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PubMed1999

[Standards, options and recommendations (SOR) for clinical care of squamous cell carcinoma of the oropharynx. Groupe de travail SOR].

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature systematic review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines according to the definitions of Standards, Options and Recommendations for the management of squamous carcinoma of the oropharynx. METHODS: Data have been identified by literature search using Medline (1991-1998) and the expert groups personal reference lists. Once the guidelines were defined, the document was submitted for review to national and international independent reviewers and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations for squamous cell carcinoma of the oropharynx management are that: 1) diagnosis and initial assessment should be based on appropriate clinical and radiological findings; 2) the therapeutic strategy is based on surgery, radiotherapy, bradytherapy and chemotherapy; 3) in limited tumours, the recommended strategy involved the use of one of these modality; 4) a multimodality approach is recommended for the treatment of extended resectable tumours. Following results of recent meta-analyses, use of neo-adjuvant chemotherapy is not recommended. The same studies have shown that association of chemotherapy and radiotherapy either in sequence or in combination significantly improve survival of extended curable tumours. These associations are recommended within the framework of clinical trials; 5) follow-up of squamous carcinoma of the oropharynx should involve physical examination of the upper aerodigestive tract and the lymph nodes areas every three months during the first year, every six months during the second year and then every year. An annual chest x-ray is recommended. Other investigations should be performed as indicated by symptoms and clinical manifestations.

Carcinoma, Squamous Cell↗
PubMed1995

Overexpression of Bcl-XL by cytotoxic drug exposure confers resistance to ionizing radiation-induced internucleosomal DNA fragmentation.

Acquired resistance to diverse chemotherapeutic agents has been associated with overexpression of the P-glycoprotein. We have selected human U-937 cells for clones resistant to the cytotoxic agents doxorubicin (U-A20) and vincristine (U-V20). The results demonstrate that P-glycoprotein-positive U-A20 and U-V20 cells exhibit resistance to inducers of internucleosomal DNA fragmentation. Although parental U-937 cells responded to ionizing radiation with the DNA laddering characteristic of physiological cell death, the drug-resistant lines were insensitive to this effect. The U-A20 and U-V20 clones were also resistant to endonucleolytic DNA cleavage associated with exposure to tumor necrosis factor or ceramide. Previous work has demonstrated that physiological cell death is inhibited by overexpression of the Bcl-2 protein. However, analysis of Bcl-2 revealed similar levels in the parental and drug-resistant cells. In contrast, we show that U-A20 and U-V20 cells overexpress the Bcl-2-related protein, Bcl-xL. Moreover, studies with a U-937 cell line transfected with a Bcl-XL expression vector confirm resistance to ionizing radiation-induced DNA fragmentation and cell killing. These findings suggest that, unlike Bcl-2, Bcl-XL may be constitutively overexpressed as a result of selection for cytotoxic drug resistance and that Bcl-XL participates in an acquired form of multimodality resistance to chemotherapeutic agents and radiation.

Base Sequence↗
PubMed2005

Effects of spatial congruity on audio-visual multimodal integration.

Spatial constraints on multisensory integration of auditory (A) and visual (V) stimuli were investigated in humans using behavioral and electrophysiological measures. The aim was to find out whether cross-modal interactions between A and V stimuli depend on their spatial congruity, as has been found for multisensory neurons in animal studies (Stein & Meredith, 1993). Randomized sequences of unimodal (A or V) and simultaneous bimodal (AV) stimuli were presented to right- or left-field locations while subjects made speeded responses to infrequent targets of greater intensity that occurred in either or both modalities. Behavioral responses to the bimodal stimuli were faster and more accurate than to the unimodal stimuli for both same-location and different-location AV pairings. The neural basis of this cross-modal facilitation was studied by comparing event-related potentials (ERPs) to the bimodal AV stimuli with the summed ERPs to the unimodal A and V stimuli. These comparisons revealed neural interactions localized to the ventral occipito-temporal cortex (at 190 msec) and to the superior temporal cortical areas (at 260 msec) for both same- and different-location AV pairings. In contrast, ERP interactions that differed according to spatial congruity included a phase and amplitude modulation of visual-evoked activity localized to the ventral occipito-temporal cortex at 100-400 msec and an amplitude modulation of activity localized to the superior temporal region at 260-280 msec. These results demonstrate overlapping but distinctive patterns of multisensory integration for spatially congruent and incongruent AV stimuli.

