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PubMed2001

Neural activity profiles of the neocortex and superior colliculus after bimodal sensory stimulation.

Current efforts at functional mapping of multisensory neurons are hampered by the need for both cellular-level resolution and the separate visualization of activity by different sensory cues. We have used a recently developed technique that exploits the differential time course of zif268 mRNA versus protein induction in neurons after sensory stimulation. Adult male rats were visually and acoustically deprived and then exposed to one of the following stimulation sequences: (i) no sensory stimulation; (ii) 2 h visual stimulation followed by 30 min auditory stimulation; (iii) 2 h auditory stimulation followed 30 min of visual stimulation; and (iv) 2 h compound visual and auditory stimulation. The neocortex and superior colliculus (SC) were then processed for fluorescent immunocytochemistry and in situ hybridization for staining of Zif268 protein and mRNA products. We have found that activity patterns in primary visual and auditory cortices were in accord with the sequence of the compound stimulus. We also show that SC superficial layers contained a pool of exclusively unimodal neurons, similar to that of visual cortex. Activity patterns of deep SC layers contained multimodal neurons with varying degrees of visual and auditory convergence. The deep SC layers also showed that auditory processing was largely carried out by a small, bimodal group of neurons whereas visual processing was coordinated by both a large unimodal and a small bimodal pool of neurons.

Acoustic Stimulation↗
PubMed1985

Management of locally advanced and inflammatory carcinoma of the breast.

From the data presented, there seems little doubt that multimodality systemic and local therapy offers the best chance of long term control and survival in patients with locally advanced noninflammatory and inflammatory carcinoma of the breast. However, the best method of sequencing these modalities remains inadequately defined. The rationale for systemic therapy is that systemic micrometastases are present at diagnosis; since almost all patients die from systemic disease, it would seem preferable to use chemotherapy first, while the disseminated tumor burden is low. Furthermore, this would allow an assessment of local response to the agents administered. However, chemotherapy almost never sterilizes bulky local disease, and local control rates are significantly improved by concurrent or sequential use of a local modality. From the information presented, it would appear that combined operation and radiotherapy may give a better outcome than either modality alone. However, in series in which chemotherapy plus one local modality are used, the five year, local failure rates were 20 to 35 per cent; with the use of two local modalities, the local failure rate was not significantly better (16, 20 and 22 per cent). The full effect of using two local modalities with systemic chemotherapy has not been satisfactorily explored to date. Many groups have suggested that the local control rate is proportional to the dose of radiotherapy given. Since iridium192 implantation permits larger doses of radiotherapy to the local tumor without an apparent increase in toxicity, it holds great promise as a means of improving local control in this disease and should be considered in all instances. Randomized studies comparing iridium192 with operation as an adjunct to external beam radiotherapy are needed. Although there is little doubt that combination systemic chemotherapy is mandatory for improved survival in these patients, the appropriate drugs, combination and scheduling are yet to be defined. Data from studies of metastatic carcinoma of the breast indicate that combinations of two to four drugs, including doxorubicin, give the best response rates. Recently, a number of anthracycline analogues have been studied, in particular mitoxantrone, with response rates comparable to doxorubicin but with less toxicity. These agents could be used effectively in future chemotherapy programs for locally advanced and inflammatory carcinoma of the breast. The place of endocrine manipulation also remains undefined. In general, women who present with carcinoma of the breast later in life are more likely to have hormone receptor positive, endocrine responsive tumors.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Agents↗
PubMed2026

