Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK ...pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance.
We have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance.
The three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38- and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models.
These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.
The response of higher plants to ionising radiation depends on factors related to both radiation properties and plant features including species, cultivar, age, and structural complexity of the ...target organ. Adult plants of dwarf tomato were irradiated with different doses of X-rays to investigate possible variations in leaf morpho-anatomical traits, photosynthetic efficiency, and genomic DNA. In order to assess if and how responses depend on leaf developmental stage, we analysed two types of leaves; nearly mature leaves (L1) and actively developing leaves (L2), whose lamina size corresponded to 70 and 25 %, respectively, of the lamina size of the fully expanded leaves. The results show that the X-rays prevented full lamina expansion of the L2 leaves at all doses and induced early death of tissue of plants irradiated with doses higher than 20 Gy. Most anatomical modifications were not clearly dose-dependent and the radiation-induced increase in phenolic compounds was irrespective of dose. At high doses of X-rays (50 and 100 Gy), photochemical efficiency decreased significantly in both leaf types, whereas total chlorophyll content significantly decreased only in the L2 leaves. The random amplification of polymorphic DNA data show that the X-rays induced mutagenic effects in the L2 leaves even at low doses despite the absence of severe phenotypic alterations. Genetic structure found in the population of samples corroborates the results of anatomical and eco-physiological analyses: the 20 Gy dose seems to mark the threshold dose above which genetic alterations, structural anomalies, and perturbations in the photosynthetic apparatus become significant, especially in the actively expanding leaves.
The watch-and-wait (WW) strategy is an alternative to anterior resection in patients with rectal cancer (RC) that have had a complete clinical response to neoadjuvant treatment. Few reports describe ...the quality of life and functional anorectal disorders (FADs) in that population.
To analyze and compare the FADs and quality of life in patients with locally advanced adenocarcinoma of the rectum treated with neoadjuvant therapy, divided into two different strategy groups: group 1 (G1), WW; and group 2 (G2), anterior resection.
Thirty patients (G1: n = 20 and G2: n = 10) that had finished neoadjuvant therapy at least 12 months prior were included. Mean patient age was 59.5 years (range: 41-79) and 15 of the patients were men. The FADs were evaluated through: a) clinical history, b) 21-day bowel diary, c) Jorge and Wexner fecal incontinence scale, d) anorectal manometry (ARM), and fecal incontinence quality of life scale (FIQL).
Bowel diary: fecal incontinence (40%) and urge to defecate (45%) in G1 vs. fecal incontinence (60%) and urge to defecate (30%) in G2, with no significant differences (p = NS). Fecal incontinence scale: fecal incontinence in G1 was significantly less severe than that in G2 (median 6.5 points vs. 13 points p = 0.0142). ARM: no differences between the two groups. Quality of life: significantly different between the two groups (FIQL/G1: 3.7 vs. FIQL/G2: 2.8; p < 0.03).
The WW follow-up strategy in patients with locally advanced rectal cancer was associated with better quality of life and reduced fecal incontinence.
La estrategia “watch and wait” (WW) es una alternativa a la resección anterior (RA) en pacientes con cáncer de recto (CR) con respuesta clínica completa a la neoadyuvancia. Existen pocos reportes que describan la calidad de vida (CV) y los trastornos funcionales anorrectales (TFA) en esta población.
Analizar y comparar los TFA y la CV en pacientes con adenocarcinoma de recto localmente avanzados tratados con neoadyuvancia con diferentes estrategias: grupo 1 (G1): WW y grupo 2 (G2): RA.
Se incluyeron 30 pacientes (G1: n = 20 y G2: n = 10) que cumplieron al menos 12 meses de finalizado el tratamiento neoadyuvante, edad mediana de 59,5 años (rango: 41-79), 15 son hombres. Los TFA fueron evaluados con: a) historia clínica, b) diario de continencia anal de 21 días, c) escala de continencia anal de Jorge y Wexner, d) manometría anorrectal (MAR) y la CV con el cuestionario de incontinencia fecal (FIQL).