Acoustic Stimulation↗
PubMed2006

Multidisciplinary therapy of locally far-advanced or inflammatory breast cancer with fixed perioperative sequence of epirubicin, vinorelbine, and Fluorouracil chemotherapy, surgery, and radiotherapy: long-term results.

BACKGROUND: Based on phase II data in advanced breast cancer (BC), the fluorouracil, epirubicin, and vinorelbine (FEN) combination was assessed as perioperative chemotherapy, integrated in a multidisciplinary treatment for locally advanced BC. PATIENTS AND METHODS: Patients with newly diagnosed inoperable (stage IIIB or inflammatory) BC. Multimodality treatment protocol consisted of four preoperative courses of fluorouracil (600 mg/m(2) day 1), epirubicin (75 mg/m(2) day 1), and vinorelbine (25 mg/m(2) day1 and day 8), all i.v. every 21 days, followed by radical or conservative surgery according to clinical response and four postoperative identical chemotherapy courses aimed to eradicate micrometastatic disease. Locoregional radiotherapy was offered to all patients after the completion of chemotherapy followed by hormonotherapy according to hormone receptor status. The primary end points of the study were: (a) clinical and pathological response, (b) downstaging and conversion to operable disease, and (c) recurrence-free survival (RFS) and overall survival (OS). RESULTS: Forty-eight women, one stage IIIA, 27 (56.2%) stage IIIB, two stage IIIC (4.1%), and 12 (25%) with inflammatory BC, aged 34-75 years (median, 52), were accrued. Thirty-eight and 34 patients completed the planned pre- and postoperative chemotherapy, respectively. Totals of 175 and 135 cycles were administered pre- and postoperatively, respectively. Toxicity of both phases, mainly hematologic, was in general acceptable without treatment-related death. Venous reactions were a frequent problem. All but three tumors were converted to operable, 31.3% with breast conservation. The clinical response rate (RR) was 77.7% (22.2% complete) and pathological RR was 73.3% (complete, 20% in both primary and axilla). After a median follow-up of 72 months, 62.5% and 16.7% of patients remain relapse free at 3 and 5 years, respectively, while 83% and 58.3% were alive 3 and 5 years, respectively, after the start of chemotherapy. Median RFS and OS have not yet been reached, and are currently 37+ and 62+ months, respectively. CONCLUSION: This fixed number of FEN perioperative courses schedule followed by radiotherapy is safe and highly active in inducing both local and distant control of locally far-advanced BC. This strategy is at least not inferior to other established regimens or strategies for locally far-advanced BC, while the integration of taxanes or new targeted agents may help show its true value for this challenging clinical entity.

Adult↗
PubMed2004

Multidisciplinary approaches in the management of advanced head and neck tumors: state of the art.

