Spatio-Temporal Changes of Extracellular Matrix (ECM) Stiffness in the Development of the Leech Hirudo verbana

The invertebrate leech Hirudo verbana represents a powerful experimental animal model for improving the knowledge about the functional interaction between the extracellular matrix (ECM) and cells within the tissue microenvironment (TME), and the key role played by ECM stiffness during development and growth. Indeed, the medicinal leech is characterized by a simple anatomical organization reproducing many aspects of the basic biological processes of vertebrates and in which a rapid spatiotemporal development is well established and easily assessed. Our results show that ECM structural organization, as well as the amount of fibrillar and non-fibrillar collagen are deeply different from hatching leeches to adult ones. In addition, the changes in ECM remodelling occurring during the different leech developmental stages, leads to a gradient of stiffness regulating both the path of migratory cells and their fates. The ability of cells to perceive and respond to changes in ECM composition and mechanics strictly depend on nuclear or cytoplasmic expression of Yes-Associated Protein 1 (YAP1), a key mediator converting mechanical signals into transcriptional outputs, expression, and activation

Dynamic relationship among extracellular matrix and body wall cells in Hirudo verbana morphogenesis

A great bulk of recent experimental evidence suggests the key role of the complex crosstalk between the extracellular matrix (ECM) and the cellular component of tissues during morphogenesis and embryogenesis. In particular, remodeling of the ECM and of its physical interactions pattern with surrounding cells represent two crucial processes that might be involved in muscle development. However, little information is available on this topic, especially on invertebrate species. To obtain new insights on how tuning the ECM microenvironment might drive cellular fate during embryonic development, we used the invertebrate medicinal leech Hirudo verbana as a valuable experimental model, due to its simple anatomy and the recapitulation of many aspects of the basic biological processes of vertebrates. Our previous studies on leech post-embryonic development have already shown the pivotal role of ECM changes during the growth of the body wall and the role of Yes-associated protein 1 (YAP1) in mechanotransduction. Here, we suggest that the interactions between stromal cell telocytes and ECM might be crucial in driving the organization of muscle layers during embryogenesis. Furthermore, we propose a possible role of the pleiotropic enzyme HvRNASET2 as a possible modulator of collagen deposition and ECM remodeling not only during regenerative processes (as previously demonstrated) but also in embryogenesis

TOLTERODINE IMPROVES QUALITY OF LIFE IN PATIENTS WITH AN OVERACTIVE BLADDER, WITH OR WITHOUT URINARY INCONTINENCE: A PROSPECTIVE MULTICENTER STUDY

AIMS: In order to analyse the effect of tolterodine on the Quality of life (QoL) of patients with overactive bladder (OB) we conducted a prospective multicentre clinical study. MATERIALS AND METHODS: Subjects were questioned at entry and 4, 12 and 24 weeks later about the number of micturitions and incontinent and urgency episodes/day, using a micturition diary. The mean volume voided per micturition and the number of pads used per day was also recorded. The QoL was measured using the Kings Health Questionnaire (KHQ) and the Incontinence Impact Questionnaire (IIQ). A total of 179 patients entered the study: 59 dropped out (4 due to lack of efficacy, 10 due to adverse events, 25 because of lack of interest in the study/other reason and 20 were lost at follow up), leaving 120 patients for analysis. One hundred and eight patients (90%) were female, their mean age was 56.5 years (SD 11.2); 87 had never received treatment for OB/UI (80.6%) and their mean weight was 70.0 Kg (SD 12.7). RESULTS: The mean number of micturitions/day was 9.3 at trial entry and it decreased to 6.8 by the end of the study. The corresponding values for the number of urge episodes, incontinence episodes and number of pads used per day were 3.5, 2.7 and 1.2 and 0.8, 0.9 and 0.4 respectively. The mean volume voided per micturition increased from 146 ml. to 178 ml. All the differences between trial entry and end of study values were statistically significant (p<0.05). Considering the results of the KHQ, the values of all the different areas/domini (?) decreased markedly and in a statistically significant way between the start of treatment and the end of study evaluations. Similar findings emerged when we considered values of the IIQ. The decrease was constant and marked during the first three months and remained constant thereafter. CONCLUSIONS: This study, conducted in a population of subjects with dry and wet OB, shows that tolterodine given for six months lowers the frequency of urgency episodes and incontinence episodes without troublesome adverse effects. These clinical effects are mirrored in the QoL, KHQ and IIQ questionnaire scores, which improved by about 50% over the same period

