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PubMed2026

Multimodal analysis of CD38 in T-cell Acute Lymphoblastic Leukemia Identifies Combinatorial Therapeutic Strategies.

Outcomes for pediatric patients with refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL) are poor, underscoring the need for improved therapeutic strategies. CD38, a type II transmembrane glycoprotein, is a promising target in T-ALL, with clinical trials evaluating CD38-targeting immunotherapies in frontline and relapsed settings. However, the biological role of CD38 in T-ALL has not been systematically defined. We interrogated CD38 biology through multimodal profiling of pediatric T-ALL samples. Bulk RNA sequencing of 1,335 primary tumors revealed that CD38 expression varies across genomic and immunophenotypic subtypes in T-ALL. Flow cytometry of 150 primary samples and CITE-sequencing of 40 cases demonstrated broad surface expression of CD38. A transcription factor CRISPR-screen identified RUNX1, RUNX3, and TP53 as candidate positive regulators of CD38. Metabolomic profiling of cell lines further revealed disruption of the polyamine pathway following CD38 perturbation. Supporting this finding, co-targeting CD38 with difluoromethylornithine (DFMO), a polyamine metabolism disruptor, improved survival in preclinical models. Across transcriptomic datasets, including primary tumors, cell lines, and patient-derived xenograft models, IL32 expression consistently decreased following CD38 loss or negativity, supporting an association between CD38 and inflammatory signaling pathways. Additionally, CD38 and LCK expression were positively correlated across majority of genomic subtypes, implicating SRC kinase signaling. Consistent with this, daratumumab in cell lines increased LCK phosphorylation, and combination therapy with dasatinib improved survival compared to monotherapy. Collectively, these findings define previously unrecognized interactions between CD38 and targetable pathways and genes in T-ALL and identify rational combinatorial strategies to enhance CD38-directed therapies and reduce relapse risk.

Journal Article↗

PubMed2006

Lack of prognostic impact of p53 gene mutation and p53 phosphorylation at serine 15 in multimodally treated adenocarcinomas of the gastroesophageal junction.

PURPOSE: As inactivation of p53 may be correlated with poor response of tumors to chemo- and/or radiotherapy the presence of p53 mutations in exons 5-8 was determined in adenocarcinomas of the gastroesophageal junction (GEJ). As p53 protein phosphorylation at serine 15 indicates stabilization and protection against mdm-2 the presence of this phosphorylation state was subsequently evaluated. METHODS: Mutations in exons 5-8 were analyzed by denaturing high pressure liquid chromatography (DHPLC) and subsequent sequence analysis in pretherapeutic biopsies of 38 adenocarcinomas of the GEJ that had undergone multimodal treatment in the course of a prospective multicentric phase III trial. The presence of p53 protein phosphorylation at serine 15 was evaluated by immunohistochemistry. RESULTS: Mutations in the DNA binding region were found in 23 samples and were only weakly associated with worse 2-year survival (P=0.083). Phosphorylation at serine 15 of p53 was detected in 14 samples, being neither associated with p53 mutation nor with patient's survival. CONCLUSION: This allows the conclusion that the determination of these two parameters does not help to select patients who do profit from multimodal treatment for adenocarcinomas of the GEJ.

Adenocarcinoma↗

PubMed2026

EGFLAM Pathogenic Variants and Congenital Stationary Night Blindness.