High-Sensitivity ctDNA Analysis Uncovers Relevant Signals Missed by NGS in Pancreatic Cancer.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) carries high mortality despite multimodal therapy, and improved biomarkers are needed to guide perioperative care. This study evaluated the prognostic significance of Kirsten rat sarcoma virus (KRAS)-mutant circulating tumor DNA (ctDNA) detected by next-generation sequencing (NGS) and digital droplet PCR (ddPCR) in localized PDAC. EXPERIMENTAL DESIGN: In this prospective cohort study (2020-2024), patients with localized PDAC undergoing neoadjuvant chemotherapy (NAC) were enrolled across multiple sites within Northwestern Medicine. Blood samples for ctDNA were assessed at diagnosis, after NAC, and after resection using tumor-agnostic NGS and ddPCR targeting KRAS G12D/V/R mutations. Overall survival (OS) was assessed using Kaplan-Meier analysis. RESULTS: The cohort included 106 patients. At diagnosis, KRAS ctDNA was detected in 17.2% (17/99) by NGS and 64.9% (63/97) by ddPCR. Detection by both platforms was associated with shorter OS, with the higher-sensitivity ddPCR assay providing greater prognostic discrimination by identifying additional patients with poor outcomes not captured by NGS (NGS median OS 11.2 vs. 30.5 months, P < 0.001; ddPCR median OS 24.7 vs. 70.9 months, P = 0.004). Stratified by detection method, median OS was shortest in patients with ctDNA detected by both NGS and ddPCR (10.9 months), longest in those not detected by either platform (40.7 months), and intermediate in patients detected only by ddPCR (26.9 months; P < 0.001). CONCLUSIONS: In localized PDAC, KRAS-mutant ctDNA detected by NGS or ddPCR was associated with worse survival. ddPCR identified additional patients missed by NGS. Integrating ddPCR with NGS ctDNA measures may improve perioperative risk stratification, although validation is needed before clinical implementation.

Humans↗
PubMed1994

Bone scintigraphy and multimodality imaging in bone neoplasia: strategies for imaging in the new health care climate.

The integration of multiple imaging modalities in the assessment of musculoskeletal neoplasia is complex. Although no two instances are identical, certain guidelines can be gleaned from our experience as well as that reported in the literature. Assessment of most soft tissue masses is best carried forth with a combination of conventional radiography and magnetic resonance imaging (MRI). Screening skeletal scintigraphy without localizing symptomatology that includes axial and appendicular skeleton is best carried out initially with bone scintigraphy. Screening the axial skeleton in the presence of clinical symptomatology or a strong suspicion of axial skeletal metastases or pathology is best implemented as a total spine screening examination with MRI and specialized pulsing sequences. Computed tomography is reserved primarily for assessment of cortical and juxtacortical lesions, fracture fragment positioning and/or configuration, and characterization of lesion matrix calcification or ossification when conventional radiographs are indeterminate. Although physical examination and conventional radiography still remain the initial medical algorithms used to evaluate possible musculoskeletal neoplasia, primary skeletal tumors may require multimodality imaging to segregate aggressive and nonaggressive processes. In this multimodality scenario, bone scintigraphy has a critical role in assisting with differentiation between malignant and benign neoplasms.

Bone Neoplasms↗
PubMedDate not supplied

Heart, body, and soul: impact of church-based smoking cessation interventions on readiness to quit.

BACKGROUND: Given the relatively low spontaneous quit rates and poor treatment outcomes among African American smokers, this study was designed to evaluate the effects of a multimodal culturally relevant intervention for smoking behavior change compared with a self-help strategy among urban African Americans in Baltimore churches. METHOD: This randomized controlled trial in urban African American churches used the stages of change model to compare the effectiveness of two interventions in moving smokers along a continuum toward smoking cessation. Twenty-two churches were randomly assigned to either an intensive culturally specific intervention or a minimal self-help intervention. Smokers were interviewed at baseline church health fairs and at a 1-year follow-up. Self-reported quitters at follow-up were evaluated using saliva cotinine and exhaled carbon monoxide levels (CO). Stages of change were measured by applying a standardized stages of change instrument to individual interview response sequences. Analysis compared the two intervention groups at 1-year follow-up with baseline stages. Outcomes included quit rates and positive progress along the stages of change. RESULTS: Multiple logistic regression results, controlling for intrachurch correlation and demographic and baseline smoking characteristics, showed that the multimodal cultural intervention group was more likely to make positive progress along the stages of change continuum, compared with self-help intervention group (OR = 1.68; P = 0.04). Church denomination and intervention status interacted in the multivariate model; Baptists in the intensive intervention were three times (OR = 3.23; P = 0.010) more likely to make progress than all the other denomination groups. CONCLUSION: The multimodal culturally relevant intervention was more likely than a self-help intervention to positively influence smoking behavior. This is the first community-based intervention study to report progress along the stages of change as a process-oriented measure of success. It is notable that a spiritually based model focusing on environmental sanctions was more likely than a standard church disseminated self-help intervention to positively influence smoking behavior in an urban African American population.

