CD8+ NKs as a potential biomarker of complete response and survival with lenalidomide plus R-GDP in the R2-GDP-GOTEL trial in recurrent/refractory diffuse large B cell lymphoma.

Background: Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. DLBCL is an aggressive disease that can be cured with upfront standard chemoimmunotherapy schedules. However, in approximately 35-40% of the patients DLBCL relapses, and therefore, especially in this setting, the search for new prognostic and predictive biomarkers is an urgent need. Natural killer (NK) are effector cells characterized by playing an important role in antitumor immunity due to their cytotoxic capacity and a subset of circulating NK that express CD8 have a higher cytotoxic function. In this substudy of the R2-GDP-GOTEL trial, we have evaluated blood CD8+ NK cells as a predictor of treatment response and survival in relapsed/refractory (R/R) DLBCL patients. Methods: 78 patients received the R2-GDP schedule in the phase II trial. Blood samples were analyzed by flow cytometry. Statistical analyses were carried out in order to identify the prognostic potential of CD8+ NKs at baseline in R/R DLBCL patients. Results: Our results showed that the number of circulating CD8+ NKs in R/R DLBCL patients were lower than in healthy donors, and it did not change during and after treatment. Nevertheless, the level of blood CD8+ NKs at baseline was associated with complete responses in patients with R/R DLBCL. In addition, we also demonstrated that CD8+ NKs levels have potential prognostic value in terms of overall survival in R/R DLBCL patients. Conclusion: CD8+ NKs represent a new biomarker with prediction and prognosis potential to be considered in the clinical management of patients with R/R DLBCL. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001620-29 EudraCT, ID:2014-001620-29.

Assessing the Heat Tolerance of Meiosis in Spanish Landraces of Tetraploid Wheat Triticum turgidum.

Heat stress alters the number and distribution of meiotic crossovers in wild and cultivated plant species. Hence, global warming may have a negative impact on meiosis, fertility, and crop productions. Assessment of germplasm collections to identify heat-tolerant genotypes is a priority for future crop improvement. Durum wheat, Triticum turgidum, is an important cultivated cereal worldwide and given the genetic diversity of the durum wheat Spanish landraces core collection, we decided to analyse the heat stress effect on chiasma formation in a sample of 16 landraces of T. turgidum ssp. turgidum and T. turgidum ssp. durum, from localities with variable climate conditions. Plants of each landrace were grown at 18-22 °C and at 30 °C during the premeiotic temperature-sensitive stage. The number of chiasmata was not affected by heat stress in three genotypes, but decreased by 0.3-2 chiasmata in ten genotypes and more than two chiasmata in the remaining three ones. Both thermotolerant and temperature-sensitive genotypes were found in the two subspecies, and in some of the agroecological zones studied, which supports that genotypes conferring a heat tolerant meiotic phenotype are not dependent on subspecies or geographical origin. Implications of heat adaptive genotypes in future research and breeding are discussed.

Lenalidomide plus R-GDP (R2-GDP) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Final Results of the R2-GDP-GOTEL Trial and Immune Biomarker Subanalysis.

PURPOSE: New therapeutic options are needed in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Lenalidomide-based schedules can reverse rituximab refractoriness in lymphoma. PATIENTS AND METHODS: In the phase II R2-GDP trial, 78 patients unsuitable for autologous stem cell transplant received treatment with the following schedule: lenalidomide 10 mg Days (D)1-14, rituximab 375 mg/m2 D1, cisplatin 60 mg/m2 D1, gemcitabine 750 mg/m2 D1 and D8, and dexamethasone 20 mg D1-3, up to 6 cycles (induction phase), followed by lenalidomide 10 mg (or last lenalidomide dose received) D1-21 every 28 days (maintenance phase). Primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and monitorization of key circulating immune biomarkers (EU Clinical Trials Register number: EudraCT 2014-001620-29). RESULTS: After a median follow-up of 37 months, ORR was 60.2% [37.1% complete responses (CR) and 23.1% partial responses (PR)]. Median OS was 12 months (47 vs. 6 months in CR vs. no CR); median PFS was 9 months (34 vs. 5 months in CR vs. no CR). In the primary refractory population, ORR was 45.5% (21.2% CR and 24.3% PR). Most common grade 3-4 adverse events were thrombocytopenia (60.2%), neutropenia (60.2%), anemia (26.9%), infections (15.3%), and febrile neutropenia (14.1%). Complete responses were associated with a sharp decrease in circulating myeloid-derived suppressor cells and regulatory T cells. CONCLUSIONS: R2-GDP schedule is feasible and highly active in R/R DLBCL, including the primary refractory population. Immune biomarkers showed differences in responders versus progressors.

