Sciatica is often caused by a herniated lumbar intervertebral disc. When conservative treatment fails, a lumbar discectomy can be performed. Surgical treatment via lumbar discectomy is not always ...successful and may depend on a variety of preoperative factors. It remains unclear which, if any, preoperative factors can predict postsurgical clinical outcomes.
This review aimed to determine preoperative predictors that are associated with postsurgical clinical outcomes in patients undergoing lumbar discectomy.
This is a systematic review.
This systematic review of the scientific literature followed the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. MEDLINE and PubMed were systematically searched through June 2014. Results were screened for relevance independently, and full-text studies were assessed for eligibility. Reporting quality was assessed using a modified Newcastle-Ottawa Scale. Quality of evidence was assessed using a modified version of Sackett's Criteria of Evidence Support. No financial support was provided for this study. No potential conflict of interest-associated biases were present from any of the authors.
The search strategy yielded 1,147 studies, of which a total of 40 high-quality studies were included. There were 17 positive predictors, 20 negative predictors, 43 non-significant predictors, and 15 conflicting predictors determined. Preoperative predictors associated with positive postoperative outcomes included more severe leg pain, better mental health status, shorter duration of symptoms, and younger age. Preoperative predictors associated with negative postoperative outcomes included intact annulus fibrosus, longer duration of sick leave, worker's compensation, and greater severity of baseline symptoms. Several preoperative factors including motor deficit, side and level of herniation, presence of type 1 Modic changes and degeneration, age, and gender had non-significant associations with postoperative clinical outcomes.
It may be possible for certain preoperative factors to be targeted for clinical evaluation by spine surgeons to assess the suitability of patients for lumbar discectomy surgery, the hope being to thereby improve postoperative clinical outcomes. Prospective cohort studies are required to increase the level of evidence with regard to significant predictive factors.
We sequenced eight melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, we found that 24% of ...melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9. Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggest that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W333* variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The Y‐box binding protein 1 (YB‐1) is a multifunctional protein that affects transcription, splicing, and translation. Overexpression of YB‐1 in breast cancers causes cisplatin resistance. The exact ...mechanism by which YB‐1 confers cisplatin resistance is unknown. The aim of the present study was to identify, using mass spectrometry, proteins that interact with YB‐1 that are important for cisplatin resistance in two breast cancer cell lines, namely MCF7 and MDA‐MB‐231. A tagged YB‐1 construct was used to identify proteins interacting directly with YB‐1 in breast cancer cells. We then focused on proteins that are potentially involved in breast cancer progression based on the ONCOMINE public microarray database. Genes encoding for these YB‐1‐interacting proteins were examined in the public NCBI comparative genomic hybridization database to determine whether they are localized to regions of chromosomes that are rearranged in breast cancer tissues. From these analyses, we generated a list of proteins potentially involved in cisplatin resistance. Cisplatin dose–response curves were constructed in MCF7 and MDA‐MB‐231 transfected with four siRNA corresponding to each of these YB‐1 interactors to identify proteins significantly affecting cisplatin sensitivity upon gene silencing. Depletion of only the X‐linked ribosomal protein S4 (RPS4X) resulted in consistent resistance to cisplatin in both cell lines with at least three different siRNA sequences against RPS4X. Further analyses indicated that the knock down of RPS4X decreased DNA synthesis, induced cisplatin resistance, and is equivalent to the overexpression of YB‐1 in both MCF7 and MDA‐MB‐231 cells. These results suggest that the RPS4X/YB‐1 complex is a significant potential target to counteract cisplatin resistance in breast cancer. (Cancer Sci 2011; 102: 1410–1417)
YB-1 is a multifunctional protein that affects transcription, splicing, and translation. Overexpression of YB-1 in breast cancers causes cisplatin resistance. Recent data have shown that YB-1 is also ...overexpress in colorectal cancer. In this study, we tested the hypothesis that YB-1 also confers oxaliplatin resistance in colorectal adenocarcinomas.
