RESUMO
The study aimed to compare the quality of perioperative analgesia, the motor block duration, and the effects on main cardiovascular parameters of dexmedetomidine (1 µg/kg/nerve block) or magnesium sulphate (2 mg/kg/nerve block) as adjuvants to 0.3% ropivacaine for sciatic and saphenous nerves block in dogs undergoing tibial plateau leveling osteotomy (TPLO). Dogs randomly received perineural dexmedetomidine-ropivacaine (D group), magnesium sulphate-ropivacaine (M group), or ropivacaine (C group). Fentanyl was administered in case of intraoperative nociception. Postoperative pain was assessed using the Short Form-Glasgow Composite Measure Pain Scale (SF-GCMPS) and VAS scale. The duration of motor blockade and intra- and postoperative cardiovascular parameters were also recorded. Group M required significantly more fentanyl than D group (p = 0.04). Group M had a significantly higher SF-GCMPS score than group C at 4 (p = 0.002) and 5 h after extubation (p = 0.01), and a significantly higher VAS score than group D at 3 h after extubation (p = 0.03), and at 4 h if compared to group C (p = 0.009). No significant differences regarding the duration of motor blockade were detected between groups (p = 0.07). The heart rate was significantly lower in group D than in M and C groups intraoperatively and during the first 1.5 h post extubation. The addition of dexmedetomidine or magnesium sulphate as adjuvants to perineural ropivacaine did not improve the quality of perioperative analgesia and did not prolong the motor blockade in dogs undergoing sciatic and saphenous nerves block for TPLO surgery.
Assuntos
Dexmedetomidina , Sulfato de Magnésio , Bloqueio Nervoso , Osteotomia , Dor Pós-Operatória , Ropivacaina , Animais , Cães , Dexmedetomidina/administração & dosagem , Dexmedetomidina/farmacologia , Ropivacaina/administração & dosagem , Ropivacaina/farmacologia , Sulfato de Magnésio/farmacologia , Sulfato de Magnésio/administração & dosagem , Osteotomia/veterinária , Dor Pós-Operatória/veterinária , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Masculino , Feminino , Bloqueio Nervoso/veterinária , Anestésicos Locais/administração & dosagem , Anestésicos Locais/farmacologia , Tíbia/cirurgiaRESUMO
Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic gene across human cancers. Mutant IDH1 (mIDH1) generates the oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in epigenetics and other processes. A hallmark of IDH1-mutant solid tumors is T cell exclusion, whereas mIDH1 inhibition in preclinical models restores antitumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1-mutant solid tumors show selective hypermethylation and silencing of the cytoplasmic double-stranded DNA (dsDNA) sensor CGAS, compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing CGAS and transposable element (TE) subclasses. dsDNA produced by TE-reverse transcriptase (TE-RT) activates cGAS, triggering viral mimicry and stimulating antitumor immunity. In summary, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous RT activity to the mechanism of action of a US Food and Drug Administration-approved oncology drug.
Assuntos
Evasão da Resposta Imune , Imunidade Inata , Isocitrato Desidrogenase , Neoplasias , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , DNA/metabolismo , Desmetilação do DNA , Metilação de DNA , Elementos de DNA Transponíveis , Epigênese Genética , Glutaratos/metabolismo , Imunidade Inata/genética , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Mutação , Neoplasias/imunologia , Neoplasias/genética , Nucleotidiltransferases/genética , Evasão Tumoral , Evasão da Resposta Imune/genéticaRESUMO
Biliary tract cancers (BTCs) are a group of deadly malignancies encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Here, we present the integrative analysis of 63 BTC cell lines via multi-omics clustering and genome- scale CRISPR screens, providing a platform to illuminate BTC biology and inform therapeutic development. We identify dependencies broadly enriched in BTC compared to other cancers as well as dependencies selective to the anatomic subtypes. Notably, cholangiocarcinoma cell lines are stratified into distinct lineage subtypes based on biliary or dual biliary/hepatocyte marker signatures, associated with dependency on specific lineage survival factors. Transcriptional analysis of patient specimens demonstrates the prognostic significance of these lineage subtypes. Additionally, we delineate strategies to enhance targeted therapies or to overcome resistance in cell lines with key driver gene mutations. Furthermore, clustering based on dependencies and proteomics data elucidates unexpected functional relationships, including a BTC subgroup with partial squamous differentiation. Thus, this cell line atlas reveals potential therapeutic targets in molecularly defined BTCs, unveils biologically distinct disease subtypes, and offers a vital resource for BTC research.
