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PubMed1998

p53 sequence analysis predicts treatment response and outcome of patients with esophageal carcinoma.

BACKGROUND: The ability to predict biologic behavior and treatment responsiveness would be a valuable asset in the multimodality approach to esophageal carcinoma. The authors examined whether alterations of the p53 gene correlate with clinicopathologic parameters, response to preoperative chemotherapy/radiotherapy, and outcome in patients with esophageal carcinoma. METHODS. Histopathologic/genetic analysis of p53 was performed on formalin fixed, paraffin embedded tissues. Tissue sections were stained immunohistochemically for p53 protein followed by topographic genotyping comprised of polymerase chain reaction amplification and direct sequencing of p53 exons 5-8. All patients received induction chemotherapy (5-fluorouracil, cisplatin, and alpha-interferon) and concurrent external beam radiotherapy (4500 centigrays) followed by resection. RESULTS: p53 analysis performed on 42 tumors from patients with potentially resectable esophageal carcinoma revealed 25 of the 42 tumors (59.5%) to be p53 immunopositive; however, only 17 of the 42 tumors (40.5%) were proven to contain p53 point mutational damage in exons 8 (n=5), 5 (n=5), 7 (n=4), and 6 (n=3). Eight cases were weakly immunopositive and had no genotype mutation suggesting hyperexpression of normal wild-type p53. Genotyping also identified two immunonegative cases with deletion-type mutations (exons 5 and 6). Tissue samples collected before and after chemotherapy/radiotherapy exhibited fidelity in p53 mutational genotype in all cases. The presence of a p53 point mutation positively correlated with pTNM stage (P=0.003) and residual disease in the resected specimen (P=0.01). Moreover, survival of patients with p53 mutations was significantly lower than that of patients without mutations (overall survival of 21.6 months vs. 40 months; P=0.0038; and disease free survival of 14.1 months vs. 38 months; P=0.0004). CONCLUSIONS: Histopathologic/genetic analysis is a better determinant of p53 mutational damage than immunohistochemistry alone and can be used as a prognostic marker for esophageal carcinoma. p53 genotyping may define a subset of patients who respond to chemotherapy/radiotherapy and may predict who potentially benefits from multimodality therapy.

Adult↗
PubMedDate not supplied

Cyclic variations of the density dispersion pattern of the spermatozoa population.

Spermatozoa were separated into fractions by density on a Percoll column and were used to created a density dispersion pattern by plotting the number of the spermatozoa in the different fractions. This pattern varies daily in every healthy individual. In order to find the sequence of the variations, dispersion patterns of the spermatozoa were prepared during a period of 3 to 11 days following abstinence. The density distribution pattern of the spermatozoa of the normozoospermic donors, after a few days of abstinence was found to be unimodal; the pattern becomes multimodal for the following 2-4 days, after which it returns to its unimodal form for a single day. These variations show a cyclic sequence with individual periodicity (3-5 days). A density dispersion pattern received from healthy donors after 3 days of abstinence is considered "normal" and is presented.

Centrifugation, Density Gradient↗
PubMed2000

Role of multimodality treatment for lung cancer.