IMPORTANCE: Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous inherited retinal disorder (IRD), and in many complete CSNB (cCSNB) cases, the underlying genetic cause remains unknown. Uncovering the genetic defects of IRDs helps to refine diagnostic methods and supports the development of specific therapeutic approaches. OBJECTIVE: To describe the phenotype and the underlying gene defect in patients with cCSNB from 2 unrelated families. DESIGN, SETTING AND PARTICIPANTS: This retrospective case series was conducted from January 2023 to July 2025. Data for 3 patients from cohorts of genetically unsolved IRD cases in France (n = 140 for CSNB) and the Netherlands (n = 2730 for IRD) were analyzed clinically and genetically. EXPOSURES: Complete ocular examination, including multimodal retinal imaging and full-field electroretinography (ffERG) incorporating the International Society for Clinical Electrophysiology of Vision standards and multimodal retinal imaging, were performed. Gene defects were identified by genome sequencing (GS) and exome sequencing (ES). MAIN OUTCOMES AND MEASURES: The main outcome was a gene defect, EGFLAM, underlying cCSNB. Measures included phenotyping, GS, ES, Sanger sequencing, and cosegregation analysis. RESULTS: The series included 3 patients from 2 unrelated families of Moroccan ancestry showing high myopia, reduced visual acuity, and night blindness. Retinal imaging depicted myopic changes. ffERG revealed electronegative Schubert-Bornschein configuration in keeping with cCSNB with ON-bipolar cell dysfunction. Patients were lacking pathogenic variants in known genes implicated in IRDs, including CSNB. Two different homozygous pathogenic variants, c.1563_1566del, p.(Val522Glufs*18) and c.1795C>T, p.(Arg599*) in EGFLAM were identified by ES and GS. The corresponding protein is localized in the outer plexiform layer and important for ON-bipolar cell signaling in the retina. CONCLUSION AND RELEVANCE: This case series reports on a gene defect in EGFLAM implicated in human cCSNB. Clinicians should be aware about this association and consider including EGFLAM in diagnostic gene panels for IRDs. This discovery may lead to faster and more accurate diagnosis of cCSNB and genetic counseling, as well as a pathway for developing therapies.

Adolescent↗

PubMed2000

Family processes and treatment outcome in the MTA: negative/ineffective parenting practices in relation to multimodal treatment.

To elucidate processes underlying therapeutic change in a large-scale randomized clinical trial, we examined whether alterations in self-reported parenting practices were associated with the effects of behavioral, medication, or combination treatments on teacher-reported outcomes (disruptive behavior, social skills, internalizing symptoms) in children with attention-deficit hyperactivity disorder (ADHD). Participants were 579 children with Combined-type ADHD, aged 7-9.9 years, in the Multimodal Treatment Study of Children with ADHD (MTA). We uncovered 2 second-order factors of parenting practices, entitled Positive Involvement and Negative/Ineffective Discipline. Although Positive Involvement was not associated with amelioration of the school-based outcome measures, reductions in Negative/Ineffective Discipline mediated improvement in children's social skills at school. For families showing the greatest reductions in Negative/Ineffective Discipline, effects of combined medication plus behavioral treatment were pronounced in relation to regular community care. Furthermore, only in combination treatment (and not in behavioral treatment alone) was decreased Negative/Ineffective Discipline associated with reduction in children's disruptive behavior at school. Here, children in families receiving combination treatment who showed the greatest reductions in Negative/Ineffective Discipline had teacher-reported disruptive behavior that was essentially normalized. Overall, the success of combination treatment for important school-related outcomes appears related to reductions in negative and ineffective parenting practices at home; we discuss problems in interpreting the temporal sequencing of such process-outcome linkages and the means by which multimodal treatment may be mediated by psychosocial processes related to parenting.

Adult↗

PubMed2001

Trends and perspectives in multimodality therapy of locoregionally advanced non-small cell lung cancer.

In recent years progress has been made in the therapy of patients with stage III non-small cell lung cancer. Induction chemotherapy and concomitant chemoradiotherapy have been proven to be superior to radiation therapy alone for unresectable stage disease. In direct comparisons of induction and concomitant chemoradiotherapy, the latter has been found to lead to higher median survival times, albeit at the cost of increased toxicity within the irradiated field. Additional trials have explored the administration of both induction chemotherapy and concomitant chemoradiotherapy in sequence and the integration of the taxanes, gemcitabine and vinorelbine and irinotecan into the multimodality therapy setting. These and other novel concepts are discussed.

Antineoplastic Agents↗

PubMed2003

Models of surgical procedures for multimodal image-guided neurosurgery.

