Addition of nocturnal pollinators modifies the structure of pollination networks.

Although the ecological network approach has substantially contributed to the study of plant-pollinator interactions, current understanding of their functional structure is biased towards diurnal pollinators. Nocturnal pollinators have been systematically ignored despite the publication of several studies that have tried to alleviate this diurnal bias. Here, we explored whether adding this neglected group of pollinators had a relevant effect on the overall architecture of three high mountain plant-pollinator networks. Including nocturnal moth pollinators modified network properties by decreasing total connectivity, connectance, nestedness and robustness to plant extinction; and increasing web asymmetry and modularity. Nocturnal moths were not preferentially connected to the most linked plants of the networks, and they were grouped into a specific "night" module in only one of the three networks. Our results indicate that ignoring the nocturnal component of plant-pollinator networks may cause changes in network properties different from those expected from random undersampling of diurnal pollinators. Consequently, the neglect of nocturnal interactions may provide a distorted view of the structure of plant-pollinator networks with relevant implications for conservation assessments.

Therapeutic potential of an anti-CCR9 mAb evidenced in xenografts of human CCR9+ tumors.

Relapsed or refractory T acute lymphoblastic leukemia (T-ALL) still carries poor prognosis. Aiming to improve outcomes, the therapeutic potential of an anti-CCR9 monoclonal antibody (mAb 92R), targeting the human chemokine-receptor CCR9 is analyzed on orthotopic xenotransplants. 92R mAb treatment of mice carrying human CCR9+ T-ALL cell lines or primary T cell leukemias inhibits tumor growth and increases survival. The therapeutic effects of 92R are specific and synergize with chemotherapeutic agents increasing survival. Furthermore, 92R decreases size of non-hematopoietic tumors with a forced CCR9 expression and of solid tumors generated by the pancreatic adenocarcinoma cell line AsPC-1. In addition, a humanized version of 92R mAb (Srb1) is also able to inhibit growth of CCR9+ T-ALL tumor cells in vivo, increasing survival 2.66-fold. Finally, 92R mAb prevents liver accumulation of infiltrates and reduces tumor cell numbers in already formed infiltrates. Thus, the humanized version of 92R mAb (Srb1), displays therapeutic potential for CCR9+ tumor treatment and might represent one of the first therapeutic antibodies for precision medicine on T-ALL patients.

Cannabinoid CB1 receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice.

Cannabinoids are known to modulate oligodendrogenesis and developmental CNS myelination. However, the cell-autonomous action of these compounds on oligodendroglial cells in vivo, and the molecular mechanisms underlying these effects have not yet been studied. Here, by using oligodendroglial precursor cell (OPC)-targeted genetic mouse models, we show that cannabinoid CB1 receptors exert an essential role in modulating OPC differentiation at the critical periods of postnatal myelination. We found that selective genetic inactivation of CB1 receptors in OPCs in vivo perturbs oligodendrogenesis and postnatal myelination by altering the RhoA/ROCK signaling pathway, leading to hypomyelination, and motor and cognitive alterations in young adult mice. Conversely, pharmacological CB1 receptor activation, by inducing E3 ubiquitin ligase-dependent RhoA proteasomal degradation, promotes oligodendrocyte development and CNS myelination in OPCs, an effect that was not evident in OPC-specific CB1 receptor-deficient mice. Moreover, pharmacological inactivation of ROCK in vivo overcomes the defects in oligodendrogenesis and CNS myelination, and behavioral alterations found in OPC-specific CB1 receptor-deficient mice. Overall, this study supports a cell-autonomous role for CB1 receptors in modulating oligodendrogenesis in vivo, which may have a profound impact on the scientific knowledge and therapeutic manipulation of CNS myelination by cannabinoids.

Cell Therapy Based on Gingiva-Derived Mesenchymal Stem Cells Seeded in a Xenogeneic Collagen Matrix for Root Coverage of RT1 Gingival Lesions: An In Vivo Experimental Study.

