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The accelerating use of combined immune checkpoint inhibitors (ICI; anti-PD-1 plus anti-CTLA-4 antibodies) enhanced therapeutic responses in various cancers while significantly increasing immune-related adverse events (irAE). The mechanism involved in the occurrence of immune-mediated diarrhea and colitis (IMDC) and its potential implication on ICI efficacy remain unclear. The gut microbiome is progressively recognized as a key biomarker of ICI efficacy and preliminary results suggest its potential association with irAE. However, the link between microbiota and IMDC still needs to be elucidated. In this study, we investigated IMDC-associated intestinal bacteria.We performed metagenomics sequencing of baseline pre-ICI fecal samples from 26 advanced melanoma patients and recorded IMDC. Culturomics using MALDI-TOF was used to isolate bacteria from 19 patient samples: 11 IMDC-free (fIMDC), 5 baseline pre-IMDC (pIMDC) and 8 during IMDC (dIMDC). Serum multiplex cytokine panel was measured for 36 patients. Then, we induced colitis with Dextran Sulfate Sodium (DSS) in MCA-205 murine tumor model treated with oral supplementation of human bacteria and ICI.Metagenomics profiling demonstrated lower α-diversity at baseline in patients that developed irAE. Moreover, pIMDC samples present a lower Simpson α-diversity than fIMDC samples (p=0.08). ß-diversity was also different between both groups (p=0.10) suggesting a different baseline microbiome composition. Lefse analysis revealed an overrepresentation of Enterococcus faecium and Bilophila wadsworthia in pIMDC samples compared to fIMDC samples. Culturomics showed that dIMDC samples exhibited a shift in gut microbiota with a significant decrease in bacterial diversity mostly anaerobic species and an enrichment of Clostridium paraputricum, Clostridium perfringens, Paraclostridium bifermentans and Paeniclostridium sordelii compared to fIMDC and pIMDC samples. Immunological analysis of serum revealed that IMDC patients had a higher concentration of pro-inflammatory cytokines including GMCSF (p=0.04), IL12-23p40 (p=0.04) and IL-16 (p=0.03) compared to fIMDC patients. In our DSS-induced colitis mouse model, we showed that P. bifermentans oral supplementation related with diarrhea and a shorter colon length, indicating more severe colitis. Moreover, we showed that P. bifermentans increased anti-CLTA-4 and anti-PD-1 anti-tumor activity.Results showed that gut microbiota composition of dIMDC patients differed from that of pIMDC and fIMDC patients with a decrease of diversity and colonization of P.bifermentans and P.sordelii. In IMDC patients, we isolated bacteria that aggravated colitis in murine models and are known to be associated with inflammatory bowel disease. These results provide more insight on potential microbiome-modifying strategies to damper IMDC and increase anti-cancer efficacy. Citation Format: Khoudia Diop, Benlaïfaoui Myriam, Wiam Belkaïd, Alexis Nolin-Lapalme, Julie Malo, Marion Tonneau, Ponce Mayra, Afnan Al-Saleh, Catalin Mihalcioiu, Ian Watson, Arielle Elkrief, Karla Lee, Meriem Messaoudene, Bertrand Routy, Corentin Richard. Role of the gut microbiota in the development of immune-mediated diarrhea and colitis induced by immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3524.

Figure S4. Mutant Y573S ER and E2 stimulated wild-type ER bind to the same enhancer regions of pro-proliferative genes. MCF-7 cells expressing wild-type ER or mutant Y537S ER demonstrates overlapping chromatin enrichment by ChIP sequencing [39] at CCND1, CDK2 and CDK6 enhancer regions following vehicle (ETOH), 100â nM Dex, 100â nM E2, or Dex/E2 (DE) at 60â min. (PDF 142 kb)

Supplementary information [20, 48â 52]. (DOCX 22 kb)

