ResearchPad - 31 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Stress granules regulate stress-induced paraspeckle assembly]]> https://www.researchpad.co/article/elastic_article_15308 Eukaryotic cells contain a variety of RNA-protein macrocomplexes termed RNP granules. Different types of granules share multiple protein components; however, the crosstalk between spatially separated granules remains unaddressed. Paraspeckles and stress granules (SGs) are prototypical RNP granules localized exclusively in the nucleus and cytoplasm, respectively. Both granules are implicated in human diseases, such as amyotrophic lateral sclerosis. We characterized the composition of affinity-purified paraspeckle-like structures and found a significant overlap between the proteomes of paraspeckles and SGs. We further show that paraspeckle hyperassembly is typical for cells subjected to SG-inducing stresses. Using chemical and genetic disruption of SGs, we demonstrate that formation of microscopically visible SGs is required to trigger and maintain stress-induced paraspeckle assembly. Mechanistically, SGs may sequester negative regulators of paraspeckle formation, such as UBAP2L, alleviating their inhibitory effect on paraspeckles. Our study reveals a novel function for SGs as positive regulators of nuclear RNP granule assembly and suggests a role for disturbed SG-paraspeckle crosstalk in human disease.

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<![CDATA[The RNA export factor Mex67 functions as a mobile nucleoporin]]> https://www.researchpad.co/article/elastic_article_15307 The RNA export factor Mex67 is essential for the transport of mRNA through the nuclear pore complex (NPC) in yeast, but the molecular mechanism of this export process remains poorly understood. Here, we use quantitative fluorescence microscopy techniques in live budding yeast cells to investigate how Mex67 facilitates mRNA export. We show that Mex67 exhibits little interaction with mRNA in the nucleus and localizes to the NPC independently of mRNA, occupying a set of binding sites offered by FG repeats in the NPC. The ATPase Dbp5, which is thought to remove Mex67 from transcripts, does not affect the interaction of Mex67 with the NPC. Strikingly, we find that the essential function of Mex67 is spatially restricted to the NPC since a fusion of Mex67 to the nucleoporin Nup116 rescues a deletion of MEX67. Thus, Mex67 functions as a mobile NPC component, which receives mRNA export substrates in the central channel of the NPC to facilitate their translocation to the cytoplasm.

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<![CDATA[Nutrients recycle and the growth of Scenedesmus obliquus in synthetic wastewater under different sodium carbonate concentrations]]> https://www.researchpad.co/article/Nd9f89941-8238-4549-a114-6c8eddec66e8

This study illustrated the growth of Scenedesmus obliquus and recycle of nutrients in wastewater combined with inorganic carbon under autotrophic conditions. Scenedesmus obliquus was cultivated under different conditions by adding sodium carbonate (Na2CO3) at 15–40 mg l−1 separately in wastewater containing high nitrogen and phosphorus content. The growth characteristics of S. obliquus, pH and dissolved inorganic carbon (DIC) changes of microalgae liquid, the recycle rate of ammonia and phosphorus and lipid content were determined. The changes of pH and DIC showed that S. obliquus could use Na2CO3 to grow, with lipid contents of 18–25%. Among all Na2CO3 concentrations, 20 mg l−1 was the optimum, of which S. obliquus had the highest NH3-N recycle of 52% and PO43P recycle of 67%. By the 14th day, its biomass production also reaches the maximum of 0.21 g l−1. However, inorganic carbon fixation rate was inversely proportional to its concentration. Moreover, the biomass was in positive correlation with the Na2CO3 concentration except 20 mg l−1, which provided a possibility that S. obliquus could be acclimatized to adjust to high concentrations of inorganic carbon to promote biomass accumulation and recycle of nutrients.