PURPOSE OF REVIEW: Head and neck cancer remains a significant cause of morbidity worldwide, with approximately 400,000 new cases per year. Ongoing advances in multidisciplinary management of this complex and multivaried disease process are resulting in improved function, quality of life, and survival. This review presents selected advances in primary research in head and neck cancer during the year 2003. RECENT FINDINGS: Successful management of head and neck cancer now requires a cooperative approach among a broad group of medical disciplines that includes head and neck surgery, radiation oncology, medical oncology, medical imaging, clinical pathology and lab medicine, social work, nutrition, and others. Translation of continued advances in these fields by cooperative work will continue to yield incremental advances in diagnosis, staging, treatment, follow-up, supportive care, and quality of life. Accordingly, this review aims to include facets of each individual field. Diagnosis and staging continue to evolve with the inclusion of nuclear medicine and in vivo molecular imaging based on the technology of positron emission tomography and single photon emission computed tomographic scanning. Multimodality approaches remain the forefront of intervention for patients with advanced disease. Facets that continue to be defined and studied include the best treatment order of the three disciplines of surgery, radiation, and chemotherapy; the refinement of radiation by altering fraction dose, sequence, and time course; radiosensitization by chemo- and biologic therapy; and the addition of novel, biologically targeted agents to these disciplines. Following from the side effects of these intensive treatments to a functionally critical part of the body are ongoing advances in supportive care and quality of life. SUMMARY: Head and neck cancer represents a collection of diseases that, although seemingly united by location and histology, on closer inspection represent a diverse collection of subcategories that often differ in pathogenesis, tumor biology, sublocation within the head and neck region, diagnosis, prognosis, treatment, and effect on quality of life. Given this complexity, it is not surprising that clinical management is also complicated and requires a cooperative effort among multiple subspecialties. This review of the current standard of care for patients with head and neck cancer aims to assist this diverse group of practitioners in caring for this complex group of patients.

Carcinoma, Squamous Cell↗
PubMed2025

A Graph Contrastive Learning Method for Enhancing Genome Recovery in Complex Microbial Communities.

Accurate genome binning is essential for resolving microbial community structure and functional potential from metagenomic data. However, existing approaches-primarily reliant on tetranucleotide frequency (TNF) and abundance profiles-often perform sub-optimally in the face of complex community compositions, low-abundance taxa, and long-read sequencing datasets. To address these limitations, we present MBGCCA, a novel metagenomic binning framework that synergistically integrates graph neural networks (GNNs), contrastive learning, and information-theoretic regularization to enhance binning accuracy, robustness, and biological coherence. MBGCCA operates in two stages: (1) multimodal information integration, where TNF and abundance profiles are fused via a deep neural network trained using a multi-view contrastive loss, and (2) self-supervised graph representation learning, which leverages assembly graph topology to refine contig embeddings. The contrastive learning objective follows the InfoMax principle by maximizing mutual information across augmented views and modalities, encouraging the model to extract globally consistent and high-information representations. By aligning perturbed graph views while preserving topological structure, MBGCCA effectively captures both global genomic characteristics and local contig relationships. Comprehensive evaluations using both synthetic and real-world datasets-including wastewater and soil microbiomes-demonstrate that MBGCCA consistently outperforms state-of-the-art binning methods, particularly in challenging scenarios marked by sparse data and high community complexity. These results highlight the value of entropy-aware, topology-preserving learning for advancing metagenomic genome reconstruction.

canonical correlation analysis↗
PubMed2003

Fluorescence multiplexing with time-resolved and spectral discrimination using a near-IR detector.

We report on the design and performance of a two-color, time-resolved detector for the acquisition of both steady-state and time-resolved fluorescence data acquired in real time during the capillary gel electrophoresis separation of DNA sequencing fragments. The detector consisted of a pair of pulsed laser diodes operating at 680 and 780 nm. The diode heads were coupled directly to single-mode fibers, which were terminated into a single fiber mounted via a FC/PC connector to the detector body. The detector contained a dichroic filter, which directed the dual-laser beams to an objective. The objective focused the laser light into a capillary gel column and also collected the resulting fluorescence emission. The dual-color emission was transmitted through the dichroic and focused onto a multimode fiber (core diameter 50 microm), which carried the luminescence to a pair of single-photon avalanche diodes (SPADs). The emission was sorted spectrally using a second dichroic onto one of two SPADs and isolated using appropriate interference filters (710- or 810-nm channel). The dual-color detector demonstrated a time response of 450 and 510 ps (fwhm) for the 710- and 810-nm channels, respectively. The mass detection limits for two near-IR dye-labeled sequencing primers electrophoresed in a capillary gel column were found to be 7.1 x 10(-21) and 3.2 x 10(-20) mol (SNR = 3) for the 710- and 810-nm detector channels, respectively. In addition, no leakage of luminescence excited at 680 nm was observed in the 810-nm channel or 780-nm excited luminescence into the 710-nm channel. An M13mp18 template was sequenced in a single capillary gel column using a two-color, two-lifetime format. The read length was found to be 650 base pairs for the test template at a calling accuracy of 95.1% using a linear poly(dimethylacrylamide) (POP6) gel column, with the read length determined primarily by the electrophoretic resolution produced by the sieving gel.