Adult↗
PubMed1998

[Electrophysiological characteristics of asymptomatic relatives of patients with type 2 spinocerebellar ataxia].

INTRODUCTION: Electrophysiological studies have been shown to be useful in hereditary ataxia, but only a small number of patients have been studied, and the duration of the illness, serial studies and molecular definition have not been taken into account. OBJECTIVE: We proposed, by means of electrophysiological techniques, to characterize the functional evolutionary state of the afferent and efferent systems in asymptomatic relations of patients with type 2 spinocerebellar ataxia (SCA2). Patients and methods. A 10 year longitudinal, prospective study was made of 59 children of patients with SCA2. The sequence included four studies: 1986, 1991, 1994 and 1996, all with informed consent for the investigation. The control group consisted of 108 volunteers. The electrophysiological studies recorded were: conduction studies in peripheral nerves and multimodal evoked potentials. For statistical analysis multivariate methods were used with a confidence interval of 95% (alpha = 0.05). RESULTS: Electrophysiological alterations were observed even in the absence of clinical signs, such as reduced amplitude of sensory potentials, morphological changes and prolonged latency of the central components of somatosensory evoked potentials, and of brain stem auditory evoked potentials, whilst the visual evoked potentials remained normal. Of 79 relations studied during the 10 year investigation, 17 had clinical signs and were considered to be patients with SCA2. CONCLUSIONS: Four stages of the illness were defined: 'healthy', presymptomatic, and patients with and without nerve conduction block. These characterized the degenerative mechanisms of the afferent and efferent systems of the relations of patients with SCA2 who became ill themselves.

Adolescent↗
PubMed2026

Cyclin-dependent kinase 4 and 6 inhibitors and the breast cancer immune ecosystem: immune remodeling, resistance, and therapeutic reprogramming.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) combined with endocrine therapy have become a therapeutic backbone for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, yet durable disease control is frequently limited by intrinsic and acquired resistance. Canonical tumor-cell mechanisms, including retinoblastoma-pathway escape, cyclin E-cyclin-dependent kinase 2 (CDK2) activation, endocrine adaptation, and phosphoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin (mTOR) signaling, explain only part of this failure because they do not fully capture dynamic immune and stromal remodeling. Preclinical and translational studies indicate that early CDK4/6 inhibition can enhance antigen presentation, activate interferon-related programs, restrain regulatory T cells, and promote a T-cell-inflamed state. These effects are conditional and may not persist during prolonged treatment. Sustained therapy can instead drive heterogeneous resistant niches characterized by stromal remodeling, myeloid recruitment, checkpoint adaptation, and T-cell dysfunction. This immune-state dependence provides a rationale for immune checkpoint blockade, although clinical combinations have shown mixed efficacy and clinically relevant hepatic, pulmonary, and hematologic toxicities. Sequential or lead-in strategies therefore warrant prospective evaluation. Oxidative phosphorylation (OXPHOS) and redox adaptation may sustain selected resistant states and expose context-dependent ferroptotic vulnerabilities. Ferroptosis may connect tumor-cell killing with immune regulation, whereas nanomedicine may improve tumor-selective delivery. Both strategies remain largely preclinical and require further evaluation of pharmacokinetics, biodistribution, toxicity, manufacturability, and immune-cell safety. This Review distinguishes intrinsic from acquired resistance across interpatient, intratumoral, spatial, and temporal dimensions. It integrates tumor-cell escape with cytokine, immune, stromal, vascular, and metabolic remodeling and summarizes emerging therapeutic strategies. We further propose a candidate biomarker-informed framework that integrates genomic profiling, spatial immune architecture, circulating biomarkers, T-cell receptor (TCR) dynamics, transcriptomic and single-cell analyses, artificial intelligence (AI)-assisted multimodal integration, and longitudinal sampling. This framework is intended to support biomarker development and prospective trial design rather than current clinical decision-making, providing a translational basis for testing state-informed and sequence-aware therapeutic strategies.