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<![CDATA[Human transposon insertion profiling by sequencing (TIPseq) to map LINE-1 insertions in single cells]]> https://www.researchpad.co/article/N7337e351-b771-4063-ad2f-b2297370daf7

Long interspersed element-1 (LINE-1, L1) sequences, which comprise about 17% of human genome, are the product of one of the most active types of mobile DNAs in modern humans. LINE-1 insertion alleles can cause inherited and de novo genetic diseases, and LINE-1-encoded proteins are highly expressed in some cancers. Genome-wide LINE-1 mapping in single cells could be useful for defining somatic and germline retrotransposition rates, and for enabling studies to characterize tumour heterogeneity, relate insertions to transcriptional and epigenetic effects at the cellular level, or describe cellular phylogenies in development. Our laboratories have reported a genome-wide LINE-1 insertion site mapping method for bulk DNA, named transposon insertion profiling by sequencing (TIPseq). There have been significant barriers applying LINE-1 mapping to single cells, owing to the chimeric artefacts and features of repetitive sequences. Here, we optimize a modified TIPseq protocol and show its utility for LINE-1 mapping in single lymphoblastoid cells. Results from single-cell TIPseq experiments compare well to known LINE-1 insertions found by whole-genome sequencing and TIPseq on bulk DNA. Among the several approaches we tested, whole-genome amplification by multiple displacement amplification followed by restriction enzyme digestion, vectorette ligation and LINE-1-targeted PCR had the best assay performance.

This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.

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<![CDATA[Analysis of Differentially Expressed MicroRNAs and Circulating Tumor Cells as Predictive Biomarkers of Platinum Chemoresistance in Primary Ovarian Carcinomas: A Prospective Study]]> https://www.researchpad.co/article/Nb04831c8-6b0f-4b9d-8693-cba873c3cb23

Abstract

Lesson Learned.

  • Circulating tumor cells, microRNA markers, or other biomarkers merit examination as part of correlative scientific analyses in prospective clinical trials.

Background.

Platinum chemotherapy resistance occurs in approximately 25% of patients with ovarian carcinoma; however, no biomarkers of ovarian carcinoma chemoresistance have been validated. We performed a prospective trial designed to identify tumor‐based predictive biomarkers of platinum resistance.

Methods.

Tumor specimens were collected from 29 women with newly diagnosed histopathologically proven primary ovarian carcinoma. Of these, 23 women had specimens accessible for assessment and outcome data available regarding chemosensitive versus chemoresistance status via review of the medical record. Tumor slices were stained with antibodies against two microRNAs (miRNAs 29b and 199a) differentially expressed in chemoresistant ovarian cancer cell lines. Additionally, blood samples obtained at the time of diagnosis were analyzed for the presence of circulating tumor cells (CTCs).

Results.

The average age of the patients was 64 years, and 82.6% had high‐grade epithelial carcinomas. The baseline median CA‐125 was 464 (range 32–2,782). No statistically significant differences were observed in miR29b or 199a expression in platinum‐resistant/refractory versus platinum‐sensitive tumors. Furthermore, the presence of CTCs was not found to be statistically significantly predictive of eventual platinum resistance.

Conclusion.

Our analysis showed no differences in miR29b and 199a expression, and differences in baseline CTCs in women with newly diagnosed ovarian tumors were not statistically significant.

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<![CDATA[Transmural impedance detects graded changes of inflammation in experimental colitis]]> https://www.researchpad.co/article/N2e83c256-376a-4b2c-868e-866407a08545

Ulcerative colitis is a chronic disease in which the mucosa of the colon or rectum becomes inflamed. An objective biomarker of inflammation will provide quantitative measures to support qualitative assessment during an endoscopic examination. Previous studies show that transmural electrical impedance is a quantifiable biomarker of inflammation. Here, we hypothesize that impedance detects spatially restricted areas of inflammation, thereby allowing the distinction between regions that differ in their severity of inflammation. A platinum ball electrode was placed into minimally inflamed (i.e. normal) or 2,4,6-trinitrobenzene sulphonic acid (TNBS)-inflamed colonic regions of rats and impedance measurements obtained by passing current between the intraluminal and subcutaneous return electrode. Histology of the colon was correlated with impedance measurements. The impedance of minimally inflamed (normal) tissue was 1.5–1.9 kΩ. Following TNBS injection, impedance significantly decreased within the inflammatory penumbra (p < 0.05), and decreased more in the inflammatory epicentre (p = 0.02). Histological damage correlated with impedance values (p < 0.05). Thus, impedance values of 1.5–1.9, 1.3–1.4 and 0.9–1.1 kΩ corresponded to minimally inflamed, mildly inflamed and moderately inflamed tissue, respectively. In conclusion, transmural impedance is an objective, spatially localized biomarker of mucosal integrity, and distinguishes between severities of intestinal inflammation.