Locally advanced non-small cell lung cancer (NSCLC) is, in fact, a systemic disease requiring a multimodality approach for optimal treatment. The role of preoperative chemotherapy has been established and is now an accepted treatment for resectable Stage IIIA NSCLC. Several studies have addressed the feasibility and efficacy of preoperative chemotherapy followed by surgery. All these induction chemotherapy trials have reported a high radiographic response rate, high respectability rate and improved survival in completely resected patients. The findings of three published randomized trials indicate that the survival rate of Stage IIIA patients is better with induction chemotherapy plus surgical resection than with resection alone. More recently, Phase II trials using concurrent chemoradiotherapy have been tested with encouraging results. Chemo-therapy combined with thoracic radiotherapy has emerged as a primary treatment option for locally advanced, unresectable NSCLC. Randomized trials and subsequent meta-analyses have shown a clear survival benefit with platinum-based combination chemotherapy administered with thoracic radiation-as compared to radiation alone-in treating inoperable Stage IIIA and IIIB lung cancer. Combined modality treatment in locally advanced NSCLC continues to evolve and is the subject of ongoing research. Despite clinical advances, many aspects of the management of these patients are yet to be fully clarified: Is surgical resection really necessary for Stage IIIA patients? What is the value of altered-fractionation radiotherapy and three-dimensional conformal radiation therapy? What is the optimal sequencing of radiotherapy and chemotherapy? In this regard, new chemotherapeutic agents may provide additional benefits in the multimodality approach, and it is for this reason that various studies are underway which have incorporated new agents in the front line setting. Finally, a better understanding of the biology of tumors could well help us to optimize treatments. In the future, molecular classification of NSCLC may provide a useful tool when making therapy-related decisions.

Carcinoma, Non-Small-Cell Lung↗
PubMed2003

Solitary hemispheric demyelination in acute disseminated encephalomyelitis: clinicoradiological correlation.

We retrospectively studied 13 patients with solitary hemispheric demyelination in acute disseminated encephalo--myelitis (solitary-ADEM) to look for specific MRI features. Thirteen patients were subjected to routine MRI with varying initial clinical diagnosis, including demyelination, neoplasm, encephalitis and infarct. The provisional MRI diagnosis was based on lesion morphology, size, location, mass effect, effect on adjacent sulci, cisterns and gyral shape. On long repetition time (TR)/long echo time (TE) spin echo sequences, the lesions were heterogeneously hyperintense, and on short TR/short TE spin echo sequences, heterogeneously hypointense. Later, the provisional MRI diagnosis was corroborated with clinical parameters such as multimode-evoked potentials, electro--physiological studies and analysis of cerebrospinal fluid (CSF) in order to establish a definitive diagnosis. The diagnosis was established in all except one patient with tumour-like clinical and MRI features. The combination of MRI features and clinical parameters can establish a definitive diagnosis in the majority of cases, and this avoids a biopsy.

Adolescent↗
PubMed1982

Immunotherapy of metastases enhances subsequent chemotherapy.

In many multimodal therapies of cancer, postsurgical chemotherapy is administered before immunotherapy for treatment of micrometastatic disease. This sequence may not be the most efficacious. Experiments in which strain 2 guinea pigs bearing syngeneic L10 hepatocarcinomas were given immunotherapy showed that infiltrating immune effector cells not only were tumoricidal but disrupted the characteristically compact structure of metastatic foci. When cytotoxic drugs were administered at the peak of this inflammatory response, the survival rate of the guinea pigs increased significantly. We conclude that postsurgical immunotherapy can enhance the effect of cytotoxic drugs administered subsequently.

Animals↗
PubMed1997

Multimodality MRI in mesial temporal sclerosis: relative sensitivity and specificity.

Our objectives were to determine the relative sensitivity and specificity of different MRI sequences and analysis techniques for the detection of mesial temporal sclerosis (MTS). Mesial temporal sclerosis is the most common pathologic finding in patients undergoing temporal lobe epilepsy surgery. Magnetic resonance imaging is the most reliable preoperative imaging technique for the detection of MTS. We analyzed the abnormalities in preoperative MRIs of 44 consecutive patients who had undergone temporal lobectomy and who had pathologic confirmation of MTS. Techniques included inversion recovery (IR); T1-weighted, volume-acquired images; hippocampal T2 relaxometry (HT2); volumetric assessment; and visual analysis. Sensitivity was 86% with IR, 90% with T1-weighted qualitative visual analysis, and 97% with quantitative volumetry. Pathologic prolongation of HT2 (> 2 SD of normal) was present in 79%. Analysis of variance showed statistically significant differences in sensitivity between HT2, volumetric measurements (p < 0.01), and qualitative visual atrophy (p < 0.05). Concordance between all MRI modalities was 68%. Inversion recovery and qualitative analysis lateralized the side of surgery in 93%. The combination of IR and T1-weighted images correctly identify MTS in most patients. Hippocampal volumetry provided localization in an additional small number of patients.