DNA, Viral↗
PubMedDate not supplied

Chemical composition distribution of bacterial copolyesters.

Poly(3-hydroxybutyrate) [P(3HB)] and its copolymers with hydroxyalkanoates are naturally occurring thermoplastic materials produced by bacteria. There are many potential uses for these copolyesters owing to their biodegradability and biocompatibility. The physical properties of the copolyesters vary depending on the chemical structure as well as the composition of the comonomers. Usually, we expect, copolymers to have a narrow chemical composition distribution (CCD). Several reports, however, have pointed out that some bacterial copolyesters have broad and/or multimodal CCD. Fractionation based on the chemical composition has also been reported for several bacterial copolyester samples. In this review, the literature concerning CCD and fractionation based on chemical composition is summarized. The width of CCD is approximated based on the data of diad sequence distribution. Generality of the complex CCD in bacterial copolyesters is also discussed.

Bacteria↗
PubMed1997

The evolutionary origin of the language areas in the human brain. A neuroanatomical perspective.

The capacity to learn syntactic rules is a hallmark of the human species, but whether this has been acquired by the process of natural selection has been the subject of controversy. Furthermore, the cortical localization of linguistic capacities has prompted some authors to suggest a modular representation of language in the brain. In this paper, we rather propose that the neural device involved in language is embedded into a large-scale neurocognitive network comprising widespread connections between the temporal, parietal and frontal (especially prefrontal) cortices. This network is involved in the temporal organization of behavior and motor sequences, and in working (active) memory, a sort of short-term memory that participates in immediate cognitive processing. In human evolution, a precondition for language was the establishment of strong cortico-cortical interactions in the postrolandic cortex that enabled the development of multimodal associations. Wernicke's area originated as a converging place in which such associations (concepts) acquired a phonological correlate. We postulate that these phonological representations projected into inferoparietal areas, which were connected to the incipient Broca's area, thus forming a working memory circuit for processing and learning complex vocalizations. As a result of selective pressure for learning capacity and memory storage, this device yielded a sophisticated system able to generate complicated utterances (precursors of syntax) as it became increasingly connected with other brain regions, especially in the prefrontal cortex. This view argues for a gradual origin of the neural substrate for language as required by natural selection.

Animals↗
PubMed1999

MR urography in the diagnosis of urinary tract obstruction.

OBJECTIVE: To evaluate the efficiency of MR urography in depicting the urinary tract. METHODS: 33 patients with urinary tract abnormalities were additionally evaluated with MR urography. 25 had dilated upper urinary tracts because of urinary obstruction and 8 had normal tracts. MR urography was performed with a 1,5T magnet using a heavy T2w sequence (3D-IR-TSE) in the coronal plane. Images were post-processed using the MIP algorithm. Both reconstructed and source images were evaluated. The results of MR urography were compared with the final diagnosis, which was established surgically in 23 cases, and with multimodality imaging workup in 10 cases. RESULTS: MR urography correctly depicted the level of obstruction and the degree of dilatation of the urinary tract in all 25 patients with hydronephrotic kidneys (sensitivity 100%). Additionally, it succeeded in suggesting the underlying pathology in 25 cases (48%). Concerning the 8 patients without dilatation of the urinary tract, there was either no depiction or depiction was bad. CONCLUSION: MR urography, a new noninvasive technique, demonstrates 100% sensitivity in diagnosing urinary tract obstruction and also suggests the underlying pathology in many cases. In nondilated systems it is not possible to get good images because MR urography only depicts fluid in the urinary tract. Thus we believe that MR urography can provide a reliable alternative in selected cases as opposed to other more invasive modalities, such as retrograde or antegrade urography, and is without the risk of contrast media and radiation exposure.