Blastic plasmacytoid dendritic cell neoplasm is a rare hematological malignancy derived from immature plasmacytoid dendritic cells. The tumor cells have an immature blastic appearance, and diagnosis is based on the expression of CD4, CD56 y CD123 in the absence of other lymphoid, natural killer, or myeloid antigens. The majority of affected individuals are older people with a mean age of 66 years. Male to female ratio is approximately 3:1. Common presentation includes cutaneous lesions followed by tumor dissemination. Treatment with conventional chemotherapy is ineffective and allogeneic hematopoietic stem cell transplantation is required to achieve remission. We report three male patients, aged 23, 27 and 51 years with the disease. All had multiple, infiltrated pink plaques and nodules on the skin of their face, neck and thorax, measuring 1 to 12 cm in diameter. All tumors were histologically characterized by a monotonous proliferation of medium size cells with blastic features. Tumor cells were positive for CD123, CD56, CD4 and CD7 in all cases. After a mean of follow-up of 14.6 months, one patient died of the disease, one patient is alive and the disease relapsed after 17 months of remission and one patient is alive with no evidence of the disease.

Abordar la investigación sobre la influencia de los métodos activos en el aprendizaje, se justifica por su impacto en la transformación didáctica. La presente investigación tuvo como objetivo estudiar la formación de nociones químicas en niños de cinco a seis años, usando la experimentación. Metodológicamente, se empleó un paradigma crítico e interpretativo, por tanto, el estudio fue de estilo cualitativo y realizado con diez menores participantes. Los resultados muestran que la actitud del grupo de niños cambia durante la actividad empírica y son capaces de describir algunos fenómenos propios de las reacciones químicas. Finalmente, se concluyó que la experimentación facilita la construcción de la noción de reacción química y favorece el proceso de aprendizaje. Focusing the research on the influence of the active methods in learning is justified due to their impact on teaching transformation. The objective of the present study was to assess the formation of chemical notions in children five and six years old, through the use of experimentation. Methodologically, a critical and interpretative paradigm was applied; therefore, the research had a qualitative style and was conducted with ten participants. Results show that in the group, the children’s attitudes change during the task-experimentation, and that they are capable of describing some phenomena which are characteristic of chemical reactions. Finally, it was concluded that experimentation not only facilitates the construction of the notion of chemical reaction but also enhances the learning process.

Figure S3. GR liganding inhibits MCF-7 mutant ER-driven proliferation and decreases proliferative gene expression. A) Doxycycline induced expression of HA-tagged ER, and GR expression remains stable in all cell lines. B) MCF-7 HA-WT, HA-Y537S, and HA-D538G cells were treated with vehicle (ETOH) and proliferation as evaluated at 6 days of treatment. HA-D538G and HA-Y537S expressing MCF-7 cells show 30–50% increase in cell proliferation, respectively, compared to HA-WT MCF-7 cells. C) Dex, C134 and C335 all significantly inhibited E2-mediated proliferation in both HA-wild type (HA-WT) and HA-D538G MCF-7 cells following 6 days of treatment (*p

Figure S5. SGRM treatment inhibits ER-mediated tumor growth with minimal toxicity in association with decreased ER-mediated pro-proliferative gene expression. A) Average tumor volume in MCF-7 HA-Y537S mouse xenografts in each treatment group, vehicle (Veh), C134 (134), and C335 (335) at the start of treatment. B) Longitudinal tumor growth following vehicle (Veh, 1 ETOH:9 sesame oil), 20 mg/kg C134 (134), or 20 mg/kg C335 (335) (**p

Figure S1. SGRM treatment-alone does not affect cell survival in ER+/GR+/PR+ tumor cells. A) Steady-state PR, GR, ER, and β-actin protein expression was evaluated in ER+/GR+ MCF-7 and T-47D cells. B) MCF-7 cells were treated with vehicle (ETOH), 10 nM E2, E2/100 nM Dex, E2/1 μM C134, or E2/1 μM C335 for 2, 4, or 6 h. Steady-state mRNA expression of canonical GR target gene, FKBP5, was significantly repressed following C134 or C335 treatment ($ p