Adolescent↗
PubMed2006

Sequential Monte Carlo for Bayesian matching of objects with occlusions.

We consider the problem of locating instances of a known object in a novel scene by matching the fiducial features of the object. The appearance of the features and the shape of the object are modeled separately and combined in a Bayesian framework. In this paper, we present a novel matching scheme based on Sequential Monte Carlo, in which the features are matched sequentially, utilizing the information about the locations of previously matched features to constrain the task. The particle representation of hypotheses about the object position allow matching in multimodal and cluttered environments, where batch algorithms may have convergence difficulties. The proposed method requires no initialization or predetermined matching order, as the sequence can be started from any feature. We also utilize a Bayesian model to deal with features that are not detected due to occlusions or abnormal appearance. In our experiments, the proposed matching system shows promising results, with performance equal to batch approaches when the target distribution is unimodal, while surpassing traditional methods under multimodal conditions. Using the occlusion model, the object can be localized from only a few visible features, with the nonvisible parts predicted from the conditional prior model.

Algorithms↗
PubMed2000

Tuning of an electrospray ionization source for maximum peptide-ion transmission into a mass spectrometer.

We describe assembly and optimization of a continuous flow nanoelectrospray source for high-performance analysis on a routine basis. It is derived from an inJection adaptable Fine Ionization Source ("JaFIS"), previously shown to be durable and easy to use (Geromanos, S.; et al. Rapid Commun. Mass Spectrom. 1998, 12, 551-556) and now modified for maximum sensitivity. Proper design, manufacturing, and quality control of spray needles with specific orifice diameters, in combination with precisely controlled helium backpressure and applied voltage, enable stable flows at 1-2 nL/min. Needle positioning and ion spray potential are hereby exceedingly important, as shifts by 0.5 mm or 25 V, respectively, cause significant reduction in signal strength. In addition to prolonged analysis times, ultralow flows also yield higher sensitivity, the result of an improved "overall ion transfer efficiency" measured to be approximately 5% at 1.6 nL/min. Used in combination with a "microtip" (Erdjument-Bromage, H.; et al. J. Chromatogr. A 1998, 826, 167-181), the optimized JaFIS implements infusion-style ESI-MS at sensitivities approaching capillary LC-MS. Spraying times in excess of 20 h allow for any number of tandem mass spectrometric analysis routines to be performed, and to average thousands of scans in every experiment, thereby further improving sensitivity. This was fully illustrated by extensive analysis of a 2-fmol peptide mixture, in a 2-microL volume, using a multimode MS approach.

Amino Acid Sequence↗
PubMed2025

Diagnostic and phylogenetic perspectives of the 2023 Murray Valley encephalitis virus outbreak in Australia: an observational study.

