julilili42/papers huggingface dataset:
Temozolomide combined with the PI3K inhibitor LY294002 or the mTOR inhibitor rapamycin inhibits melanoma cell growth, survival and invasion
2007-06-20

8559 Background: Potential therapeutic targets in the treatment of metastatic melanoma have emerged, to which pharmacological inhibitors have been designed, which may enhance tumor chemosensitivity. In melanoma, dacarbazine is considered to be the most effective agent although total responses do not exceed 20% The clinical activity of temozolomide is similar to that of dacarbazine, but temozolomide has the advantages of being absorbed orally and of crossing the blood-brain barrier. Many clinical trials of targeted therapy and chemotherapy combinations lack rigorous preclinical evaluation and may neglect relevant mechanistic interactions. The PI3K-AKT-mTOR (AKT) and RAS-RAF- MEK-ERK (MAPK) signaling pathways are constitutively activated in melanoma, and appear to play a role in chemoresistance. Methods: In this study, a panel of pharmacological inhibitors was utilized in order to block the AKT and MAPK signaling pathways at different levels (AKT: PI3K, mTOR; MAPK: RAF, MEK) in 5 human metastatic melanoma cell lines. The effects on chemosensitivity to temozolomide and cisplatin was then investigated. Results: The effects of most inhibitors on chemosensitivity varied significantly between the different cell lines. However, LY294002, a PI3K inhibitor and rapamycin, an mTOR inhibitor, consistently enhanced chemosensitivity. Treatment of melanoma cells with temozolomide or cisplatin combined with LY294002 or rapamycin had a strong effect on melanoma cell growth and survival. Invasive melanoma growth in organotypic cultures of human skin was suppressed completely. The most pronounced potentiation of efficacy was seen with temozolomide in combination with rapamycin. Conclusions: These data suggest that LY294002 and rapamycin can render melanoma cells susceptible to apoptosis, induced by chemotherapeutic agents such as temozolomide and cisplatin. Since both temozolomide and rapamycin are used clinically, the combination of temozolomide with rapamycin might potentially be utilized as an approach in melanoma treatment. This combination merits clinical investigation. No significant financial relationships to disclose.
Sorafenib but not sunitinib affects the induction of immune responses
2007-06-20

3504 Background: The tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib are approved for the treatment of patients with metastatic renal cell cancer. To analyze the possible use of these compounds in combination with immunotherapeutic approaches we investigated the effects of both TKIs on function of human dendritic cells (DCs) and induction of primary immune responses in vitro and in vivo. Methods: Human monocytes-derived DCs were treated with DMSO, sorafenib or sunitinib. Functional and phenotypic analyses as well as the possible impact on signal transduction pathways were performed. Furthermore, induction of immune responses in vivo was analyzed in animals treated with both compounds. Results: Sorafenib but not sunitinib inhibits function of DCs. Exposure of DCs to sorafenib reduces expression of CD1a, MHC and costimulatory molecules in response to stimuli via TLR ligands. Sorafenib reduces cytokine production by DCs as well as their ability to migrate and stimulate T cell (TC) responses. We found that these inhibitory effects of sorafenib are mediated via inhibition of PI3K, MAP kinases and NFκB signaling. The TKIs have no influence on phenotype and proliferation of TCs. To analyze the effects of TKIs on the generation of immune responses in vivo, induction of TC responses was assessed by peptide vaccination with the model antigen OVA-001 in C57BL/6 mice. When mice were pretreated with both TKIs which were also given during vaccination, it was observed that sorafenib, but not sunitinib significantly reduces the generation of vaccine-specific CD8+ TCs. Numbers of CD4+ CD25+ regulatory TCs are reduced in sunitinib-treated mice, but not in sorafenib-treated animals. All effects of the TKIs are reversible, and the immune responses go back to normal levels if mice are immunized after discontinuation of treatment. Conclusions: In summary, sunitinib represents an interesting compound to be used in combination with immunotherapeutic approaches to treat cancer patients. No significant financial relationships to disclose.
Estrogen receptor (ER) status of disseminated tumor cells in the bone marrow of breast cancer patients
2007-06-20

