GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.</p

Effectiveness of the minima caste of the Leafcutter Ant (Atta cephalotes) on cleaning harvested leaves

Leafcutter ants have been practicing agriculture longer than humans themselves. Leafcutter ant species, Atta cephalotes, common to Central and South America, cultivate a unique fungus, Leucocoprinus gonogylophora, that sustains the lives of millions of leafcutter ants within a single colony. In order to be efficient farmers, A. cephalotes have developed a caste system consisting of a queen, soldiers, workers, and minima. Each caste has a specific role within the colony, however, the role of the minima is still highly debated among scientists. It is hypothesized that the minima clean the surface of the leaves collected from nearby plants on the trail from the plant source to the entrance of the colony. Using two different methods, the cleanliness of the leaves at the leaf source and the entrance to the colony were observed. The first method consisted of placing the leaf sample onto an agar plate, while the second method consisted of swabbing the leaf surface of the samples onto an agar plate and observing whether the samples presented fungal growth or not. Overall, it was shown that there was little difference between leaf cleanliness, as both the leaf source and the colony entrance had 60% of the samples grow fungus, however, other patterns, such as fungal diversity and presence of mites were observed and analyzed. On average, there was a higher diversity of fungi at the leaf source compared to the entrance of the colony which may suggest that the minima may only be cleaning for certain types of fungi. A presence of mites found exclusively on samples taken from the leaf source could suggest that minima also clean off pests from the leaves. These results seem to indicate that the role of the minima is crucial to the colony, as they perform multiple unique tasks in order to protect their precious food source. Las hormigas cortadoras de hojas han estado practicando agricultura inclusive por más tiempo que los seres humanos. La especie Atta cephalotes, nativa de Centro y Suramérica, cultiva al hongo Leucocoprinus gonogylophora, el cual sirve de alimento para millones de hormigas dentro de una misma colonia. Para que el cultivo del hongo sea existoso, A. cephalotes ha desarrollado un sistema de castas conformado por una reina, soldados, obreras y mínimas. Cada una de estas castas juega un rol específico dentro de la colonia, sin embargo el papel de las mínimas es motivo de debate en la comunidad científica. Una hipótesis es que estas hormigas limpian la superficie de las hojas colectadas a lo largo del camino entre la planta y la entrada de la colonia. Utilizando dos métodos, determiné la presencia de hongos en hojas recién cortadas de la planta y hojas antes de ingresar a la colonia. El primer método consistió en poner la hoja sobre una placa de agar, y el segundo en frotar la superficie de la hoja sobre la placa de agar. Posteriormente determiné la presencia o ausencia de crecimiento de hongos y el número de morfoespecies de los mismos. Se encontró poca diferencia en cuanto al crecimiento de hongos en muestras provenientes de la planta y muestras provenientes de la entrada de la colonia. Ambos grupos presentaron crecimiento de hongos en un 60% de las muestras, sin embargo las hojas recién cortadas presentaron ligeramente mayor riqueza de especies de hongos, así como la presencia de ácaros. Esto podría indicar que las mínimas solamente limpian las hojas de ciertos hongos que potencialmente puedan llegar a ser perjudiciales para L. gonogylophora. La presencia de ácaros exclusivamente en las hojas recién cortadas sugiere que las mínimas también limpian las hojas de estos organismos. En conjunto, estos resultados parecen indicar que el rol de la mínima es crucial, al realizar múltiples tareas que ayudan a proteger su recurso alimenticio.https://digitalcommons.usf.edu/tropical_ecology/1185/thumbnail.jp

Effectiveness of the minima caste of the Leafcutter Ant (Atta cephalotes) on cleaning harvested leaves

