tbuckley/cabot-search huggingface dataset:
KLF5 downregulation desensitizes castration-resistant prostate cancer cells to docetaxel by increasing BECN1 expression and inducing cell autophagy
Authors: Jing Jia, Hai-Bao Zhang, Qi Shi, Chao Yang, Jian-Bin Ma, Bin Jin, Xinyang Wang, Dalin He, Peng Guo
Journal: Theranostics (2019)

KLF5 is frequently deleted or downregulated in prostate cancer.However, it is not known whether downregulation of KLF5 is associated with the response of prostate cancer cells to chemotherapy and/or prognosis of patients.Methods: We monitored cell growth by MTT and colony formation assays, and cell autophagy through tandem fluorescence microscopy and transmission electron microscopy.Gene expression was analyzed by RT-qPCR and Western blotting.We determined the binding of KLF5 together with HDAC3 on the beclin-1 (BECN1) promoter by the ChIP assay, oligonucleotides pulldown, and co-immunoprecipitation.The effect of docetaxel on cell growth in vivo was examined in a CWR22RV1 xenograft tumor mouse model. Results:In the present study, we found that KLF5 down-regulation was associated with progression of prostate cancer and poor prognosis of patients.KLF5 knockdown reduced the sensitivity of prostate cancer cells to docetaxel in vitro and in vivo, and docetaxel treatment decreased the expression of KLF5.Moreover, we confirmed that docetaxel treatment inhibited cell death by inducing autophagy in prostate cancer cells.Thus, we hypothesized that KLF5 could be a regulator of cell autophagy.Interestingly, KLF5 could inhibit prostate cancer cell autophagy by suppressing the transcription of BECN1 cooperatively with HDAC3.Another significant finding was that docetaxel treatment repressed KLF5 expression through AMPK/mTOR/p70S6K signaling pathway resulting in increased BECN1, induction of cell autophagy, and promotion of cell survival in castration-resistant prostate cancer cells.Conclusions: Our results indicated that downregulation of KLF5 promoted cell autophagy in prostate cancer.Furthermore, reduced KLF5 also facilitated cell autophagy induced by docetaxel resulting in desensitization to the drug and cell survival.Decreased levels of KLF5 led to increased BECN1 via AMPK/mTOR/p70S6K signaling.Thus, repression of BECN1 and cell autophagy was critical for KLF5 to increase the sensitivity of prostate cancer cells to docetaxel.
Mass spectrometry based proteomic analysis of tissue and serum for breast cancer biomarkers
Authors: Ming Lu, Stephen Whelan, Jianbo He, Julian Whitelegge, Kym Faull, Romaine Saxton, Helena Chang
Journal: Cancer Research (2008)

3953  It is known that early detection of breast cancer by screening may save lives. Our goal is to identify breast cancer biomarkers for early detection. In this study, we search for the breast cancer biomarkers in cancer tissue and serum with combined liquid chromatography-mass spectrometry using the LTQ-Orbitrap XL/ESI instrument.  Membrane proteins perform vital cellular functions and frequently are important drug targets. Components from the cell surface continuously shed as membrane-derived vesicles, which pass through the draining lymphatics and end up in the circulation. Our previous study demonstrated that hydrophobic proteins are enriched with acylated membrane proteins. We hypothesize that exploring hydrophobic proteins in cancer tissue and serum from breast cancer patients can lead to the discovery of promising biomarkers.  Breast cancer tissue, normal breast tissue and serum samples were collected from breast cancer patients. All specimens were processed and stored in -80°C until analysis. Serum high abundant proteins were depleted using the IgY column (Beckman Coulter). No depletion for protein extraction from tissue samples. Hydrophobic proteins from all specimens were enriched with a reverse-phase chromatographic step using a polymeric stationary phase. Proteins retained on the reverse phase column were eluted by injection of formic acid and fractions were collected. After processing steps of reduction, alkylation, trypsin digestion and desalting, samples were then further analyzed by nanoLC (Eksigent) and LTQ-Orbitrap XL/ESI (ThermoFisher Scientific).  All MS/MS spectra were searched by the SEQUEST algorithm incorporated into the Thermo Finnigan Bioworks software (v3.2) (Eng and Yates III, University of Washington, WA, USA). We applied more stringent data filtering criteria than suggested by HUPO PPP using Xcorr ≥2.00 with charge state 1+, Xcorr ≥2.5 with charge state 2+, Xcorr ≥3.75 with charge state 3+, DeltCn ≥0.1 and Rsp=1. For protein level, the required consensus score was more than 15.0, and the identified proteins based on identification of at least two different peptides sequences. Additionally, proteins with less than three peptide hits were manually evaluated to confirm the identification.  We identified more than 350 proteins from each specimen. Many of the proteins with known vital cellular functions, such as heat shock proteins, translation elongation factors, endothelial cell growth factors, mucin, annexin and keratins have been identified. Protein profiles of cancer, normal tissue and serum of the same patients were systematically examined and compared.  The initial results are promising and we conclude that mass spectrometric approaches coupled with depletion/partitioning and bioinformatic tools are effective for biomarker discovery. When sufficiently refined, these technologies may pave the way for early detection and better treatment of breast cancer.
Abstract #4119: Regulation of UVB induced cutaneous carcinogenesis by T-cells
Authors: Nabiha Yusuf, Tahseen Nasti, Santosh Katiyar, Craig Elmets
Journal: Cancer Research (2009)