BACKGROUND: An outbreak of Murray Valley encephalitis virus (MVEV), the largest since 1974, was observed in Australia between Jan 1 and July 31, 2023. This study aims to characterise the utility of diagnostic platforms, testing algorithms, and genomic characteristics of MVEV to facilitate a comprehensive framework for MVEV testing and surveillance in the outbreak setting. METHODS: In this observational study, we assessed flavivirus diagnostics for all patients with suspected Murray Valley encephalitis in Australia from Jan 1 to July 31, 2023. We included all patients with confirmed Murray Valley encephalitis, probable Murray Valley encephalitis, or acute unspecified flavivirus infection using the Communicable Diseases Network Australia case definition. Cases were excluded if an alternative diagnosis was identified. We collected blood, serum, cerebrospinal fluid, brain tissue, urine, or a combination of these samples, as appropriate and at the discretion of the treating clinician. We conducted multimodal diagnostic testing, which included flavivirus-specific serological and nucleic acid amplification testing. Metagenomic next-generation sequencing, including next-generation deep sequencing, target-enrichment, and targeted amplification, was conducted on human and representative mosquito-derived samples obtained from established mosquito population surveillance programmes for phylogenetic analysis. FINDINGS: 27 patients with encephalitis were assessed for MVEV between Jan 1, 2023, and July 31, 2023, 23 (85%) of whom fulfilled national case definitions for confirmed Murray Valley encephalitis. Patient ages ranged from 6 weeks to 83 years (median 62&#xb7;0 years [IQR 31&#xb7;0-67&#xb7;5]) and patients were mostly male (21 [78%] male patients and six [22%] female patients). Incidence varied widely by geographical region and was highest in the Northern Territory (32&#xb7;0 per 1&#x2009;000&#x2009;000 population). Diagnostic specimen collection generally occurred promptly (median 6&#xb7;0 days [IQR 4&#xb7;0-14&#xb7;5] from symptom onset to diagnostic specimen collection). In seven patients, case assignation relied on convalescent serum samples to assess for seroconversion or an appropriate rise in antibody titre (to four times the initial value or greater), or both. MVEV-specific IgM was detectable in serum samples of 17 (81%) of 21 patients tested by day 7 and MVEV IgG or total antibody (TAb) were detected in 18 (100%) of 18 patients tested by day 30. MVEV-specific IgM (or TAb) and MVEV RNA were detected in cerebrospinal fluid collected within 14 days of symptom onset in nine (39%) of 23 patients and seven (28%) of 25 patients, respectively. Phylogenetic analysis revealed two circulating MVEV genotypes, G1A and G2, in mosquitoes and humans in 2023. In southeast Australia, only G1A was detected and probably introduced from enzootic foci in northern Australia. INTERPRETATION: This study provides a comprehensive overview of the diagnostic workflows and phylogenetic evaluations used during the 2023 MVEV outbreak in Australia, emphasising the importance of a multimodal approach for accurate and timely confirmation of flavivirus infection. Further One Health surveillance for MVEV and other zoonotic flaviviruses is key, given potential expanded ecological niches in the context of episodic climatic events. FUNDING: None.

Humans↗
PubMed2003

Multimodal magnetic resonance imaging of the central nervous system.

The physiological and biochemical properties of the diseased brain that can be explored with magnetic resonance imaging (MRI) are increasing. Progress in MR-based technology affords a large panel of MRI sequences that explore different phenomena and, thus, provide complementary informations. The diagnostic accuracy of MRI is improved by the combination of all MR modalities. However, this abundance of data requires an efficient multiparametric analysis to fully achieve the goal of the multimodal strategy. We will discuss the potential impact of this advanced MRI analysis in the clinical management and the therapeutical strategies of the most common brain pathologies (intracranial tumors, multiple sclerosis, stroke, epilepsy and dementia). This non-invasive approach is of utmost importance since it already improves the diagnosis and the therapeutic choice in the management of several central nervous system diseases.

Central Nervous System Diseases↗
PubMed2005

A gamma mixture model better accounts for among site rate heterogeneity.

MOTIVATION: Variation of substitution rates across nucleotide and amino acid sites has long been recognized as a characteristic of molecular sequence evolution. Evolutionary models that account for this rate heterogeneity usually use a gamma density function to model the rate distribution across sites. This density function, however, may not fit real datasets, especially when there is a multimodal distribution of rates. Here, we present a novel evolutionary model based on a mixture of gamma density functions. This model better describes the among-site rate variation characteristic of molecular sequence evolution. The use of this model may improve the accuracy of various phylogenetic methods, such as reconstructing phylogenetic trees, dating divergence events, inferring ancestral sequences and detecting conserved sites in proteins. RESULTS: Using diverse sets of protein sequences we show that the gamma mixture model better describes the stochastic process underlying protein evolution. We show that the proposed gamma mixture model fits protein datasets significantly better than the single-gamma model in 9 out of 10 datasets tested. We further show that using the gamma mixture model improves the accuracy of model-based prediction of conserved residues in proteins. AVAILABILITY: C++ source codes are available from the authors upon request.