Improvement of image guided surgery systems requires a better anticipation of the surgical procedure. This anticipation may be provided by a better understanding of surgical procedures and/or the use of information models related to neurosurgical procedures. We are introducing a generic model of surgical procedures in the context of multimodal image-guided craniotomies. The basic principle of the model is to break down the surgical procedure into a sequence of steps defining the surgical script. Each step is defined by an action; the model assigns to each surgical step a list of image entities extracted from multimodal preoperative images (anatomical and/or functional images) which are relevant to the performance of that particular step. The model has been built in two phases: creation and consolidation. Besides, a planning software prototype based on the generic model has been built. The resulting generic model is described by an UML class diagram and textual description. Some initial benefits of this approach can already be outlined: improvement of multimodal information management, enhancement of the preparation and the guidance of the surgical act.

Humans↗

PubMed1997

The effect of cisplatin pretreatment on the accumulation of MIBG by neuroblastoma cells in vitro.

[131I]meta-iodobenzylguanidine ([131I]MIBG) provides a means of selectively delivering radiation to neuroblastoma cells and is a promising addition to the range of agents used to treat neuroblastoma. As MIBG is now being incorporated into multimodal approaches to therapy, important questions arise about the appropriate scheduling and sequencing of the various agents employed. As the ability of neuroblastoma cells to actively accumulate MIBG is crucial to the success of this therapy, the effect of chemotherapeutic agents on this uptake capacity needs to be investigated. We report here our initial findings on the effect of cisplatin pretreatment on the neuroblastoma cell line SK-N-BE (2c). After treating these cells with therapeutically relevant concentrations of cisplatin (2 microM and 20 microM), a stimulation in uptake of [131I]MIBG was observed. Reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that this effect was due to increased expression of the noradrenaline transporter. These results suggest that appropriate scheduling of cisplatin and [131I]MIBG may lead to an increase in tumour uptake of this radiopharmaceutical with consequent increases in radiation dose to the tumour.

3-Iodobenzylguanidine↗

PubMed1996

Diagnosis and Treatment of Early-Stage Non-Small Cell Lung Cancer.

Current recommendations for the diagnostic work-up and treatment of early-stage non-small cell lung cancer are presented, and the rationale behind these recommendations is reviewed. Early-stage disease is found in approximately 30% of patients at initial presentation. Surgeons continue to be uncertain with regard to how extensively they should look for metastatic disease, especially in asymptomatic patients with newly diagnosed lung cancer. While it is generally agreed that surgery is an important component of treatment for stage I and II non-small cell lung cancer, the role of adjuvant therapies in early-stage disease merits further study. Stage IIIa lung cancer is evolving as a disease for which multimodality therapy is likely to play a role, but the timing and sequence of treatment is an area of intense investigation. The recommendations made in this article are based upon the results of randomized clinical trials whenever possible.

Journal Article↗

PubMedDate not supplied

[Personal identification by complex study of characteristics of the teeth and dentition structures].

A multimodality dental examination was made and anatomomorphological features of teeth and tooth sequences were studied in 200 policemen using clinical examination, morphological investigation of plaster jaw models, analysis of x-rays and statistics, intraoral videocamera pictures, computer processing. The scheme of creation of dental data bank applicable in personal identification is offered.

Dentition↗

PubMed2026

An Integrative Morphological and Genomic Analysis With a Refined Fluorescence In Situ Hybridization (FISH) Threshold and Novel Kinase Fusions in a Large Asian Cohort of Spitzoid Neoplasms.