(1) Background: To investigate the effect of a xenogeneic collagen matrix (CMX) seeded with autologous gingiva-derived mesenchymal cells (GMSCs) when combined with a coronally advanced flap (CAF) in the treatment of localized gingival recession type 1 (RT1). (2) Methods: Dehiscence-type defects were created in seven dogs. GMSCs were isolated, transfected with a vector carrying green fluorescent protein (GFP) and expanded. Once chronified, the defects were randomly treated with (1) CAF plus the combination of CMX and GFP+ GMSCs, (2) CAF plus CMX with autologous fibroblasts, (3) CAF plus CMX and (4) CAF alone. Histological and clinical outcomes at 2- and 6-week healing periods were analyzed and compared among groups. (3) Results: Histologically, the addition of autologous cells to the CMX resulted in reduced inflammation and a variable degree of new cementum/bone formation. CMX plus GMSCs resulted in greater mean recession reduction (1.42; SD = 1.88 mm) and percentage of teeth with recession reduction of ≥2 mm (57%) when compared to the other groups, although these differences were not statistically significant. (4) Conclusions: The histometric and clinical results indicated a positive trend favouring the combination of CMX and GMSCs with the CAF when compared to the groups without cells, although these differences were not statistically significant.

Periodontal regeneration using a xenogeneic bone substitute seeded with autologous periodontal ligament-derived mesenchymal stem cells: A 12-month quasi-randomized controlled pilot clinical trial.

AIM: To evaluate the safety and efficacy of autologous periodontal ligament-derived mesenchymal stem cells (PDL-MSCs) embedded in a xenogeneic bone substitute (XBS) for the regenerative treatment of intra-bony periodontal defects. MATERIAL AND METHODS: This quasi-randomized controlled pilot phase II clinical trial included patients requiring a tooth extraction and presence of one intra-bony lesion (1-2 walls). Patients were allocated to either the experimental (XBS + 10 × 106 PDL-MSCs/100 mg) or the control group (XBS). Clinical and radiographical parameters were recorded at baseline, 6, 9 and 12 months. The presence of adverse events was also evaluated. Chi-square, Student's t test, Mann-Whitney U, repeated-measures ANOVA and regression models were used. RESULTS: Twenty patients were included. No serious adverse events were reported. Patients in the experimental group (n = 9) showed greater clinical attachment level (CAL) gain (1.44, standard deviation [SD] = 1.87) and probing pocket depth (PPD) reduction (2.33, SD = 1.32) than the control group (n = 10; CAL gain = 0.88, SD = 1.68, and PPD reduction = 2.10, SD = 2.46), without statistically significant differences. CONCLUSION: The application of PDL-MSCs to XBS for the treatment of one- to two-wall intra-bony lesions was safe and resulted in low postoperative morbidity and appropriate healing, although its additional benefit, when compared with the XBS alone, was not demonstrated.

Diet composition of the lizard Podarcis lilfordi (Lacertidae) on 2 small islands: an individual-resource network approach.

Despite it is widely accepted that intrapopulation variation is fundamental to ecological and evolutionary processes, this level of information has only recently been included into network analysis of species/population interactions. When done, it has revealed non-random patterns in the distribution of trophic resources. Nestedness in resource use among individuals is the most recurrent observed pattern, often accompanied by an absence of modularity, but no previous studies examine bipartite modularity. We use network analysis to describe the diet composition of the Balearic endemic lizard Podarcis lilfordi in 2 islets at population and individual levels, based on the occurrence of food items in fecal samples. Our objectives are to 1) compare niche structure at both levels, 2) characterize niche partition using nestedness and modularity, and 3) assess how size, sex, season, and spatial location influence niche structure. At population-level niche width was wide, but narrow at the level of the individual. Both islet networks were nested, indicating similar ranking of the food preferences among individuals, but also modular, which was partially explained by seasonality. Sex and body size did not notably affect diet composition. Large niche overlap and therefore possibly relaxed competition were observed among females in one of the islets and during spring on both islets. Likewise, higher modularity in autumn suggests that higher competition could lead to specialization in both populations, because resources are usually scarce in this season. The absence of spatial location influence on niche might respond to fine-grained spatio-temporally distribution of food resources. Behavioral traits, not included in this study, could also influence resource partitioning.

11PS04 is a new chemical entity identified by microRNA-based biosensing with promising therapeutic potential against cancer stem cells.