Diario de continencia anal: G1: incontinencia fecal (40%) y urgencia defecatoria (45%) vs G2 incontinencia fecal (60%) y urgencia defecatoria (30%) sin diferencias significativas (p = NS). Escala de continencia anal: la incontinencia fecal de G1 fue significativamente menos severa que la de G2 mediana 6,5 puntos vs 13 puntos; (p = 0,0142). MAR: sin diferencias entre los grupos. CV: es significativamente diferente entre ambos grupos (FIQL/G1: 3,7 vs FIQL/G2: 2,8; p < 0,03).
La estrategia de seguimiento WW en pacientes con CR localmente avanzado estaría asociada con una mejor CV y menor incontinencia fecal.
•Groin incisional hernia may result like late complication of deep pelvic dissection.•When this type of inguinal ventral hernia develops, the surgeon is facing some problems different to the common ...ventral hernia repair.•Most of these difficulties may be overcome using laparoscopic approach.•We present a case of successful laparoscopic repair of a giant ventral hernia developed like late complication of deep pelvic dissection for melanoma.•To our knowledge, no other laparoscopic repair of this type of ventral hernia has been previously reported.
Deep pelvic lymph node dissection for cancer may result in incisional inguinal hernias. We present a case report of successful laparoscopic trans-peritoneal repair of a large ventral inguinal hernia that developed following ileo-inguinal lymph node dissection (CLND) for melanoma.
A successful 3 port laparoscopic trans-peritoneal procedure was performed on a 56-year-old female for the repair of a left inguinal hernia, developed 13 months following CLND for melanoma. The large oval 18 × 14 cm inguinal defect, with superior margins bordering the conjoint tendon and inferior margins bordering the ileo-psoas muscle, femoral vessels and nerve, was not closed in order to avoid excessive tension and was repaired by fixing a 25 × 20 cm intra-peritoneal mesh to abdominal borders at superior and lateral margins with permanent fasteners and at the inferior margin by a cyanoacrylate-glued overlap to protect femoral vessels and nerves from damage. No hernia recurrence was observed 8 months following this procedure.
Incisional inguinal hernias, following CLND, are rare but present a challenge to surgeons due to the difficulty in identifying both anatomical plains and safe sites for stable repair.
We report a laparoscopic trans-peritoneal approach for the safe, reproducible and efficacious repair of incisional inguinal hernias that result from CLND. In our opinion prevention of hernia recurrence can be achieved by a intraperitoneal large mesh fixed at superior and lateral margin borders with permanent fasteners and using cyanoacrylate glue to overlap inferior margin borders in order to prevent vessels and/or nerve injury.
La estrategia watch and wait (WW) es una alternativa a la resección anterior (RA) en pacientes con cáncer de recto (CR), con respuesta clínica completa a la neoadyuvancia. Existen pocos reportes que ...describan la calidad de vida (CV) y los trastornos funcionales anorrectales (TFA) en esta población.
Analizar y comparar los TFA y la CV en pacientes con adenocarcinoma de recto localmente avanzados tratados con neoadyuvancia con diferentes estrategias: grupo 1 (G1): WW y grupo 2 (G2): RA.
Se incluyeron 30 pacientes (G1: n = 20 y G2: n = 10) que cumplieron al menos 12 meses de finalizado el tratamiento neoadyuvante, edad mediana de 59.5 años (rango: 41-79), 15 son hombres. Los TFA fueron evaluados con: a) historia clínica, b) diario de continencia anal de 21 días, c) escala de continencia anal de Jorge y Wexner, d) manometría anorrectal (MAR) y la CV con el cuestionario de incontinencia fecal (FIQL).
Diario de continencia anal: G1: incontinencia fecal (40%) y urgencia defecatoria (45%) vs. G2 incontinencia fecal (60%) y urgencia defecatoria (30%), sin diferencias significativas (p = NS). Escala de continencia anal: la incontinencia fecal de G1 fue significativamente menos severa que la de G2 mediana 6.5 puntos vs. 13 puntos; (p = 0.0142). MAR: sin diferencias entre los grupos. CV: es significativamente diferente entre ambos grupos (FIQL/G1: 3.7 vs. FIQL/G2: 2.8; p < 0.03).
La estrategia de seguimiento WW en pacientes con CR localmente avanzado estaría asociada con una mejor CV y menor incontinencia fecal.