21013 Background: The presence of disseminated tumor cells (DTC) in bone marrow (BM) of primary breast cancer patients is associated with poor prognosis. These patients may benefit from adjuvant endocrine therapy since cytotoxic agents are not able to completely eliminate DTCs as previously shown. Only patients with hormone receptor positive breast cancer are eligible for hormonal treatment. The ERa status is routinely defined in primary tumor tissue. However, the ERa status of DTC may differ compared to the primary tumor. Therefore, the aims of this study were (1) to determine the ERa status of DTC in BM of breast cancer patients, (2) and to compare the ERa status of DTC and corresponding primary tumors. Methods: BM aspirates from 251 primary breast cancer patients were included into the study. A double immunofluorescence staining procedure was established for the identification of cytokeratin-positive (CK)/ERa positive cells. ERa status of the primary tumor was immunohistochemically assessed using the same antibody against ERa. Results: In 105 of 251 (42%) breast cancer patients CK-positive cells could be detected in BM. The number of detected cells ranged between 1 and 13 / cells per 2*106 mononuclear cells. Disseminated tumor cells demonstrated ERa positivity in 13 (12%) of these 105 patients. The ERa expression on DTC was heterogeneous in 10 of 13 (79%) patients. Concordance rate of ERa status between primary tumor and DTC was 27%. Only 11 of 83 patients with ER a positive tumors had also ERa positives DTC. Conclusions: (1)The hormone receptor status between primary tumor and corresponding DTC is disconcordant. (2)This discrepancy may explain the rate of non-responders to adjuvant endocrine therapy despite ER-positive primary tumors. (3)These patients may benefit from adjuvant therapy regimens based on antibody strategies or bisphosphonates. No significant financial relationships to disclose.
Bisphosphonate-induced osteonecrosis of the jaw: Incidence and risk factors in patients with breast cancer and gynecological malignancies
2007-06-20

1113 Background: Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption. They are successfully used in conditions of increased bone turnover such as osteoporosis or bone metastases. Since 2003 multiple cases of bisphosphonate-induced osteonecrosis of the jaw (ONJ) were reported. Our purpose was to describe the incidence and risk factors of ONJ in patients with breast cancer or gynecological malignancies. Patients and Methods: ONJ was assessed retrospectively for all patients with breast cancer or gynecological malignancies treated with bisphosphonates at the Department of Gynecology and Obstetrics, University Hospital Tuebingen during April 1999 until May 2006. Results: 10 of 310 (3%) patients with breast cancer or gynecological malignancies developed ONJ while receiving bisphosphonate therapy. All patients with ONJ were treated for bone metastases. Except one all patients with ONJ had a history of recent dental procedures. All patients had received zoledronic acid as part of their bisphosphonate regimen. In 4 of 10 patients this was the only bisphosphonate given. The remaining 6 patients had received at least one of the other bisphosphonates (alendronate, ibandronate, clodronate or pamidronate) before or after zoledronic acid therapy during their course of disease. Time of exposure to bisphosphonates and the number of treatment cycles were significant risk factors for the development of ONJ (p&lt;0.001). In patients diagnosed with ONJ the mean number of treatment cycles was 27 ±18 cycles (median: 21 cycles, range 6–62 cycles) and the mean duration of bisphosphonate therapy was 29 ±20 months (median: 22 months, range 1–67 months). In contrast, the mean number of treatment cycles in patients without manifestation of ONJ was 11 ±12 cycles (median: 6 cycles, range 1–90 cycles). The mean duration of therapy was 12 months (median: 7 months, range 1–81 months). Conclusion: Osteonecrosis of the jaw is regarded a major side effect of bisphosphonate therapy. Length of exposure to bisphosphonates and the number of treatment cycles seem to be the most important risk factors for the development of ONJ. In addition, recent dental procedures favours the development of an ONJ. No significant financial relationships to disclose.
Radiation-induced sarcoma: A single center experience with 36 cases
2007-06-20