RNASET2 as a tumor antagonizing gene in a melanoma cancer model

The RNASET2 gene, mapped in 6q27, was previously found to exert control of tumorigenesis in an ovarian cancer system. We present here results indicating a similar control in a melanoma cancer model. Thus, this gene is most likely involved in a common general pathway of tumorigenesis. Moreover, its antitumorigenic activity is manifested in vivo but not in vitro, suggesting that this gene belongs to the growing category of tumor antagonizing/malignancy suppressor genes. A possible role of RNASET2 in the activation of a senescence program, whose responsible locus was mapped in the same chromosomal 6q27 region, seems to be inconsistent with our data

OTX genes in adult tissues

OTX homeobox genes have been extensively studied for their role in development, especially in neuroectoderm formation. Recently, their expression has also been reported in adult physiological and pathological tissues, including retina, mammary and pituitary glands, sinonasal mucosa, in several types of cancer, and in response to inflammatory, ischemic, and hypoxic stimuli. Reactivation of OTX genes in adult tissues supports the notion of the evolutionary amplification of functions of genes by varying their temporal expression, with the selection of homeobox genes from the “toolbox” to drive or contribute to different processes at different stages of life. OTX involvement in pathologies points toward these genes as potential diagnostic and/or prognostic markers as well as possible therapeutic targets

tolterodine improves quality of life in patients with an overactive bladder with or without urinary incontinence a prospective multicenter study

AIMS: In order to analyse the effect of tolterodine on the Quality of life (QoL) of patients with overactive bladder (OB) we conducted a prospective multicentre clinical study. MATERIALS AND METHODS: Subjects were questioned at entry and 4, 12 and 24 weeks later about the number of micturitions and incontinent and urgency episodes/day, using a micturition diary. The mean volume voided per micturition and the number of pads used per day was also recorded. The QoL was measured using the Kings Health Questionnaire (KHQ) and the Incontinence Impact Questionnaire (IIQ). A total of 179 patients entered the study: 59 dropped out (4 due to lack of efficacy, 10 due to adverse events, 25 because of lack of interest in the study/other reason and 20 were lost at follow up), leaving 120 patients for analysis. One hundred and eight patients (90%) were female, their mean age was 56.5 years (SD 11.2); 87 had never received treatment for OB/UI (80.6%) and their mean weight was 70.0 Kg (SD 12.7). RESULTS: The mean number of micturitions/day was 9.3 at trial entry and it decreased to 6.8 by the end of the study. The corresponding values for the number of urge episodes, incontinence episodes and number of pads used per day were 3.5, 2.7 and 1.2 and 0.8, 0.9 and 0.4 respectively. The mean volume voided per micturition increased from 146 ml. to 178 ml. All the differences between trial entry and end of study values were statistically significant (p&lt;0.05). Considering the results of the KHQ, the values of all the different areas/domini (?) decreased markedly and in a statistically significant way between the start of treatment and the end of study evaluations. Similar findings emerged when we considered values of the IIQ. The decrease was constant and marked during the first three months and remained constant thereafter. CONCLUSIONS: This study, conducted in a population of subjects with dry and wet OB, shows that tolterodine given for six months lowers the frequency of urgency episodes and incontinence episodes without troublesome adverse effects. These clinical effects are mirrored in the QoL, KHQ and IIQ questionnaire scores, which improved by about 50% over the same period

Donor cell acute myeloid leukemia after hematopoietic stem cell transplantation for chronic granulomatous disease: a case report and literature review