Ultraviolet (UV) irradiation, in particular the mid-wave range (UVB;290-320 nm), is one of the most significant risk factors for the development of non-melanoma skin cancer (basal cell and squamous cell carcinoma). UVB radiation-induced immunosuppression, which occurs in both humans and laboratory animals, contributes to their pathogenesis. However, there are conflicting reports on the relative role of CD4+ and CD8+ T-cells in UVB induced skin cancer. The purpose of this study was to delineate the contribution of these two cell subpopulations to UVB induced immunosuppression and tumor development using CD4 knockout (CD4-/-) and CD8 knockout (CD8-/-) mice. We observed that UVB induced skin carcinogenesis was retarded in mice deficient in CD4+ T-cells compared to wildtype mice, whereas significantly greater (p  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4119.
Resectability and indication for chemotherapy in patients with colorectal liver metastases as assessed by medical oncologists and surgeons.
Authors: Kia Homayounfar, Annalen Bleckmann, Hans-Joachim Helms, Florian Lordick, Josef Rüschoff, Lena-Christin Conradi, Thilo Sprenger, Thomas Lorf, Heinz Becker, B. Michael Ghadimi, Torsten Liersch
Journal: Journal of Clinical Oncology (2012)

e14167 Background: Multidisciplinary treatment in patients with colorectal liver metastases (CRLM) is standard in modern oncology. However, for interdisciplinary discussion assessing complimentary disciplines' potential and changes in personal views is crucial. We evaluated experienced medical oncologists' (MO) and surgeons' (SG) assessment of resectability and indication for chemotherapy (CTx) in patients with CRLM. Methods: Thirty patients who underwent R0-resection of CRLM between 2001 and 2011 at our department were selected. Medical history and staging data were presented to MO (n=10) and SG (n=11) in a virtual tumor board (TB1). Standardized blinded TED-voting answers (9 options) included assessment of resectability and the indication for pre- and/or postoperative CTx. The virtual tumor board was followed by training in terms of state-of-the-art lectures on potential of CTx and surgery. Assessment was then repeated in a second virtual tumor board (TB2). Results: 630 (21x30) answers were obtained per tumor board. In TB1 resectability, borderline resectability and definite unresectability were expected in 433, 161 and 36 answers, respectively. Resectability was significantly more often expected by SG (p&lt;0.001). In TB2 57% of answers were different from TB1 (p&lt;0.001). Assessment shifted from borderline resectable to resectable CRLM in 81 of 161 and from unresectable to (borderline) resectable CRLM in 29 of 36 answers (p&lt;0.001). The shift was significant in MO (p=0.012) and SG (p&lt;0.001). Preoperative CTx was significantly more often indicated by MO (p=0.041) and included in 255 answers (44%) in TB1 compared to only 157 answers (27%) in TB2 (p&lt;0.001). With 55% of answers voting for postoperative CTx remained stable in TB1 and TB2 without a significant difference between MO and SG in either TB1 (p=0.099) or TB2 (p=0.353). Conclusions: Resectability and indication for pre- but not postoperative CTx were discrepantly assessed by MO and SG. Training had a strong influence on decision making in MO and SG resulting in a higher rate of patients deemed (borderline) resectable. Furthermore, following training MO and SG opted less often for preoperative CTx.
Genetic and epigenetic alterations of tumor related genes in hepatocellular carcinomas
Authors: Reiko Makino, Kumiko Ueda, Takuya Matsumura, Keiji Mitamura
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