Figure S3. GR liganding inhibits MCF-7 mutant ER-driven proliferation and decreases proliferative gene expression. A) Doxycycline induced expression of HA-tagged ER, and GR expression remains stable in all cell lines. B) MCF-7 HA-WT, HA-Y537S, and HA-D538G cells were treated with vehicle (ETOH) and proliferation as evaluated at 6 days of treatment. HA-D538G and HA-Y537S expressing MCF-7 cells show 30–50% increase in cell proliferation, respectively, compared to HA-WT MCF-7 cells. C) Dex, C134 and C335 all significantly inhibited E2-mediated proliferation in both HA-wild type (HA-WT) and HA-D538G MCF-7 cells following 6 days of treatment (*p

Figure S6. MCF-7 Y537S xenograft tumor IHC shows decreased Ki-67 positivity and no change in ER expression following SGRM treatment. A) Anti-ERα IHC staining (H-score) showed no difference among vehicle (Veh), C134 (134), or C335 (335) treatment groups (p = 0.931, One-way ANOVA, Dunnett’s post hoc test, n = 5 per group). B) Anti-Ki-67 IHC staining. Tumors treated in vivo with C134 or C335 showed a decreased trend in Ki-67 percentage compared to vehicle treatment (p = 0.384, Veh vs 134; p = 0.142, Veh vs 335; one-way ANOVA, Dunnett’s post hoc test, n = 5 per group). C) Representative images of anti-ERα, anti-Ki-67, and anti-Cyclin D1 IHC immunostaining. Scale bar shown in red is 100 μm. (PDF 618 kb)

Figure S6. MCF-7 Y537S xenograft tumor IHC shows decreased Ki-67 positivity and no change in ER expression following SGRM treatment. A) Anti-ERα IHC staining (H-score) showed no difference among vehicle (Veh), C134 (134), or C335 (335) treatment groups (p = 0.931, One-way ANOVA, Dunnett’s post hoc test, n = 5 per group). B) Anti-Ki-67 IHC staining. Tumors treated in vivo with C134 or C335 showed a decreased trend in Ki-67 percentage compared to vehicle treatment (p = 0.384, Veh vs 134; p = 0.142, Veh vs 335; one-way ANOVA, Dunnett’s post hoc test, n = 5 per group). C) Representative images of anti-ERα, anti-Ki-67, and anti-Cyclin D1 IHC immunostaining. Scale bar shown in red is 100 μm. (PDF 618 kb)

Figure S5. SGRM treatment inhibits ER-mediated tumor growth with minimal toxicity in association with decreased ER-mediated pro-proliferative gene expression. A) Average tumor volume in MCF-7 HA-Y537S mouse xenografts in each treatment group, vehicle (Veh), C134 (134), and C335 (335) at the start of treatment. B) Longitudinal tumor growth following vehicle (Veh, 1 ETOH:9 sesame oil), 20 mg/kg C134 (134), or 20 mg/kg C335 (335) (**p

Figure S1. SGRM treatment-alone does not affect cell survival in ER+/GR+/PR+ tumor cells. A) Steady-state PR, GR, ER, and β-actin protein expression was evaluated in ER+/GR+ MCF-7 and T-47D cells. B) MCF-7 cells were treated with vehicle (ETOH), 10 nM E2, E2/100 nM Dex, E2/1 μM C134, or E2/1 μM C335 for 2, 4, or 6 h. Steady-state mRNA expression of canonical GR target gene, FKBP5, was significantly repressed following C134 or C335 treatment ($ p

Figure S2. SGRMs do not effect ER-mediated T47D-Y (GR-negative) cell proliferation or bind to purified ER LBD. A) Steady-state GR, ER-α, and β-actin expression was evaluated in parental T47-D and ER+/GR-negative T47D-Y cells. B) T47D-Y cell proliferation during 8 days vehicle (ETOH, Veh), 10 nM E2, E2/100 nM Dex, E2/1 μM C297, or E2/1 μM C335 treatment. GR liganding (Dex, C297, or C335) does not inhibit E2-mediated proliferation (****p

