Lipotoxicity is a metabolic stress response implicated in the pathogenesis of diabetes complications and has been shown to involve lipid-induced oxidative stress. To elucidate the molecular ...mechanisms of lipotoxicity, we used retroviral promoter trap mutagenesis to isolate a cell line that is resistant to lipotoxic and oxidative stress. We show that loss of three box C/D small nucleolar RNAs (snoRNAs) encoded in the ribosomal protein L13a (rpL13a) locus is sufficient to confer resistance to lipotoxic and oxidative stress in vitro and prevents the propagation of oxidative stress in vivo. Our results provide evidence for a previously unappreciated, non-canonical role for box C/D snoRNAs as regulators of metabolic stress response pathways in mammalian cells.
► Lipotoxic and oxidative stress induce rpL13a snoRNAs, U32a, U33, and U35a ► rpL13a snoRNAs are critical mediators of oxidative stress and lipotoxicity ► Metabolic stress induces rpL13a snoRNAs in the cytosol ► rpL13a snoRNAs are induced and required for propagation of oxidative stress in vivo
Metal-Free Deoxygenation of Carbohydrates Adduci, Laura L.; McLaughlin, Matthew P.; Bender, Trandon A. ...
Angewandte Chemie (International ed.),
February 3, 2014, Letnik:
53, Številka:
6
Journal Article
Recenzirano
The conversion of readily available cellulosic biomass to valuable feedstocks and fuels is an attrative goal but a challenging transformation that requires the cleavage of multiple nonactivated CO ...bonds. Herein, the Lewis acid trispentafluorophenylborane (B(C6F5)3) is shown to catalyze the metal‐free hydrosilylative reduction of monosaccharides and polysaccharides to give hydrocarbons with reduced oxygen content. The choice of the silane reductant influences the degree of deoxygenation, with diethylsilane effecting the complete reduction to produce hexanes while tertiary silanes give partially deoxygenated tetraol and triol products.
A spoonful of sugar: The Lewis acid B(C6F5)3 catalyzes the complete deoxygenation of carbohydrates to give a mixture of hexane and hexene isomers, with diethylsilane (Et2SiH2) providing the hydride equivalent. A variety of carbohydrates including methyl cellulose can be deoxygenated by this metal‐free method, and the system can be tuned for selective deoxygenation at certain sites.
Crude oil currently provides much of the world's energy, but it is also the source of many feedstock chemicals. Methodology for the conversion of biomass into useful chemicals has often focused on ...either complete deoxygenation or the production of high-volume platform chemicals. Here, we describe the chemoselective partial reduction of silyl-protected C6O6-derived polyols to produce a diverse set of oxygen-functionalized chiral synthons. The combination of B(C6F5)3 and a tertiary silane efficiently generates a reactive equivalent of an electrophilic silylium ion (R3Si(+)) and a hydride (H(-)) reducing agent. The mechanism of oxygen loss does not involve a dehydrative elimination and thus avoids ablation of stereochemistry. Neighbouring group participation and the formation of cyclic intermediates is key to achieving selectivity in these reactions and, where both primary and secondary C-O bonds are present, the mechanism allows further control. The method provides--in one or two synthetic steps--highly improved syntheses of many C6On synthons as well as several previously undescribed products.
In light of diminishing petroleum feedstocks, there is significant interest in developing carbohydrate defunctionalization reactions. In this context we have examined the use of iridium pincer ...catalysts for the hydrosilylative reduction of sugars, and we report herein complete reduction of silyl-protected glucose to a mixture of hexane isomers.
Geminal diauration of Ph3PAu(aryl) complexes has been investigated to model the intermediacy of geminally diaurated gold(I)–vinyl complexes in catalysis (see scheme). The results advance our ...understanding of the factors influencing the stability, reactivity, and dynamics of these organometallic intermediates.
Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm ...optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA-sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92–0.96; p < 0.001; n = 106 early-stage validation cohort, accuracy, 81%; AUC, 0.89; 95% CI, 0.83–0.95; p < 0.001), independent of age of the individuals, smoking habits, whole-blood storage time, and various inflammatory conditions. PSO enabled selection of gene panels to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources.
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•Tumor-educated platelet (TEP) RNA profiles allow for blood-based cancer diagnostics•Inflammatory conditions only minimally confound TEP-based cancer detection•Swarm intelligence algorithms enable efficient selection of biomarker gene panels•TEP gene panels enable support vector machine-based classification of lung cancer
Best et al. use particle-swarm optimization algorithms and RNA-seq of tumor-educated platelets from patients to generate RNA sets capable of identifying patients with non-small-cell lung cancer, including those having early stage, from individuals without cancer, including those having inflammatory conditions.
Background
The proliferation marker Ki-67 is a major pathological feature for the description of the state of disease in breast cancer. It helps to define the molecular subtype and to stratify ...between therapy regimens in early breast cancer and helps to assess the therapy response. Circulating tumor cells (CTCs) are a negative prognostic biomarker for progression free (PFS) and overall survival (OS) in patients with metastatic breast cancer. Therefore, the CTC count is often described as surrogate for the tumor burden. Both, decrease of Ki-67 and CTC count are considered as evidence for therapy response. The presented work analyzed the correlation between the Ki-67 indices of metastatic tissue biopsies and CTC counts in biopsy time-adjacent peripheral blood samples.
Patients and methods
Blood samples from 70 metastatic breast cancer patients were obtained before the start of a new line of systemic therapy. CTCs were enumerated using CellSearch® (Menarini Silicon Biosystems, Bologna, Italy) whereas intact CTCs (iCTCs) and non-intact or apoptotic CTCs (aCTCs) were distinguished using morphologic criteria. The proportion of cells expressing Ki-67 was evaluated using immunohistochemistry on biopsies of metastases obtained concurrently with CTC sampling before the start of a new line of systemic therapy.
Results
65.7% of patients had a Ki-67 index of > 25%. 28.6% of patients had ≥ 5, 47.1% ≥ 1 iCTCs. 37.1% had ≥ 5, 51.4% ≥ 1 aCTCs. No correlation was shown between Ki-67 index and iCTC and aCTC count (r = 0.05 resp. r = 0.05, Spearman’s correlation index). High CTC-counts did not coincide with high Ki-67 index. High Ki-67, ≥ 5 iCTCs and aCTCs are associated with poor progression free (PFS) and overall survival (OS).
Conclusion
CTCs and Ki-67 are independent prognostic markers in metastatic breast cancer. High Ki-67 in metastatic tumor tissue is not correlated to high iCTC or aCTC counts in peripheral blood.
Locoregional recurrence after neoadjuvant chemotherapy for primary breast cancer is associated with poor prognosis. It is essential to identify patients at high risk of locoregional recurrence who ...may benefit from extended local therapy. Here, we examined the prediction accuracy and clinical applicability of the MD Anderson Prognostic Index (MDAPI).
Prospective clinical data from 456 patients treated between 2003 and 2011 was analyzed. The Kaplan-Meier method was used to examine the probabilities of locoregional recurrence, local recurrence and distant metastases according to individual prognosis score, stratified by type of surgery (breast conserving therapy or mastectomy). The possible confounding of the relationship between recurrence risk and MDAPI by established risk factors was accounted for in multiple survival regression models. To define the clinical utility of the MDAPI we analyzed its performance to predict locoregional recurrence censoring patients with prior or simultaneous distant metastases.
Mastectomized patients (42% of the patients) presented with more advanced tumor stage, lower tumor grade, hormone-receptor positive disease and consequently lower pathological complete response rates. Only a few patients presented with high-risk scores (2,7% MDAPI≥3). All patients with high-risk MDAPI score (MDAPI ≥3) who developed locoregional recurrence were simultaneously affected by distant metastases.
Our data do not support a clinical utility of the MDAPI to guide local therapy.