The patient reported here underwent hematopoietic stem cell transplantation (HSCT) due to chronic granulomatous disease (CGD) caused by biallelic mutations of the NCF1 gene. Two years later, he developed AML, which was unexpected and was recognized via sex-mismatched chromosomes as deriving from the donor cells; the patient was male, and the donor was his sister. Donor cell leukemia (DCL) is very rare, and it had never been reported in patients with CGD after HSCT. In the subsequent ten years, the AML relapsed three times and the patient underwent chemotherapy and three further HSCTs; donors were the same sister from the first HSCT, an unrelated donor, and his mother. The patient died during the third relapse. The DCL was characterized since onset by an acquired translocation between chromosomes 9 and 11, with a molecular rearrangement between the MLL and MLLT3 genes-a quite frequent cause of AML. In all of the relapses, the malignant clone had XX sex chromosomes and this rearrangement, thus indicating that it was always the original clone derived from the transplanted sister's cells. It exhibited the ability to remain quiescent in the BM during repeated chemotherapy courses, remission periods and HSCT. The leukemic clone then acquired different additional anomalies during the ten years of follow-up, with cytogenetic results characterized both by anomalies frequent in AML and by different, non-recurrent changes. This type of cytogenetic course is uncommon in AML

Transmembrane Protein TMEM230, Regulator of Glial Cell Vascular Mimicry and Endothelial Cell Angiogenesis in High-Grade Heterogeneous Infiltrating Gliomas and Glioblastoma

High-grade gliomas (HGGs) and glioblastoma multiforme (GBM) are characterized by a heterogeneous and aggressive population of tissue-infiltrating cells that promote both destructive tissue remodeling and aberrant vascularization of the brain. The formation of defective and permeable blood vessels and microchannels and destructive tissue remodeling prevent efficient vascular delivery of pharmacological agents to tumor cells and are the significant reason why therapeutic chemotherapy and immunotherapy intervention are primarily ineffective. Vessel-forming endothelial cells and microchannel-forming glial cells that recapitulate vascular mimicry have both infiltration and destructive remodeling tissue capacities. The transmembrane protein TMEM230 (C20orf30) is a master regulator of infiltration, sprouting of endothelial cells, and microchannel formation of glial and phagocytic cells. A high level of TMEM230 expression was identified in patients with HGG, GBM, and U87-MG cells. In this study, we identified candidate genes and molecular pathways that support that aberrantly elevated levels of TMEM230 play an important role in regulating genes associated with the initial stages of cell infiltration and blood vessel and microchannel (also referred to as tumor microtubule) formation in the progression from low-grade to high-grade gliomas. As TMEM230 regulates infiltration, vascularization, and tissue destruction capacities of diverse cell types in the brain, TMEM230 is a promising cancer target for heterogeneous HGG tumors

Safety of extended interval dosing immune checkpoint inhibitors: a multicenter cohort study

BACKGROUND: Real-life spectrum and survival implications of immune-related adverse events (irAEs) in patients treated with extended interval dosing (ED) immune checkpoint inhibitors (ICIs) are unknown. METHODS: Characteristics of 812 consecutive solid cancer patients who received at least 1 cycle of ED monotherapy (pembrolizumab 400 mg Q6W or nivolumab 480 mg Q4W) after switching from canonical interval dosing (CD; pembrolizumab 200 mg Q3W or nivolumab 240 mg Q2W) or treated upfront with ED were retrieved. The primary objective was to compare irAEs patterns within the same population (before and after switch to ED). irAEs spectrum in patients treated upfront with ED and association between irAEs and overall survival were also described. RESULTS: A total of 550 (68%) patients started ICIs with CD and switched to ED. During CD, 225 (41%) patients developed any grade and 17 (3%) G3 or G4 irAEs; after switching to ED, any grade and G3 or G4 irAEs were experienced by 155 (36%) and 20 (5%) patients. Switching to ED was associated with a lower probability of any grade irAEs (adjusted odds ratio [aOR] = 0.83, 95% confidence interval [CI] = 0.64 to 0.99; P = .047), whereas no difference for G3 or G4 events was noted (aOR = 1.55, 95% CI = 0.81 to 2.94; P = .18). Among patients who started upfront with ED (n = 232, 32%), 107 (41%) developed any grade and 14 (5%) G3 or G4 irAEs during ED. Patients with irAEs during ED had improved overall survival (adjusted hazard ratio [aHR] = 0.53, 95% CI = 0.34 to 0.82; P = .004 after switching; aHR = 0.57, 95% CI = 0.35 to 0.93; P = .025 upfront). CONCLUSIONS: Switching ICI treatment from CD and ED did not increase the incidence of irAEs and represents a safe option also outside clinical trials