The complexity of cancer immunotherapy illustrated through skin tumors.

Skin tumours are among the cancer types most sensitive to immunotherapy, due to their unique immunogenic features including skin-associated lymphoid tissue, high mutational load, overexpression of tumour antigens, and high frequency of viral antigens. Despite this high immunotherapy response rate, however, ultimately most skin tumours develop similar treatment resistance to most other malignant tumours, which highlights the need for in-depth study of mechanisms of response and resistance to immunotherapy. A bibliographic review of the most recent publications regarding currently in use and emerging biomarkers on skin tumors has been done. Predictive biomarkers of treatment response, biomarkers that warn of possible resistance, and emerging markers, the majority of a systemic nature, are described. Including factors affecting not only genomics, but also the immune system, nervous system, microbiota, tumour microenvironment, metabolism and stress. For accurate diagnosis of tumour type, knowledge of its functional mechanisms and selection of a comprehensive therapeutic protocol, this inclusive view of biology, health and disease is fundamental. This field of study could also become a valuable source of practical information applicable to other areas of oncology and immunotherapy.

Ex Vivo and In Vivo Biocompatibility Assessment (Blood and Tissue) of Three-Dimensional Bacterial Nanocellulose Biomaterials for Soft Tissue Implants.

Bacterial nanocellulose (BNC) is a promising biomedical material. However, the haemocompatibility (haemolysis and thrombogenicity) and acute and sub-chronic immune responses to three-dimensional (3D) BNC biomaterials have not been evaluated. Accordingly, this manuscript focused on the effect of 3D microporosity on BNC haemocompatibility and a comparison with 2D BNC architecture, followed by the evaluation of the immune response to 3D BNC. Blood ex vivo studies indicated that compared with other 2D and 3D BNC architectures, never-dried 2D BNC presented antihemolytic and antithrombogenic effects. Nevertheless, in vivo studies indicated that 3D BNC did not interfere with wound haemostasis and elicited a mild acute inflammatory response, not a foreign body or chronic inflammatory response. Moreover, compared with the polyethylene controls, the implant design with micropores ca. 60 µm in diameter showed a high level of collagen, neovascularization and low fibrosis. Cell/tissue infiltration increased to 91% after 12 weeks and was characterized by fibroblastic, capillary and extracellular matrix infiltration. Accordingly, 3D BNC biomaterials can be considered a potential implantable biomaterial for soft tissue augmentation or replacement.

Novel surface modification of three-dimensional bacterial nanocellulose with cell-derived adhesion proteins for soft tissue engineering.

Bacterial nanocellulose (BNC) is a natural polymer composed of glucose units with an important application as a two and three-dimensional scaffold for tissue engineering. However, as a polysaccharide, BNC does not have the biological signals of protein biomaterials. Therefore, this paper aims to develop a novel methodology to biomimic soft extracellular matrix (ECM) chemistry on to 3D BNC using the bioengineering of fibroblasts (the cells responsible for producing and regenerating the ECM) to immobilise adhesion proteins such as collagen and fibronectin. Modified 3D BNC (Mod-BNC) biomaterials were morphologically, thermally, and chemically characterised, and furthermore, the cell response was analysed by adhesion studies using atomic force microscopy (AFM), XTT assay, and confocal microscopy. Cell-derived proteins were deposited on the BNC nanoribbon network to modify its surface. The contact angle was increased from 40° to 60°, reducing the wettability of the biomaterial, and during thermogravimetry, the proteins in Mod-BNC exhibited an enhanced thermal stability because of the interactions between themselves and BNC. Chemical and immunocytochemistry analyses confirmed the presence of collagen type I and fibronectin on 3D BNC. These proteins activate integrin adhesion pathways that generate stronger cell adhesions. AFM experiments showed higher forces and energies on modified biomaterials, and moreover, the cells that adhered on to Mod-BNC exhibited higher mitochondrial activity and higher cell populations per cubic millimetre than non-modified surfaces (NMod-BNC). Accordingly, it was established that this novel methodology is robust and able to biomimic the chemical surface of soft ECM and immobilise cell-derived adhesion proteins from fibroblast; moreover, the Mod-BNC exhibited better cell response than NMod-BNC because of the biological signals in 3D BNC.