Differentiating atypical Spitz tumors (ASTs) from true Spitz melanomas (SMs) and conventional melanomas with spitzoid features (MSFs) remains a formidable diagnostic challenge. Because current molecular epidemiological data are overwhelmingly derived from Caucasian cohorts, the genomic landscape of Asian populations remains largely unexplored. To elucidate the molecular progression landscape and refine the diagnostic criteria, we performed a comprehensive multimodal analysis-integrating histomorphology, immunohistochemistry, multiprobe fluorescence in situ hybridization (FISH), and targeted RNA/DNA-based next-generation sequencing (NGS)-on a cohort of 140 spitzoid neoplasms. This cohort, comprising 126 ASTs, 8 SMs, and 6 MSFs, represents the largest Asian cohort to date. Malignant phenotype strongly correlated with lesional asymmetry, deep atypical mitoses, a sheet-like growth pattern, diffuse preferentially expressed antigen of melanoma positivity, and significant loss of p16 expression (64.3% in SM/MSF vs 9.5% in ASTs; P < .0001). Building upon the established melanoma FISH criteria, we optimized a prognostic threshold of ≥2 FISH abnormalities specifically tailored for spitzoid neoplasms. We demonstrated that isolated single chromosomal aberrations (particularly MYB loss) are relatively stable events that are frequent in indolent ASTs, whereas our refined ≥2 threshold yielded 100% sensitivity and 92.5% specificity for predicting regional lymph node metastasis/local recurrence. Molecularly, NGS identified mutually exclusive initiating driver alterations (comprising kinase fusions and HRAS mutations) in 89.9% of true Spitz neoplasms, a remarkably high prevalence suggesting a distinct genetic background in Asian populations. We also characterized 5 entirely novel kinase fusions (ZNF24::ROS1, PCBP1::ROS1, NUMA1::RET, CBWD1::ALK, and TPR::NTRK1). Furthermore, NGS definitively segregated true Spitz neoplasms from morphological mimics (MSF), which lacked fusions and were driven by canonical genomic alterations of the conventional melanoma pathway. Integrating these genomic landscapes validated a stepwise progression model. Although isolated kinase fusions drove indolent ASTs, malignant SM invariably harbored concurrent pathogenic secondary alterations, demonstrating a profound reliance on CDKN2A/B, TP53, and CDK4 aberrations. Ultimately, we propose an integrated diagnostic algorithm combining morphological evaluation, the refined FISH threshold, and comprehensive NGS profiling, providing a precise, evidence-based framework for pathway classification and clinical management of spitzoid neoplasms.

fluorescence in situ hybridization↗

PubMed2004

The modal distribution of protein isoelectric points reflects amino acid properties rather than sequence evolution.

Two-dimensional gel electrophoresis, a routine application in proteomics, separates proteins according to their molecular mass (M(r)) and isoelectric point (pI). As the genomic sequences for more and more organisms are determined, the M(r) and pI of all their proteins can be estimated computationally. The examination of several of these theoretical proteome plots has revealed a multimodal pI distribution, however, no conclusive explanation for this unusual distribution has so far been presented. We examined the pI distribution of 115 fully sequenced genomes and observed that the modal distribution does not reflect phylogeny or sequence evolution, but rather the chemical properties of amino acids. We provide a statistical explanation of why the observed distributions of pI values are multimodal.

Algorithms↗

PubMed2003

Model of surgical procedures for multimodal image-guided neurosurgery.

OBJECTIVE: Improvement of the planning stage of image-guided surgery requires a better anticipation of the surgical procedure and its anatomical and functional environment. This anticipation should be provided by acquisition of multimodal medical images of the patient and by a better understanding of surgical procedures. In this paper, we propose improvements to the planning and performance of multimodal image-guided neurosurgery through the use of information models related to neurosurgical procedures. MATERIALS AND METHODS: A new generic model of surgical procedures is introduced in the context of multimodal image-guided craniotomies. The basic principle of the model is to break down the surgical procedure into a sequence of steps defining the surgical script. In the model, a step is defined by an action. The model assigns to each surgical step a list of image entities extracted from multimodal preoperative images (i.e., anatomical and/or functional images) which are relevant to the performance of that particular step. A semantic validation of the model was performed by instantiating the model entities for 29 surgical procedures. RESULTS: The resulting generic model is described by a UML class diagram and a textual description. The validation showed the relevance of the model, confirming the main underlying assumptions. It also provided some leads to improve the model. CONCLUSION: While further validation is needed, the initial benefits of this approach can already be outlined. It should add real value to the different levels of image-guided surgery, from preprocessing to planning, as well as during surgery. Models of surgical procedures can manage image data according to the surgical script, which should lead to better anticipation of surgery through the development of simulation tools. Furthermore, the models may improve the performance of surgery using microscope-based neuronavigation systems by making it possible to adapt both visualization and interaction features of multimodal preoperative images according to the model.