Genomic and Meiotic Changes Accompanying Polyploidization.

Hybridization and polyploidy have been considered as significant evolutionary forces in adaptation and speciation, especially among plants. Interspecific gene flow generates novel genetic variants adaptable to different environments, but it is also a gene introgression mechanism in crops to increase their agronomical yield. An estimate of 9% of interspecific hybridization has been reported although the frequency varies among taxa. Homoploid hybrid speciation is rare compared to allopolyploidy. Chromosome doubling after hybridization is the result of cellular defects produced mainly during meiosis. Unreduced gametes, which are formed at an average frequency of 2.52% across species, are the result of altered spindle organization or orientation, disturbed kinetochore functioning, abnormal cytokinesis, or loss of any meiotic division. Meiotic changes and their genetic basis, leading to the cytological diploidization of allopolyploids, are just beginning to be understood especially in wheat. However, the nature and mode of action of homoeologous recombination suppressor genes are poorly understood in other allopolyploids. The merger of two independent genomes causes a deep modification of their architecture, gene expression, and molecular interactions leading to the phenotype. We provide an overview of genomic changes and transcriptomic modifications that particularly occur at the early stages of allopolyploid formation.

Immunometabolism Modulation in Therapy.

The study of cancer biology should be based around a comprehensive vision of the entire tumor ecosystem, considering the functional, bioenergetic and metabolic state of tumor cells and those of their microenvironment, and placing particular importance on immune system cells. Enhanced understanding of the molecular bases that give rise to alterations of pathways related to tumor development can open up new therapeutic intervention opportunities, such as metabolic regulation applied to immunotherapy. This review outlines the role of various oncometabolites and immunometabolites, such as TCA intermediates, in shaping pro/anti-inflammatory activity of immune cells such as MDSCs, T lymphocytes, TAMs and DCs in cancer. We also discuss the extraordinary plasticity of the immune response and its implication in immunotherapy efficacy, and highlight different therapeutic intervention possibilities based on controlling the balanced systems of specific metabolites with antagonistic functions.

Metabolic Classification and Intervention Opportunities for Tumor Energy Dysfunction.

A comprehensive view of cell metabolism provides a new vision of cancer, conceptualized as tissue with cellular-altered metabolism and energetic dysfunction, which can shed light on pathophysiological mechanisms. Cancer is now considered a heterogeneous ecosystem, formed by tumor cells and the microenvironment, which is molecularly, phenotypically, and metabolically reprogrammable. A wealth of evidence confirms metabolic reprogramming activity as the minimum common denominator of cancer, grouping together a wide variety of aberrations that can affect any of the different metabolic pathways involved in cell physiology. This forms the basis for a new proposed classification of cancer according to the altered metabolic pathway(s) and degree of energy dysfunction. Enhanced understanding of the metabolic reprogramming pathways of fatty acids, amino acids, carbohydrates, hypoxia, and acidosis can bring about new therapeutic intervention possibilities from a metabolic perspective of cancer.

Integrating the Tumor Microenvironment into Cancer Therapy.

Tumor progression is mediated by reciprocal interaction between tumor cells and their surrounding tumor microenvironment (TME), which among other factors encompasses the extracellular milieu, immune cells, fibroblasts, and the vascular system. However, the complexity of cancer goes beyond the local interaction of tumor cells with their microenvironment. We are on the path to understanding cancer from a systemic viewpoint where the host macroenvironment also plays a crucial role in determining tumor progression. Indeed, growing evidence is emerging on the impact of the gut microbiota, metabolism, biomechanics, and the neuroimmunological axis on cancer. Thus, external factors capable of influencing the entire body system, such as emotional stress, surgery, or psychosocial factors, must be taken into consideration for enhanced management and treatment of cancer patients. In this article, we review prognostic and predictive biomarkers, as well as their potential evaluation and quantitative analysis. Our overarching aim is to open up new fields of study and intervention possibilities, within the framework of an integral vision of cancer as a functional tissue with the capacity to respond to different non-cytotoxic factors, hormonal, immunological, and mechanical forces, and others inducing stroma and tumor reprogramming.