Phenotypic drug discovery must take advantage of the large amount of clinical data currently available. In this sense, the impact of microRNAs (miRs) on human disease and clinical therapeutic responses is becoming increasingly well documented. Accordingly, it might be possible to use miR-based signatures as phenotypic read-outs of pathological status, for example in cancer. Here, we propose to use the information accumulating regarding the biology of miRs from clinical research in the preclinical arena, adapting it to the use of miR biosensors in the earliest steps of drug screening. Thus, we have used an amperometric dual magnetosensor capable of monitoring a miR-21/miR-205 signature to screen for new drugs that restore these miRs to non-tumorigenic levels in cell models of breast cancer and glioblastoma. In this way we have been able to identify a new chemical entity, 11PS04 ((3aR,7aS)-2-(3-propoxyphenyl)-7,7a-dihydro-3aH-pyrano[3,4-d]oxazol-6(4H)-one), the therapeutic potential of which was suggested in mechanistic assays of disease models, including 3D cell culture (oncospheres) and xenografts. These assays highlighted the potential of this compound to attack cancer stem cells, reducing the growth of breast and glioblastoma tumors in vivo. These data demonstrate the enhanced chain of translatability of this strategy, opening up new perspectives for drug-discovery pipelines and highlighting the potential of miR-based electro-analytical sensors as efficient tools in modern drug discovery.

Sfrp3 modulates stromal-epithelial crosstalk during mammary gland development by regulating Wnt levels.

Mammary stroma is essential for epithelial morphogenesis and development. Indeed, postnatal mammary gland (MG) development is controlled locally by the repetitive and bi-directional cross-talk between the epithelial and the stromal compartment. However, the signalling pathways involved in stromal-epithelial communication are not entirely understood. Here, we identify Sfrp3 as a mediator of the stromal-epithelial communication that is required for normal mouse MG development. Using Drosophila wing imaginal disc, we demonstrate that Sfrp3 functions as an extracellular transporter of Wnts that facilitates their diffusion, and thus, their levels in the boundaries of different compartments. Indeed, loss of Sfrp3 in mice leads to an increase of ductal invasion and branching mirroring an early pregnancy state. Finally, we observe that loss of Sfrp3 predisposes for invasive breast cancer. Altogether, our study shows that Sfrp3 controls MG morphogenesis by modulating the stromal-epithelial cross-talk during pubertal development.

92R Monoclonal Antibody Inhibits Human CCR9+ Leukemia Cells Growth in NSG Mice Xenografts.

CCR9 is as an interesting target for the treatment of human CCR9+-T cell acute lymphoblastic leukemia, since its expression is limited to immature cells in the thymus, infiltrating leukocytes in the small intestine and a small fraction of mature circulating T lymphocytes. 92R, a new mouse mAb (IgG2a isotype), was raised using the A-isoform of hCCR9 as immunogen. Its initial characterization demonstrates that binds with high affinity to the CCR9 N-terminal domain, competing with the previously described 91R mAb for receptor binding. 92R inhibits human CCR9+ tumor growth in T and B-cell deficient Rag2-/- mice. In vitro assays suggested complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity as possible in vivo mechanisms of action. Unexpectedly, 92R strongly inhibited tumor growth also in a model with compromised NK and complement activities, suggesting that other mechanisms, including phagocytosis or apoptosis, might also be playing a role on 92R-mediated tumor elimination. Taken together, these data contribute to strengthen the hypothesis of the immune system's opportunistic nature.

Cell therapy with allogenic canine periodontal ligament-derived cells in periodontal regeneration of critical size defects.

AIM: The objective of this in vivo experimental study to evaluate the regenerative potential of a cell therapy combining allogenic periodontal ligament-derived cells within a xenogeneic bone substitute in a similar experimental model. METHODS: In nine beagle dogs, critical size 6-mm supra-alveolar periodontal defects were created around the PIII and PIV. The resulting supra-alveolar defects were randomly treated with either 1.4 × 106 allogenic canine periodontal ligament-derived cells seeded on de-proteinized bovine bone mineral with 10% collagen (DBBM-C) (test group) or DBBM-C without cells (control group). Specimens were obtained at 3 months, and histological outcomes were studied. RESULTS: The histological analysis showed that total furcation closure occurred very seldom in both groups, being the extent of periodontal regeneration located in the apical third of the defect. The calculated amount of periodontal regeneration at the furcation area was comparable in both the test and control groups (1.93 ± 1.14 mm (17%) versus 2.35 ± 1.74 mm (22%), respectively (p = .37). Similarly, there were no significant differences in the amount of new cementum formation 4.49 ± 1.56 mm (41%) versus 4.97 ± 1.05 mm (47%), respectively (p = .45). CONCLUSIONS: This experimental study was unable to demonstrate the added value of allogenic cell therapy in supra-crestal periodontal regeneration.