3549 

Hepatocellular carcinoma (HCC) is a malignant cancer with poor prognosis. HCC is developed from chronic hepatitis or liver cirrhosis by hepatitis B virus or hepatitis C virus infection, or drinking. It is important to clarify the characteristics of tumors to prevention of tumor progression and develop treatment for HCCs. In the present study, we examined the genetic and epigenetic alterations of tumor related genes in 38 HCCs. Surgically resected HCCs and their adjacent non-tumorous tissues were used for the analysis. Tissues were collected with informed consent. We analyzed genetic alterations in p53, β-catenin, E-cadherin, TGFβ receptor, and ARF/INK4A locus in HCCs. Mutations were analyzed by fluorescence-based PCR-SSCP method using automated DNA sequencer or Genetic Analyser 3100 (ABI). Loss of heterozygosity (LOH) and promoter CpG hypermethylation of tumor suppressor genes were also analyzed. We found mutations and LOH of the p53 gene in 58% and genetic alterations and CpG hypermethylation of ARF/INK4A locus in 42% of HCCs. Mutations of the β-catenin gene was found in 33%, and LOH and CpG hypermethylation of the E-cadherin gene in 58% of HCCs. But, mutation of TGFβRII was observed in 5% of HCCs. In this study, we found most of HCCs had several genetic alterations, however in some HCCs, we did not find genetic and epigenetic alterations of the genes we examined.
Alteration of apoptotic signaling molecules as a function of time after radiation in human neuroblastoma cells
Authors: Natarajan Aravindan, Rakhesh Madhusoodhanan, Mohan Natarajan, Nisha Singh, Terence Herman
Journal: Cancer Research (2008)

5757  Ascertaining the time dependent regulation of induced apoptosis and radioresistance is important to understand the relationship between the level of spontaneous apoptosis in cells and their radiosensitivity. Accordingly, we investigated the time dependent expression of apoptosis related genes and radioresistance in neuroblastoma cells. Serum starved human SK-N-MC cells were exposed to low linear energy transfer (LET) radiation (2Gy) and incubated for 15, 30, 45min and 48h. Radioresistance was investigated by examining the NFκB DNA-binding activity, cellular toxicity, DNA fragmentation and expression of apoptotic signal transduction molecules. NFκB DNA binding activity was analyzed using electrophoretic mobility shift assay (EMSA). Cellular toxicity was measured using MTT assay, and DNA fragmentation was quantified by labeling with fluorescein conjugated deoxynucleotides. Microarray analysis was performed using cDNA microarray and relative gene expression was measured as % GAPDH and, subsequently validated using Q-PCR. Induction of NFκB analyzed using EMSA showed an increased DNA binding activity at all time points investigated. Induced DNA fragmentation was observed after 15, 30 and 45 min post-radiation. Relatively, induced fragmentation was reduced after 48 h. Compared to the untreated controls cellular toxicity was induced with low LET radiation after 15, 30 and 45min. Conversely, cytotoxicity was relatively less at 48 h after low LET radiation. Microarray analysis after low LET radiation revealed time dependent modulation of apoptosis-related genes that are involved in radio-adaptation, spontaneous apoptosis related early-responsive genes and late response genes. These results suggest that the time dependent regulation of apoptotic response may determine the relationship between the level of spontaneous apoptosis in cells and their radiosensitivity.
Crizotinib in<i>MET</i>-Deregulated or<i>ROS1</i>-Rearranged Pretreated Non–Small Cell Lung Cancer (METROS): A Phase II, Prospective, Multicenter, Two-Arms Trial
Authors: Lorenza Landi, Rita Chiari, Marcello Tiseo, Federica D'Incà, Claudio Dazzi, Antonio Chella, Angelo Delmonte, Laura Bonanno, Diana Giannarelli, Diego Luigi Cortinovis, Filippo de Marinis, Gloria Borra, Alessandro Morabito, Cesare Gridelli, Domenico Galetta, Fausto Barbieri, Francesco Grossi, Enrica Capelletto, Gabriele Minuti, Francesca Mazzoni, Claudio Verusio, Emilio Bria, Greta Alì, Rossella Bruno, Agnese Proietti, Gabriella Fontanini, Lucio Crinò, Federico Cappuzzo
Journal: Clinical Cancer Research (2019)