[An integral view of cancer (III). Evaluation of new biomarkers and treatment strategies]. / Una visión integral del cáncer (III). Evaluación de nuevos biomarcadores y posibilidades de intervención.

We propose a comprehensive approach to oncological disease, based on a systemic consideration of biology, health and disease. Our two previous review articles focused on tumour microenvironment and the discovery of new biomarkers; here we discuss the practical application of these principles to pathology, through the identification, evaluation and quantitative analysis of new prognostic and predictive factors (Immunoscore, TIME). We also consider the clinical use of promising, better tolerated treatments, such as immunotherapy. The integrative pathologist now has access to the latest improved oncology stratification tools designed to identify effective treatment strategies, based on the natural evolution of clinical and scientific knowledge that transcend the gene-centric theory of cancer.

Analytical Methodology of Meiosis in Autopolyploid and Allopolyploid Plants.

Meiosis is the cellular process responsible for producing gametes with half the genetic content of the parent cells. Integral parts of the process in most diploid organisms include the recognition, pairing, synapsis, and recombination of homologous chromosomes, which are prerequisites for balanced segregation of half-bivalents during meiosis I. In polyploids, the presence of more than two sets of chromosomes adds to the basic meiotic program of their diploid progenitors the possibility of interactions between more than two chromosomes and the formation of multivalents, which has implications on chromosome segregations and fertility. The mode of how chromosomes behave in meiosis in competitive situations has been the aim of many studies in polyploid species, some of which are considered here. But polyploids are also of interest in the study of meiosis because some of them tolerate the loss of chromosome segments or complete chromosomes as well as the addition of chromosomes from related species. Deletions allow to assess the effect of specific chromosome segments on meiotic behavior. Introgression lines are excellent materials to monitor the behavior of a given chromosome in the genetic background of the recipient species. We focus on this approach here as based on studies carried out in bread wheat, which is commonly used as a model species for meiosis studies. In addition to highlighting the relevance of the use of materials derived from polyploids in the study of meiosis, cytogenetics tools such as fluorescence in situ hybridization and the immunolabeling of proteins interacting with DNA are also emphasized.

Una visión integral del cáncer (II). Campos de estudio y biomarcadores emergentes / An integral view of cancer (II). Fields of investigation and emerging biomarkers

El mundo de la Patología cobra sentido de la mano de la Oncología Clínica, donde técnicas y tratamientos, biomarcadores y anticuerpos, comparten el objetivo de hallar nuevas posibilidades de intervención, más eficaces, menos agresivas y más integrales. En esta búsqueda, la evidencia muestra como la mecánica tisular afecta la carcinogénesis y como la heterogeneidad tumoral depende de la alteración metabólica del estroma y del efecto Warburg de las células malignas, regulado directamente por PD-1 y diana del tratamiento inmunoterápico. Proliferación y apoptosis dependen de la disfunción mitocondrial de la célula tumoral que determina el grado de quimio- y radiorresistencia. El estado de la microbiota intestinal determina la respuesta inmune, la estructura del microambiente del tumor y la respuesta al tratamiento oncológico, y el receptor de la vitamina D permite la reprogramación del estroma tumoral. En la actualidad, la colaboración entre los mundos de la investigación básica y clínica establece como zonas de desarrollo próximo el estudio del microambiente tumoral y la mecanoterapia molecular, el metabolismo y la inmunoterapia, la mitocondria y la oncogénesis, la microbiota y la quimioterapia, el eje psiconeuroendocrino y el desequilibrio homeostático, la epigenética y las posibilidades de reprogramación del fenotipo tumoral. De todos estos campos de conocimiento surgen nuevos biomarcadores, pronósticos y predictivos, que revisamos en este artículo al servicio de nuevas posibilidades de intervención terapéutica