Chromosome Mapping↗
PubMed1991

Branching pattern in the evolutionary tree for human mitochondrial DNA.

Eighty-eight types of mitochondrial (mt) DNA were found by sequencing the most variable part of the control region from 117 Caucasians. In the tree relating those types, most of the branching events occur about two-thirds of the way from the root of the tree to the tips of the branches. Moreover, the distribution of sequence differences between all possible pairs of individuals is approximately Poisson. Other non-African populations show a similar pattern. Assuming a neutral model, these findings imply that the probability of survival of new lineages has undergone dramatic changes, probably due to population expansion. Conversely, African populations show multimodal distributions fitting with a model of constant population size.

Animals↗
PubMed2026

Follicular Lymphoma Transformation is Characterized by Cytokine-associated Remodeling of Stromal and Macrophage Compartments.

Across cancer, one of the most frequent examples of histologic transformation is the evolution of follicular lymphoma (FL) to an aggressive large cell lymphoma. Despite recent progress, understanding of the molecular and cellular underpinnings of transformation remains incomplete. Here, we dissect the interplay of tumor and microenvironment cell populations across transformation through a multimodal investigation of 95 FL and transformed FL (tFL) samples, including single-cell and bulk RNA-sequencing alongside spatial transcriptomics and proteomics, and validate findings across independent FL-tFL pairs. Upon transformation, fibroblasts and GPNMB+ macrophages increase while lymph-node organizing follicular dendritic and CCL21+ fibroblastic reticular cells were lost, resulting in an altered spatial distribution of cytokines that impacts T cell infiltration and macrophage differentiation and function. Secreted stromal and macrophage signals were further evident by non-invasive plasma proteomics. Taken together, our data reveal expansion of macrophages and fibroblasts as key features of transformation with potential diagnostic and therapeutic implications.

Journal Article↗
PubMed2004

Multimodal and ubiquitous computing systems: supporting independent-living older users.

We document the rationale and design of a multimodal interface to a pervasive/ubiquitous computing system that supports independent living by older people in their own homes. The Millennium Home system involves fitting a resident's home with sensors--these sensors can be used to trigger sequences of interaction with the resident to warn them about dangerous events, or to check if they need external help. We draw lessons from the design process and conclude the paper with implications for the design of multimodal interfaces to ubiquitous systems developed for the elderly and in healthcare, as well as for more general ubiquitous computing applications.

Activities of Daily Living↗
PubMed2005

Multimodality agents for tumor imaging (PET, fluorescence) and photodynamic therapy. A possible "see and treat" approach.

Methyl 3-(1'-m-iodobenzyloxyethyl)-3-devinylpyropheophorbide-a (2), obtained in a sequence of reactions from pyropheophorbide-a (a chlorophyll-a derivative), was found to be a promising imaging agent and a photosensitizer for photodynamic therapy (PDT). The electrophilic aromatic iodination of the corresponding trimethylstannyl intermediate with Na124I in the presence of an Iodogen bead afforded 124I-labeled photosensitizer 4 with >95% radioactive specificity. In addition to drug-uptake, the light fluence and fluence rate that were used for the light treatment had a significant impact in long-term tumor cure. The iodo photosensitizer 2 (nonlabeled analogue of 4) produced 100% tumor cure (5/5 mice were tumor free on day 60) at a dose of 1.5 micromol/kg and a light dose of 128 J/cm2, 14 mW/cm2 for 2.5 h (lambda(max) 665 nm) at 24 h postinjection. The photosensitizer also showed promising tumor fluorescence and PET imaging ability. Our present work demonstrates the utility of the first 124I-labeled photosensitizer as a "multimodality agent", which could further be improved by using more tumor-avid and/or target-specific photosensitizers.

Animals↗
PubMed2003

Locally advanced breast cancer in developing countries: the place of surgery.