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<![CDATA[The RNA exosome nuclease complex regulates human embryonic stem cell differentiation]]> https://www.researchpad.co/article/Ne8da9728-a5df-4d19-b6d8-4a6e659197f5

This work shows that the exosome modulates the levels of LINE-1 retrotransposons and specific miRNAs, lncRNAs, and mRNAs that encode developmental regulators or affect their expression. The exosome restrains stem cell differentiation in part by degrading transcripts encoding FOXH1, a transcription factor crucial for mesendoderm formation.

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<![CDATA[Bicalutamide plus Aromatase Inhibitor in Patients with Estrogen Receptor‐Positive/Androgen Receptor‐Positive Advanced Breast Cancer]]> https://www.researchpad.co/article/N5b93a253-26b1-49eb-a144-7f52ec909340

Abstract

Lessons Learned

  • Studies targeting the androgen receptor (AR) signaling pathway in aromatase inhibitor (AI)‐resistant breast cancer are limited.

  • Bicalutamide, one of the commonly used AR inhibitors in prostate cancer, in combination with AI, did not show synergistic activity in patients with estrogen receptor‐positive and AI‐resistant disease in this phase II, single‐arm study.

  • The clinical benefit rate and objective response rate at 6 months were 16.7% and 0%, respectively, and the study was terminated after the first stage.

Background

Endocrine resistance is a major problem in clinical practice. Studies have shown that androgen receptor (AR) signaling activation may be one of the mechanisms, and targeting AR showed some promising results in AR‐positive triple‐negative breast cancer. The aim of this study was to assess the efficacy and safety of bicalutamide plus another aromatase inhibitor in patients with nonsteroidal aromatase inhibitor (AI) or steroidal AI resistance and estrogen receptor (ER)‐positive and AR‐positive advanced breast cancer.

Methods

A Simon's two‐stage, phase II, single‐arm study was conducted. We assumed the clinical benefit rate (CBR) of 40% would be significant in clinical practice. In this case, if ≥4 patients of the 19 patients in the first stage benefited from treatment, the CBR would achieve the assumed endpoint. If fewer than four patients benefited from treatment in the first stage, the trial would be terminated. All patients received bicalutamide 50 mg per day orally plus another aromatase inhibitor. The primary outcome was CBR; secondary outcomes included objective response rate (ORR), progression‐free survival (PFS), and tolerability.

Results

A total of 19 patients enrolled in the first stage, and 18 patients met all criteria for analysis. The trial terminated according to protocol after the first stage. After a median follow‐up of 14 months, the CBR at 6 months was 16.7% (3/18); no patients with partial or complete response were observed. The median PFS was 2.7 months. Bicalutamide in combination with AI was well tolerated.

Conclusion

Bicalutamide in combination with another AI did not show synergistic activity in patients with ER‐positive breast cancer and AI resistance. Results suggest that no more large‐sample clinical trials should be conducted in this population for overcoming endocrine resistance.

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<![CDATA[Randomized Phase II Study of Weekly Paclitaxel plus Carboplatin Versus Biweekly Paclitaxel plus Carboplatin for Patients with Previously Untreated Advanced Non‐Small Cell Lung Cancer]]> https://www.researchpad.co/article/N3b5c56b5-312c-42cb-911a-32738a338a3f

Abstract

Lessons Learned.

  • This clinical trial, evaluating the efficacy and safety of a carboplatin plus paclitaxel regimen in a biweekly or weekly schedule instead of the more toxic 3‐weekly administration, showed that the weekly regimen was better in efficacy than the biweekly regimen, with mild toxicities, for patients with non‐small cell lung cancer (NSCLC).

