DNAJB1-PRKACA fusion drives fibrolamellar liver cancer through impaired SIK signaling and CRTC2/p300-mediated transcriptional reprogramming.

Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived FLC models, engineered systems, and patient samples.

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.

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).

Loss of ribonuclease DIS3 hampers genome integrity in myeloma by disrupting DNA:RNA hybrid metabolism.

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).

Therapeutic synergy between tigecycline and venetoclax in a preclinical model of / double-hit B cell lymphoma.

High-grade B cell lymphomas with concurrent activation of the and oncogenes, also known as double-hit lymphomas (DHL), show dismal prognosis with current therapies. 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 -driven lymphoma. We now addressed the utility of this antibiotic for treatment of DHL.

The mitochondrial translation machinery as a therapeutic target in Myc-driven lymphomas.

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.

Behavioral and degeneration changes in the basal forebrain systems of aged rats: a quantitative study in the region of the basal forebrain after levo-acetyl-carnitine treatments assessed by Abercrombie estimation.

One group of six male control rats [21 months old] and one group of six male rats of the same age, singularly stored in a cage, and treated with acetyl-l-carnitine-HCl (ALCAR: 60 mg/kg/day/p.o.) for six months were tested in the spatial learning/memory Morris maze-water task and for atrophy and cell loss in seven myelo- and cytostructurally defined basal forebrain (BF) cholinergic regions [Gritti et al.

Stereological estimates of the basal forebrain cell population in the rat, including neurons containing choline acetyltransferase, glutamic acid decarboxylase or phosphate-activated glutaminase and colocalizing vesicular glutamate transporters.

The basal forebrain (BF) plays an important role in modulating cortical activity and influencing attention, learning and memory. These activities are fulfilled importantly yet not entirely by cholinergic neurons. Noncholinergic neurons also contribute and comprise GABAergic neurons and other possibly glutamatergic neurons.

Parvalbumin, calbindin, or calretinin in cortically projecting and GABAergic, cholinergic, or glutamatergic basal forebrain neurons of the rat.

The basal forebrain (BF) plays an important role in modulating cortical activity and facilitating processes of attention, learning, and memory. This role is subserved by cholinergic neurons but also requires the participation of other noncholinergic neurons. Noncholinergic neurons include gamma-amino butyric acidergic (GABAergic) neurons, some of which project in parallel with the cholinergic cells to the cerebral cortex, others of which project caudally or locally.

The synchronizing influence of Substantia Innominata on the thalamus of the cat.

We examined the stimulating effect of Substantia Innominata pars anterior (SIa), during the waking state, on the 'central' part of the Mediodorsal nucleus of the thalamus (MD), combining electrophysiological and anatomical techniques in restrained, undrugged, unanaesthetized cats. Thalamic MD units were recorded, after electrical stimulation of the Substantia Innominata, at 1 Hz, with a single pulse or short trains of four pulses. Responses were studied by poststimulus histograms.

Pepsinogens: physiology, pharmacology pathophysiology and exercise.

Human gastric mucosa contains aspartic proteinases that can be separated electrophoretically on the basis of their physical properties into two major groups: Pepsinogen I (PGA, PGI); and Pepsinogen II (PGC, PGII). Pepsinogens consist of a single polypeptide chain with molecular weight of approximately 42,000 Da. Pepsinogens are mainly synthesized and secreted by the gastric chief cells of the human stomach before being converted into the proteolytic enzyme pepsin, which is crucial for the digestive processes in the stomach.

GABAergic and cholinergic basal forebrain and preoptic-anterior hypothalamic projections to the mediodorsal nucleus of the thalamus in the cat.

The present study examined projections of GABAergic and cholinergic neurons from the basal forebrain and preoptic-anterior hypothalamus to the "intermediate" part of the mediodorsal nucleus of the thalamus. Retrograde transport from this region of the mediodorsal nucleus was investigated using horseradish peroxidase-conjugated wheatgerm agglutinin in combination with peroxidase-antiperoxidase immunohistochemical staining for glutamic acid decarboxylase and choline acetyltransferase. A relatively large number of retrogradely-labelled glutamic acid decarboxylase-positive neurons are located in the basal forebrain, amounting to more than 7% of the total population of glutamic acid decarboxylase-positive cells in this region.

GABAergic and other noncholinergic basal forebrain neurons, together with cholinergic neurons, project to the mesocortex and isocortex in the rat.

The extrathalamic relay from the brainstem reticular formation to the cerebral cortex in the basal forebrain has been thought to be constituted predominantly, if not exclusively, by cholinergic neurons. In contrast, the septohippocampal projection has been shown to contain an important contingent of gamma-aminobutyric acid (GABA)ergic neurons. In the present study, we investigated whether GABAergic neurons also contribute to the projection from the basal forebrain to neocortical regions, including the mesocortex (limbic) and the isocortex in the rat.

Pepsinogens and gastrointestinal symptoms in mountain marathon runners.

Although there are various descriptive reports concerning exercise-induced gastrointestinal distress, the role of gastrointestinal hormones and/or enzymes is not definitively established. In this study we investigated the behaviour of pepsinogens (PGI and PGII) after an endurance race performed at an altitude of 4,300 m by 13 well-trained marathon runners, with the aim to establish their interrelationship with gastrointestinal distress and with the modifications of gastrin and cortisol. The athletes showed a significant rise in gastrin (p < 0.