MET-deregulated NSCLC represents an urgent clinical need because of unfavorable prognosis and lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET amplification or exon 14 mutations, no conclusive data are currently available. This study aimed at investigating activity of crizotinib in patients harboring MET or ROS1 alterations.Patients with pretreated advanced NSCLC and evidence of ROS1 rearrangements (cohort A) or MET deregulation (amplification, ratio MET/CEP7 >2.2 or MET exon 14 mutations, cohort B) were treated with crizotinib 250 mg twice daily orally. The coprimary endpoint was objective response rate in the two cohorts.From December 2014 to March 2017, 505 patients were screened and a total of 52 patients (26 patients per cohort) were enrolled onto the study. At data cutoff of September 2017, in cohort A, objective response rate was 65%, and median progression-free survival and overall survival were 22.8 months [95% confidence interval (CI) 15.2-30.3] and not reached, respectively. In cohort B, objective response rate was 27%, median progression-free survival was 4.4 months (95% CI 3.0-5.8), and overall survival was 5.4 months (95% CI, 4.2-6.5). No difference in any clinical endpoint was observed between MET-amplified and exon 14-mutated patients. No response was observed among the 5 patients with cooccurrence of a second gene alteration. No unexpected toxicity was observed in both cohorts.Crizotinib induces response in a fraction of MET-deregulated NSCLC. Additional studies and innovative therapies are urgently needed.
Downregulation of Bim by BDNF/TrkB protects neuroblastoma cells from chemotherapy-induced cell death
Authors: Robert Z. Luo, Zhen Lu, Yilin Lu, Shilpi Khare, Siji Kondo, Yiki Kondo, Yinhua Yu, Warren S-L. Liao, Gordon B. Mills, Robert C. Bast
Journal: Cancer Research (2006)

4092  Chemoresistance and increased tumor expression of TrkB and Brain-derived neurotrophic factor (BDNF) are two biomarkers of poor prognosis in neuroblastoma (NB) patients. Understanding the signal transduction pathways that affect the sensitivity of NB cells to chemotherapy is important for developing more effective therapies. Previously we found that BDNF activation of TrkB through PI3K/Akt protects NB from etoposide/cisplatin induced cell death. Bim, a BH3-only member of death activators in the Bcl-2 superfamily, modulates the intrinsic mitochondrial death pathway and is regulated by multiple growth factor signaling pathways. In this study we investigated the role of Bim in the brain-derived neurotrophic factor (BDNF)/TrkB protection of NB cells from chemotherapy-induced cell death. The three chemotherapeutic drugs paclitaxel, etoposide and cisplatin were used in this study to investigate the role of Bim in the brain-derived neurotrophic factor (BDNF)/TrkB protection of NB cells from chemotherapy-induced cell death. Gene silencing experiments showed that silencing of Bim with siRNA protected the NB cells from paclitaxel but not etoposide or cisplatin-induced cell death. Using pharmacological and genetic methods, we found that BDNF-induced reduction of Bim was regulated by the MAPK pathway, but not by the PI3K/Akt pathway. Both MAPK and PI3K pathways were involved in the BDNF protection of NB cells from paclitaxel-induced cell death, while PI3K pathway only was involved in BDNF protection of NB cells from etoposide or cisplatin-induced cell death. Thus the role of Bim in BDNF protection of NB cells from chemotherapy depended on the chemotherapeutic drugs used. These data indicate that different chemotherapeutic drugs induce distinct death pathways and that growth factors utilize different signal transduction pathways to modulate the effects of chemotherapy on cells.
Responding to mental health needs after terror attacks
Authors: Kate Allsopp, Chris R Brewin, Alan Barrett, Richard Williams, Daniel Hind, Prathiba Chitsabesan, Paul French
Journal: BMJ (2019)