  • The weekly carboplatin plus paclitaxel regimen could be considered as an alternative to the 3‐weekly regimen in Japanese patients with NSCLC.

Background.

Combination therapy comprising carboplatin (C) and paclitaxel (P) is the most commonly used regimen for the treatment of advanced non‐small cell lung cancer (NSCLC). Common toxicities associated with the regimen, such as neuropathy and myelosuppression, cause its discontinuation. In the present study, we conducted a clinical trial evaluating the efficacy of biweekly (B) and weekly (W) PC therapy to identify the appropriate chemotherapy schedule for Asian patients.

Methods.

Chemonaive patients with IIIB/IV NSCLC and a performance status of 0–1 were randomly assigned to a biweekly regimen (paclitaxel 135 mg/m2 with carboplatin area under the curve [AUC] 3 on days 1 and 15 of every 4 weeks) or to a weekly regimen (paclitaxel 90 mg/m2 on days 1, 8, and 15 with carboplatin AUC 6 on day 1 of every 4 weeks).

Results.

A total of 140 patients were enrolled in the study. The objective response rates (ORRs) were 28.1% (B) and 38.0% (W). The most common toxicity was neutropenia, with incidence rates of 62.0% (B) and 57.8% (W). Progression‐free survivals (PFSs) were 4.3 months (B) and 5.1 months (W), and overall survival durations were 14.2 months (B) and 13.3 months (W).

Conclusion.

The ORR and PFS in the weekly regimen were better than those in the biweekly schedule, although a statistical difference was not observed. The toxicity profile was generally mild for both regimens. The weekly CP regimen was suitable to be considered as an alternative to the current 3‐weekly regimen in NSCLC treatment.

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<![CDATA[Mesenchymal stem cells for inflammatory airway disorders: promises and challenges]]> https://www.researchpad.co/article/5c6863c6d5eed0c484023b2f

The regenerative and immunomodulatory characteristics of mesenchymal stem cells (MSCs) make them attractive in the treatment of many diseases. Although they have shown promising preclinical studies of immunomodulation and paracrine effects in inflammatory airway disorders and other lung diseases, there are still challenges that have to be overcome before MSCs can be safely, effectively, and routinely applied in the clinical setting. A good understanding of the roles and mechanisms of the MSC immunomodulatory effects will benefit the application of MSC-based clinical therapy. In this review, we summarize the promises and challenges of the preclinical and clinical trials of MSC therapies, aiming to better understand the role that MSCs play in attempt to treat inflammatory airway disorders.

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<![CDATA[miR-134 inhibits chondrogenic differentiation of bone marrow mesenchymal stem cells by targetting SMAD6]]> https://www.researchpad.co/article/5c6863c8d5eed0c484023b42

Various miRNAs have been reported to regulate the chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs); however, whether miR-134 plays a role in this biological process remains undetermined. In the present study, we first evaluated the chondrogenic differentiation of BMSCs by Alcian blue staining, and examined the miR-134 expression by quantitative real-time PCR (qRT-PCR) during this process. And miR-134 inhibitor was used to investigate the functions of miR-134 in chondrogenic differentiation of BMSCs by Alcian blue staining, qRT-PCR, and Western blot. Subsequently, the correlation between miR-134 and SMAD6 was assessed via bioinformatics analysis and dual-luciferase reporter assay. Finally, the role of SMAD6 in chondrogenic differentiation of BMSCs was also determined through Alcian blue staining, qRT-PCR, and Western blot. As results showed that miR-134 expression was significantly down-regulated during chondrogenic differentiation, and inhibition of miR-134 obviously promoted chondrogenic differentiation. Dual-luciferase reporter assay indicated that miR-134 could directly target the 3′-UTRs of SMAD6, inhibit miR-134 expression in BMSCs, and up-regulate SMAD6 expression. Moreover, we found that overexpression of SMAD6 significantly promoted chondrogenic differentiation, and that SMAD6-induced promotion of chondrogenic differentiation could be reversed by miR-134 mimics. In conclusion, our findings suggest that miR-134 may act as a negative regulator during chondrogenic differentiation of BMSCs by interacting with SMAD6.