Linfoma intravascular de células B grandes como causa inusual de ictus isquémico / Intravascular large B-cell lymphoma as an unusual cause of ischemic stroke

El linfoma intravascular es un tipo de linfoma extraganglionar, generalmente de células B, definido por una proliferación de linfocitos atípicos dentro de la luz de vasos de pequeño y mediano calibre. Desde su descripción en 1959 ha recibido diferentes denominaciones. En la actualidad, la Organización Mundial de la Salud se refiere a esta entidad como linfoma intravascular de células B grandes. Presentamos un caso caracterizado por deterioro neurológico de evolución rápida y progresiva consecutivo a eventos isquémicos multifocales y recurrentes de etiología inicialmente indeterminada. En el estudio post mortem limitado a la cavidad craneal se detectó una proliferación celular atípica en la luz de vasos de pequeño y mediano calibre. Con técnicas inmunohistoquímicas se confirmó el origen linfoide de las células neoplásicas intravasculares y se estableció el diagnóstico de linfoma intravascular de células B grandes (AU)

Intravascular lymphoma is a type of extranodal lymphoma, usually composed of B-cells, resulting from a proliferation of atypical lymphocytes within the lumina of small to medium sized vessels. Since its initial description in 1959, it has had many names but currently the World Health Organization refers to this entity as intravascular large B-cell lymphoma. We present a case which presented with rapid progressive neurological deterioration and consecutive progressive multifocal and recurrent ischemic events of unknown origin. The postmortem study of the cranial cavity revealed atypical cell proliferation within the lumina of small to medium sized vessels. The lymphoid origin of intravascular tumor cells was confirmed by immunohistochemistry, establishing a diagnosis of intravascular large B-cell lymphoma (AU)

Will a mAb-Based Immunotherapy Directed against Cancer Stem Cells Be Feasible?

The cancer stem cell (CSC) hypothesis suggests that within a tumor, there is a small subpopulation of cells with stem cell properties responsible for tumor maintenance and metastasis generation. This hypothesis also implies that new antitumor drugs, rather than targeting the bulk of the tumor mass, would be more effective if they directly targeted the CSC subpopulation. The CSCs from several types of tumors have been identified with mAbs recognizing surface antigens in these cells; however, antigens specifically or exclusively expressed in the CSC population have not yet been identified. Thus, questioning the possibility of using therapeutic antibodies directed against the CSCs. Here, we review the possibilities of using antibodies directly targeting the CSCs as therapeutic agents in the form of naked antibodies, antibodies conjugated to nanoparticles, or antibody cocktails.

Comparison of periodontal ligament and gingiva-derived mesenchymal stem cells for regenerative therapies.

OBJECTIVES: Tissue-engineering therapies using undifferentiated mesenchymal cells (MSCs) from intra-oral origin have been tested in experimental animals. This experimental study compared the characteristics of undifferentiated mesenchymal stem cells from either periodontal ligament or gingival origin, aiming to establish the basis for the future use of these cells on regenerative therapies. MATERIALS AND METHODS: Gingiva-derived mesenchymal stem cells (GMSCs) were obtained from de-epithelialized gingival biopsies, enzymatically digested and expanded in conditions of exponential growth. Their growth characteristics, phenotype, and differentiation ability were compared with those of periodontal ligament-derived mesenchymal stem cells (PDLMSCs). RESULTS: Both periodontal ligament- and gingiva-derived cells displayed a MSC-like phenotype and were able to differentiate into osteoblasts, chondroblasts, and adipocytes. These cells were genetically stable following in vitro expansion and did not generate tumors when implanted in immunocompromised mice. Furthermore, under suboptimal growth conditions, GMSCs proliferated with higher rates than PDLMSCs. CONCLUSIONS: Stem cells derived from gingival biopsies represent bona fide MSCs and have demonstrated genetic stability and lack of tumorigenicity. CLINICAL RELEVANCE: Gingiva-derived MSCs may represent an accessible source of messenchymal stem cells to be used in future periodontal regenerative therapies.

