Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to ...hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents.
•Reviewed the mechanisms underlying drug-induced steatohepatitis for many compounds•Mitochondrial dysfunction is critical in the development of drug-induced steatohepatitis.•Majority of drugs that induce steatohepatitis are cationic amphiphilic drugs.•Chemotherapeutics that induce CASH are cationic amphiphilic drugs.•Majority of drugs that induce steatohepatitis are carnitine palmitoyltransferase-I inhibitors.
Previous studies suggest that the lipid-lowering effect of berberine (BBR) involves actions on the low-density lipoprotein receptor and the AMP-activated protein kinase signaling pathways. However, ...the implication of these mechanisms is unclear because of the low bioavailability of BBR. Because the main action site of BBR is the gut and intestinal farnesoid X receptor (FXR) plays a pivotal role in the regulation of lipid metabolism, we hypothesized that the effects of BBR on intestinal FXR signaling pathway might account for its pharmacological effectiveness. Using wild type (WT) and intestine-specific FXR knockout (FXR
) mice, we found that BBR prevented the development of high-fat-diet-induced obesity and ameliorated triglyceride accumulation in livers of WT, but not FXR
mice. BBR increased conjugated bile acids in serum and their excretion in feces. Furthermore, BBR inhibited bile salt hydrolase (BSH) activity in gut microbiota, and significantly increased the levels of tauro-conjugated bile acids, especially tauro-cholic acid(TCA), in the intestine. Both BBR and TCA treatment activated the intestinal FXR pathway and reduced the expression of fatty-acid translocase Cd36 in the liver. These results indicate that BBR may exert its lipid-lowering effect primarily in the gut by modulating the turnover of bile acids and subsequently the ileal FXR signaling pathway. In summary, we provide the first evidence to suggest a new mechanism of BBR action in the intestine that involves, sequentially, inhibiting BSH, elevating TCA, and activating FXR, which lead to the suppression of hepatic expression of Cd36 that results in reduced uptake of long-chain fatty acids in the liver.
The energy deposition of ions in dense plasmas is a key process in inertial confinement fusion that determines the α-particle heating expected to trigger a burn wave in the hydrogen pellet and ...resulting in high thermonuclear gain. However, measurements of ion stopping in plasmas are scarce and mostly restricted to high ion velocities where theory agrees with the data. Here, we report experimental data at low projectile velocities near the Bragg peak, where the stopping force reaches its maximum. This parameter range features the largest theoretical uncertainties and conclusive data are missing until today. The precision of our measurements, combined with a reliable knowledge of the plasma parameters, allows to disprove several standard models for the stopping power for beam velocities typically encountered in inertial fusion. On the other hand, our data support theories that include a detailed treatment of strong ion-electron collisions.
We report on the first successful proof-of-principle experiment to manipulate laser-matter interactions on microscales using highly ordered Si microwire arrays. The interaction of a high-contrast ...short-pulse laser with a flat target via periodic Si microwires yields a substantial enhancement in both the total and cutoff energies of the produced electron beam. The self-generated electric and magnetic fields behave as an electromagnetic lens that confines and guides electrons between the microwires as they acquire relativistic energies via direct laser acceleration.
Fibroblast growth factors (FGFs) are a family of growth factors critically involved in developmental, physiological, and pathological processes, including embryogenesis, angiogenesis, wound healing, ...and endocrine functions. In the liver, several FGFs are produced basally by hepatocytes and hepatic stellate cells (HSCs). Upon insult to the liver, expression of FGFs in HSCs is greatly upregulated, stimulating hepatocyte regeneration and growth. Various FGF isoforms have also been shown to directly induce HSC proliferation and activation thereby enabling autocrine and paracrine regulation of HSC function. Regulation of HSCs by the endocrine FGFs, namely, FGF15/19 and FGF21, has also recently been identified. With the ability to modulate HSC proliferation and transdifferentiation, targeting FGF signaling pathways constitutes a promising new therapeutic strategy to treat hepatic fibrosis.
We present an experimental study investigating laser-driven proton acceleration via target normal sheath acceleration (TNSA) over a target thickness range spanning the typical TNSA-dominant regime ...(∼1 m) down to below the onset of relativistic laser-transparency (<40 nm). This is done with a single target material in the form of freely adjustable films of liquid crystals along with high contrast (via plasma mirror) laser interaction (∼2.65 J, 30 fs, I > 1 × 10 21 W cm−2). Thickness dependent maximum proton energies scale well with TNSA models down to the thinnest targets, while those under ∼40 nm indicate the influence of relativistic transparency on TNSA, observed via differences in light transmission, maximum proton energy, and proton beam spatial profile. Oblique laser incidence (45°) allowed the fielding of numerous diagnostics to determine the interaction quality and details: ion energy and spatial distribution was measured along the laser axis and both front and rear target normal directions; these along with reflected and transmitted light measurements on-shot verify TNSA as dominant during high contrast interaction, even for ultra-thin targets. Additionally, 3D particle-in-cell simulations qualitatively support the experimental observations of target-normal-directed proton acceleration from ultra-thin films.