Leafcutter ants have been practicing agriculture longer than humans themselves. Leafcutter ant species, Atta cephalotes, common to Central and South America, cultivate a unique fungus, Leucocoprinus gonogylophora, that sustains the lives of millions of leafcutter ants within a single colony. In order to be efficient farmers, A. cephalotes have developed a caste system consisting of a queen, soldiers, workers, and minima. Each caste has a specific role within the colony, however, the role of the minima is still highly debated among scientists. It is hypothesized that the minima clean the surface of the leaves collected from nearby plants on the trail from the plant source to the entrance of the colony. Using two different methods, the cleanliness of the leaves at the leaf source and the entrance to the colony were observed. The first method consisted of placing the leaf sample onto an agar plate, while the second method consisted of swabbing the leaf surface of the samples onto an agar plate and observing whether the samples presented fungal growth or not. Overall, it was shown that there was little difference between leaf cleanliness, as both the leaf source and the colony entrance had 60% of the samples grow fungus, however, other patterns, such as fungal diversity and presence of mites were observed and analyzed. On average, there was a higher diversity of fungi at the leaf source compared to the entrance of the colony which may suggest that the minima may only be cleaning for certain types of fungi. A presence of mites found exclusively on samples taken from the leaf source could suggest that minima also clean off pests from the leaves. These results seem to indicate that the role of the minima is crucial to the colony, as they perform multiple unique tasks in order to protect their precious food source. Las hormigas cortadoras de hojas han estado practicando agricultura inclusive por más tiempo que los seres humanos. La especie Atta cephalotes, nativa de Centro y Suramérica, cultiva al hongo Leucocoprinus gonogylophora, el cual sirve de alimento para millones de hormigas dentro de una misma colonia. Para que el cultivo del hongo sea existoso, A. cephalotes ha desarrollado un sistema de castas conformado por una reina, soldados, obreras y mínimas. Cada una de estas castas juega un rol específico dentro de la colonia, sin embargo el papel de las mínimas es motivo de debate en la comunidad científica. Una hipótesis es que estas hormigas limpian la superficie de las hojas colectadas a lo largo del camino entre la planta y la entrada de la colonia. Utilizando dos métodos, determiné la presencia de hongos en hojas recién cortadas de la planta y hojas antes de ingresar a la colonia. El primer método consistió en poner la hoja sobre una placa de agar, y el segundo en frotar la superficie de la hoja sobre la placa de agar. Posteriormente determiné la presencia o ausencia de crecimiento de hongos y el número de morfoespecies de los mismos. Se encontró poca diferencia en cuanto al crecimiento de hongos en muestras provenientes de la planta y muestras provenientes de la entrada de la colonia. Ambos grupos presentaron crecimiento de hongos en un 60% de las muestras, sin embargo las hojas recién cortadas presentaron ligeramente mayor riqueza de especies de hongos, así como la presencia de ácaros. Esto podría indicar que las mínimas solamente limpian las hojas de ciertos hongos que potencialmente puedan llegar a ser perjudiciales para L. gonogylophora. La presencia de ácaros exclusivamente en las hojas recién cortadas sugiere que las mínimas también limpian las hojas de estos organismos. En conjunto, estos resultados parecen indicar que el rol de la mínima es crucial, al realizar múltiples tareas que ayudan a proteger su recurso alimenticio.https://digitalcommons.usf.edu/tropical_ecology/1185/thumbnail.jp