Correlations between impairment, psychological distress, disability, and quality of life in peripheral facial palsy. / Correlación entre deficiencia, afectación psicológica, discapacidad y calidad de vida en la parálisis facial periférica.

INTRODUCTION: This paper analyses the correlations between scores on scales assessing impairment, psychological distress, disability, and quality of life in patients with peripheral facial palsy (PFP). MATERIAL AND METHODS: We conducted a retrospective cross-sectional study including 30 patients in whom PFP had not resolved completely. We used tools for assessing impairment (Sunnybrook Facial Grading System [FGS]), psychological distress (Hospital Anxiety and Depression Scale [HADS]), disability (Facial Disability Index [FDI]), and quality of life (Facial Clinimetric Evaluation [FaCE] scale). RESULTS: We found no correlations between FGS and HADS scores, or between FGS and FDI social function scores. However, we did find a correlation between FGS and FDI physical function scores (r=0.54; P<.01), FDI total score (r=0.4; P<.05), FaCE total scores (ρ=0.66; P<.01), and FaCE social function scores (ρ=0.5; P<.01). We also observed a correlation between HADS Anxiety scores and FDI physical function (r=-0.47; P<.01), FDI social function (r=-0.47; P<.01), FDI total (r=-0.55; P<.01), FaCE total (ρ=-0.49; P<.01), and FaCE social scores (ρ=-0.46; P<.05). Significant correlations were also found between HADS Depression scores and FDI physical function (r=-0.61; P<.01), FDI social function (r=-0.53; P<.01), FDI total (r=-0.66; P<.01), FaCE total (ρ=-0.67; P<.01), and FaCE social scores (ρ=-0.68; P<.01), between FDI physical function scores and FaCE total scores (ρ=0.87; P<.01) and FaCE social function (ρ=0.74; P<.01), between FDI social function and FaCE total (ρ=0.66; P<.01) and FaCE social function scores (ρ=0.72; P<.01), and between FDI total scores and FaCE total (ρ = 0,87; P<.01) and FaCE social function scores (ρ=0.84; P<.01). CONCLUSION: In our sample, patients with more severe impairment displayed greater physical and global disability and poorer quality of life without significantly higher levels of social disability and psychological distress. Patients with more disability experienced greater psychological distress and had a poorer quality of life. Lastly, patients with more psychological distress also had a poorer quality of life.

[Surgical results among 100 patients with type A aortic dissection: retrospective review]. / Disección aórtica tipo A: Resultados operatorios y seguimiento a mediano plazo.

BACKGROUND: Tipe A aortic dissection involves the ascending aorta and has high mortality rates without surgical treatment. AIM: To report the results of surgical treatment of type A aortic dissection. MATERIAL AND METHODS: Retrospective review of medical records of 100 patients aged 17 to 78 years (73% males) operated between January 2000 and August 2008, for type A aortic dissection. Follow up was performed with telephone interviews and review of national death records. RESULTS: Eighty three percent of patients had an acute dissection. Operative mortality was 27 and 20% for patients with acute and chronic dissection, respectively. Mortality was 50% among patients aged 70 years or more, compared with 21% among their younger counterparts, The most common complication was bleeding that required a new surgical procedure in 18% of patients. Actuarial survival was 70% at five years. Cardiovascular problems caused the death of two of the nine patients that died during follow up. CONCLUSIONS: Surgical mortality among patients with type A aortic dissection was higher among patients with acute episodes and those aged 70 years or more.