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<![CDATA[Phase I/II Trial of Vandetanib and Bortezomib in Adults with Locally Advanced or Metastatic Medullary Thyroid Cancer]]> https://www.researchpad.co/article/5c4b91d6d5eed0c4848773ef

Lessons Learned.

  • Vandetanib at a dose of 300 mg orally every day plus bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 could be administered safely.

  • Assessing outcomes in 17 patients with medullary thyroid cancer, investigators considered the combination to be more difficult to administer than single‐agent vandetanib and that achieving better outcomes was unlikely. Consequently, a planned phase II study was terminated early.

Background.

The proto‐oncogene RET (REarranged during Transfection) has a critical role in the pathogenesis of medullary thyroid cancer (MTC). Vandetanib (V), a multitargeted tyrosine kinase inhibitor approved for the treatment of MTC, is thought to inhibit RET in MTC. Supported by preclinical studies demonstrating that bortezomib (B) administration lowered RET mRNA and protein levels, we conducted a phase I study in advanced solid tumors of vandetanib in combination with bortezomib. The goal was to establish an RP2D (recommended phase II dose) for the combination of vandetanib plus bortezomib, a regimen envisioned as a dual strategy for targeting RET in MTC.

Methods.

Patients with advanced solid tumors were treated with escalating doses of bortezomib or vandetanib to assess the safety and tolerability of daily oral vandetanib and intravenous (IV) bortezomib administered on days 1, 4, 8, and 11 of a 28‐day cycle. Intrapatient dose escalation was allowed.

Results.

Twenty‐two patients were enrolled and received escalating mg/m2 bortezomib and mg vandetanib (number of patients) at initial doses of 1 and 100 (3), 1.3 and 100 (6), 1.3 and 200 (6), and 1.3 and 300 (7), respectively. Patients received a median of four cycles of bortezomib/vandetanib (range: 1–10), with 13 patients escalating to 1.3/200 and 10 to 1.3/300. G3 toxicities occurring in more than one patient included hypertension (24%), fatigue (19%), thrombocytopenia (10%), diarrhea (10%), and arthralgia (10%). There were no drug‐related G4/5 toxicities. There was one dose‐limiting toxicity, G3 thrombocytopenia, at bortezomib/vandetanib doses of 1.3/200 in cycle 2 that resolved without intervention. Four patients with a diagnosis of MTC (27%) had a partial response (PR).

Conclusion.

The MTD of the combination was established as bortezomib, 1.3 mg/m2 IV days 1, 4, 8, and 11 with vandetanib 300 mg p.o. daily. RECIST responses were observed in patients with a diagnosis of MTC.

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<![CDATA[A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus nab ‐Paclitaxel and Gemcitabine in Advanced Solid Tumors]]> https://www.researchpad.co/article/5c4b91d4d5eed0c48487738e

Abstract

Lessons Learned.

  • Itacitinib in combination with nab‐paclitaxel plus gemcitabine demonstrated an acceptable safety profile with clinical activity in patients with advanced solid tumors including pancreatic cancer.

  • The results support future studies of itacitinib as a component of combination regimens with other immunologic and targeted small molecule anticancer agents.

Background.

Cytokine‐mediated signaling via JAK/STAT is central to tumor growth, survival, and systemic inflammation, which is associated with cancer cachexia, particularly in pancreatic cancer. Because of their centrality in the pathogenesis of cancer cachexia and progression, JAK isozymes have emerged as promising therapeutic targets. Preclinical studies have demonstrated antiproliferative effects of JAK/STAT pathway inhibition in both in vitro and in vivo models of cancer, including pancreatic cancer.

Methods.

This phase Ib/II dose‐optimization study assessed itacitinib, a selective JAK1 inhibitor, combined with nab‐paclitaxel plus gemcitabine in adults with treatment‐naïve advanced/metastatic disease (Part 1) or pancreatic adenocarcinoma (Parts 2/2A; NCT01858883). Starting doses (Part 1) were itacitinib 400 mg, nab‐paclitaxel 125 mg/m2, and gemcitabine 1,000 mg/m2. Additional dose levels incorporated were granulocyte colony‐stimulating factor, de‐escalations of itacitinib to 300 mg once daily (QD), nab‐paclitaxel to 100 mg/m2, and gemcitabine to 750 mg/m2.