Analizar la percepción de los docentes en su rol en la Inclusión Educativa de estudiantes con necesidades educativas específicas asociadas o no a la discapacidad de la Escuela de Educación Básica “Ciudad Guayaquil”. La Escuela de Educación Básica “Ciudad Guayaquil” brinda una inclusión educativa a estudiantes con necesidades educativas específica asociadas y no asociadas a la discapacidad. En este sentido, la atención de este grupo de estudiantes requiere de educadores proactivos y con una actitud favorable hacia esa atención. No obstante, existe un desconocimiento de las percepciones de los docentes en su rol en la inclusión educativa, que permita ajustar los acompañamientos o formas de atender al profesorado. Por ello, la investigación tiene como objetivo analizar la percepción de los docentes en su rol en la inclusión educativa de estudiantes con necesidades educativas específicas asociadas o no a la discapacidad de la Escuela de Educación Básica “Ciudad Guayaquil”. El enfoque cualitativo de esta investigación permitió la aplicación de la entrevista escrita de Badia (2017) que facilita explorar la percepción del trabajo del maestro; en esta investigación participaron 13 profesores de manera voluntaria. Para el procesamiento y análisis de datos se empleó el software cualitativo MAXQDA 2022, que permitió el análisis de categorías establecidas y emergentes, permitiendo identificar la percepción del rol que asume el docente frente estudiantes con NEE, la descripción de las actividades concretas y el análisis del tipo de atención que estos brindan. Además, se evidenció que hay una ausencia en la formación docente sobre lenguaje de señas, método braille, manejo de TIC’s especializadas y procesos de diagnósticos presuntivos iniciales, no obstante, los educadores investigan en su tiempo libre para la necesidad educativa a sus estudiantes. Partiendo de estos hallazgos se concluyó que las percepciones de los docentes son positivas. Se recomienda a la institución gestionar talleres o encuentros con el DECE, psicopedagogos y docentes especialistas con la finalidad de brindar apoyo a su personal docente. Maestría

Desarrollar habilidades adaptativas en niños y niñas con Necesidades Educativas Especiales asociadas a la discapacidad del nivel Inicial 2 de la Unidad Educativa Especializada "Beatriz Jarrin" Ibarra-Imbabura”. La presente investigación se refiere al “Desarrollo de habilidades adaptativas para niños y niñas de nivel Inicial 2 con Necesidades Educativas Especiales asociadas a la discapacidad” cuyo objetivo fundamental fue evaluar el nivel de desarrollo de habilidades adaptativas en niños y niñas con Necesidades Educativas Especiales asociadas a la discapacidad, posteriormente proponer estrategias para el desarrollo de habilidades adaptativas enfocadas en la necesidad particular de cada estudiante evaluado y finalmente socializar la propuesta. Posterior a ello se elaboró el marco teórico desarrollando sus respectivas variables que fundamentaron el objeto de estudio. Siguiendo con el desarrollo de la parte metodológica, su enfoque es el cualitativo y el tipo de investigación es el descriptivo, bibliográfico y su método de investigación se refiere a la Investigación acción participativa a través de esta técnica, se desencadena intercambios constructivos entre investigador y comunidad en los que se abordan conjuntamente todas las etapas del proceso investigativo. Para recabar la información relacionada con el problema de investigación se aplicó entrevistas a los señores padres de familia y docentes, los mismos que proporcionaron información valiosa para elaborar los talleres que coadyuven al mejoramiento, también se utilizó la Metodología ABA (Applied Behavior Analysis). Este método que sus siglas en ingles significan “Análisis de comportamiento aplicado”, es una técnica que se aplica en el tratamiento y la enseñanza de desiguales destrezas mediante la reforma conductual. Este método se utiliza con educandos con discapacidad intelectual y trastorno del espectro autista, así como para el progreso de áreas específicas: de lenguaje (expresivo/receptivo), social, sensorial, de comportamiento o académicas. Con los resultados de la aplicación de estas técnicas se diseñaron estrategias interactivas, cuyo objetivo fundamental es el reforzar los aprendizajes que proporcionan las maestras. Maestría