RESUMO
The ribonuclease DIS3 is one of the most frequently mutated genes in the hematological cancer multiple myeloma, yet the basis of its tumor suppressor function in this disease remains unclear. Herein, exploiting the TCGA dataset, we found that DIS3 plays a prominent role in the DNA damage response. DIS3 inactivation causes genomic instability by increasing mutational load, and a pervasive accumulation of DNA:RNA hybrids that induces genomic DNA double-strand breaks (DSBs). DNA:RNA hybrid accumulation also prevents binding of the homologous recombination (HR) machinery to double-strand breaks, hampering DSB repair. DIS3-inactivated cells become sensitive to PARP inhibitors, suggestive of a defect in homologous recombination repair. Accordingly, multiple myeloma patient cells mutated for DIS3 harbor an increased mutational burden and a pervasive overexpression of pro-inflammatory interferon, correlating with the accumulation of DNA:RNA hybrids. We propose DIS3 loss in myeloma to be a driving force for tumorigenesis via DNA:RNA hybrid-dependent enhanced genome instability and increased mutational rate. At the same time, DIS3 loss represents a liability that might be therapeutically exploited in patients whose cancer cells harbor DIS3 mutations.
Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Ribonucleases/metabolismo , Reparo de DNA por Recombinação , Recombinação Homóloga , Instabilidade Genômica , Reparo do DNA , DNA/metabolismo , RNA , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismoRESUMO
High-grade B cell lymphomas with concurrent activation of the MYC and BCL2 oncogenes, also known as double-hit lymphomas (DHL), show dismal prognosis with current therapies. MYC activation sensitizes cells to inhibition of mitochondrial translation by the antibiotic tigecycline, and treatment with this compound provides a therapeutic window in a mouse model of MYC-driven lymphoma. We now addressed the utility of this antibiotic for treatment of DHL. BCL2 activation in mouse Eµ-myc lymphomas antagonized tigecycline-induced cell death, which was specifically restored by combined treatment with the BCL2 inhibitor venetoclax. In line with these findings, tigecycline and two related antibiotics, tetracycline and doxycycline, synergized with venetoclax in killing human MYC/BCL2 DHL cells. Treatment of mice engrafted with either DHL cell lines or a patient-derived xenograft revealed strong antitumoral effects of the tigecycline/venetoclax combination, including long-term tumor eradication with one of the cell lines. This drug combination also had the potential to cooperate with rituximab, a component of current front-line regimens. Venetoclax and tigecycline are currently in the clinic with distinct indications: Our preclinical results warrant the repurposing of these drugs for combinatorial treatment of DHL.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Sulfonamidas/uso terapêutico , Tigeciclina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidoresRESUMO
The oncogenic transcription factor Myc is required for the progression and maintenance of diverse tumors. This has led to the concept that Myc itself, Myc-activated gene products, or associated biological processes might constitute prime targets for cancer therapy. Here, we present an in vivo reverse-genetic screen targeting a set of 241 Myc-activated mRNAs in mouse B-cell lymphomas, unraveling a critical role for the mitochondrial ribosomal protein (MRP) Ptcd3 in tumor maintenance. Other MRP-coding genes were also up regulated in Myc-induced lymphoma, pointing to a coordinate activation of the mitochondrial translation machinery. Inhibition of mitochondrial translation with the antibiotic Tigecycline was synthetic-lethal with Myc activation, impaired respiratory activity and tumor cell survival in vitro, and significantly extended lifespan in lymphoma-bearing mice. We have thus identified a novel Myc-induced metabolic dependency that can be targeted by common antibiotics, opening new therapeutic perspectives in Myc-overexpressing tumors.