is to present a rare case of еxtraosseous Ewing’s sarcoma in the sternocleidomastoid muscle. To the best of our knowledge, this is the first case of extraskeletal Ewing’s sarcoma at this location. The patient was admitted to our clinic because of a neck tumefaction. The computerized tomography finding showed a tumor mass, most of which was in the V region of the neck, measuring 40 × 27 × 35 mm. Pathohistological and immunohistochemical findings showed that it was Ewing’s sarcoma. Unfortunately, the patient passed away nine months after the initial diagnosis. Extraosseous Ewing sarcoma is a rare, fast-growing malignant tumor manifesting histomorphological similarities to bone Ewing’s sarcoma. Most reports state that extraosseous Ewing sarcoma has a worse prognosis than skeletal. Extraosseous Ewing sarcoma should be borne in mind in the differential diagnosis of soft tissue tumors of the neck.
Cancer is a global burden due to high incidence and mortality rates and is ranked the second most diagnosed disease amongst non-communicable diseases in South Africa. A high expression level of the ...37kDa/67kDa laminin receptor (LRP/LR) is one characteristic of cancer cells. This receptor is implicated in the pathogenesis of cancer cells by supporting tumor angiogenesis, metastasis and especially for this study, the evasion of apoptosis. In the current study, the role of LRP/LR on cellular viability of breast MCF-7, MDA-MB 231 and WHCO1 oesophageal cancer cells was investigated. Western blot analysis revealed that total LRP expression levels of MCF-7, MDA-MB 231 and WHCO1 were significantly downregulated by targeting LRP mRNA using siRNA-LAMR1. This knockdown of LRP/LR resulted in a significant decrease of viability in the breast and oesophageal cancer cells as determined by an MTT assay. Transfection of MDA-MB 231 cells with esiRNA-RPSA directed against a different region of the LRP mRNA had similar effects on LRP/LR expression and cell viability compared to siRNA-LAMR1, excluding an off-target effect of siRNA-LAMR1. This reduction in cellular viability is as a consequence of apoptosis induction as indicated by the exposure of the phosphatidylserine protein on the surface of breast MCF-7, MDA-MB 231 and oesophageal WHCO1 cancer cells, respectively, detected by an Annexin-V/FITC assay as well as nuclear morphological changes observed post-staining with Hoechst. These observations indicate that LRP/LR is crucial for the maintenance of cellular viability of breast and oesophageal cancer cells and recommend siRNA technology targeting LRP expression as a possible novel alternative technique for breast and oesophageal cancer treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Three square-planar complexes of nickel(II) with the tridentate condensation derivative of 2-(diphenylphosphino)benzaldehyde and ethyl carbazate, and monodentate pseudohalides, have been synthesized. ...Their crystal structures have been determined. All the complexes showed a significant antifungal activity, while only the azido complex displayed antibacterial activity. All the complexes were cytotoxic to a panel of six tumor cell lines, the azido complex showing a similar activity as cisplatin to leukemia cell line K562 and lower toxicity to normal MRC-5 cells than that anticancer agent. The complexes interfered with cell cycle of tumor cells and induced plasmid DNA cleavage.
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•Square-planar complexes of Ni(II) with PNO set of donor atoms.•Antifungal and cytotoxic activities.•Selectivity to leukemia cells in comparison to normal cells.•Effect on cell cycle progression in tumor cells.
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