Small inhibitor of Bcl-2, HA14-1, selectively enhanced the apoptotic effect of cisplatin by modulating Bcl-2 family members in MDA-MB-231 breast cancer cells

Inhibition or downregulation of Bcl-2 represents a new therapeutic approach to by-pass chemoresistance in cancer cells. Therefore, we explored the potential of this approach in breast cancer cells. Cisplatin and paclitaxel induced apoptosis in a dose-dependent manner in MCF-7 (drug-sensitive) and MDA-MB-231 (drug-insensitive) cells. Furthermore, when we transiently silenced Bcl-2, both cisplatin and paclitaxel induced apoptosis more than parental cells. Dose dependent induction of apoptosis by drugs was enhanced by the pre-treatment of these cells with HA14-1, a Bcl-2 inhibitor. Although the effect of cisplatin was significant on both cell lines, the effect of paclitaxel was much less potent only in MDA-MB-231 cells. To further understand the distinct role of drugs in MDA-MB-231 cells pretreated with HA14-1, caspases and Bcl-2 family proteins were studied. The apoptotic effect of cisplatin with or without HA14-1 pre-treatment is shown to be caspase-dependent. Among pro-apoptotic Bcl-2 proteins, Bax and Puma were found to be up-regulated whereas Bcl-2 and Bcl-x(L) were down-regulated when cells were pretreated with HA14-1 followed by paclitaxel or cisplatin. Enforced Bcl-2 expression in MDA-MB-231 cells abrogated the sensitizing effect of HA14-1 in cisplatin induced apoptosis. These results suggest that the potentiating effect of HA14-1 is drug and cell type specific and may not only depend on the inhibition of Bcl-2. Importantly, alteration of other pro-apoptotic or anti-apoptotic Bcl-2 family members may dictate the apoptotic response when HA14-1 is combined with chemotherapeutic drugs

A p53-regulated apoptotic gene signature predicts treatment response and outcome in pediatric acute lymphoblastic leukemia

Russell O Bainer,1 Matthew R Trendowski,2 Cheng Cheng,3 Deqing Pei,3 Wenjian Yang,3 Steven W Paugh,4 Kathleen H Goss,5 Andrew D Skol,6 Paul Pavlidis,7 Ching-Hon Pui,4,8 T Conrad Gilliam,1 William E Evans,4,9,* Kenan Onel10–13,* 1Department of Human Genetics, 2Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, IL, 3Department of Biostatistics, 4Hematological Malignancy Program, St Jude Children’s Research Hospital, Memphis, TN, 5University of Chicago Medicine Comprehensive Cancer Center, 6Department of Pediatrics, The University of Chicago, Chicago, IL, USA; 7Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada; 8Department of Oncology, 9Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, 10Division of Human Genetics and Genomics, 11Division of Hematology/Oncology and Stem Cell Transplantation, Cohen Children’s Medical Center, New Hyde Park, 12The Feinstein Institute for Medical Research, Manhasset, NY, 13Hofstra Northwell School of Medicine, Hofstra University, Hempstead, NY, USA *These authors contributed equally to this work Abstract: Gene signatures have been associated with outcome in pediatric acute lymphoblastic leukemia (ALL) and other malignancies. However, determining the molecular drivers of these expression changes remains challenging. In ALL blasts, the p53 tumor suppressor is the primary regulator of the apoptotic response to genotoxic chemotherapy, which is predictive of outcome. Consequently, we hypothesized that the normal p53-regulated apoptotic response to DNA damage would be altered in ALL and that this alteration would influence drug response and treatment outcome. To test this, we first used global expression profiling in related human B-lineage lymphoblastoid cell lines with either wild type or mutant TP53 to characterize the normal p53-mediated transcriptional response to ionizing radiation (IR) and identified 747 p53-regulated apoptotic target genes. We then sorted these genes into six temporal expression clusters (TECs) based upon differences over time in their IR-induced p53-regulated gene expression patterns, and found that one cluster (TEC1) was associated with multidrug resistance in leukemic blasts in one cohort of children with ALL and was an independent predictor of survival in two others. Therefore, by investigating p53-mediated apoptosis in vitro, we identified a gene signature significantly associated with drug resistance and treatment outcome in ALL. These results suggest that intersecting pathway-derived and clinically derived expression data may be a powerful method to discover driver gene signatures with functional and clinical implications in pediatric ALL and perhaps other cancers as well. Keywords: pediatric acute lymphoblastic leukemia, p53, gene expression signature, outcomes analysi

Dedifferentiated liposarcoma with leukocytosis. A case report of G-CSF-producing soft-tissue tumors, possible association with undifferentiated liposarcoma lineage

<p>Abstract</p> <p>Background</p> <p>Granulocyte-colony-stimulating factor (G-CSF) functions as a hematopoietic growth factor and it is responsible for leukocytosis. G-CSF-producing tumors associated with leukocytosis include various types of malignancies.</p> <p>Case presentation</p> <p>We report the case of a 72-year-old man with dedifferentiated liposarcoma characterized by dedifferentiated components of malignant fibrous histiocytoma (MFH)-like features in addition to well-differentiated lipoma-like liposarcoma, arising from his upper arm. Preoperative laboratory data showed leukocytosis (103,700/μl). The serum level of G-CSF was also elevated (620 pg/ml [normal, <8 pg/ml]). Nine days after the surgery, the leukocytosis was relieved (WBC; 6,920/μl) and the elevated serum G-CSF level was significantly decreased (G-CSF; 12 pg/ml). One month after the surgery, leukocytosis gradually began to appear again. Three months after the surgery metastatic lung lesions were confirmed, and the patient subsequently died of respiratory problems. In the English literature regarding soft-tissue tumors with leukocytosis, including the current case, we could review a total of 6 cases of liposarcoma with leukocytosis. The subtype of these 6 liposarcoma cases was undifferentiated liposarcoma, comprising dedifferentiated liposarcoma in 4 cases and pleomorphic liposarcoma in 2 cases.</p> <p>Conclusion</p> <p>Since the only other soft-tissue tumor that was associated with leukocytosis was MFH, and since MFH is characterized by the absence of any specific differentiation, we would like to propose a possible association between G-CSF-producing soft-tissue tumors and an undifferentiated liposarcoma lineage, such as dedifferentiated liposarcoma or pleomorphic liposarcoma.</p