Humans↗
PubMed2003

The NITE XML Toolkit: flexible annotation for multimodal language data.

Multimodal corpora that show humans interacting via language are now relatively easy to collect. Current tools allow one either to apply sets of time-stamped codes to the data and consider their timing and sequencing or to describe some specific linguistic structure that is present in the data, built over the top of some form of transcription. To further our understanding of human communication, the research community needs code sets with both timings and structure, designed flexibly to address the research questions at hand. The NITE XML Toolkit offers library support that software developers can call upon when writing tools for such code sets and, thus, enables richer analyses than have previously been possible. It includes data handling, a query language containing both structural and temporal constructs, components that can be used to build graphical interfaces, sample programs that demonstrate how to use the libraries, a tool for running queries, and an experimental engine that builds interfaces on the basis of declarative specifications.

Communication↗
PubMed1999

A standardized MRI stroke protocol: comparison with CT in hyperacute intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Diagnostic imaging in hyperacute ischemic stroke has been revolutionized by the introduction of diffusion- and perfusion-weighted MRI (DWI and PWI). CT, however, is still needed to exclude intracerebral hemorrhage (ICH). The purpose of our study was to determine the diagnostic accuracy of a standardized, multimodal MRI (mMRI) stroke protocol in the qualitative and quantitative assessment of hyperacute ICH (<6 hours). METHODS: We investigated 9 patients with hyperacute ICH with CT followed immediately by a standardized mMRI stroke protocol (DWI, PWI [T2*-WI], FLAIR, T2-WI, and MRA). The time interval between MRI and symptom onset ranged from 3 hours to 5 hours 45 minutes. We analyzed and compared the size of the hematoma on CT and all mMRI images by semiautomatic volumetry. RESULTS: ICH was unambiguously identified on the basis of all mMRI sequences. With increasing susceptibility effect (T2*-WI), the ICH, appearing as an area of hyperintensity with central signal loss, became qualitatively most evident. Regarding quantitation, T2*-WI overestimated (median and mean difference, 18.9%/17.8%; SD final sigma=24.4%) and DWI correlated best (median and mean difference, 3.97%/-4.36%; SD final sigma=37. 42%) with hematoma size on CT. CONCLUSIONS: Multimodal stroke MRI is as reliable as CT in the assessment of hyperacute ICH. Therefore, additional CT is no longer necessary to rule out ICH in hyperacute stroke. The use of mMRI alone in the diagnostic workup of a hyperacute stroke patient saves time and costs while rendering all the critical information needed to initiate an optimal treatment.

Acute Disease↗
PubMed2000

Distribution of escape times for a deterministically driven bistable system

In this paper, we analyze the sequence of escape times for a particle in a symmetric double-well potential coupled to a chain of monodimensional oscillators and we find that, in some range of energies, the probability of escape exhibits the multimodal form that is characteristic of bistable systems driven by a periodic signal embedded in noise. We identify two different modes contributing to the overall hopping dynamics of the particle, each one having a definite dependence on the energy of the chain. Those findings suggest a model for internal fluctuations that could be useful in the study of some problems of interest in physics and biology.

Journal Article↗
PubMed2003

[Anxiety patients before and after hospitalization for psychotherapy - from a psychophysiological standpoint].