20525 Background: Radiation-induced sarcoma (RIS) is a rare complication of radiation therapy for any cause. With increasing numbers of patients receiving radiotherapy, data concerning the incidence and treatment outcome of RIS are urgently needed. Methods: We screened our local sarcoma registry for patients with RIS. 36 cases of RIS that had developed after radiation for malignant disease were identified and analyzed retrospectively over a 12 year period (1994–2006). Results: All patients had received radiation therapy between 1968 and 2002. The most frequent primary tumors were breast cancer (n = 19) and lymphoma (including Hodgkin`s and non-Hodgkin`s lymphoma, n = 9). The remainder received radiation therapy for tumors of the female reproductive organs (n = 2), head and neck cancer (n = 4), neuroblastoma (n = 1), and seminoma (n = 1).The median of delivered total radiation dose per patient was 50 Gy (35 to 72 Gray). Sources of irradiation were photons (n = 9), cobalt (n = 6), electrons (n = 2), and unknown in 19 cases. The median time interval from the start of irradiation the detection of the sarcoma was 11 years (1 - 35 years). The tumors arose within the radiation field in 29 cases, on the border of the field in 6 cases, and out of field in 1 case. The histology of RIS was angiosarcoma in most cases (n = 12), followed by pleomorphic sarcomas (n = 11), leiomyosarcoma (n = 4), fibrosarcoma (n = 2), osteosarcoma (n = 2), and others (n =5). Most cases were detected in a localized stage of disease (n = 33), and therefore, complete surgical removal was achieved in almost 50% (n = 17). However, this did not translate into long term survival within the overall study population. Only 11 patients remain free of disease during a mean follow-up period of 29 months (range, 0 - 51). Conclusions: Angiosarcomas within or on the border of the radiation field are the most common histological subentity of RIS. Therefore, follow-up of previously irradiated patients should include examination of irradiated regions with a high level of suspicion if cutaneous atypical vascular lesions are found. However, the clinician should be aware of the fact that RIS also occurs out of field and can be of non-angiogenic subtype as well. As far as treatment is concerned, RIS is treated the same as non-radiation induced sarcoma. No significant financial relationships to disclose.
Improving Lesion-Symptom Mapping
2007-06-21

Abstract Measures of brain activation (e.g., changes in scalp electrical potentials) have become the most popular method for inferring brain function. However, examining brain disruption (e.g., examining behavior after brain injury) can complement activation studies. Activation techniques identify regions involved with a task, whereas disruption techniques are able to discover which regions are crucial for a task. Voxel-based lesion mapping can be used to determine relationships between behavioral measures and the location of brain injury, revealing the function of brain regions. Lesion mapping can also correlate the effectiveness of neurosurgery with the location of brain resection, identifying optimal surgical targets. Traditionally, voxel-based lesion mapping has employed the chi-square test when the clinical measure is binomial and the Student's t test when measures are continuous. Here we suggest that the Liebermeister approach for binomial data is more sensitive than the chi-square test. We also suggest that a test described by Brunner and Munzel is more appropriate than the t test for nonbinomial data because clinical and neuropsychological data often violate the assumptions of the t test. We test our hypotheses comparing statistical tests using both simulated data and data obtained from a sample of stroke patients with disturbed spatial perception. We also developed software to implement these tests (MRIcron), made freely available to the scientific community.
Cortical Plasticity in Amyotrophic Lateral Sclerosis: Motor Imagery and Function
2007-06-21