Pathology and clinical oncology work hand in hand so that techniques and treatments, biomarkers and antibodies share the common goal of identifying integral new treatment regimens that are more effective and less aggressive. Evidence shows how tissue mechanics affect carcinogenesis and that tumor heterogeneity depends on metabolic stromal alteration and the Warburg effect of malignant cells, regulated directly by PD-1, becoming a target for immunotherapy. Proliferation and apoptosis depend on mitochondrial dysfunction in tumor cells, determining the grade of chemo/radio-resistance. The status of intestinal microbiota regulates immune response, tumor microenvironment structure and oncologic treatment response, whilst the Vitamin D receptor allows reprogramming of tumor stroma. Current collaboration between basic and clinical research paves the way for future investigation into areas such as tumor microenvironment and molecular mechanotherapy, metabolism and immunotherapy, mitochondria and oncogenesis, microbiota and chemotherapy, psychoneuroendocrine axis and homeostatic imbalance, epigenetics and reprogramming possibilities of the tumor phenotype. We review new prognostic and predictive biomarkers emerging from these fields of knowledge, opening up new therapeutic possibilities

[An integral view of cancer (II). Fields of investigation and emerging biomarkers]. / Una visión integral del cáncer (II). Campos de estudio y biomarcadores emergentes.

Pathology and clinical oncology work hand in hand so that techniques and treatments, biomarkers and antibodies share the common goal of identifying integral new treatment regimens that are more effective and less aggressive. Evidence shows how tissue mechanics affect carcinogenesis and that tumor heterogeneity depends on metabolic stromal alteration and the Warburg effect of malignant cells, regulated directly by PD-1, becoming a target for immunotherapy. Proliferation and apoptosis depend on mitochondrial dysfunction in tumor cells, determining the grade of chemo/radio-resistance. The status of intestinal microbiota regulates immune response, tumor microenvironment structure and oncologic treatment response, whilst the Vitamin D receptor allows reprogramming of tumor stroma. Current collaboration between basic and clinical research paves the way for future investigation into areas such as tumor microenvironment and molecular mechanotherapy, metabolism and immunotherapy, mitochondria and oncogenesis, microbiota and chemotherapy, psychoneuroendocrine axis and homeostatic imbalance, epigenetics and reprogramming possibilities of the tumor phenotype. We review new prognostic and predictive biomarkers emerging from these fields of knowledge, opening up new therapeutic possibilities.

La medicina del cáncer: ¿están los remedios en nuestro propio jardín? / The medicine of cancer: can the solutions be found in our own back yard?

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Una visión integral del cáncer (I). Microambiente tumoral: estudio, clasificación y reprogramación / An integral view of cancer (I). The study, classification and reprogramming of the tumoral microclimate

El grupo de enfermedades al que nos referimos como «cáncer» comparte una estructura biológica conformada por un ecosistema complejo, donde se han alterado las relaciones intercelulares, los campos de información, el desarrollo y la función tisular. Más allá de las alteraciones genéticas de la célula tumoral, la demostración de un ecosistema alterado, con sus interconexiones a nivel sistémico, abre una nueva perspectiva de la biología y del comportamiento del cáncer. Diversas facetas del tumor, su morfología, clasificación, agresividad clínica, pronóstico y respuesta al tratamiento aparecen ahora bajo una visión integral que ofrece un nuevo horizonte de estudio, investigación y manejo clínico. La Teoría de la Mutación Somática en cáncer, vigente desde hace más de 100 años, se ve hoy completada por el estudio del microambiente tumoral, la matriz extracelular, las células estromales, la respuesta inmune, la inervación, la nutrición, la mitocondria, el metabolismo, el fluido intersticial, las propiedades mecánicas y electromagnéticas del tejido, y muchas otras áreas de conocimiento emergente, que abren la puerta a un ejercicio de reprogramación del fenotipo tumoral a través de la modificación de las claves ofrecidas por este nuevo paradigma. Su reconocimiento permite pasar de considerar el proceso oncológico como un problema celular a una alteración supracelular basada en la desorganización de los tejidos, inmersos en las relaciones del sistema complejo que conforma un ser vivo