Heat generation and transfer in automotive dry clutch engagement

Dynamic behaviour of automotive dry clutches depends on the frictional characteristics of the contact between the friction lining material, the flywheel, and the pressure plate during the clutch engagement process. During engagement due to high interfacial slip and relatively high contact pressures, generated friction gives rise to contact heat, which affects the material behaviour and the associated frictional characteristics. In practice excess interfacial slipping and generated heat during torque transmission can result in wear of the lining, thermal distortion of the friction disc, and reduced useful life of the clutch. This paper provides measurement of friction lining characteristics for dry clutches for new and worn state under representative operating conditions pertaining to interfacial slipping during clutch engagement, applied contact pressures, and generated temperatures. An analytical thermal partitioning network model of the clutch assembly, incorporating the flywheel, friction lining, and the pressure plate is presented, based upon the principle of conservation of energy. The results of the analysis show a higher coefficient of friction for the new lining material which reduces the extent of interfacial slipping during clutch engagement, thus reducing the frictional power loss and generated interfacial heating. The generated heat is removed less efficiently from worn lining. This might be affected by different factors observed such as the reduced lining thickness and the reduction of density of the material but mainly because of poorer thermal conductivity due to the depletion of copper particles in its microstructure as the result of wear. The study integrates frictional characteristics, microstructural composition, mechanisms of heat generation, effect of lining wear, and heat transfer in a fundamental manner, an approach not hitherto reported in literature

Search for Heavy Neutral and Charged Leptons in e+^+e−^- Annihilation at s\sqrt{s} = 183 and 189 GeV

A search for unstable neutral and charged heavy leptons as well as for stable charged heavy leptons is performed at center-of-mass energies $\sqrt{s}$ = 183 and 189 GeV with the L3 detector at LEP. No evidence for their existence is found. We exclude neutral heavy leptons which couple to the electron, muon or tau family, of the Dirac type for masses below 92.4, 93.3 and 83.3 GeV, and of the Majorana type for masses below 81.8, 84.1 and 73.5 GeV, respectively. We exclude unstable charged heavy leptons for masses below 93.9 GeV for a wide range of the associated neutral heavy lepton mass. If the unstable charged heavy lepton decays to a light neutrino, we exclude masses below 92.4 GeV. The production of stable charged heavy leptons with mass less than 93.5 GeV is also excluded

Measurement of an Elongation of the Pion Source in Z Decays

We measure Bose-Einstein correlations between like-sign charged pion pairs in hadronic Z decays with the L3 detector at LEP. The analysis is performed in three dimensions in the longitudinal center-of-mass system. The pion source is found to be elongated along the thrust axis with a ratio of transverse to longitudinal radius of $0.81\pm 0.02 ^{+0.03}_{-0.19}$

Partial sequencing of the bottle gourd genome reveals markers useful for phylogenetic analysis and breeding

<p>Abstract</p> <p>Background</p> <p>Bottle gourd [<it>Lagenaria siceraria </it>(Mol.) Standl.] is an important cucurbit crop worldwide. Archaeological research indicates that bottle gourd was domesticated more than 10,000 years ago, making it one of the earliest plants cultivated by man. In spite of its widespread importance and long history of cultivation almost nothing has been known about the genome of this species thus far.</p> <p>Results</p> <p>We report here the partial sequencing of bottle gourd genome using the 454 GS-FLX Titanium sequencing platform. A total of 150,253 sequence reads, which were assembled into 3,994 contigs and 82,522 singletons were generated. The total length of the non-redundant singletons/assemblies is 32 Mb, theoretically covering ~ 10% of the bottle gourd genome. Functional annotation of the sequences revealed a broad range of functional types, covering all the three top-level ontologies. Comparison of the gene sequences between bottle gourd and the model cucurbit cucumber (<it>Cucumis sativus</it>) revealed a 90% sequence similarity on average. Using the sequence information, 4395 microsatellite-containing sequences were identified and 400 SSR markers were developed, of which 94% amplified bands of anticipated sizes. Transferability of these markers to four other cucurbit species showed obvious decline with increasing phylogenetic distance. From analyzing polymorphisms of a subset of 14 SSR markers assayed on 44 representative China bottle gourd varieties/landraces, a principal coordinates (PCo) analysis output and a UPGMA-based dendrogram were constructed. Bottle gourd accessions tended to group by fruit shape rather than geographic origin, although in certain subclades the lines from the same or close origin did tend to cluster.</p> <p>Conclusions</p> <p>This work provides an initial basis for genome characterization, gene isolation and comparative genomics analysis in bottle gourd. The SSR markers developed would facilitate marker assisted breeding schemes for efficient introduction of desired traits.</p