Disección aórtica tipo A: Resultados operatorios y seguimiento a mediano plazo / Surgical results among 100 patients with type A aortic dissection: Retrospective review

Background: Tipe A aortic dissection involves the ascending aorta and has high mortality rates without surgical treatment. Aim: To report the results of surgical treatment of type A aortic dissection. Material and Methods: Retrospective review of medical records of 100 patients aged 17 to 78 years (73 percent males) operated between January 2000 and August 2008, for type A aortic dissection. Follow up was performed with telephone interviews and review of national death records. Results: Eighty three percent of patients had an acute dissection. Operative mortality was 27 and 20 percent for patients with acute and chronic dissection, respectively. Mortality was 50 percent among patients aged 70 years or more, compared with 21 percent among their younger counterparts, The most common complication was bleeding that required a new surgical procedure in 18 percent of patients. Actuarial survival was 70 percent at five years. Cardiovascular problems caused the death of two of the nine patients that died during follow up. Conclusions: Surgical mortality among patients with type A aortic dissection was higher among patients with acute episodes and those aged 70 years or more.

Chiasma frequency is region specific and chromosome conformation dependent in a rye chromosome added to wheat.

In many plant species synapsis starts at, or close to, the chromosome ends and this has been considered to be related to the distal location of chiasmata. In this regard we have studied the meiotic behavior of rye chromosome pair 5R in a wheat background using fluorescence in situ hybridization. The use of different DNA probes allowed the identification of the 2 rye homologues, their centromeres and subtelomeric heterochromatic chromomeres, and the telomeres of all chromosomes in prophase I and metaphase I. Three types of plants were analyzed: homozygotes for the standard chromosome 5R, homozygotes for a deficient chromosome 5R (del5R) with only the proximal 30% of its long arm (del5RL) and heterozygotes. Synapsis of the deficient chromosome arm pair del5RL was completed in most meiocytes at pachytene but the number of chiasmata formed was much lower than in the intact 5RL arm. Deletion facilitated the migration of the telomere of the accompanying chromosome arm 5RS during bouquet organization. This was followed by an increase of synapsis and chiasma frequency in this arm with regard to its counterpart of the intact chromosome. Results demonstrate that crossover formation depends on the DNA sequence or the chromatin organization of each chromosome region and that homologous alignment, synapsis and chiasma formation may be conditioned by chromosome conformation.

Nuclear architecture and chromosome dynamics in the search of the pairing partner in meiosis in plants.

The formation of haploid gametes in organisms with sexual reproduction requires regular bivalent chromosome pairing in meiosis. In many species, homologous chromosomes occupy separate territories at the onset of meiosis. To be paired at metaphase I, they need to be brought into a close proximity for interactions that include homology recognition and the establishment of some form of bonds. How homologues find each other is one of the least understood meiotic events. Plant species with large or medium sized genomes, such as wheat or maize, are excellent materials for the cytological analysis of chromosome dynamics at early meiosis, but genes that control meiosis have been identified mainly in small genome species such as Arabidopsis thaliana. This review is focused on the contribution studies on plants are providing to the knowledge of the initial steps of the meiotic process.

Physical and genetic mapping of amplified fragment length polymorphisms and the leaf rust resistance Lr3 gene on chromosome 6BL of wheat.

The Argentinian wheat cultivar Sinvalocho MA carries the Lr3 gene for leaf rust resistance on distal chromosome 6BL. In this cultivar, 33 spontaneous susceptible lines were isolated and cytogenetically characterized by C-banding. The analysis revealed deletions on chromosome 6BL in most lines. One line was nulli-6B, two lines were ditelo 6BS, two, three, and ten lines had long terminal deletions of 40, 30, and 20%, respectively, three lines showed very small terminal deletions, and one line had an intercalary deletion of 11%. Physical mapping of 55 amplified fragment length polymorphism (AFLP) markers detected differences between deletions and led to the division of 6BL into seven bins delimited by deletion breakpoints. The most distal bin, with a length smaller than 5% of 6BL, contained 22 AFLP markers and the Lr3 gene. Polymorphism for nine AFLPs between Sinvalocho MA and the rust leaf susceptible cultivar Gamma 6 was used to construct a linkage map of Lr3. This gene is at a genetic distance of 0.9 cM from a group of seven closely linked AFLPs. The location of the gene in a high recombinogenic region indicated a physical distance of approximately 1 Mb to the markers.