The group of diseases that we call cancer share a biological structure formed by a complex ecosystem, with altered intercellular communication, information fields, development and tissue function. Beyond the genetic alterations of the tumor cell, the demonstration of an altered ecosystem, with interconnections at systemic levels, opens up a new perspective on cancer biology and behavior. Different tumor facets, such as morphology, classification, clinical aggressiveness, prognosis and response to treatment now appear under a comprehensive vision that offers a new horizon of study, research and clinical management. The Somatic Mutation Theory in cancer, in force for more than one hundred years, is now completed by the study of the tumor microenvironment, the extracellular matrix, the stromal cells, the immune response, the innervation, the nutrition, the mitochondria, the metabolism, the interstitial fluid, the mechanical and electromagnetic properties of the tissue and many other areas of emerging knowledge; thus opening the door to a reprogramming exercise of the tumor phenotype through the modification of the keys offered by this new paradigm. Its recognition makes it possible to go from considering the oncological process as a cellular problem to a supracellular alteration based on the disorganization of tissues, immersed in the relationships of the complex system of the living being

[An integral view of cancer (I). The study, classification and reprogramming of the tumoral microclimate]. / Una visión integral del cáncer (I). Microambiente tumoral: estudio, clasificación y reprogramación.

The group of diseases that we call cancer share a biological structure formed by a complex ecosystem, with altered intercellular communication, information fields, development and tissue function. Beyond the genetic alterations of the tumor cell, the demonstration of an altered ecosystem, with interconnections at systemic levels, opens up a new perspective on cancer biology and behavior. Different tumor facets, such as morphology, classification, clinical aggressiveness, prognosis and response to treatment now appear under a comprehensive vision that offers a new horizon of study, research and clinical management. The Somatic Mutation Theory in cancer, in force for more than one hundred years, is now completed by the study of the tumor microenvironment, the extracellular matrix, the stromal cells, the immune response, the innervation, the nutrition, the mitochondria, the metabolism, the interstitial fluid, the mechanical and electromagnetic properties of the tissue and many other areas of emerging knowledge; thus opening the door to a reprogramming exercise of the tumor phenotype through the modification of the keys offered by this new paradigm. Its recognition makes it possible to go from considering the oncological process as a cellular problem to a supracellular alteration based on the disorganization of tissues, immersed in the relationships of the complex system of the living being.

Variable Patterning of Chromatin Remodeling, Telomere Positioning, Synapsis, and Chiasma Formation of Individual Rye Chromosomes in Meiosis of Wheat-Rye Additions.

Meiosis, the type of cell division that halves the chromosome number, shows a considerable degree of diversity among species. Unraveling molecular mechanisms of the meiotic machinery has been mainly based on meiotic mutants, where the effects of a change were assessed on chromosomes of the particular species. An alternative approach is to study the meiotic behavior of the chromosomes introgressed into different genetic backgrounds. As an allohexaploid, common wheat tolerates introgression of chromosomes from related species, such as rye. The behavior of individual pairs of rye homologues added to wheat has been monitored in meiotic prophase I and metaphase I. Chromosome 4R increased its length in early prophase I much more than other chromosomes studied, implying chromosome specific patterns of chromatin organization. Chromosome conformation affected clustering of telomeres but not their dispersion. Telomeres of the short arm of submetacentric chromosomes 4R, 5R, and 6R failed more often to be included in the telomere cluster either than the telomeres of the long arms or telomeres of metacentrics such as 2R, 3R, and 7R. The disturbed migration of the telomeres of 5RS and 6RS was associated with failure of synapsis and chiasma formation. However, despite the failed convergence of its telomere, the 4RS arm developed normal synapsis, perhaps because the strong increase of its length in early prophase I facilitated homologous encounters in intercalary regions. Surprisingly, chiasma frequencies in both arms of 4R were reduced. Similarly, the short arm of metacentric chromosome 2R often failed to form chiasmata despite normal synapsis. Chromosomes 1R, 3R, and 7R showed a regular meiotic behavior. These observations are discussed in the context of the behavior that these chromosomes show in rye itself.