Most breast cancer patients in developing countries still present with locally advanced breast cancer (LABC). Because surgery is the most widely available treatment modality, we examine its place in the management of LABC. Historically, single local treatment modalities have had disappointing results, and multimodality therapy has become the norm for combatting LABC. Combining surgery and radiotherapy will lead to superior local control rates. Surgery should precede radiotherapy. Preoperative systemic treatment-with the possible exception of cyclophosphamide, methotrexate, 5-fluououracil (CMF) chemotherapy-does not influence surgical complication rates. Hormonal therapy is understudied and underutilized; its benefits become apparent only in prolonged follow-up. Sequencing of local and systemic treatments does not influence oncologic outcome, but failure to respond to preoperative systemic therapy may identify patients with a poor prognosis. With multimodality management including hormonal therapy, chemotherapy, radiotherapy, and surgery, local control rates of more than 80% and 5-year survival rates of more than 50% have become the norm.

Breast Neoplasms↗
PubMed2006

[Multimodal treatment of colon cancer?].

Surgical therapy is still the basis of therapy of patients with colon carcinoma. Multimodal therapeutical concepts are presently applied as a therapeutical standard in the adjuvant therapy and increasingly in the systemic therapy of patients with primarily inoperable metastases of the liver to reach a secondary operability. Interdisciplinary multimodal therapeutical concepts are even accepted within the therapy of metastasized colon carcinomas. There are still unanswered questions regarding sequences of palliative systemic therapies and their combinations with local ablative methods.

Antineoplastic Agents↗
PubMed2004

Multimodality image-guided surgery for the treatment of medically refractory epilepsy.

OBJECT: The aim of this study was to review seizure outcome, imaging modalities used, and complications following surgery in patients with epilepsy who had undergone multimodality image-guided surgery at our institution. METHODS: Data from patients with epilepsy who had undergone surgery between April 1999 and October 2001 were reviewed. During this time period, 116 operations were performed in 109 patients with medically refractory epilepsy. Among these patients, 22 were selected to undergo multimodality image-guided surgery primarily on the basis of whether they had no lesion visible on conventional magnetic resonance (MR) imaging sequences, multiple lesions, or one very large lesion that could not be completely resected without the risk of significant postoperative morbidity. A fourth group of patients in whom there was a single lesion in the eloquent cortex, a location associated with a significant risk of postoperative morbidity, was also included in the analysis. This latter group was assessed with the aid of intracranial grid electrodes that were coregistered to the MR image and were used intraoperatively to minimize electrode position error. Other imaging modalities used included positron emission tomography (PET), fluid-attenuated inversion recovery (FLAIR) MR imaging, and subtracted ictal-interictal single-photon positron emission computerized tomography (SPECT) coregistered with MR imaging (SISCOM). After coregistration, images were then downloaded onto an image-guided surgical system and the epileptogenic area was then resected. The mean patient age was 33 years (range 17-46 years), and there was a mean follow up of 27 months (range 14-41 months). Multimodality coregistrations used were as follows: nine PET scans, seven subdural electrode grids, four SISCOM studies, one FLAIR MR image, and one combined PET/subdural grid. Seizure outcome was excellent in 17 patients (77%) and not excellent in five (23%), or favorable in 19 (86%) and unfavorable in three (14%). Six patients (27%) had a transient neurological deficit, one patient (5%) a permanent major deficit, and three patients (15%) a permanent minor deficit. Five patients (24%) had a transient psychiatric problem postoperatively. CONCLUSIONS: Multimodality image-guided surgery offers a new perspective in surgery for epilepsy. Functional imaging modalities previously lateralized and often localized a seizure focus, but did not provide enough anatomical information to resect the epileptogenic zone confidently and safely. The coregistration of these modalities to a volumetric MR image and their incorporation into an image-guided system has allowed surgeons to offer surgery to patients who may not previously have been considered eligible, with outcomes comparable to those in patients with more straightforward lesional epilepsy.

Adolescent↗