Results.

Among 55 patients in Part 1, 6 developed seven hematologic dose‐limiting toxicities (Cycle 1). Itacitinib 300 mg plus nab‐paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 was tolerated and expanded in Part 2. Treatment discontinuation and grade 3/4 neutropenia rates prompted itacitinib de‐escalation to 200 mg QD in Part 2A. The most common grade 3/4 toxicities were fatigue and neutropenia. Partial responses occurred across all itacitinib doses and several tumor types (overall response rate, 24%).

Conclusion.

Itacitinib plus chemotherapy demonstrated acceptable safety and clinical activity in patients with advanced solid tumors including pancreatic cancers. This study was terminated early (sponsor's decision) based on negative phase III results for a JAK1/2 inhibitor in previously treated advanced pancreatic cancer.

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<![CDATA[A Phase III Study to Compare the Efficacy and Safety of Paclitaxel Versus Irinotecan in Patients with Metastatic or Recurrent Gastric Cancer Who Failed in First‐line Therapy (KCSG ST10‐01)]]> https://www.researchpad.co/article/5c4b91cfd5eed0c484877273

Abstract

Lessons Learned.

  • Irinotecan could not be proven noninferior to paclitaxel as a second‐line treatment for patients with metastatic or recurrent gastric cancer.

  • The failure to demonstrate noninferiority may have been a result of insufficient patient enrollment.

  • Both agents were tolerable but showed different toxicity profiles.

Background.

This phase III study compared the efficacy and safety of paclitaxel versus irinotecan in patients with metastatic or recurrent gastric cancer (MRGC) who had experienced disease progression following first‐line chemotherapy.

Methods.

Patients were randomized to receive either paclitaxel (70 mg/m2; days 1, 8, 15, every 4 weeks) or irinotecan (150 mg/m2 every other week). The primary endpoint was progression‐free survival (PFS).

Results.

This study was stopped early due to low accrual rate. A total of 112 patients were enrolled; 54 were allocated to paclitaxel and 58 to irinotecan. Median PFS for the paclitaxel and irinotecan groups was 3.5 and 2.1 months, respectively (hazard ratio [HR], 1.27; 95% confidence interval [CI], 0.86–1.88; p = .234). Noninferiority of irinotecan to paclitaxel was not proved because the upper boundary of the 95% CI (1.88) exceeded the predefined upper margin of noninferiority (1.32). Median overall survival (OS) was 8.6 months in the paclitaxel group and 7.0 months in the irinotecan group (HR, 1.39; 95% CI, 0.91–2.11; p = .126). Among toxicities greater than or equal to grade 3, neutropenia (11.5%) was the most common, followed by peripheral neuropathy (7.7%) in the paclitaxel group, and neutropenia (34.5%) followed by nausea, vomiting, and anemia (8.6%, respectively) in the irinotecan group.

Conclusion.

Although paclitaxel showed numerically longer PFS and OS compared with irinotecan, this was statistically insignificant. Both irinotecan and paclitaxel are valid second‐line treatment options in MRGC.

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<![CDATA[A Phase II Trial of Pazopanib in Patients with Metastatic Alveolar Soft Part Sarcoma]]> https://www.researchpad.co/article/5c4b91d8d5eed0c48487744f

Lessons Learned.

  • Pazopanib shows a modest efficacy in metastatic alveolar soft part sarcoma.

  • Clinical outcomes were comparable to those in previous studies using antiangiogenic drugs.

  • Further prospective studies evaluating the benefit of pazopanib in alveolar soft part sarcoma with a larger sample are warranted to validate results.

Background.

Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignant tumor characterized by an unbalanced translocation, t(X;17)(p11.2;q25), which leads to the fusion of ASPSCR1 to the TFE3 transcription factor. Because this results in the upregulation of angiogenesis‐related transcripts, antiangiogenic drugs have been used in ASPS patients.