Estudio comparativo de la supervivencia del cáncer de mama según diagnóstico asistencial versus programa de detección precoz / Comparison of breast cancer survival by diagnosis in the clinical setting versus screening

Objetivo. Comparar la supervivencia del cáncer de mama en mujeres que han sido cribadas en el programa de Detección Precoz del Cáncer de Mama (DPCM) y en las que no han participado en él. Pacientes y métodos. Es un estudio descriptivo y longitudinal en el que se han estudiado todos los cánceres de mama registrados en el servicio de Anatomía Patológica del Hospital de Tortosa Verge de la Cinta (Tarragona) de mujeres de 50-65 años, que se habían detectado la enfermedad ellas mismas o que la había detectado el programa DPCM, desde junio de 1999 hasta junio de 2003. Se registraron 101 pacientes con cáncer de mama, de las que en 84 se pudieron recoger todos los datos relativos al tumor, la cirugía y el tratamiento. En el 2014, tras un seguimiento de 11,6 ± 1,8 años, se anotó el estado actual. Resultados. No hay diferencia estadísticamente significativa en la supervivencia de los 2 grupos. Pacientes con carcinoma in situ y sin ganglios metastásicos se encuentran entre las fallecidas, mientras que ninguna paciente con carcinoma bien diferenciado falleció. Conclusiones. En nuestro estudio, el cribado del cáncer de mama no mejora la supervivencia y determinados factores en los que se apoyan los programas de cribado, como la detección de carcinomas no infiltrantes y/o de ganglios no metastásicos, no aseguran la curación (AU)

Objective. To compare survival in breast cancer between women diagnosed in an early breast cancer detection programme and those not attending this programme. Patients and methods. We conducted a descriptive and longitudinal study that analysed all types of breast cancer registered in the Pathology Service of the Hospital de Tortosa Verge de la Cinta (Tarragona, Spain). Tumour samples were obtained from 50-65-year-old women who had detected alterations on self-examination and from those attending the early breast cancer detection programme from June 1999 to June 2003. All the information relating to the tumour, surgery or treatment was registered. In 2014, after a follow-up of 11.6 ± 1.8 years, the current status of each patient was recorded. Results. There was no significant statistical difference in survival between the two groups of patients. Non-survivors included patients with in situ carcinoma and without lymph node metastases. Survival was 100% in patients with well differentiated carcinoma. Conclusions. Breast cancer screening did not improve survival in our study. The elements on which screening programs are based, such as non-invasive carcinoma detection and/or non- metastatic lymph nodes, do not ensure recovery (AU)

Contribution of Structural Chromosome Mutants to the Study of Meiosis in Plants.

Dissection of the molecular mechanisms underlying the transition through the complex events of the meiotic process requires the use of gene mutants or RNAi-mediated gene silencing. A considerable number of meiotic mutants have been isolated in plant species such as Arabidopsis thaliana, maize or rice. However, structural chromosome mutants are also important for the identification of the role developed by different chromosome domains in the meiotic process. This review summarizes the contribution of studies carried out in plants using structural chromosome variations. Meiotic events concerning the search of the homologous partner, the control of number and distribution of chiasmata, the mechanism of pairing correction, and chromosome segregation are considered.

Forcing the shift of the crossover site to proximal regions in wheat chromosomes.

Terminal deletions obligate the first crossover to be formed in more proximal positions. This increases the recombination rate in intercalary intervals but not in the proximity of the centromere. Crossovers are not uniformly distributed along chromosomes in wheat. They take place preferentially in distal positions. The effect of the chromosomal architecture on crossover positioning has been analyzed from the chiasmate bonds at metaphase I formed by the truncated arms of 51 terminal deletion lines of eight wheat chromosomes. Chromosome 4A and the B genome chromosomes, in their standard or truncated conformation, and their arms, were identified by C-banding. Chromosomes studied show a similar chiasma distribution. Reduction of the size of the truncated arms is accompanied by a gradual decrease of the chiasma frequency in chromosome arms 1BL, 3BS, 3BL, 4BL, 5BS, 5BL, 6BL, 7BS, 7BL and 4AL. In chromosome arm 1BS, most chiasmata are concentrated in the distal half of the satellite and, in 4AS, in the distal 24 %. The arms 2BS, 2BL and 6BS do not show a simple decreasing gradient of the recombination rate, the chiasma frequency increases in subdistal intervals compared to more distal regions. Although terminal deletions usually induce an increase of chiasma frequency in intercalary regions, the level of intact chromosome arms is maintained in only a few deletion lines. Truncated arms containing only the 20 % proximal of the intact arm do not form chiasmata. The relationships of chiasma positioning with chromatin structure and genome organization is discussed.