Adult↗
PubMed2004

Radiation and phylogeography in the Japanese macaque, Macaca fuscata.

The Japanese macaque (Macaca fuscata) presumably differentiated from eastern rhesus macaque (Macaca mulatta) populations during the Pleistocene and the two species are closely related. In order to analyse speciation and subspeciation events in the Japanese macaque and to describe historical and current relationships among their populations, we sequenced and analysed a fragment of 392bp of mitochondrial DNA (mtDNA) control region in 50 individuals belonging to six populations of Japanese macaque and compared these sequences with 89 eastern rhesus macaque control region sequences from GenBank/EMBL database. There were high genetic similarities between both species and only two positions were fixed within each species, which supports the inclusion of the Japanese macaque in a single species with eastern populations of rhesus macaques. Japanese macaque ancestors colonised Japan after the separation of the two species, estimated at between 0.31 and 0.88 million years ago (Mya). The star-like phylogeny, multimodal mismatch distribution, and lack of correlation between geographic and genetic distances are in accordance with a rapid dispersion of macaques throughout the archipelago after the arrival into Japan. The species shows low genetic variation within populations and high levels of genetic differentiation among populations with no mtDNA haplotype shared across populations. Genetic distances between Yakushima macaques (Macaca fuscata yakui) and any other population of Macaca fuscata fuscata subspecies are comparable to the distances between populations of Honshu, Awajishima, and Kyushu, not supporting the classification of Yakushima macaques as a different subspecies.

Animals↗
PubMed1998

Effects of combined treatment of chemotherapeutics and hyperthermia on survival and the regulation of heat shock proteins in Dunning R3327 prostate carcinoma cells.

BACKGROUND: Hyperthermia can enhance the clinical response of chemotherapeutic agents in prostate cancer, but optimal sequencing of this combination therapy needs to be developed. Given the role of heat shock proteins (HSPs) in the development of resistance (thermotolerance) to subsequent hyperthermic stresses as well as to certain chemotherapeutics, the study of HSP regulation is important in the establishment of effective schedules in multimodal treatment strategies. METHODS: In this study we evaluated the effects of the chemotherapeutic agents cisplatin, 5-fluorouracil, and adriamycin in combination with hyperthermia. (43 degrees C, 1 h) on clonogenic survival and inducible HSP70 regulation in Dunning rat adenocarcinoma of the prostate. HSP70 was analyzed by Western blot and by measuring beta-galactosidase produced by cells stably transfected with a gene construct containing the E. coli beta-galactosidase gene driven by the Drosophila HSP70 promoter. RESULTS: Colony formation assays revealed a sensitizing effect of hyperthermia when simultaneously combined with each chemotherapeutic agent, resulting in a potentiated cytotoxicity compared to subsequenced treatments. Thermotolerant cells showed a significantly better survival when treated with adriamycin alone, but also when each chemotherapeutic agent was combined with hyperthermia. This enhanced survival was correlated with inducible HSP70 accumulation. The chemotherapeutics modified the HSP70 promoter activation induced by hyperthermia, suggesting changes in the development of cellular thermotolerance. CONCLUSIONS: Our data reveal synergistic cytotoxic effects of the synchronous application of chemotherapeutic agents and hyperthermia on this model of prostate cancer. Furthermore, they demonstrate that the induction of HSPs in thermotolerant cells, as measured by HSP70 induction, results in a modulation the chemotherapeutic-mediated cytotoxicity. Therefore, HSP70 is a useful marker of cellular resistance in multimodal approaches combining hyperthermia and chemotherapeutic agents in the treatment of locally advanced prostate carcinoma.

