A phase II multicenter, randomized, double-blind, placebo-control clinical study evaluating the safety and efficacy of UA007 of preventing chemotherapy induced diarrhea in patients with colorectal cancer receiving chemotherapy containing FOLFIRI
Ontology highlight
ABSTRACT:
DISEASE(S): Chemotherapy-induced Diarrhea
PROVIDER: 47645 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:The Cdc48 AAA+ ATPase is an abundant and essential enzyme that unfolds substrates in multiple protein quality control pathways. The enzyme includes two conserved AAA+ ATPase cassettes, D1 and D2, that assemble as hexameric rings with D1 stacked above D2. Here, we report an ensemble of structures of Cdc48 affinity purified from lysate in complex with the adaptor Shp1 in the act of unfolding substrate. Our analysis reveals a continuum of structural snapshots that spans the entire translocation cycle. These data reveal new elements of Shp1-Cdc48 binding and support a “hand-over-hand” mechanism in which the sequential movement of individual subunits is closely coordinated. D1 hydrolyzes ATP and disengages from substrate prior to D2, while D2 rebinds ATP and re-engages with substrate prior to D1, thereby explaining the dominant role played by D2 in substrate translocation/unfolding.
2024-10-17 | PXD048280 | Pride
Project description:This dataset includes: Proteome Discoverer result files for D1, D2, and D3. Quantification result files for D1, D2, and D3. raw data files for D1 and D2. Raw data files for D3 are deposited via PRIDE with identifer PXD003881.
2022-10-28 | MSV000090606 | MassIVE
Project description:The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSNs identity and repressing D1-MSNs identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2 like-MSNs survived normally in adulthood. Taken together, our finding supported that Sp9 was sufficient to promote D2-MSNs identity and repress D1-MSNs identity, and Sp9 was a negative regulator of D1-MSNs fate. The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSNs identity and repressing D1-MSNs identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2 like-MSNs survived normally in adulthood. Taken together, our finding supported that Sp9 was sufficient to promote D2-MSNs identity and repress D1-MSNs identity, and Sp9 was a negative regulator of D1-MSNs fate.
2022-07-06 | GSE202550 | GEO
Project description:The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSNs identity and repressing D1-MSNs identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2 like-MSNs survived normally in adulthood. Taken together, our finding supported that Sp9 was sufficient to promote D2-MSNs identity and repress D1-MSNs identity, and Sp9 was a negative regulator of D1-MSNs fate.
2022-07-06 | GSE202523 | GEO
Project description:This phase II study examined the pathological complete response (pCR) rate and safety of two gemcitabine-based combinations administered sequentially in breast cancer. We also examined gene expression profiles from tumor biopsies to identify biomarkers predictive of response. Methods: Indian women with large or locally advanced breast cancer received 4 cycles of gemcitabine 1200 mg/m2 plus doxorubicin 60 mg/m2 (Gem+Dox), then 4 cycles of gemcitabine 1000 mg/m2 plus cisplatin 70 mg/m2 (Gem+Cis), and surgery. To examine dynamic changes in molecular profiles after one dose of therapy, we used three alternate sequences during cycle 1 (Gem d1, 8; Dox d2; Gem d1, 8; Dox d1; or Gem d2, 8; Dox d1). Results: Of 65 women (median age 46) treated, 13 (24.5% of 53 patients with surgery) had a pCR and 22 (33.8%) had a complete clinical response. Patients who received Gem d1, 8 and Dox d2 in cycle 1 (20/65) reported more toxicities, with G3/4 neutropenic infection/febrile neutropenia (7/20) and vomiting (5/20) as the most common cycle 1 events. Four drug-related deaths occurred. 46/65 patients yielded successful pretreatment gene expression profiles. Ten-fold cross-validated supervised analyses identified gene expression patterns that predicted with >73% accuracy (1) clinical complete response after eight cycles, (2) overall clinical complete response, and (3) pCR. Conclusions: This neoadjuvant regimen showed strong activity. A subset of patients receiving Gem d1, 8 and Dox d2 experienced unacceptable toxicity, whereas patients on other sequences had more manageable safety profiles. The predictive gene expression patterns may provide a method for selecting patients most likely to benefit from gemcitabine-containing neoadjuvant therapy. Key words: breast cancer, chemotherapy, gemcitabine, , gene expression, microarrays, neoadjuvant therapy Keywords: Dose response
2008-01-12 | GSE8465 | GEO
Project description:The main objective of this study will be to obtain data on the efficacy of elsiglutide in preventing Chemotherapy Induced Diarrhea (CID) in patients with colorectal cancer receiving 5-FU based chemotherapy (FOLFOX4 or FOLFIRI regimen) in comparison to placebo.
| 2121148 | ecrin-mdr-crc
Project description:Interventions: XELIRI+ bevacizumab Capecitabine:2000mg/m2/day d1-8 Irinotecan:180mg/m2 d1 Bevacizumab:5mg/kg d1 Q2w
Primary outcome(s): Phase I part To determine Safety in 1st cycle by Bi-weekly XELIRI+bevacizumab. Phase II part Progression Free Survival
Study Design: Single arm Non-randomized
| 2619445 | ecrin-mdr-crc
Project description:p97/Cdc48 is a hexameric AAA ATPase in which each monomer consists of an N-terminal domain (NTD) and two ATPase domains (D1 and D2), which cooperate in substrate recruitment and processing. In vitro experiments and cryo-EM structures of p97 and its cofactor, Ufd1/Npl4 (UN), revealed mechanistic insights regarding substrate processing. Yet, dynamics and the intermediate structures of the related ATPase cycle upon UN binding remain unresolved. Using novel mutations, we captured two discrete functional conformations associated with specific nucleotide states: a functional conformation in which D1 protomers are ATP bound, while the D2 subunits are in the ADP state. A configuration that is presumably required for the initial substrate engagement with the D2 pore. We also report on a heterologous nucleotide state within the D1 ring in which only 2NTDs are in the “up” ATP state. Based on the elevated affinity and structural insights, we propose that this conformation favors UN binding. Further analysis suggests that p97-UN complex formation entails a two-state mechanism. Initially, UN binds p97's non-symmetrical conformation (2NTDs in an "up" state), this association promotes a structural transition upon which five NTDs shift to an "up" state and are poised to bind ATP. The UBXL domain of Npl4 selectively binds p97's downed NTD demonstrating a new conformation that may introduce directionality to incoming substrate.
2024-05-16 | PXD045179 | Pride
Project description:The main goal of this study was to analyze transcriptional differences between AKP CRC organoids treated or not with chemotherapy (FOLFIRI) by RNA-seq.
2022-09-16 | GSE207974 | GEO
Project description:Variations in the human FTO gene have been linked to obesity and altered connectivity and function of the dopaminergic neurocircuitry. Here we report that FTO in D2 medium spiny neurons (MSNs) of mice regulates the excitability of these cells in vitro and in vivo as well as controls D2 MSN globus pallidus external projections. Lack of FTO in D2 MSNs translates into increased locomotor responses to novelty, associated with altered timing behavior without affecting reward responses to drugs of abuse and highly palatable food, or the ability to discount rewards. Pharmacological manipulation of D1R- and D2R-dependent pathways in these animals reveals an altered balance between D1 MSN- and D2 MSN-mediated control of motor output. These findings hold the potential to target a novel avenue for control of basal ganglia motor function, where modulation of FTO-dependent signaling in D2 MSNs may promote D1 MSN regulated locomotor behavior without altering reward signaling or inciting impulsivity.
2019-06-14 | PXD013738 | Pride