Resultados del reemplazo valvular aórtico con prótesis mecánica en el Instituto Nacional del Tórax / Early and long term results of mechanical aortic valve replacement at the Instituto Nacional del Torax in Chile

Background: Mechanical aortic valve replacement (AVR) results have been published extensively in industrialized countries. Aim: To assess our immediate and late results in patients subjected to AVR. Patients and Methods: We retrospectively studied 194 patients subjected to isolated AVR between 1995 and 2003. Mean age was 57 ± 13 years and 119 (61%) were male. One hundred thirty nine (73%) were in functional class III-IV, 20 (10%) had a previous cardiac operation and 25 (13%) were operated as an emergency. Surgical indication was stenosis in 110 (58%), regurgitation in 49 (26%) and stenosis/regurgitation in 31 (16%). Etiology was bicuspid valve 56 (29%), degenerative lesions 55 (28%), rheumatic valve disease 38 (20%) and endocarditis 27 (14%). Medtronic Hall was the most common prosthesis used in 157 patients (81%). Mean cardiopulmonary bypass time 97 ± 29 min and mean cross clamp time was 69 ± 21 min. Results: Operative mortality was 4.6% (3% in elective surgery, 16% in emergency surgery and 0% in reoperations). Follow-up was complete in 100% of cases, totalizing 636 patients-year. Survival was 91 ± 2%, 80 ± 4% and 73 ± 6%, at 1, 5 and 7 years, respectively. Multivariate risk analysis identified renal failure and endocarditis as predictors of early and late mortality. During follow up, the linear incidence rate for hemorrhage was 3.29% /patients-year, thromboembolism 2.04% patients-year and endocarditis 1.1% patients-year. Conclusions: AVR has low overall and elective mortality. Midterm survival is good but linear event rates related to anticoagulant treatment are higher than those previously published in industrialized countries. Renal failure and endocarditis were risk factors for early and late death.

The positioning of rye homologous chromosomes added to wheat through the cell cycle in somatic cells untreated and treated with colchicine.

The arrangement of chromosome pairs 5RL and 7R added to the wild type and the ph1b mutant line of hexaploid wheat are analyzed in 2N somatic root tip cells during the cell cycle relative to the arrangement that chromosomes 5RL show in 4N tapetal cells produced after colchicine treatment. Both homologous chromosome pairs are identified at interphase and mitosis by fluorescence in situ hybridization. In nuclei at interphase, chromosomes appear as discrete domains that show the Rabl orientation. Homologous chromosomes are predominantly non-associated and their positioning seems not to be influenced by the Ph1 gene that suppresses homoeologous meiotic pairing. This pattern of arrangement contrasts with the high level of somatic pairing that sister chromosomes show in the interphase that follows chromosome duplication induced by colchicine. Disruption of pairing observed in some 4N nuclei is produced at c-anaphase which suggests no topological redistribution of homologues during conformation of the new nucleus. Homologous chromosomes show no predominant arrangement in ellipsoidal metaphase plates, which contrasts with the preferential opposite location of homologues in human prometaphase rosettes. Differences between chromosomes in the variation of the length through the cell cycle and in the chromatin morphology when the Ph1 is absent suggest different patterns of chromatin condensation in both chromosomes.

CD20-negative DLBCL transformation after rituximab treatment in follicular lymphoma: a new case report and review of the literature.

Rituximab is a monoclonal antibody against the CD20 molecule which is used to treat B-cell lymphomas. In 60% of low-grade B lymphomas in which rituximab was effective at first, there was no clinical response in a second treatment and a few cases of follicular lymphomas (FL) with transformation to diffuse large B-cell lymphoma (DLBCL) have been reported. We describe a new case and hypothesize about the mechanisms of transformation: a 52-year-old man, in follow-up during 8 years for FL, who after rituximab treatment and complete remission of FL showed progressive disease involving the liver and duodenal mucosa. Immunohistochemical and molecular studies were performed on paraffin-embedded tissue samples of lymph nodes, the small intestine, and liver tumors. After rituximab treatment, biopsies of a liver lesion and the small bowel both showed CD20-negative large B-cell lymphoma. Molecular study of the initial and relapse specimens shows a CDR2 IgH rearrangement with the same height and t14;18 (MBR). The rapid relapse with the same rearrangement of IgH seems to support the interpretation that the change of grade of lymphoma and loss of CD20 expression occurred before rituximab treatment. The existence of a varying proportion of a CD20-negative cell population in every B-cell lymphoma which does not respond to rituximab should therefore be considered. The reduction of CD20 expression could be a resistance mechanism to rituximab retreatment in DLBCL as a consequence of the progression of low-grade B-cell non-Hodgkin's lymphoma (B-NHL). It is necessary to perform new biopsies to evaluate CD20 expression in relapse or the progression of B-cell lymphoma after rituximab treatment.