Animals↗
PubMed2026

Anaplastic lymphoma kinase immunohistochemical positivity in high-grade pulmonary neuroendocrine carcinoma: an actionable signal or merely a shadow?

AIMS: Anaplastic lymphoma kinase (ALK) rearrangements are actionable drivers in non-small cell lung carcinoma (NSCLC), but the biological significance of ALK-immunohistochemistry (IHC) positivity in high-grade pulmonary neuroendocrine carcinoma (NEC) remains unclear. This study evaluated the diagnostic and therapeutic implications of discordant ALK IHC and genomic findings and the role of multimodal molecular testing in resolving them. METHODS: We retrospectively analysed eight South Asian patients (Indian and Nepali) with de novo high-grade pulmonary NEC and diffuse ALK immunoreactivity treated at a tertiary cancer centre in India. Comprehensive molecular profiling using DNA- and RNA-based next-generation sequencing (NGS) and ALK fluorescence in situ hybridisation (where tissue was adequate) was performed. Clinical outcomes and responses to ALK-targeted tyrosine kinase inhibitors (TKIs) were assessed. RESULTS: ALK IHC positivity was observed in 8 of 100 selectively tested cases among 319 high-grade pulmonary NECs diagnosed between 2019 and 2025. The cohort included seven SCLCs (one combined adenocarcinoma-SCLC) and one large-cell neuroendocrine carcinoma (LCNEC). Median age was 51 years; 75% were female and 87.5% never-smokers. Among five comprehensively profiled cases, true ALK rearrangements were confirmed in two (one LCNEC and one SCLC), both detectable only by RNA sequencing. Durable benefit from ALK-TKI therapy was seen only in the molecularly confirmed LCNEC case (>16 months), whereas ALK IHC-positive but NGS-negative cases progressed rapidly. CONCLUSIONS: True ALK rearrangements in high-grade pulmonary NEC are rare but highly actionable. ALK IHC alone is an unreliable predictor of therapeutic benefit. RNA-based sequencing is essential for fusion detection. Comprehensive molecular confirmation, with RNA sequencing as the preferred modality, should precede any initiation of ALK-targeted therapy in high-grade pulmonary NEC.

IMMUNOHISTOCHEMISTRY↗
PubMed2004

Multimodal imaging in the congenital pulmonary lymphangiectasia-congenital chylothorax-hydrops fetalis continuum.

We report on three infants with congenital chylothorax (CC) and congenital pulmonary lymphangiectasia (CPL). CPL appears to be a characteristic pathological finding in CC. Through the use of lymphoscintigraphy and computed tomography, this study suggests that CC and CPL are strongly correlated entities and that the dysplasia of the lymphatic system results in a pulmonary lymphatic obstruction sequence. The initial microscopic dilatation of the lymph channels may lead to progressive weeping of lymphatics and, consequently, to pleural effusion. Non-Immune Hydrops Fetalis (NIHF) may be the final consequence of impaired systemic venous return and may help to explain pleural-pulmonary involvement in this generalized lymph-vessel malformation syndrome.

Abnormalities, Multiple↗
PubMed2005

Combination of gemcitabine and Ad5/3-Delta24, a tropism modified conditionally replicating adenovirus, for the treatment of ovarian cancer.