Humans↗

PubMed2001

Hyperthermic radiosensitization: mode of action and clinical relevance.

PURPOSE: To provide an update on the recent knowledge about the molecular mechanisms of thermal radiosensitization and its possible relevance to thermoradiotherapy. SUMMARY: Hyperthermia is probably the most potent cellular radiosensitizer known to date. Heat interacts with radiation and potentiates the cellular action of radiation by interfering with the cells' capability to deal with radiation-induced DNA damage. For ionizing irradiation, heat inhibits the repair of all types of DNA damage. Genetic and biochemical data suggest that the main pathways for DNA double-strand break (DSB) rejoining, non-homologous end-joining and homologous recombination, are not the likely primary targets for heat-induced radiosensitization. Rather, heat is suggested to affect primarily the religation step of base excision repair. Subsequently additional DSB arise during the DNA repair process in irradiated and heated cells and these additional DSB are all repaired with slow kinetics, the repair of which is highly error prone. Both mis- and non-rejoined DSB lead to an elevated number of lethal chromosome aberrations, finally causing additional cell killing. Heat-induced inhibition of DNA repair is considered not to result from altered signalling or enzyme inactivation but rather from alterations in higher-order chromatin structure. Although, the detailed mechanisms are not yet known, a substantial body of indirect and correlative data suggests that heat-induced protein aggregation at the level of attachment of looped DNA to the nuclear matrix impairs the accessibility of the damaged DNA for the repair machinery or impairs the processivity of the repair machinery itself. CONCLUSION: Since recent phase III clinical trials have shown significant benefit of adding hyperthermia to radiotherapy regimens for a number of malignancies, it will become more important again to determine the molecular effects underlying this success. Such information could eventually also improve treatment quality in terms of patient selection, improved sequencing of the heat and radiation treatments, the number of heat treatments, and multimodality treatments (i.e. thermochemoradiotherapy).

Chromatin↗

PubMed1994

Artificial neural networks and simulated molecular evolution are potential tools for sequence-oriented protein design.

The potential of artificial neural filter systems for feature extraction from amino acid sequences is discussed. Analysis of signal peptidase I cleavage-sites in protein precursor sequences serves as an example application. Trained neural networks can be used as the fitness function in an evolutionary protein design cycle termed 'simulated molecular evolution' which is an entirely computer-based method for the rational design of locally encoded amino acid sequence features. The design procedure itself is regarded as an optimization process which can follow several schemes. Gradient search, diffusive search, and evolution strategy have been compared with regard to their usefulness for optimization. It turns out that gradient search is well suited for optimization in smooth fitness landscapes without local minima, whereas evolution strategy seems to be a method of choice for optimization in a high-dimensional multimodal search space. This is concluded from optimization experiments using a multimodal example function.

Amino Acid Sequence↗

PubMed1996

Fiber-optic fluorometric sensing of polymerase chain reaction-amplified DNA using an immobilized DNA capture protein.

A fiber-optic assay for amplified DNA products has been developed. Modifications of the DNA capture strategy described previously by Kemp et al. [Proc. Natl. Acad. Sci. USA 86, 2423-2427 (1989)] were made that allowed selective binding of DNA labeled during the amplification process to the sensing surface of fused silica fibers. The gene for a chimeric protein composed of the IgG-binding beta 2 subdomain of streptococcal protein G fused with the DNA binding domain of yeast GCN4 was constructed, and this PG/GCN4 protein was overexpressed in Escherichia coli. The purified protein was noncovalently bound to IgG-modified fibers utilizing strong and specific interactions between the protein G beta 2 domain and goat IgG that had been covalently immobilized on the fiber surface. Nanomolar concentrations of amplified DNA labeled with the fluorophore tetramethylrhodamine and the AP-1 consensus nucleotide sequence recognized by GCN4 (5'-ATGACTCAT) were rapidly and selectively bound within the evanescent zone of multimode laser-illuminated fibers. Signal from unincorporated fluorescent PCR primer was negligible. Individual fibers could be used for multiple sequential assays, since the fluorescent double-stranded DNA was rapidly and completely stripped from their surfaces with high salt solutions, leaving the IgG-PG/GCN4 DNA binding complex intact to accept another PCR sample.

