Assessment of Hydroxyethyl Starch (6% HES 130/0.4) Kidney Storage in Critically Ill Dogs: A Post-mortem Prospective Study.

Objective: Intravenous hydroxyethyl starch (HES) solutions are potentially nephrotoxic due to rapid renal tissue uptake, subsequent osmotic nephrosis, and long-lasting intracellular storage. This study aimed to investigate the severity of intracellular storage of HES in renal tissue samples from critically ill dogs receiving 6% HES 130/0.4. Materials and Methods: Fresh, post-mortem (<2 h after death) renal tissue samples were analyzed through histology, immunohistochemistry (HES 130/0.4-specific antibodies), and electron microscopy for the severity of renal tubular vacuolization (VAC), intravacuolar HES accumulation (ACC), and ultra-structure impairment. Moreover, we investigated the relationship between VAC or ACC grade and HES dose (mL/kg), duration of HES administration (h), and pre-HES plasma creatinine concentrations. Results: Histology revealed that 2/20 dogs (10%) had no, 11/20 dogs (55%) had mild, 5/20 dogs (25%) had moderate, and 2/20 dogs (10%) had severe VAC. Immunohistochemistry revealed that 5/20 dogs (25%) had no, 6/20 dogs (30%) had mild, 7/20 dogs (35%) had moderate, and 2/20 dogs (10%) had severe ACC. Both changes were predominantly found in the distal tubular epithelium of mild and moderate cases, and all tubular segments were affected in severe cases. Seven of 20 dogs (35%) had osmotic nephrosis (ON). On electron microscopy, large granules with an electron-dense content were repeatedly detected in individual cells, mainly in the distal tubules. No correlation was found between cumulative HES dose or duration of HES administration and VAC grade, ACC grade, or presence/absence of ON. Conclusion: A high percentage of dogs had renal tubular HES storage and one-third of dogs showed HES-induced ON. Short-term HES administration caused VAC and ACC, regardless of the dose or duration of administration. In contrast to previous studies, HES 130/0.4 deposits were mainly located in the renal distal tubule

Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa

The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

Abstract: Resistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reported, with the majority of acquired resistance mechanisms relying on bypass signaling. To proactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome-wide CRISPR activation screens of NB cell lines treated with brigatinib or ceritinib, identifying PIM1 as a putative resistance gene, whose high expression is associated with high-risk disease and poor survival. Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status

Clinoptilolite in Dextran Sulphate Sodium-Induced Murine Colitis: Efficacy and Safety of a Microparticulate Preparation.

Clinoptilolite is an aluminium silicate of natural origin; the microporous structure and the net negative charge of its crystal lattice allows for adsorption of ions, toxins, inflammatory mediators, and some microorganisms. We generated 2 preparations of purified clinoptilolite, which differed by about 10-fold in particle size, ie, a standard powder (GHC1) and a microparticulate fraction (GHC2) with a size of 3.6 µm and 0.39 µm (d50) respectively. These were examined for their ability to accelerate the recovery of mice from DSS (dextran sulphate sodium)-induced intestinal inflammation. Efficacy of clinoptilolite preparations was investigated by administering DSS-treated mice twice daily with 30 mg GHC2 or GHC1 for 5 consecutive days, followed by 5 days of recovery without DSS. To explore the safety of the microparticulate preparation (GHC2), mice were subjected to 4 cycles of DSS-exposure. We specifically verified that clinoptilolite microparticles were not systemically bioavailable by examining the gut tissue and the liver for the accumulation of microparticles by transmission electron microscopy. Treatment of mice with GHC2 was superior to GHC1 and as effective as the reference compound 5-aminosalicylic acid in ameliorating the damage induced by the exposure to DSS. In addition, no clinoptilolite particle was observed in the intestinal epithelial layer, gut-associated lymph follicles, or in the liver. Our observations confirm that a microparticulate preparation of clinoptilolite is safe and effective in a murine model of inflammatory bowel disease and supports the hypothesis that the adsorptive capacity of clinoptilolite is of potential therapeutic relevance

sj-tif-29-tpx-10.1177_01926233231182115 – Supplemental material for Results of the European Society of Toxicologic Pathology Survey on the Use of Artificial Intelligence in Toxicologic Pathology

Supplemental material, sj-tif-29-tpx-10.1177_01926233231182115 for Results of the European Society of Toxicologic Pathology Survey on the Use of Artificial Intelligence in Toxicologic Pathology by Xavier Palazzi, Erio Barale-Thomas, Bhupinder Bawa, Jonathan Carter, Kyathanahalli Janardhan, Heike Marxfeld, Abraham Nyska, Chandrassegar Saravanan, Dirk Schaudien, Vanessa L. Schumacher, Robert H. Spaet, Simone Tangermann, Oliver C Turner and Enrico Vezzali in Toxicologic Pathology</p

sj-tif-27-tpx-10.1177_01926233231182115 – Supplemental material for Results of the European Society of Toxicologic Pathology Survey on the Use of Artificial Intelligence in Toxicologic Pathology

Supplemental material, sj-tif-27-tpx-10.1177_01926233231182115 for Results of the European Society of Toxicologic Pathology Survey on the Use of Artificial Intelligence in Toxicologic Pathology by Xavier Palazzi, Erio Barale-Thomas, Bhupinder Bawa, Jonathan Carter, Kyathanahalli Janardhan, Heike Marxfeld, Abraham Nyska, Chandrassegar Saravanan, Dirk Schaudien, Vanessa L. Schumacher, Robert H. Spaet, Simone Tangermann, Oliver C Turner and Enrico Vezzali in Toxicologic Pathology</p

sj-tif-1-tpx-10.1177_01926233231182115 – Supplemental material for Results of the European Society of Toxicologic Pathology Survey on the Use of Artificial Intelligence in Toxicologic Pathology

Supplemental material, sj-tif-1-tpx-10.1177_01926233231182115 for Results of the European Society of Toxicologic Pathology Survey on the Use of Artificial Intelligence in Toxicologic Pathology by Xavier Palazzi, Erio Barale-Thomas, Bhupinder Bawa, Jonathan Carter, Kyathanahalli Janardhan, Heike Marxfeld, Abraham Nyska, Chandrassegar Saravanan, Dirk Schaudien, Vanessa L. Schumacher, Robert H. Spaet, Simone Tangermann, Oliver C Turner and Enrico Vezzali in Toxicologic Pathology</p

sj-tif-16-tpx-10.1177_01926233231182115 – Supplemental material for Results of the European Society of Toxicologic Pathology Survey on the Use of Artificial Intelligence in Toxicologic Pathology

Supplemental material, sj-tif-16-tpx-10.1177_01926233231182115 for Results of the European Society of Toxicologic Pathology Survey on the Use of Artificial Intelligence in Toxicologic Pathology by Xavier Palazzi, Erio Barale-Thomas, Bhupinder Bawa, Jonathan Carter, Kyathanahalli Janardhan, Heike Marxfeld, Abraham Nyska, Chandrassegar Saravanan, Dirk Schaudien, Vanessa L. Schumacher, Robert H. Spaet, Simone Tangermann, Oliver C Turner and Enrico Vezzali in Toxicologic Pathology</p