We show for the first time that transfection of YB-1 cDNA confers oxaliplatin resistance in two colorectal cancer cell lines (SW480 and HT29 cell lines). Furthermore, we identified by mass spectrometry analyses important YB-1 interactors required for such oxaliplatin resistance in these colorectal cancer cell lines. A tagged YB-1 construct was used to identify proteins interacting directly to YB-1 in such cells. We then focused on proteins that are potentially involved in colorectal cancer progression based on the Oncomine microarray database. Genes encoding for these YB-1 interactors were also examined in the public NCBI comparative genomic hybridization database to determine whether these genes are localized to regions of chromosomes rearranged in colorectal cancer tissues. From these analyses, we obtained a list of proteins interacting with YB-1 and potentially involved in oxaliplatin resistance. Oxaliplatin dose response curves of SW480 and HT29 colorectal cancer cell lines transfected with several siRNAs corresponding to each of these YB-1 interactors were obtained to identify proteins significantly affecting oxaliplatin sensitivity upon gene silencing. Only the depletion of either NONO or RALY sensitized both colorectal cancer cell lines to oxaliplatin. Furthermore, depletion of NONO or RALY sensitized otherwise oxaliplatin resistant overexpressing YB-1 SW480 or HT29 cells.
These results suggest knocking down NONO or RALY significant counteracts oxaliplatin resistance in colorectal cancers overexpressing the YB-1 protein.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Synucleinopathies are a broad class of neurodegenerative disorders characterized by the presence of intracellular protein aggregates containing α-synuclein protein. The aggregated α-synuclein protein ...is hyperphosphorylated on serine 129 (S129) compared to the unaggregated form of the protein. While the precise functional consequences of S129 hyperphosphorylation are still being clarified, numerous in vitro and in vivo studies suggest that S129 phosphorylation is an early event in α-synuclein dysfunction and aggregation. Identifying the kinases and phosphatases that regulate this critical phosphorylation event may ultimately prove beneficial by allowing pharmacological mitigation of synuclein dysfunction and toxicity in Parkinson's disease and other synucleinopathies. We report here the development of a high-content, fluorescence-based assay to quantitate levels of total and S129 phosphorylated α-synuclein protein. We have applied this assay to conduct high-throughput loss-of-function screens with siRNA libraries targeting 711 known and predicted human kinases and 206 phosphatases. Specifically, knockdown of the phosphatidylinositol 3-kinase related kinase SMG1 resulted in significant increases in the expression of pS129 phosphorylated α-synuclein (p-syn). Moreover, SMG1 protein levels were significantly reduced in brain regions with high p-syn levels in both dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). These findings suggest that SMG1 may play an important role in increased α-synuclein pathology during the course of PDD, DLB, and possibly other synucleinopathies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A novel series of benzo
acarbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. Members of this series have been identified which are full agonists with functional ...potency <50
nM and oral bioavailability in mice.
A novel series of benzo
acarbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. Starting from a 3.4
μM high throughput screen hit, members of this series have been identified which are full agonists with functional potency <50
nM and oral bioavailability in mice.
Abstract
Background: Triple-negative breast cancer (TNBC) is an aggressive subtype that is more likely to develop in African-American women and younger females. TNBCs have higher rates of metastasis, ...recurrence, and mortality and also lack effective targeted treatments. We have found that compared to normal tissue, expression levels of the mitotic kinase TTK are elevated in metastatic TNBC tumors, particularly in African-American patients. We have demonstrated in TNBC cell lines that inhibiting TTK reduces cell viability, proliferation, and survival. Unfortunately, none of TTK inhibitors currently available are suitable for clinical use. Therefore, in an effort to generate an accessible treatment, we targeted an interaction between TTK and the chaperone protein, HSPA9. This events leads to super-activation of TTK and we hypothesized that disrupting this event may serve as an alternative and more effective method for targeting TTK as a TNBC chemotherapeutic.
Methods: We analyzed the effects of individual and combined inhibition of TTK and HSPA9 on cell viability in eight TNBC cell lines (i.e., BT-20, BT-549, CAL-51, HCC38, MDA-MB-231, MDA-MB-436, MDA-MB-453, and MDA-MB-468). AZ3146 and MKT-077 were used to inhibit TTK and HSPA9, respectively. The cells were first treated with each agent individually to determine the dose response profile and IC50 values. Then, to achieve therapeutically relevant dose combinations, cells were treated with IC20 doses of AZ3146 and sub-nanomolar (<IC10) doses of MKT-077.