Psychophysiological course studies are still the exception in AP hospitalized for psychotherapy. The aim of this study was to perform a more precise psychophysiological analysis of anxiety patients (AP) before and after hospital treatment. From a sample of 28 AP, 13 were psychophysiologically and psychodiagnostically examined and compared to controls (CG) at the beginning and end of in-patient psychotherapy and 4 months later. APs showed higher heart rate (HR) and electrodermal spontaneous fluctuation (SF) than control patients but did not differ in their resting systolic (SBP) and diastolic blood pressure (DBP). Under cognitive stress, the controls had a significantly stronger HR and SBP reaction, while the AP showed more SF during the tone sequence and while being asked about their subjectively experienced anxiety. Following inpatient psychotherapy, the two groups showed correlation in their vegetative reaction patterns. The study clearly demonstrates the effectiveness of the applied depth psychology-oriented multimodal therapy from a psychophysiological standpoint.

Adult↗
PubMed2003

Population structure and variation in red snapper (Lutjanus campechanus) from the Gulf of Mexico and Atlantic coast of Florida as determined from mitochondrial DNA control region sequence.

The mitochondrial DNA control regions of red snapper (Lutjanus campechanus) from the Gulf of Mexico (n = 140) and Atlantic coast of Florida (n = 35) were sequenced to generate a prestocking genetic baseline for planned stock enhancement. Intrasample haplotype and nucleotide diversities ranged from 0.94 to 1.00 and 1.8% to 2.5%, respectively. All population analyses were consistent with the hypothesis that red snapper constitute a single, panmictic population over the sampled range. A ubiquitous, predominant haplotype, shared by 23% of the specimens, appeared to be evolutionarily recent, in contrast to previous findings based on restriction fragment length polymorphism data. Tajima's D values were suggestive of a recent bottleneck. Mismatch distributions from Gulf samples were smooth and unimodal, characteristic of recent population expansion. However, the Atlantic sample exhibited a comparatively broader, possibly multimodal distribution, suggestive of a more stable population history. Additional control-region data may clarify potentially disparate demographic histories of Gulf and Atlantic snapper.

Animals↗
PubMed1993

Progressive dissociation of pectin.

The structural organization of alkaline soluble peach pectin was investigated over size ranges extending from micrometers to tenths of nanometers. Analysis was by electron microscopy and high-performance anion-exchange chromatography (HPAEC). Superimposed and individual circular microgels in the micrometer size range were isolated from mesocarp tissue of cell walls and visualized by rotary shadowing. Dilute NaCl and 50% aqueous glycerol disaggregated these microgels into rods, segmented rods, and kinked rods, which collectively comprised the internal gel network of the microgels. Image analysis of the shadowed specimens before and after disaggregation followed by curve fitting of the smoothed distributions revealed a multimodal distribution of lengths. HPAEC revealed that the multimodal aggregates were stable for the most part to further dissociation by increasing ionic strength.

Carbohydrate Sequence↗
PubMed2004

An in vitro model to optimize dose scheduling of multimodal radioimmunotherapy and chemotherapy: effects of p53 expression.