GeparOcto demonstrated that pathological complete response (pCR) of intense dose-dense epirubicin, paclitaxel and cyclophosphamide (iddEPC) was comparable to weekly paclitaxel/non-pegylated liposomal ...doxorubicin (plus carboplatin (PM(Cb) in triple-negative breast cancer TNBC) in high-risk early breast cancer (BC). Here, we report time-to-event secondary end-points.
Patients were randomised to receive 18 weeks of E (150 mg/m2) followed by P (225 mg/m2) followed by C (2000 mg/m2), each q2w or weekly P (80 mg/m2) plus M (20 mg/m2) plus, in TNBC, Cb (AUC 1.5). Patients with human epidermal growth factor receptor 2-positive (HER2+)BC received trastuzumab (6loading dose 8mg/kg q3w) and pertuzumab (420840mg q3w) with P and C cycles.
945 patients started treatment (iddEPC n = 470; PM(Cb) n = 475). After a median follow-up of 47.0 (range 1.6–61.5) months, 162 (75 in iddEPC; 87 in PM(Cb)) invasive disease-free survival (iDFS) events and 79 (41 in iddEPC; 38 in PM(Cb)) deaths were reported. No significant difference was observed in 4-year iDFS (81.9% iddEPC versus 79.7% PM(Cb), HR = 1.16 95%CI 0.85–1.59, log-rank p = 0.334) or 4-year overall survival (OS) (90.3% iddEPC versus 90.6% PM(Cb), HR = 0.90 95%CI 0.58–1.40, log-rank p = 0.637) overall and in HER2+ and TNBC subgroups. HR+/HER2- BC patients, however, had significantly better 4-year iDFS (77.9% iddEPC versus 62.5% PM, HR = 2.11 95%CI 1.08–4.10, log-rank p = 0.025) and 4-year OS with iddEPC (94.7% iddEPC versus 80.1% PM, HR = 3.26 95%CI 1.06–10.00, log-rank p = 0.029).
While there was no difference in survival for the entire cohort, the HR+/HER2-subgroup significantly benefits from iddEPC. This supports the concept of an additional effect of NACT beyond pCR in patients with HR+/HER2- BC.
NCT02125344.
•No significant survival difference for the entire cohort, HER2+ and TNBC subgroups.•Patients with HR+/HER2-patients benefit from iddEPC despite no difference in pCR rate.•Effect of neoadjuvant chemotherapy beyond pCR in the HR+/HER2- subgroup.
Triple-negative breast cancer constitutes ~ 15% of all breast cancer subtypes. Because of the negative hormone receptor and human epidermal growth factor receptor 2 status, therapy is mainly based on ...chemotherapy with a poor median overall survival in the metastatic setting of ~ 18 months. Compared to other breast cancer subtypes, triple-negative breast cancer is characterized by a higher mutational load, which renders the tumor immunogenic and amenable to immunotherapeutic intervention. Based on the promising results of immunotherapy in other cancer entities, including melanoma or non-small cell lung cancer, a vast number of studies are currently assessing immunotherapeutic approaches in patients with triple-negative breast cancer. While monotherapies with antibodies against programmed death-1 and programmed death ligand-1 have shown little efficacy in patients with heavily pretreated metastatic triple-negative breast cancer, treatment efficacy likely depends on the therapeutic setting, the treatment line, and the combination of immunotherapies with other anticancer drugs. Several studies are currently evaluating the safety and efficacy of immune checkpoint inhibition in combination with chemotherapy, angiogenesis inhibitors, poly(ADP-ribose) polymerase inhibitors, as well as radiotherapy in the metastatic and (neo-)adjuvant settings. The US Food and Drug Administration approval of nab-paclitaxel in combination with atezolizumab in 2019 presented a landmark therapeutic development for patients with triple-negative breast cancer, given the limited treatment options available for this highly aggressive disease. In this review, we provide an overview on important ongoing and completed immunotherapeutic studies in triple-negative breast cancer and their possible implications for clinical practice.
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