Methods.

This open‐label, single‐arm, multicenter, investigator‐initiated phase II trial was designed to evaluate efficacy and safety of pazopanib 800 mg once daily in patients with metastatic ASPS. The primary endpoint was investigator‐assessed overall response rate (ORR), and secondary endpoints were toxicity, progression‐free survival (PFS), and overall survival (OS). 68Ga‐RGD (Arg‐Gly‐Asp) positron emission tomography (PET) scan and gene expression profiling using NanoString platform were performed for biomarker analysis.

Results.

Six patients with histologically confirmed metastatic ASPS were enrolled between December 2013 and November 2014. Among six patients, one achieved a partial response (PR) (ORR 16.7%) and five patients showed stable disease (SD). With a median follow‐up of 33 months (range 18.7–39.3 months), median PFS was 5.5 months (95% confidence interval [CI] 3.4–7.6 months), and median OS was not reached. There were no severe toxicities except one patient with grade 3 diarrhea.

Conclusion.

Pazopanib showed modest antitumor activity with manageable toxicities for patients with metastatic ASPS.

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<![CDATA[Selection of Protein Kinase Inhibitors Based on Tumor Tissue Kinase Activity Profiles in Patients with Refractory Solid Malignancies: An Interventional Molecular Profiling Study]]> https://www.researchpad.co/article/5c16d223d5eed0c484539bfc

Abstract

Lessons Learned.

  • Clinically applicable tools are needed for treatment selection and repurposing of available protein kinase inhibitors (PKIs) in patients with advanced solid tumors refractory to standard treatment.

  • Using a tyrosine kinase peptide substrate microarray, observed inhibitory activity in vitro could not sufficiently predict clinical benefit of treatment with the selected PKI.

Background.

This exploratory molecular profiling study determined the feasibility and benefit of the selection of protein kinase inhibitors (PKIs) based on kinase activity profiling in patients with refractory solid malignancies.

Methods.

Adult patients with biopsy‐accessible refractory solid tumors were eligible. Per patient, the inhibitory potency of sunitinib, dasatinib, erlotinib, sorafenib, everolimus, and lapatinib was determined in tumor lysates from fresh biopsies using a tyrosine kinase peptide substrate microarray. The most active PKI in this in vitro assay was selected for treatment.

Results.

Thirteen patients were enrolled in the feasibility part and underwent tumor biopsy. Of 12 patients in whom kinase activity profiling was performed, 11 started treatment with a selected PKI: dasatinib in 8, sunitinib in 2, and erlotinib in 1 patient(s). Eight patients were evaluable for response. One patient had stable disease (SD) >4 months on sunitinib; one patient had SD at 6 weeks but progressive disease (PD) at 12 weeks. The remaining patients had PD after 6 weeks of treatment.

Conclusion.

Kinase inhibition profiles of multiple PKIs can be reliably determined using fresh tumor biopsies from patients with refractory solid tumors. However, the current in vitro microarray selection approach insufficiently predicted clinical benefit of PKI treatment in these patients.

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<![CDATA[The role of mTOR-mediated signals during haemopoiesis and lineage commitment]]> https://www.researchpad.co/article/5c114491d5eed0c4845d40e9

The serine/threonine protein kinase mechanistic target of rapamycin (mTOR) has been implicated in the regulation of an array of cellular functions including protein and lipid synthesis, proliferation, cell size and survival. Here, we describe the role of mTOR during haemopoiesis within the context of mTORC1 and mTORC2, the distinct complexes in which it functions. The use of conditional transgenic mouse models specifically targeting individual mTOR signalling components, together with selective inhibitors, have generated a significant body of research emphasising the critical roles played by mTOR, and individual mTOR complexes, in haemopoietic lineage commitment and development. This review will describe the profound role of mTOR in embryogenesis and haemopoiesis, underscoring the importance of mTORC1 at the early stages of haemopoietic cell development, through modulation of stem cell potentiation and self-renewal, and erythroid and B cell lineage commitment. Furthermore, the relatively discrete role of mTORC2 in haemopoiesis will be explored during T cell development and B cell maturation. Collectively, this review aims to highlight the functional diversity of mTOR signalling and underline the importance of this pathway in haemopoiesis.