Background
No study has determined the incidence of long‐term opioid use, or risk factors for long‐term use, ≥1 year after radiotherapy.
Methods
Medical records of 276 head/neck cancer patients were ...retrospectively assessed for persistent opioid use 1‐year after curative‐intent radiotherapy. Numerous potential risk factors were assessed and the physicians' documented reasons for continued use were qualitatively categorized as suspected opioid use disorder (OUD) or as medically indicated for control of ongoing pain.
Results
Of note, 20 of 276 patients continued using opioids long‐term. High maximum opioid dose and the use of opioids and/or psychotropics/non‐opioid analgesics at the radiation oncology intake visit were associated with this outcome. Three patients continued due to suspected OUD and 17 due to medical indications.
Conclusion
Of note, 7.2% of patients developed long‐term opioid use, which was associated with high maximum opioid dose and early initiation of opioids and/or psychotropics/non‐opioid analgesics. Physicians cited medical indications as the primary reason for continued use.
In late June 2021, western North America, and in particular the Pacific Northwest experienced a heatwave with temperatures usually only encountered in hot desert climates. Using a blend of reanalysis ...data and Earth System Model (ESM) simulations, we disentangle the physical drivers underlying this exceptional event. Our analysis highlights the role of the anticyclonic circulation aloft, which converted previously gained potential energy—some of which by intense latent heating thousands of kilometers upwind over the North Pacific—back into sensible heat through subsidence. We demonstrate that this upwind latent heat release did not only result in a hot troposphere above the heatwave region, but also contributed directly to escalating near‐surface temperatures. Facilitated by the mountainous terrain and dry soils in the region, deep atmospheric boundary layers were established over the course of several days, connecting the air close to Earth's surface to a massive heat reservoir many kilometers above. Anomalous soil moisture acted to raise the heatwave temperatures by 3°C in a large region during the peak of the event, with local anomalies exceeding 5°C. Overall, we conclude that this heatwave was the outcome of an intricate interplay between dynamic and thermodynamic processes. ESM experiments suggest that the same large‐scale atmospheric circulation fueled by enhanced thermodynamic drivers, such as more available moisture for condensation upwind, could enable even more extreme near‐surface temperatures, in particular in a warmer climate.
Plain Language Summary
In late June 2021, western North America, and in particular the Pacific Northwest, experienced temperatures normally encountered in hot deserts. Our analysis highlights the role of the anticyclonic circulation aloft, whose downward spiraling air masses converted previously gained potential energy back into sensible heat. We show that in addition to heating through sinking, the air was previously heated by condensation in ascending air streams thousands of kilometers upwind, over the North Pacific. Together, these processes fostered a massive heat reservoir above the heatwave region, which contributed to escalating near‐surface temperatures through strong vertical mixing. Dry soils in the region intensified surface heating, boosting maximum temperatures in excess of 5°C. Overall, we conclude that this heatwave was the outcome of an intricate interplay of the atmospheric flow and processes such as condensational and surface heating, further exacerbated by human‐induced background warming. Our experiments suggest that if fueled by more available moisture for condensation upwind, the same large‐scale atmospheric circulation could enable even more extreme near‐surface temperatures.
Key Points
A strong “Omega Block” enabled the heatwave, yet near‐surface air temperatures were more extreme than suggested by the large‐scale flow
Sinking air aloft previously experienced strong latent heating over the North Pacific, contributing to the high near‐surface temperatures
Deep atmospheric boundary layers brought the extreme heat down to the surface, with local soil moisture effects in excess of 5°C
Background
We had previously analyzed the variables that determine the rates of opioid use at 1‐year postradiotherapy in patients with head and neck cancer. Here we analyze the variables associated ...with opioid abstinence during and in the 12 months after radiotherapy at our institution.
Methods
We identified a cohort of patients with head and neck cancer who received radiotherapy as part of curative treatment at our institution. Logistic regression analyses were performed to determine socioeconomic and clinical factors associated with opioid abstinence.
Results
The cohort included 376 patients. On multivariable analysis, patients from an upper‐income class (p = 0.004), black race (p = 0.004), older (p = 0.008), with dependent children (p < 0.001) or receiving surgery (p = 0.002) were more likely to abstain from opioids, while patients using analgesic mouthwash (p = 0.009) or higher pain scale (p = 0.002) were less likely.
Conclusion
Socioeconomic and treatment characteristics are associated with opioid abstinence during and following radiation treatment in patients with head and neck cancer.
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