The watch-and-wait (WW) strategy is an alternative to anterior resection in patients with rectal cancer (RC) that have had a complete clinical response to neoadjuvant treatment. Few reports describe the quality of life and functional anorectal disorders (FADs) in that population.
To analyze and compare the FADs and quality of life in patients with locally advanced adenocarcinoma of the rectum treated with neoadjuvant therapy, divided into two different strategy groups: group 1 (G1), WW; and group 2 (G2), anterior resection.
Thirty patients (G1: n = 20 and G2: n = 10) that had finished neoadjuvant therapy at least 12 months prior were included. Mean patient age was 59.5 years (range: 41-79) and 15 of the patients were men. The FADs were evaluated through: a) clinical history, b) 21-day bowel diary, c) Jorge and Wexner fecal incontinence scale, d) anorectal manometry (ARM), and fecal incontinence quality of life scale (FIQL).
Bowel diary: fecal incontinence (40%) and urge to defecate (45%) in G1 vs. fecal incontinence (60%) and urge to defecate (30%) in G2, with no significant differences (p = NS). Fecal incontinence scale: fecal incontinence in G1 was significantly less severe than that in G2 (median 6.5 points vs. 13 points p = 0.0142). ARM: no differences between the two groups. Quality of life: significantly different between the two groups (FIQL/G1: 3.7 vs. FIQL/G2: 2.8; p < 0.03).
The WW follow-up strategy in patients with locally advanced rectal cancer was associated with better quality of life and reduced fecal incontinence.
The watch-and-wait (WW) strategy is an alternative to anterior resection in patients with rectal cancer (RC) that have had a complete clinical response to neoadjuvant treatment. Few reports describe ...the quality of life and functional anorectal disorders (FADs) in that population.
To analyze and compare the FADs and quality of life in patients with locally advanced adenocarcinoma of the rectum treated with neoadjuvant therapy, divided into two different strategy groups: group 1 (G1), WW; and group 2 (G2), anterior resection.
Thirty patients (G1: n = 20 and G2: n = 10) that had finished neoadjuvant therapy at least 12 months prior were included. Mean patient age was 59.5 years (range: 41-79) and 15 of the patients were men. The FADs were evaluated through: a) clinical history, b) 21-day bowel diary, c) Jorge and Wexner fecal incontinence scale, d) anorectal manometry (ARM), and fecal incontinence quality of life scale (FIQL).
Bowel diary: fecal incontinence (40%) and urge to defecate (45%) in G1 vs. fecal incontinence (60%) and urge to defecate (30%) in G2, with no significant differences (p = NS). Fecal incontinence scale: fecal incontinence in G1 was significantly less severe than that in G2 (median 6.5 points vs. 13 points p = 0.0142). ARM: no differences between the two groups. Quality of life: significantly different between the two groups (FIQL/G1: 3.7 vs. FIQL/G2: 2.8; p < 0.03).
The WW follow-up strategy in patients with locally advanced rectal cancer was associated with better quality of life and reduced fecal incontinence.
Many developing tissues display regenerative capability that allows them to compensate cell loss and preserve tissue homeostasis. Because of their remarkable regenerative capability, Drosophila wing ...discs are extensively used for the study of regenerative phenomena. We thus used the developing wing to investigate the role played in tissue homeostasis by the evolutionarily conserved eukaryotic H/ACA small nucleolar ribonucleoprotein pseudouridine synthase. Here we show that localized depletion of this enzyme can act as an endogenous stimulus capable of triggering apoptosis-induced proliferation, and that context-dependent effects are elicited in different sub-populations of the silenced cells. In fact, some cells undergo apoptosis, whereas those surrounding the apoptotic foci, although identically depleted, overproliferate. This overproliferation correlates with ectopic induction of the Wg and JAK-STAT (Janus kinase-signal transducer and activator of transcription) mitogenic pathways. Expression of a p35 transgene, which blocks the complete execution of the death program and generates the so-called 'undead cells', amplifies the proliferative response. Pseudouridine synthase depletion also causes loss of apicobasal polarity, disruption of adherens cell junctions and ectopic induction of JNK (c-Jun N-terminal kinase) and Mmp1 (matrix metalloproteinase-1) activity, leading to a significant epithelial reorganization. Unexpectedly, cell-nonautonomous effects, such as epithelial mesenchymal transition in the contiguous unsilenced squamous epithelium, are also promoted. Collectively, these data point out that cell-cell communication and long-range signaling can take a relevant role in the response to pseudouridine synthase decline. Considering that all the affected pathways are highly conserved throughout evolution, it is plausible that the response to pseudouridine synthase depletion has been widely preserved. On this account, our results can add new light on the still unexplained tumor predisposition that characterizes X-linked dyskeratosis, the human disease caused by reduced pseudouridine synthase activity.