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<![CDATA[Weekly Docetaxel, Cisplatin, and Cetuximab in Palliative Treatment of Patients with Squamous Cell Carcinoma of the Head and Neck]]> https://www.researchpad.co/article/5b693b39463d7e32f55a16b8

Abstract

Lessons Learned.

  • Chemotherapy for recurrent, metastatic squamous cell carcinoma of the head and neck need not be known for extreme toxicity.

  • The weekly regimen studied here has been demonstrated to be tolerable and effective.

Background.

The objective of this study was to establish the response rate, progression‐free survival (PFS) and overall survival (OS), and safety profile of weekly docetaxel, platinum, and cetuximab (TPC) in patients with relapsed or metastatic squamous cell carcinoma of the head and neck (SCCHN).

Materials and Methods.

Twenty‐nine patients with metastatic or recurrent SCCHN with an Eastern Cooperative Oncology Group (ECOG) performance status <3 were enrolled in an institutional review board‐approved phase II trial. This study permitted prior chemoradiation, radiation, and/or surgery, provided that 3 months had elapsed since the end of the potentially curative treatment. Patients received cisplatin 30 mg/m2 or carboplatin area under the curve (AUC) 2, docetaxel 30 mg/m2, and cetuximab 250 mg/m2 weekly for 3 weeks, followed by a break during the fourth week, for a 28‐day cycle. Planned intrapatient dose modifications were based on individual toxicity.

Results.

Twenty‐seven patients received TPC and were evaluable for response and toxicity. Rates of complete response (CR), partial response (PR), and confirmed PR were 3%, 52%, and 30%, respectively. The overall objective response rate was 56%. Estimated median PFS and OS were 4.8 and 14.7 months, respectively. The rates of grade 3 and 4 worst‐grade adverse events (AEs) per patient were 85% and 7%, respectively. Dose density through cycle 4 was preserved for all patients; however, treatment beyond cycle 6 with the TPC regimen proved unfeasible.

Conclusion.

Weekly docetaxel, cisplatin, and cetuximab is an effective regimen for patients with metastatic or recurrent SCCHN. Response rates, PFS, and OS compare favorably with other combination chemotherapy treatments. Grade 4 toxicity rates observed in this study were substantially lower than those described with regimens using less frequent, higher‐dose chemotherapy schedules.

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<![CDATA[BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells]]> https://www.researchpad.co/article/5c01f8f7d5eed0c4842bf59e

Cancer cells frequently exhibit aerobic glycolysis, known as the Warburg effect. An et al. identify a novel RNA regulatory activity of BAG3, a protein implicated in various cancers. BAG3 enhances posttranscriptionally the expression of Hexokinase 2, the first enzyme involved in glycolysis, and it reprograms glucose metabolism by pancreatic cancer cells.

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<![CDATA[Designer human tissue: coming to a lab near you]]> https://www.researchpad.co/article/5b5a1470463d7e01569afeaa

Human pluripotent stem cells (PSCs) offer a scalable alternative to primary and transformed human tissue. PSCs include human embryonic stem cells, derived from the inner cell mass of blastocysts unsuitable for human implantation; and induced PSCs, generated by the reprogramming of somatic cells. Both cell types display the ability to self-renew and retain pluripotency, promising an unlimited supply of human somatic cells for biomedical application. A distinct advantage of using PSCs is the ability to select for genetic background, promising personalized modelling of human biology ‘in a dish’ or immune-matched cell-based therapies for the clinic. This special issue will guide the reader through stem cell self-renewal, pluripotency and differentiation. The first articles focus on improving cell fidelity, understanding the innate immune system and the importance of materials chemistry, biofabrication and bioengineering. These are followed by articles that focus on industrial application, commercialization and label-free assessment of tissue formation. The special issue concludes with an article discussing human liver cell-based therapies past, present and future.

This article is part of the theme issue ‘Designer human tissue: coming to a lab near you’.

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