Amino Acid Sequence↗

PubMed1993

Exploring a psychotherapeutic change sequence: relating process to intersessional and posttreatment outcome.

Process was related to intermediate and posttreatment outcomes for 34 patients undergoing multimodal group therapy. Exploratory time series analysis suggested that process variable effects differed with the phase of the therapy. It appeared that an emotionally warm bond occurred between patient and therapist in the sessions prior to therapist-rated improvement. A patient rating of insight followed in subsequent sessions. A negative feedback loop between patient symptom levels and therapist negative patient-directed feelings was demonstrated. Patient dysphoria in later therapy sessions seemed to reflect an earlier therapeutic failure. Ego strength directly exerted its positive influence on outcome in later sessions. The relation between in-therapy process trends and overall outcome supported these findings.

Adult↗

PubMedDate not supplied

Basics of cancer gene therapy.

Gene therapy is a rapidly evolving concept for the therapy of different forms of cancer. A number of phase-I clinical trials have recently been initiated world wide. This review discusses the technical concepts underlying the protocols currently coming into clinics. Two tools essentially constitute such concepts, the vector for efficient transfer and expression of the transgene in the cancer cell, and the therapeutic gene. The most advanced vectors ready for clinical use are the retrovirus- and adenovirus-derived vectors. The application of a broad spectrum of therapeutic genes can be classified into gene replacement of replace e.g. mutated tumor suppressor genes, gene addition to increase immunogenicity by cytokine genes or introduce prodrug genes for suicide induction and, thirdly, targeted affection of gene expression by antisense oligonucleotides or expression of ribozymes e.g. directed against oncogene sequences. Cancer gene therapy holds great promise to become an important addition to the multimodality in the therapy of some forms of cancer.

Gene Transfer Techniques↗

PubMed2025

Single-cell profiling of trabecular meshwork identifies mitochondrial dysfunction in a glaucoma model that is protected by vitamin B3 treatment.

Since the trabecular meshwork (TM) is central to intraocular pressure (IOP) regulation and glaucoma, a deeper understanding of its genomic landscape is needed. We present a multimodal, single-cell resolution analysis of mouse limbal cells (includes TM). In total, we sequenced 9,394 wild-type TM cell transcriptomes. We discovered three TM cell subtypes with characteristic signature genes validated by immunofluorescence on tissue sections and whole-mounts. The subtypes are robust, being detected in datasets for two diverse mouse strains and in independent data from two institutions. Results show compartmentalized enrichment of critical pathways in specific TM cell subtypes. Distinctive signatures include increased expression of genes responsible for 1) extracellular matrix structure and metabolism (TM1 subtype), 2) secreted ligand signaling to support Schlemm's canal cells (TM2), and 3) contractile and mitochondrial/metabolic activity (TM3). ATAC-sequencing data identified active transcription factors in TM cells, including LMX1B. Mutations in LMX1B cause high IOP and glaucoma. LMX1B is emerging as a key transcription factor for normal mitochondrial function and its expression is much higher in TM3 cells than other limbal cells. To understand the role of LMX1B in TM function and glaucoma, we single-cell sequenced limbal cells from Lmx1b V265D/+ mutant mice (2,491 TM cells). In V265D/+ mice, TM3 cells were uniquely affected by pronounced mitochondrial pathway changes. Mitochondria in TM cells of V265D/+ mice are swollen with a reduced cristae area, further supporting a role for mitochondrial dysfunction in the initiation of IOP elevation in these mice. Importantly, treatment with vitamin B3 (nicotinamide), to enhance mitochondrial function and metabolic resilience, significantly protected Lmx1b mutant mice from IOP elevation.

Journal Article↗