Several reports have appeared on the use of combined radioimmunotherapy (RAIT) and chemotherapy. The choice of drug to use with RAIT and how to space the two treatments has not been completely addressed. Because every patient's cancer presents with a specific molecular phenotype, we hypothesized that it may be necessary to tailor therapy based on specific gene expression. We addressed how the form of expression of a single gene, the p53 tumor suppressor, would impact the choice of agents, as well as sequence and spacing of agents. p53 regulates cell cycle arrest to allow for DNA repair after therapy-induced small DNA damage or induction of apoptosis if damage is great and has been shown to affect chemo- and radiosensitivity of cancer cells. We established 3 stable p53 transfectants of the SKOV-3 p53null parental line (p53(wt), p53(143mut) or p53(273mut)). p53 expression was confirmed using flow cytometry, using the DO1 pan-p53 Ab and the PAb240 anti-p53mut Ab. The colorimetric MTT assay was then used to measure dose-dependent growth inhibition from single modality chemotherapy (doxorubicin, carboplatin, paclitaxel or topotecan) or radioimmunotherapy (90Y-RS-7 IgG anti-EGP1). The % survival vs. log [drug] were plotted to obtain the IC50. We then used a matrix design in which we varied the sequence of the first and second modality of treatment and the spacing between the 2 treatments to determine the most synergistic and antagonistic combinations for the parental SKOV-3 and each of the 3 transfectants. The IC50 for each therapeutic agent varied as a function of the form of p53 expressed. For example, of the 4 lines, the p53wt transfectant was the most resistant to topotecan and the 143mut was the most resistant to carboplatin. The 273mut was quite sensitive to both doxorubicin and paclitaxel, whereas the p53null and wt were not. For multimodal treatments, most combinations of RAIT and chemotherapy resulted in a 30-40% growth inhibition (GI) and were either additive or moderately antagonistic. The 3 best (>60% GI) and 3 worst (<25% GI) combinations were identified and were unique to the parental p53null and to the 3 transfectants. Certain combinations showed clear synergy and others were antagonistic, with the first treatment modality blocking the growth inhibitory effects of the second treatment modality. The form of p53 expressed affects chemosensitivity and radiosensitivity and will influence optimal multimodal therapy with RAIT and chemotherapy and the dose-schedule (sequential with RAIT first or with drug first) when more than 1 agent is used.

Antineoplastic Agents↗
PubMed1999

The recognition and correction of involuntary prosaccades in an antisaccade task.

This paper reports a striking misperception associated with involuntary saccadic eye movements: when subjects are instructed to look to the opposite side of a suddenly presented stimulus (antisaccade), they produce a certain number of involuntary prosaccades to the stimulus before they move their eyes to the other side by a corrective saccade of approximately twice the size. When asked to indicate at the end of each trial whether they believed that they made such a detour sequence of two saccades, one finds that, on average, 50+/-25% of these involuntary movements are not recognized. The average size and correction time for recognized prosaccades is larger than unrecognized prosaccades, while their mean reaction times are the same. The corrective saccades compensate for the size of both the recognized and unrecognized errors. When similar sequences of saccades are made voluntarily, the time spent at the stimulus side was 222 ms compared with 95 ms for unrecognized and 145 ms for recognized errors. The distributions of the corresponding correction times differ in their multimodal composition. Whether voluntary and involuntary saccades and their corrections are associated with different effects on the updating of the perceptual spatial frame and attention allocation is discussed.

Attention↗
PubMed2003

High-efficiency peptide analysis on monolithic multimode capillary columns: Pressure-assisted capillary electrochromatography/capillary electrophoresis coupled to UV and electrospray ionization-mass spectrometry.

High-efficiency peptide analysis using multimode pressure-assisted capillary electrochromatography/capillary electrophoresis (pCEC/pCE) monolithic polymeric columns and the separation of model peptide mixtures and protein digests by isocratic and gradient elution under an applied electric field with UV and electrospray ionization-mass spectrometry (ESI-MS) detection is demonstrated. Capillary multipurpose columns were prepared in silanized fused-silica capillaries of 50, 75, and 100 microm inner diameters by thermally induced in situ copolymerization of methacrylic monomers in the presence of n-propanol and formamide as porogens and azobisisobutyronitrile as initiator. N-Ethylbutylamine was used to modify the chromatographic surface of the monolith from neutral to cationic. Monolithic columns were termed as multipurpose or multimode columns because they showed mixed modes of separation mechanisms under different conditions. Anion-exchange separation ability in the liquid chromatography (LC) mode can be determined by the cationic chromatographic surface of the monolith. At acidic pH and high voltage across the column, the monolithic stationary phase provided conditions for predominantly capillary electrophoretic migration of peptides. At basic pH and electric field across the column, enhanced chromatographic retention of peptides on monolithic capillary column made CEC mechanisms of migration responsible for separation. The role of pressure, ionic strength, pH, and organic content of the mobile phase on chromatographic performance was investigated. High efficiencies (exceeding 300 000 plates/m) of the monolithic columns for peptide separations are shown using volatile and nonvolatile, acidic and basic buffers. Good reproducibility and robustness of isocratic and gradient elution pressure-assisted CEC/CE separations were achieved for both UV and ESI-MS detection. Manipulation of the electric field and gradient conditions allowed high-throughput analysis of complex peptide mixtures. A simple design of sheathless electrospray emitter provided effective and robust low dead volume interfacing of monolithic multimode columns with ESI-MS. Gradient elution pressure-assisted mixed-mode separation CE/CEC-ESI-MS mass fingerprinting and data-dependent pCE/pCEC-ESI-MS/MS analysis of a bovine serum albumin (BSA) tryptic digest in less than 5 min yielding high sequence coverage (73%) demonstrated the potential of the method.