Serious problems identified after the 2005 London bombings still remain, argue Kate Allsopp and colleagues Mental health responses for people caught up in terror attacks are often inadequate. Internationally, existing services repeatedly fail to identify those with short and long term needs, resulting in an increased prevalence of post-traumatic stress disorder, depression, and anxiety disorders compared with the general population.1 Health services should plan for short and longer term psychosocial care and mental health treatment for the substantial minority who need interventions.2 But the UK has been slow to learn. Many shortcomings in the response to the 2005 London bombings remained at the time of the 2017 Manchester Arena bombing, despite proposals for a new approach. Here, we discuss how services have evolved since 2005 and what still needs to be done. The demographics of the affected population are central to the design of any mental health response (box 1). The organisational challenges include specifying a responsible lead and chain of command; obtaining funding; providing reassurance, guidance, and messaging on trauma responses aimed at health services, other organisations, and the public; and identifying those affected and creating information handling arrangements that are flexible but compliant with data protection legislation. Coordination of a cross-agency response, involving health services, the third sector, and voluntary organisations is necessary to identify people who may develop mental health needs, arrange equitable access to evidence based care, and monitor use and outcomes. Box 1 ### Matching the mental health response to the population affected by mass casualty incidentsRETURN TO TEXT
The moderating role of allergy immunotherapy in asthma progression: Results of a population‐based cohort study
Authors: Jochen Schmitt, Eike Wüstenberg, Denise Küster, Victoria Mücke, Niels Serup‐Hansen, Falko Tesch
Journal: Allergy (2019)

Abstract Background Allergic asthma causes substantial morbidity and constitutes a public health burden, which increases with asthma severity. There is evidence that allergy immunotherapy (AIT) prevents the progression of allergic rhinitis (AR) to asthma. However, evidence is missing on the potential of AIT to prevent progression from milder to more severe asthma. Methods This population‐based cohort study utilized healthcare data (2005 to 2014) from a statutory health insurance in Germany. The severity of asthma was classified according to the treatment steps recommended by the global initiative for asthma (GINA). The effect of AIT on the transition between the GINA steps was analyzed using multivariable Cox regression models adjusted for age and sex. Results From the total cohort of 1,739,440 patients, 39,167 individuals aged 14 years or older were classified as having incident asthma during the observation period and were included in the study. From these, 4111 patients (10.5%) received AIT. AIT exposure was associated with a significantly decreased likelihood of asthma progression from GINA step 1 to GINA step 3 (HR 0.87; 95% CI 0.80‐0.95) and GINA step 3 to GINA step 4 (HR 0.66; 95% CI 0.60‐0.74). GINA medication for step 2 and step 5 was rarely prescribed. Conclusions This observational study in a real‐world setting indicates that patients with allergic asthma who receive AIT are less likely to experience progression of asthma severity than asthma patients not receiving AIT.
Exosomes promote pre-metastatic niche formation in ovarian cancer
Authors: Wenlong Feng, Dylan C. Dean, Francis J. Hornicek, Huirong Shi, Zhenfeng Duan
Journal: Molecular Cancer (2019)

Ovarian cancer is one of the most common gynecological malignancies. Upon initial diagnosis, the majority of patients present with widespread metastatic growth within the peritoneal cavity. This metastatic growth occurs in stages, with the formation of a pre-metastatic niche occurring prior to macroscopic tumor cell invasion. Exosomes released by the primary ovarian tumor are small extracellular vesicles which prepare the distant tumor microenvironment for accelerated metastatic invasion. They regulate intercellular communication between tumor cells and normal stroma, cancer-associated fibroblasts, and local immune cells within the tumor microenvironment. In this review, we highlight the emerging roles of ovarian cancer exosomes as coordinators of pre-metastatic niche formation, biomarkers amenable to liquid biopsy, and targets of chemotherapy.