Oxigenoterapia domiciliaria a largo plazo: necesidad apremiante en enfermos con insuficiencia respiratoria crónica / Long term domiciliary oxygen therapy: an urgent need in chronic obstructive pulmonary disease patients

La EPOC y la insuficiencia respiratoria crónica constituyen un importante problema de salud pública. Está demostrado que la oxigenoterapía domiciliaria a largo plazo mejora la sobrevida y calidad de vida de estos pacientes. Por ello el Instituto Nacional del Tórax organizó en 1984 el Programa de Oxigenoterapia Domiciliaria, con el trabajo de un equipo de profesionales y con una estructura operacionalmente eficiente. Hasta diciembre 2001 han ingresado al programa 560 pacientes, actualmente 112 de ellos están en el programa. El 67,9 por ciento tiene el diagnóstico de EPOC y el 72 por ciento presenta insuficiencia respiratoria global. En una cohorte de 118 pacientes estudiados a su ingreso y 1 año después no encontramos diferencias en la gasometría arterial ni en la espirometría. Si se observó una disminución del número de hospitalizaciones y días cama utilizadas por los pacientes. La calidad de vida evaluada en los primeros 50 pacientes demostró disminución de sintomas angustiosos y depresivos, como también de los elementos de deterioro psico-orgánico. El mayor problema del programa es la lista de espera por la alta demanda de la terapia y los limitados recursos financieros. La oxigenoterapia domiciliaria es un tratamiento efectivo que mejora tanto la sobrevida como la calidad de vida de los enfermos. Es un servicio absolutamente necesario para los pacientes respiratorios crónicos y por la magnitud del problema requeriría de un Programa Nacional de Oxigeno-terapia Domiciliaria

[Primary cardiac lymphoma: presentation of two cases in immunocompetent patients]. / Linfoma cardiaco primario. Presentación de dos casos en pacientes inmunocompetentes.

BACKGROUND: Primary cardiac lymphomas (PCL) are extremely rare in immunocompetent patients. Their pathogenesis seems obscure and a few studies which have sought Epstein Barr virus (EBV) agree that this is generally not demonstrable. CASES: Two cases of cardiac lymphoma have been described. In both cases, as usually occurs, the histological diagnosis was performed after post-mortem examination. Histological examinations revealed a B large cell lymphoma in both patients. Autopsy material from both cases showed an inflammatory focus distant from the tumoral mass. EBERs and LMP for EBV were negative. CONCLUSIONS: PCLs are often fast-growing tumours with a highly unfavorable prognosis. Epstein-Barr virus appears to play no role in the development of this malignant condition.

Estudio comparativo de costos anuales en salud entre usuarios de oxígeno domiciliario y pacientes en lista de espera / Comparative study of health care costs for patients using home oxygen therapy or those in waiting lists

Background: Home oxygen therapy is the only intervention that significantly prolongs survival of patients with chronic obstructive pulmonary disease. Since this therapy is expensive, it is imperative to calculate its cost-benefit ratio. Aim: To compare health care costs for patients in a home oxygen therapy program, with those of a similar group of patients in a waiting list for this therapy. Material and methods: A retrospective analysis of 21 patients on home oxygen therapy for 36 months or less and a group of 13 patients in the waiting list during a similar lapse. Medical consultations, drugs delivered and the cost of oxygen therapy were considered among ambulatory costs. Hospitalization costs included the number of days on regular or intermediary care beds, laboratory tests and drugs delivered. Results: The annual health care costs for patients on home oxygen therapy were 709,656 Chilean pesos and the costs for patients in the waiting list were 797,320 Chilean pesos. Conclusions: The overall health care costs of home oxygen therapy are similar to the costs required by patients with chronic obstructive pulmonary disease remaining in waiting lists

The synaptic behaviour of the wild forms of Triticum turgidum and T. timopheevii.