Electrophoresis, Capillary↗
PubMed2004

Nucleotide-based therapies targeting clusterin chemosensitize human lung adenocarcinoma cells both in vitro and in vivo.

INTRODUCTION: Lung cancer is highly lethal and resistant to most anticancer interventions. Treatment resistance is mediated, in part, by enhanced expression of cell survival proteins that help facilitate tumor progression. Clusterin is a stress-associated cytoprotective protein up-regulated by various apoptotic triggers in many cancers and confers treatment resistance when overexpressed. The objectives in this study were to evaluate clusterin expression levels in human lung cancer tissue, and to test effects of clusterin silencing using antisense oligonucleotides (ASOs) and short interfering double-stranded RNAs (siRNAs) on chemosensitivity in human lung cancer A549 cells. METHODS: Clusterin immunostaining was evaluated in a tissue microarray of 149 spotted human lung cancers. The effects of clusterin ASO or siRNA treatment on clusterin expression and chemosensitivity to paclitaxel was examined in A549 cells in vitro while the ability of clusterin ASO to chemosensitize in vivo was evaluated in immunocompromised mice bearing A549 tumors. RESULTS: More than 80% of human non-small cell lung cancers are immunoreactive for clusterin. Clusterin ASO or siRNA decreased clusterin mRNA expression in A549 cells >75% in a dose-dependent, sequence-specific manner, and significantly enhanced chemosensitivity to paclitaxel in vitro. Characteristic apoptotic DNA laddering was observed after combined treatment with ASO plus paclitaxel, but not with either agent alone. In vivo administration of clusterin ASO, compared to mismatch control oligonucleotide, synergistically enhanced the effects of paclitaxel or gemcitibine to significantly delay A549 tumor growth. CONCLUSION: These findings identify clusterin as a valid therapeutic target in strategies employing novel multimodality therapy for advanced lung cancer.

Adenocarcinoma↗
PubMed2004

Stage-III NSClC: multimodality therapy for inoperable tumours.

The combination of radiotherapy and chemotherapy (RCT) has improved the treatment results of patients with inoperable stage-III NSCLC in comparison to irradiation alone and is seen as the standard treatment at present. Concomitant RCT was significantly superior to sequential RCT in three of four studies, so that the simultaneous therapy sequence is seen today as the best modality. Nevertheless, the results, with median survival times of 15-18 months and a 5-year survival rate between 10 and 20%, are still not satisfactory so that further possibilities of optimisation are being looked for: --Can the results of concomitant RCT be improved by an induction chemotherapy or subsequent chemotherapy? --Is there an additional benefit of operative measures for tumours which through the application of RCT get operable? --What is the additional benefit of biological response modifiers applied together with RCT? --Is there a place for RCT of elderly patients or patients in poor general condition? The rationale as well as the initial results shall be discussed in this overview.

Antineoplastic Combined Chemotherapy Protocols↗