Background. Cortical networks underlying motor imagery are functionally close to motor performance networks and can be activated by patients with severe motor disabilities. Objective. The aim of the study was to examine the longitudinal effect of progressive motoneuron degeneration on cortical representation of motor imagery and function in amyotrophic lateral sclerosis. Methods. The authors studied 14 amyotrophic lateral sclerosis patients and 15 healthy controls and a subgroup of 11 patients and 14 controls after 6 months with a grip force paradigm comprising imagery and execution tasks using functional magnetic resonance imaging. Results. Motor imagery activated similar neural networks as motor execution in amyotrophic lateral sclerosis patients and healthy subjects in the primary motor (BA 4), premotor, and supplementary motor (BA 6) cortex. Amyotrophic lateral sclerosis patients presented a stronger response within premotor and primary motor areas for imagery and execution compared to controls. After 6 months, these differences persisted with additional activity in the precentral gyrus in patients as well as in a frontoparietal network for motor imagery, in which activity increased with impairment. Conclusion. The findings suggest an ongoing compensatory process within the higher order motor-processing system of amyotrophic lateral sclerosis patients, probably to overcome loss of function in primary motor and motor imagery-specific networks. The increased activity in precentral and frontoparietal networks in motor imagery might be used to control brain-computer interfaces to drive communication and limb prosthetic devices in patients with loss of motor control such as severely disabled amyotrophic lateral sclerosis patients in a locked-in-like state.
Concentration Gradient Along the Scala Tympani After Local Application of Gentamicin to the Round Window Membrane
2007-06-22

Abstract Objectives: The distribution of gentamicin along the fluid spaces of the cochlea after local applications has never previously been demonstrated. Computer simulations have predicted that significant basal‐apical concentration gradients might be expected, and histologic studies indicate that hair cell damage is greater at the base than at the apex after local gentamicin application. In the present study, gradients of gentamicin along the cochlea were measured. Methods: A recently developed method of sampling perilymph from the cochlear apex of guinea pigs was used in which the samples represent fluid originating from different regions along the scala tympani. Gentamicin concentration was determined in sequential apical samples that were taken after up to 3 hours of local application to the round window niche. Results: Substantial gradients of gentamicin along the length of the scala tympani were demonstrated and quantified, averaging more than 4,000 times greater concentration at the base compared with the apex at the time of sampling. Peak concentrations and gradients for gentamicin varied considerably between animals, likely resulting from variations in round window membrane permeability and rates of perilymph flow. Conclusions: The large gradients for gentamicin demonstrated here in guinea pigs account for how it is possible to suppress vestibular function in some patients with a local application of gentamicin without damaging auditory function. Variations in round window membrane permeability and in perilymph flow could account for why hearing losses are observed in some patients.
Alpha synchronization during auditory spatial short-term memory
2007-06-22

Recent studies have suggested an active role of cortical alpha oscillations for cognitive functions including short-term memory. We used magnetoencephalography to assess alpha activity during an auditory spatial delayed matching-to-sample task compared with a nonmemory control condition. In the memory task, participants had to memorize the lateralization angle of a noise stimulus S1 and compare it with another lateralized sound S2 presented after an 800-ms delay phase. Whereas alpha desynchronization following S1 was observed over superior temporal areas under both conditions, only the memory task was accompanied by posterior parietal alpha synchronization during the subsequent delay period. The findings are consistent with the notion of alpha activity reflecting active inhibition of interfering processes during memory maintenance of spatial sounds.
Spirodionic Acid, a Novel Metabolite from Streptomyces sp., Part 1: Structure Elucidation and Diels–Alder‐Type Biosynthesis
2007-06-22

Abstract Spirodionic acid ( 1 ), a novel microbial metabolite with a spiro[4.5]decene skeleton, the 6‐ethyl‐2 H ‐pyrone 5 , dihydrosarkomycin ( 6 ), and other metabolites were isolated from the strain Streptomyces sp. Tü 6077. Structural elucidation was accomplished by NMR spectroscopic and mass‐spectrometric studies, and the biosyntheses of compounds 1 , 5 , and 6 were investigated by feeding experiments with 13 C‐labeled precursors. All results indicate a biogenetic sequence with metabolite 5 and sarkomycin ( 7 ) as precursors in the formation of spirocyclus 1 through an intermolecular Diels–Alder‐type reaction.
BeppoSAX observation of 4U 1705-44: detection of hard X-ray emission in the soft state
2007-06-26

