Clinical effects of perineural dexmedetomidine or magnesium sulphate as adjuvants to ropivacaine in dogs undergoing tibial plateau leveling osteotomy.

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.

Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity.

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.

Generation of a biliary tract cancer cell line atlas reveals molecular subtypes and therapeutic targets.

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.