Different wild allopolyploid species of Triticeae show extensive bivalent formation at zygotene while a considerable number of multivalents is present in cultivated polyploid wheats. To study the chromosome behaviour at early meiotic stages in wild forms of tetraploid wheats Triticum turgidum and T timopheevii (2n = 4x = 28) we have analysed the synaptic pattern in fully traced spread nuclei at mid- and late zygotene and at pachytene of wild accessions of these species. The mean number of synaptonemal complex (SC) bivalents at mid-zygotene ranged from 12.22 to 13.14 among the accessions studied indicating a strong restriction of synapsis initiation to homologous chromosomes. The mean of bivalents increased at pachytene because of the transformation of multivalents into bivalents. Ring bivalents observed at metaphase I support that SC bivalents were formed by homologous chromosomes. The average values of SC bivalents at mid-zygotene in the wild forms are much higher than the average values observed in the cultivated tetraploid wheats but similar to that of a mutant line of T turgidum with a duplication that includes Ph1, the major homoeologous pairing suppressor locus. These results suggest that the efficiency of the mechanism operating in the homologous recognition for synapsis is higher in wild wheat populations than in cultivated varieties. Apparently, a relatively detrimental modification of the pairing regulating genetic system accompanied the domestication of the wild wheat forms.

Meiosis in primary trisomics of rye: considerations for models of chromosome pairing.

Meiotic chromosome pairing of primary trisomics of rye was analysed by electron microscopy in surface-spread prophase I nuclei and compared with light-microscopic observations of metaphase I cells. Despite the large-sized chromosomes of rye, prophase I trivalent frequencies were close to the two thirds expected on a simple model with two terminal independent pairing initiation sites per trisome (set of three homologous chromosomes). Direct observations mostly reveal one pairing partner switch (PPS) in prophase I trivalents, which confirms this supposition. There were no significant differences between the number of trivalent and bivalent plus univalent configurations observed at prophase and metaphase I; therefore, synapsed segments form chiasmata. In all of the trisomics, the three homologues showed variations not only in the number of telomeric C-bands but also in the amount of heterochromatin of these bands, which allowed identification of chromosomes or chromosome arms associated in most metaphase I configurations. In trisomics for chromosomes 2, 3 and 5, some metaphase I chromosome configuration frequencies did not fit those expected under the assumption of random chromosome association among all partners, suggesting the existence of preferences for pairing between two given chromosome arms of the trisome. No preferential associations either at metaphase I or pachytene were observed in the trisomics for chromosome 6. The fit between theoretical pairing models and the experimental data is also discussed.

Pairing affinities of the B- and G-genome chromosomes of polyploid wheats with those of Aegilops speltoides.

Chromosome pairing at metaphase I was studied in different interspecific hybrids involving Aegilops speltoides (SS) and polyploid wheats Triticum timopheevii (AtAtGG), T. turgidum (AABB), and T. aestivum (AABBDD) to study the relationships between the S, G, and B genomes. Individual chromosomes and their arms were identified by means of C-banding. Pairing between chromosomes of the G and S genomes in T. timopheevii x Ae. speltoides (AtGS) hybrids reached a frequency much higher than pairing between chromosomes of the B and S genomes in T. turgidum x Ae. speltoides (ABS) hybrids and T. aestivum x Ae. speltoides (ABDS) hybrids, and pairing between B- and G-genome chromosomes in T. turgidum x T. timopheevii (AAtBG) hybrids or T. aestivum x T. timopheevii (AAtBGD) hybrids. These results support a higher degree of closeness of the G and S genomes to each other than to the B genome. Such relationships are consistent with independent origins of tetraploid wheats T. turgidum and T. timopheevii and with a more recent formation of the timopheevi lineage.