\\n Context.4U 1705-44 is one of the best-studied type I X-ray burster and atoll sources.\\n Aims.Since it covers a wide range in luminosity (from a few to 50 \\n1036 erg s-1) and shows clear spectral state transitions, it\\nrepresents a good laboratory for testing the accretion models proposed for\\natoll sources.\\n Methods.We analyzed the energy spectrum accumulated with BeppoSAX observations (43.5 ks) in August 2000 when the source was in\\n a soft spectral state.\\n Results.The continuum of the wide-band energy spectrum is well-described by the sum of\\na blackbody ( 0.56 keV) and a Comptonized component (seed-photon\\ntemperature ∼1 keV, electron temperature 2.7 keV, and\\noptical depth 11). A hard tail was detected at energies above\\n~25 keV. The latter can be modeled by a power law having a photon index\\n~2.9, which contributes ~11% of the total flux in the range 0.1–200 keV. A broad emission line, possibly from a relativistic accretion disk, models\\nthe feature in the Fe K line region of the spectrum.\\n Conclusions.This is the first time that a high-energy tail has been observed during a soft\\nstate of the source.\\n
Serum Response Factor Contributes Selectively to Lymphocyte Development
2007-06-26

Serum response factor (SRF), is a crucial transcription factor for murine embryonic development and for the function of muscle cells and neurons. Gene expression data show that SRF and its transcriptional cofactors are also expressed in lymphocyte precursors and mature lymphocytes. However, the role of SRF in lymphocyte development has not been addressed in vivo so far, attributed in part to early embryonic lethality of conventional Srf-null mice. To determine the in vivo role of SRF in developing lymphocytes, we specifically inactivated the murine Srf gene during T or B cell development using lymphocyte-specific Cre transgenic mouse lines. T cell-specific Srf deletion led to a severe block in thymocyte development at the transition from CD4/CD8 double to single positive stage. The few residual T cells detectable in the periphery retained at least one functional Srf allele, thereby demonstrating the importance of SRF in T cell development. In contrast, deletion of Srf in developing B cells did not interfere with the growth and survival of B cells in general, yet led to a complete loss of marginal zone B cells and a marked reduction of the CD5+ B cell subset. Our study also revealed a contribution of SRF to the expression of the surface molecules IgM, CD19, and the chemokine receptor 4 in B lymphocytes. We conclude that SRF fulfills essential and distinct functions in the differentiation of different types of lymphocytes.
Dendritic cell–regulatory T‐cell interactions control self‐directed immunity
2007-06-26

In addition to their immunostimulatory capacity, dendritic cells (DCs) play a crucial role in central and peripheral tolerance mechanisms. In the absence of an infection, immature DCs constantly take up, process and present self‐antigens to specific T cells, which leads to the induction of T‐cell anergy or deletion. In recent years, several additional mechanisms have been identified by which DCs constantly downregulate immune responses to maintain immunological tolerance. Among these are the complex interactions between several DC subtypes and different types of regulatory T cells. In this review, we summarize recent key findings and concepts in this field.
Aptamer-Based Strategies for Stem Cell Research
2007-06-26

Aptamers have been introduced to analytical applications, target validation, and drug discovery processes and, recently, applied directly as therapeutic agents. Aptamers can be generated by a method called SELEX (Systematic Evolution of Ligands by Exponential Enrichment). This is quite remarkable for such a young technology, which is only created in the early 1990s. This paper reviews recent new applications of aptamers in stem cell research and tissue engineering.
Human WIPI‐1 puncta‐formation: A novel assay to assess mammalian autophagy
2007-06-27

Autophagy depends on the activity of phosphoinositide‐3 kinase class III to generate PI(3)P. We identified the human WIPI protein family of PI(3)P‐binding factors and showed that WIPI‐1 (Atg18) is linked to autophagy in human cells. Induction of autophagy by rapamycin, gleevec, thapsigargin and amino acid deprivation led to an accumulation of WIPI‐1 at LC3‐positive membrane structures (WIPI‐1 puncta‐formation), suggested to represent autophagosomal isolation membranes. WIPI‐1 puncta‐formation is inhibited by wortmannin and LY294002, and PI(3)P‐binding‐deficient WIPI‐1 is puncta‐formation‐incompetent. Quantification of WIPI‐1 puncta should be suitable to assay mammalian autophagy.