Initial Safety Results from a Phase II Study of Acalabrutinib Plus RICE Followed By Autologous Hematopoietic Cell Transplantation and/or Acalabrutinib Maintenance Therapy for Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Background: Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) often have a poor prognosis despite therapies using second-line chemoimmunotherapy (CIT). Achievement of complete response (CR) with second-line therapy is associated with improved long-term outcomes. Unfortunately, only 25-35% of patients achieve CR with standard CIT regimens alone. The addition of novel targeted agents such as Bruton Tyrosine Kinase inhibitors (BTKi) to second-line therapy may offer improved treatment responses given the importance of B-cell receptor (BCR) signaling in DLBCL. BTK has been shown to be essential for BCR-mediated activation of the NF- κB/Rel family of transcription factors and BCR signaling has been recognized as a key pathway in the pathogenesis of DLBCL. Moreover, NF-κB activity relies upon chronic active BCR signaling in activated B-cell-like DLBCL, which can be potentially blocked by kinase inhibitors targeting BTK. In this study we examine the feasibility and efficacy of adding the BTKi, acalabrutinib (A), to standard second-line therapy to improve disease response in patients with R/R DLBCL. Here we present initial safety and tolerability data for the ongoing study. Study Design and Methods: This is an open-label, prospective phase II trial (NCT03736616). Cohort A is open to R/R DLBCL patients eligible for autologous hematopoietic transplantation (HCT). Cohort B is open to R/R DLBCL patients considered ineligible for autologous HCT. The primary endpoint for cohort A is to estimate the confirmed CR rate (RECIL 2017 criteria) prior to autologous HCT in patients undergoing second-line CIT. The primary endpoint for cohort B is defined as the estimate of one-year progression-free survival in patients undergoing second-line induction and maintenance acalabrutinib therapy. Cohort A receive 2 cycles of standard RICE salvage CIT in combination with acalabrutinib, 100mg BID days 1-21 of a 21-day cycle (RICE+A). After 2 cycles of therapy, patients undergo autologous stem cell mobilization and collection. Patients then receive a 3 rd cycle of RICE in combination with acalabrutinib. PET-CT (PET3) is to be performed on day 15 of cycle 3 to assess response. Patients with CR or partial response (PR) after PET3 proceed to autologous HCT with BEAM conditioning within 28-42 days of PET3. Post-HCT CR patients receive acalabrutinib 100mg BID as maintenance therapy for 12 additional months. Protocol amendment in May 2021 allows for PET assessment (C2D15) prior to autologous stem cell collection (after cycle 3). Cohort B receive 3 cycles of RICE+A in 21-day cycles followed by PET-CT (PET3) on day 15 of cycle 3. Patients without progressive disease at PET3 continue with acalabrutinib maintenance up to 12 additional cycles until disease progression or unacceptable toxicity. Patients demonstrating progressive disease are withdrawn from study treatment but followed for outcomes. Results: Here we report initial safety and tolerability data for the ongoing study with data cutoff July 28, 2021. Twenty-two patients have been screened and 20 patients have received at least 1 cycle of RICE+A. Patient characteristics are shown in Table 1. Fifteen patients (79%) have completed 3 cycles of RICE+A. One patient (5%) discontinued due to an adverse event (AE; recurrent appendicitis), 3 patients (16%) discontinued due to progressive disease, and 1 patient is receiving ongoing RICE+A as of data cutoff. Hematologic AE have been observed in 17 patients (89%) with 74% being Grade 3/4. Amongst these, neutropenia was the most common AE occurring in 47% with all being Grade 3/4, and thrombocytopenia occurring in 32% with all being Grade 3/4. All hematologic AE recovered to baseline or grade 1 in median 7 days. Amongst non-hematologic AE, diarrhea occurred in 21% and 0% were Grade 3/4, nausea 16% with 0% Grade 3/4, and headache in 16% with 0% Grade 3/4. Discontinuation of therapy due to AE occurred in 1 patient (recurrent appendicitis) and dose reduction occurred in 1 patient (Gr 4 neutropenia). Temporary (per protocol) dose holds of A occurred in 9 patients (45%), primarily for cytopenias during concurrent RICE+A. Median duration for dose holds of A was 5.5 days. Conclusion: RICE+A is feasible with manageable primarily hematologic AEs similar to those reported for RICE alone. Enrollment and follow up is ongoing for efficacy endpoints and further toxicity assessment

Effects of developmental manganese, stress, and the combination of both on monoamines, growth, and corticosterone

Developmental exposure to manganese (Mn) or stress can each be detrimental to brain development. Here, Sprague-Dawley rats were exposed to two housing conditions and Mn from postnatal day (P)4–28. Within each litter two males and two females were assigned to the following groups: 0 (vehicle), 50, or 100 mg/kg Mn by gavage every other day. Half the litters were reared in cages with standard bedding and half with no bedding. One pair/group in each litter had an acute shallow water stressor before tissue collection (i.e., standing in shallow water). Separate litters were assessed at P11, 19, or 29. Mn-treated rats raised in standard cages showed no change in baseline corticosterone but following acute stress increased more than controls on P19; no Mn effects were seen on P11 or P29. Mn increased neostriatal dopamine in females at P19 and norepinephrine at P11 and P29. Mn increased hippocampal dopamine at P11 and P29 and 5-HT at P29 regardless of housing or sex. Mn had no effect on hypothalamic dopamine, but increased norepinephrine in males at P29 and 5-HT in males at all ages irrespective of rearing condition. Barren reared rats showed no or opposite effects of Mn, i.e., barren rearing + Mn attenuated corticosterone increases to acute stress. Barren rearing also altered the Mn-induced changes in dopamine and norepinephrine in the neostriatum, but not in the hippocampus. Barren rearing caused a Mn-associated increase in hypothalamic dopamine at P19 and P29 not seen in standard reared Mn-treated groups. Developmental Mn alters monoamines and corticosterone as a function of age, stress (acute and chronic), and sex