Projections of GABAergic and cholinergic basal forebrain and GABAergic preoptic-anterior hypothalamic neurons to the posterior lateral hypothalamus of the rat.

Within the basal forebrain, gamma-aminobutyric acid (GABA)-synthesizing neurons are codistributed with acetylcholine-synthesizing neurons (Gritti et al. [1993] J. Comp.

Codistribution of GABA- with acetylcholine-synthesizing neurons in the basal forebrain of the rat.

In recent years, GABAergic neurons have been identified in the basal forebrain where cholinergic cortically projecting neurons are located and known to be important in mechanisms of cortical activation. In the present study in the rat, the relationship of the GABA-synthesizing neurons to the acetylcholine-synthesizing neurons was examined by application of a sequential double staining immunohistochemical procedure involving the peroxidase-antiperoxidase technique for glutamic acid decarboxylase (GAD) and choline acetyltransferase (ChAT). In these double and adjacent single immunostained series of sections, the GAD+ and ChAT+ cells were mapped, counted and measured with the aid of a computerized image analysis system.

Enhancement of tonic and phasic events of rapid eye movement sleep following bilateral ibotenic acid injections into centralis lateralis thalamic nucleus of cats.

The excitotoxin ibotenic acid (1.2-2.6 microliters of 50 micrograms/microliters) was injected bilaterally into the thalamic centralis lateralis nucleus of chronically implanted cats in order to study the effects of tonic excitation followed by destruction of perikarya on the sleep-waking cycle and its electrographic correlates.

Recurrent and reciprocal inhibition of the human monosynaptic reflex shows opposite changes following intravenous administration of acetylcarnitine.

A long-latency, long-lasting increase in the recurrent inhibitory effect on the soleus monosynaptic (Hoffmann, H) reflex was induced after intravenous administration of L-acetylcarnitine, a substance known to process central cholinergic activity. This effect was paralleled by disappearance of the H reflex inhibition (functionally disinhibition) induced by stimulation of Ia afferent fibres from the tibialis anterior (reciprocal inhibition) and gastrocnemius medialis muscle. Magnitude and time course of the L-acetylcarnitine-induced effects were significantly correlated.

Stress-related changes in calcitonin gene-related peptide binding sites in the cat central nervous system.

The possibility of area-specific changes in binding sites for CGRP in response to stress was studied in cat CNS after repeated sleep-deprivation and restriction of movement. Brain sections were obtained from a cat placed under stressful conditions for 2 h the 1st day, 6 h the 2nd day and 24 h the 3rd day. Changes in CGRP binding sites were evaluated by an in vitro autoradiographic technique with 125I-Tyr-rat-CGRP as a ligand.

Convergence of Ia fibres from synergistic and antagonistic muscles onto interneurones inhibitory to soleus in humans.

1. The possibility that Ia afferent fibres from the gastrocnemius medialis (GM) and from the tibialis anterior (TA) muscle could converge on to a single interneuronal pool inhibitory to the soleus motoneurones was investigated. 2.

Changes in EEG spindle activity induced by ibotenic acid lesions of medialis dorsalis thalamic nuclei in the cat.

The injection of an excitotoxin into medialis dorsalis thalamic nuclei (MD) elicited a short-term increase followed by a depression on EEG spindle waves in chronically implanted cats. This biphasic action provides further evidence to the hypothesis that MD plays a crucial role in transferring and inducing spindling on frontal cortex. In addition, retrograde horseradish peroxidase transport from previously lesioned MD labeled subcortical structures such as basal forebrain, anterior hypothalamus, reticular thalamic nucleus, ventral tegmental area, and locus coeruleus.

Short-latency inhibition of soleus motoneurones by impulses in Ia afferents from the gastrocnemius muscle in humans.

1. The possibility that the Ia afferent fibres from the gastrocnemius medialis muscle could be responsible for a decrease in excitability of the soleus motor pool was investigated. 2.

Binding sites for [3H]2-oxo-quazepam in the brain of the cat: evidence for heterogeneity of benzodiazepine recognition sites.

In the present study, the distribution of benzodiazepine recognition site subtypes in the brain of the cat was investigated. To this aim, the binding properties of [3H]2-oxo-quazepam ([3H]2OXOQ) and [3H]beta-CCE, two ligands with preferential affinity for Type I benzodiazepine recognition sites, were compared to binding parameters for [3H]flunitrazepam ([3H]FNT) in different areas of the cat brain. The ratio of [3H]2OXOQ to [3H]FNT binding sites indicated that, in the cerebellum, Type I sites accounted for 90% of the total number of benzodiazepine recognition sites.

Motoneurone recurrent inhibition is enhanced by L-acetylcarnitine in humans.

Renshaw cells, which mediate the recurrent inhibition of spinal a-motoneurones, are activated by acetylcholine, both through motoneurone collaterals and the reticulo-spinal system. Since it is known that L-acetylcarnitine (L-AC) has central cholinergic effects, we tested in ten normal subjects and three spastic patients the ability of L-AC to induce changes in excitability of the Renshaw cells. These were activated by a conditioning monosynaptic reflex of the soleus muscle, evoked by electrical stimulation of the tibial nerve, and the resulting recurrent inhibition of the motoneurones was assessed by a subsequent monosynaptic reflex (H').