New Strategies Using Antibody Combinations to Increase Cancer Treatment Effectiveness.

Antibodies have proven their high value in antitumor therapy over the last two decades. They are currently being used as the first-choice to treat some of the most frequent metastatic cancers, like HER2+ breast cancers or colorectal cancers, currently treated with trastuzumab (Herceptin) and bevacizumab (Avastin), respectively. The impressive therapeutic success of antibodies inhibiting immune checkpoints has extended the use of therapeutic antibodies to previously unanticipated tumor types. These anti-immune checkpoint antibodies allowed the cure of patients devoid of other therapeutic options, through the recovery of the patient's own immune response against the tumor. In this review, we describe how the antibody-based therapies will evolve, including the use of antibodies in combinations, their main characteristics, advantages, and how they could contribute to significantly increase the chances of success in cancer therapy. Indeed, novel combinations will consist of mixtures of antibodies against either different epitopes of the same molecule or different targets on the same tumor cell; bispecific or multispecific antibodies able of simultaneously binding tumor cells, immune cells or extracellular molecules; immunomodulatory antibodies; antibody-based molecules, including fusion proteins between a ligand or a receptor domain and the IgG Fab or Fc fragments; autologous or heterologous cells; and different formats of vaccines. Through complementary mechanisms of action, these combinations could contribute to elude the current limitations of a single antibody which recognizes only one particular epitope. These combinations may allow the simultaneous attack of the cancer cells by using the help of the own immune cells and exerting wider therapeutic effects, based on a more specific, fast, and robust response, trying to mimic the action of the immune system.

Paraganglioma gangliocítico en la ampolla de Vater. Una entidad a tener en cuenta en la patología ampular / Gangliocytic paraganglioma in the ampulla of Vater. An entity to be considered in ampullary pathology

El paraganglioma gangliocítico es un tumor infrecuente que se desarrolla casi exclusivamente en el duodeno, aunque puede aparecer en otras localizaciones. Se presenta como una masa polipoide, sésil o pediculada. Atendiendo a su localización y a la tendencia a ulcerarse suele manifestarse con hemorragias digestivas altas, dolor abdominal o anemia. Es un tumor de naturaleza benigna y de pronóstico favorable, si bien hay algunos casos descritos de recidivas y de metástasis ganglionares. Histológicamente se compone de 3 poblaciones celulares de morfología y características inmunohistoquímicas bien definidas y distintivas (AU)

The gangliocytic paraganglioma is a rare tumour that develops almost exclusively in the duodenum although it may also appear in other locations. It presents as a sessile or pedunculated polypoid mass. Depending on location and the tendency to ulcerate, they often present as upper gastrointestinal bleeding, abdominal pain or anemia. It is a benign tumour with a favorable prognosis, although some cases of recurrence and lymph node metastasis have been reported. Histologically it is composed of three cell populations with characteristic, well defined morphological features and immunohistochemistry (AU)

Rinoscleroma. Una entidad a considerar en la rutina diaria del patólogo / Rhinoscleroma: an entity to consider in the daily routine of the pathologist

El rinoscleroma es una enfermedad infrecuente en España, pero endémica en ciertas regiones del mundo. Se presenta como una enfermedad inflamatoria crónica granulomatosa progresiva que típicamente compromete la mucosa nasal, pero puede presentarse en otras localizaciones del tracto aereodigestivo superior. Su diagnóstico se apoya en estudios de imagen y en hallazgos clínicos como la deformidad nasal o la obstrucción de la vía aérea con disnea, disfonía y estridor respiratorio. Sin embargo, usualmente requiere confirmación histopatológica, aunque la detección de la bacteria Klebsiella rhinoscleromatis en etapas iniciales sería definitivo. Esta es una enfermedad que precisa un grado alto de sospecha y que debe tenerse en cuenta en la actualidad ante el incremento de la inmigración a nuestro medio desde regiones endémicas (AU)