Papanicolaou screening is feasible anywhere that screening for cervical cancer, the leading cause of cancer-related death among women in developing countries, is appropriate. After documenting that ...the Vietnam War had contributed to the problem of cervical cancer in Vietnam, we participated in a grass roots effort to establish a nationwide cervical cancer prevention program in that country and performed root cause analyses of program deficiencies. We found that real-world obstacles to successful cervical cancer prevention in developing countries involve people far more than technology and that such obstacles can be appropriately managed through a systems approach focused on programmatic quality rather than through ideological commitments to technology. A focus on quality satisfies public health goals, whereas a focus on technology is compatible with market forces.
Resumen Introducción La dispepsia funcional (DF), según Roma III , se clasifica en síndrome de distrés posprandial (SDP) y síndrome de dolor epigástrico (SDE). El test de saciedad (TS) se utilizó ...previamente para evaluar la acomodación y el vaciamiento gástrico, y permitió diferenciar individuos sanos de dispépticos. Objetivos 1) Estimar si el TS permite diferenciar a individuos dispépticos de sanos, y 2) evaluar si es útil para diferenciar ambos subtipos de DF. Métodos Estudio transversal. Se incluyó consecutivamente a adultos con DF y controles sanos entre agosto del 2011 y octubre del 2012. El TS consistió en la ingesta de un suplemento nutricional (Fortisip® , Nutricia Bagó® ) a velocidad constante; la saciedad se calificó cada 5 min (1 a 5 puntos). La ingesta se suspendió cuando se reportó puntaje máximo. Se registraron el volumen y las calorías totales ingeridos. Análisis estadístico: test Mann-Whitney. Resultados Se incluyó a 39 dispépticos y 20 controles. Los pacientes fueron predominantemente mujeres (84.6 vs. 25%; p < 0.0001) y similares en edad (39.59 ± 13.53 vs. 34.70 ± 9.85 años) e índice de masa corporal (24.32 ± 3.52 vs. 25.82 ± 3.34 kg/m2 ) respecto de los controles. Subtipos de DF: SDP: 61%, SDE 31% y síndrome mixto: 8%. 1) Los dispépticos toleraron menor volumen y calorías (185 vs. 300 ml y 277 vs. 520 Kcal, respectivamente p < 0.001), y 2) no se observaron diferencias en el TS entre ambos subtipos puros de dispepsia. Conclusiones El TS fue diferente entre individuos sanos y dispépticos, aunque presentó similar volumen y calorías en ambos subtipos de DF.
Motivation: In eukaryotes, the family of non-coding RNA genes includes a number of genes encoding small nucleolar RNAs (mainly C/D and H/ACA snoRNAs), which act as guides in the maturation or ...post-transcriptional modifications of target RNA molecules. Since in Drosophila melanogaster (Dm) only few examples of snoRNAs have been identified so far by cDNA libraries screening, integration of the molecular data with in silico identification of these types of genes could throw light on their organization in the Dm genome. Results: We have performed a computational screening of the Dm genome for C/D snoRNA genes, followed by experimental validation of the putative candidates. Few of the 26 confirmed snoRNAs had been recognized by cDNA library analysis. Organization of the Dm genome was also found to be more variegated than previously suspected, with snoRNA genes nested in both the introns and exons of protein-coding genes. This finding suggests that the presence of additional mechanisms of snoRNA biogenesis based on the alternative production of overlapping mRNA/snoRNA molecules. Availability: Additional information is available at http://www.bioinformatica.unito.it/bioinformatics/snoRNAs
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