Results: For the single agent treatments, cells were more sensitive to MKT-077 alone than AZ3146. MKT-077 IC50 values ranged between 0.96-4.24μM, while AZ3146 values were 1.55-52.4μM. AZ3146+MKT-077 resulted in significantly lower viability compared to treatment with either agent alone (p=0.04-2.0x10-10). The combination was particularly effective in BT-549, MDA-MB-231, and MDA-MB-436 cells since they exhibited little sensitivity to AZ3146 as a single agent (IC50≥22.8μM). However, when each of these cell lines was treated with an IC20 dose of AZ3146 and 0.05-100nM of MKT-077, we observed a statistically significant decease in cell viability (p = 0.03-8.5x10-10).
Conclusions: Our findings show that simultaneously treating TNBC cells with low doses of TTK and HSPA9 inhibitors results in a substantially greater reduction in viability. Although previous data suggest that TTK inhibitors cause selective cancer cell death, none of these agents are clinically available. Additionally, MKT-077 was shown to exhibit significant antitumor activity in a variety of in vitro and in vivo model systems. However, we have shown that TNBC cells can be effectively treated with a TTK inhibitor combined with very low doses of MKT-077. More importantly, since these proteins are both overexpressed in tumor cells, dual inhibition of TTK and HSPA9 may be a selective, safe, and highly effective chemotherapeutic strategy for TNBC.
Citation Format: Nicole A. Lavender, Donald Chow, Holly Yin, John Carpten. Dual inhibition of TTK and HSPA9 functions to synergistically decrease viability in triple-negative breast cancer cell lines. abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5564. doi:10.1158/1538-7445.AM2014-5564
To identify rational therapeutic combinations with cytarabine (Ara-C), we developed a high-throughput, small-interference RNA (siRNA) platform for myeloid leukemia cells. Of 572 kinases individually ...silenced in combination with Ara-C, silencing of 10 (1.7%) and 8 (1.4%) kinases strongly increased Ara-C activity in TF-1 and THP-1 cells, respectively. The strongest molecular concepts emerged around kinases involved in cell-cycle checkpoints and DNA-damage repair. In confirmatory siRNA assays, inhibition of WEE1 resulted in more potent and universal sensitization across myeloid cell lines than siRNA inhibition of PKMYT1, CHEK1, or ATR. Treatment of 8 acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) cell lines with commercial and the first-in-class clinical WEE1 kinase inhibitor MK1775 confirmed sensitization to Ara-C up to 97-fold. Ex vivo, adding MK1775 substantially reduced viability in 13 of 14 AML, CML, and myelodysplastic syndrome patient samples compared with Ara-C alone. Maximum sensitization occurred at lower to moderate concentrations of both drugs. Induction of apoptosis was increased using a combination of Ara-C and MK1775 compared with using either drug alone. WEE1 is expressed in primary AML, ALL, and CML specimens. Data from this first siRNA-kinome sensitizer screen suggests that inhibiting WEE1 in combination with Ara-C is a rational combination for the treatment of myeloid and lymphoid leukemias.
Service Quality in Grocery Retailing Siu, Noel Y. M.; Chow, Donald K. H.
Journal of international consumer marketing,
1/15/2004, 2004-01-15, Letnik:
16, Številka:
1
Journal Article
Recenzirano
Current measures of service quality of retail grocery in the global market are scarce. A Retail Service Quality instrument is adopted to examine the service quality of a Japanese supermarket in Hong ...Kong and its impact on customer satisfaction and future consumption behavior. Five service dimensions emerged in the study. They are namely, Personal Interaction, Trustworthiness, Physical Aspect, Policy and Reliability. Of these dimensions, Personal Interaction and Physical Aspect are shown to be the salient elements in determining customer satisfaction and future consumption behavior. Implications and recommendation for retailers are discussed.
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