The rhinoscleroma is a rare pathology in Spain, but endemic in certain regions of the world. It presents as a chronic, progressive and granulamatous entity, typically compromises the nasal mucosa, but it can occur in other locations of the upper aerodigestive tract. The diagnosis is based on clinical findings as nasal deformity or obstruction of the airways with dyspnoea, dysphonia and stridor and it relies on imaging techniques. However, ususally requires confirmatory histopathological diagnosis although detecting the bacterium Klebsiella rhinoscleromatis not in advance stages would be definitive. This is a disease that accurate a high degree of suspicion and should be taken into consideration currently due to the increase of immigration to our country from endemic regions (AU)

Hamartoma mesenquimal multifocal de la pared torácica: Presentación de caso / Multifocal Mesenchymal Hamartoma of the Chest Wall: A Case Report

Los hamartomas mesenquimales de la pared torácica son lesiones raras que generalmente se presentan en la infancia temprana y que se manifiestan como una masa que deforma la pared torácica y puede acompañarse de disnea. Hasta el momento, en la literatura mundial se ha informado de 100 casos, aproximadamente. Los diferentes métodos de imagen, como la radiografía de tórax, la tomografía computarizada (TC) o la resonancia magnética son útiles para realizar el diagnóstico; sin embargo, la TC es más útil en el diagnóstico, porque logra demostrar el origen óseo y las calcificaciones intralesionales. Es importante conocer las características imaginológicas de este tipo de lesiones, ya que pueden ser fácilmente confundidas con un tumor maligno.

Mesenchymal hamartomas of the chest wall are extremely rare lesions that usually affect children and newborns and whose most common manifestation is a large mass that deforms the chest wall and can cause dyspnea. Up to this date, approximately 100 cases have been reported worldwide in the literature. Different imaging methods such as chest X-ray, computed tomography (CT) or magnetic resonance imaging (MRI) are useful for diagnosis; nevertheless, CT is the best in diagnostic aid because it manages to demonstrate bony origin and intralesional calcifications. It is important to identify the imaginological features of such lesions because they can easily be mistaken for a malignant tumor.

Intrinsic cues and hormones control mouse mammary epithelial tree size.

Organ size control is a long-standing question in biology. In mammals, using conditional cell ablation, two mutually exclusive mechanisms involving either intrinsic or extrinsic programs have been described to control organ size. The mammary gland is an ideal model for such studies, since it undergoes size and morphological changes during puberty and pregnancy. The role of stem cells in controlling mammary epithelial tree size is unclear, although mammary stem cells are able to reconstitute a functional organ on transplantation. Here, we show that mammary gland cellularity was strictly dependent on mammary stem cell number, even following a 20-fold expansion of the mammary stem cell pool at puberty and transient 3-fold expansions with each pregnancy. In addition, the expansion of the mammary stem cell pool was hormone dependent, as demonstrated by female bilateral ovariectomies during puberty and transplants of male-derived cells into female recipients. In these transplants, apart from a mammary stem cell expansion, we also observed the donor cells reconstituting functional mammary glands, developing alveolar structures, and secreting milk after the recipient's parturition. Taken together, these data suggest that in the mammary gland, there is a third organ size control mechanism, combining intrinsic cues throughout the organism's lifetime, with extrinsic hormone signals at particular developmental windows (puberty, pregnancy), where an expansion of the mammary stem cell pool occurs. This mechanism might have strong implications for the understanding of mammary tumorigenesis, since the expansion of the mammary stem cell pool precedes the generation of breast tumors.

Uro-TAC, más allá del cálculo / Unenhanced tomography of the urinary tract, beyond the stones

La tomografía no contrastada con énfasis en el tracto urinario (uro-TAC) ha reemplazado a la urografía excretora en la evaluación de los pacientes con síndrome doloroso sugestivo de urolitiasis, lo cual ha permitido realizar un diagnóstico de obstrucción en cualquier segmento del tracto urinario con alta especificidad y sensibilidad. A pesar de ser una técnica en la cual no se administra un medio de contraste oral o endovenoso, la uro-TAC provee importante información adicional sobre otras causas potenciales de los síntomas, incluso de enfermedades con gran impacto sobre la morbilidad y mortalidad de los pacientes. Nuestro objetivo es realizar una revisión de las imágenes de los hallazgos en la uro-TAC, describiendo algunas de las múltiples enfermedades que pueden constituir diagnósticos diferenciales de la urolitiasis.