Conditionally replicating adenoviruses (CRAds) represent a novel approach for the treatment of cancers resistant to conventional therapies. The efficacy of CRAds might be further improved by using chemotherapeutic agents in a multimodal antitumor approach. We have evaluated the use of Ad5/3-Delta24, a serotype 3 receptor targeted Rb/p16 pathway selective CRAd, in combination with gemcitabine against human ovarian adenocarcinoma. The combination of these agents showed synergistic cell killing in vitro compared to single treatments. However, the effect was dependent on dose and sequencing of the agents. Our results also indicate that gemcitabine reduces the initial rate of Ad5/3-Delta24 replication without affecting the total amount of virus produced. Possible reasons for synergy between Ad5/3-Delta24 and gemcitabine include the chemosensitizing activity of E1A and/or altered replication kinetics. In an orthotopic murine model of peritoneally disseminated ovarian cancer, the combination increased the survival of mice over either agent alone, and almost 60% of treated mice were cured. Sequencing of the agents was critical for toxicity versus efficacy. Mice remained free from intraperitoneal disease, but some succumbed to treatment-related hepatic or bone marrow toxicity. This suggests that improved efficacy may uncover treatment-related toxicity, which needs to be monitored closely in clinical trials.

Adenocarcinoma↗
PubMed1998

[Barrett carcinoma as a tumor entity with special therapy consequences].

The development of columnar lined epithelium with intestinal metaplasia in the distal esophagus is a possible, but not a necessary, end stage of advanced gastroesophageal reflux disease. Currently, research is focused on the carcinogenesis of Barrett's carcinoma and the metaplasia-dysplasia carcinoma sequence, since it is a malignoma with the highest increasing incidence in Western industrial countries. Possible causes of the above-mentioned sequence are excessive acid, duodenogastric reflux, and genetic factors. A curative surgical approach is the radical R-0 resection. Some centers prefer the transmediastinal esophagectomy. Others prefer the transthoracic en bloc esophagectomy. Reconstruction can be done with the stomach and the colon. Patients with advanced disease probably benefit best from multimodal therapy with neoadjuvant radiochemotherapy.

Barrett Esophagus↗
PubMed2006

Dynamic usage of transcription start sites within core promoters.

BACKGROUND: Mammalian promoters do not initiate transcription at single, well defined base pairs, but rather at multiple, alternative start sites spread across a region. We previously characterized the static structures of transcription start site usage within promoters at the base pair level, based on large-scale sequencing of transcript 5' ends. RESULTS: In the present study we begin to explore the internal dynamics of mammalian promoters, and demonstrate that start site selection within many mouse core promoters varies among tissues. We also show that this dynamic usage of start sites is associated with CpG islands, broad and multimodal promoter structures, and imprinting. CONCLUSION: Our results reveal a new level of biologic complexity within promoters--fine-scale regulation of transcription starting events at the base pair level. These events are likely to be related to epigenetic transcriptional regulation.

Animals↗
PubMed2005

Current strategies in whole-brain radiation therapy for brain metastases.

Whole-brain radiation therapy (WBRT) has been the primary treatment for patients with brain metastases for more than 50 years and provides effective palliative relief in most patients. Although advancements in radiotherapeutic technique continue to improve local and locoregional control, median survival for patients treated with WBRT monotherapy remains fixed at approximately 4 to 6 months. Key issues in the use of WBRT include optimizing its efficacy when it is used in conjunction with surgery, radiosurgery, radiosensitizers, and new chemotherapeutic agents. These multimodal approaches to brain metastases have resulted in significant increases in the median survival time in many patients. Radiosurgery is part of a continuing effort to improve the effects of radiation therapy, especially in brain metastases. The optimal combination of WBRT and radiosurgery remains to be elucidated, including appropriate timing or sequence and use in conjunction with other modalities. Newer radiosensitizing agents (e.g., efaproxiral [RSR-13] and motexafin gadolinium) have shown promise in the treatment of brain tumors, especially in specific patient subsets. Recently developed systemic chemotherapy agents, such as temozolomide, which crosses the blood-brain barrier, have a synergistic effect on brain metastases when used in conjunction with radiation. In addition, the use of interstitial chemotherapy agents provides highly focused local chemotherapy in the brain without increasing systemic toxicity; carmustine polymer wafer, in combination with WBRT, has shown promising results in treating brain metastases.

Biocompatible Materials↗