Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH

Development and potential role of type-2 sodium-glucose transporter inhibitors for management of type 2 diabetes

There is a recognized need for new treatment options for type 2 diabetes mellitus (T2DM). Recovery of glucose from the glomerular filtrate represents an important mechanism in maintaining glucose homeostasis and represents a novel target for the management of T2DM. Recovery of glucose from the glomerular filtrate is executed principally by the type 2 sodium-glucose cotransporter (SGLT2). Inhibition of SGLT2 promotes glucose excretion and normalizes glycemia in animal models. First reports of specifically designed SGLT2 inhibitors began to appear in the second half of the 1990s. Several candidate SGLT2 inhibitors are currently under development, with four in the later stages of clinical testing. The safety profile of SGLT2 inhibitors is expected to be good, as their target is a highly specific membrane transporter expressed almost exclusively within the renal tubules. One safety concern is that of glycosuria, which could predispose patients to increased urinary tract infections. So far the reported safety profile of SGLT2 inhibitors in clinical studies appears to confirm that the class is well tolerated. Where SGLT2 inhibitors will fit in the current cascade of treatments for T2DM has yet to be established. The expected favorable safety profile and insulin-independent mechanism of action appear to support their use in combination with other antidiabetic drugs. Promotion of glucose excretion introduces the opportunity to clear calories (80–90 g [300–400 calories] of glucose per day) in patients that are generally overweight, and is expected to work synergistically with weight reduction programs. Experience will most likely lead to better understanding of which patients are likely to respond best to SGLT2 inhibitors, and under what circumstances

Hepatic insulin resistance and increased hepatic glucose production in mice lacking Fgf21.

Fibroblast growth factor 21 (FGF21) is an important regulator of hepatic glucose and lipid metabolism and represents a potential pharmacological agent for the treatment of type 2 diabetes and obesity. Mice fed a ketogenic diet (KD) develop hepatic insulin resistance in association with high levels of FGF21, suggesting a state of FGF21 resistance. To address the role of FGF21 in hepatic insulin resistance, we assessed insulin action in FGF21 whole-body knock-out (FGF21 KO) male mice and their littermate WT controls fed a KD. Here, we report that FGF21 KO mice have hepatic insulin resistance and increased hepatic glucose production associated with an increase in plasma glucagon levels. FGF21 KO mice are also hypometabolic and display increased fat mass compared with their WT littermates. Taken together, these findings support a major role of FGF21 in regulating energy expenditure and hepatic glucose and lipid metabolism, and its potential role as a candidate in the treatment of diseases associated with insulin resistance

Formation of the early canine CL and the role of prostaglandin E2 (PGE2) in regulation of its function: An invivo approach

The mechanisms governing corpus luteum (CL) function in domestic dogs remain not fully elucidated. The upregulated expression of cyclooxygenase 2 and prostaglandin (PG) E2 synthase (PGES) at the beginning of the canine luteal phase indicated their luteotrophic roles, and the steroidogenic activity of PGE2 in the early canine CL has been confirmed in vitro. Recently, by applying a cyclooxygenase 2 (COX2)-specific inhibitor (firocoxib [Previcox]; Merial) from the day of ovulation until the midluteal phase, the luteotrophic effects of PGs have been shown in vivo. This is a follow-up study investigating the underlying endocrine mechanisms associated with the firocoxib-mediated effects on the canine CL. Experimental groups were formed with ovariohysterectomies performed on Days 5, 10, 20, or 30 of firocoxib treatments (10 mg/kg bw/24h; TGs = treated groups). Untreated dogs served as controls. A decrease of steroidogenic acute regulatory (STAR) protein expression was observed in TGs. The expression of PGE2 synthase was significantly suppressed in TGs 5 and 10, and both PGE2 and PGF2α levels were decreased in luteal homogenates, particularly from CL in TG 5. Similarly, expression of the prolactin receptor (PRLR) was diminished in TGs 5 and 20. The expression of PGE2 receptors PTGER2 (EP2) and PTGER4 (EP4), the PG- transporter (PGT) , and 15-hydroxy PG dehydrogenase (HPGD) was not affected in TGs. Our results substantiate a direct luteotrophic role of PGs in the early canine CL, i.e., by upregulating the steroidogenic machinery. Additionally, the possibility of an indirect effect on PRL function arises from the increased prolactin receptor expression in response to PGE2 treatment in canine lutein cells observed in vitro

CHRONOS‐3: Randomized phase III study of copanlisib plus rituximab/placebo in relapsed indolent Non-Hodgkin Lymphoma (INHL)

Introduction: Rituximab (R)-based therapies are standard for patients (pts) with relapsed advanced iNHL. Copanlisib (C) is a PI3K inhibitor approved as monotherapy for relapsed follicular lymphoma (FL) in pts who have had ≥2 prior systemic therapies. We report primary data from the Phase III CHRONOS-3 study of treatment with C+R vs placebo (P)+R in relapsed iNHL (NCT02367040). Methods: Pts with relapsed iNHL who were progression-free and treatment-free for ≥12 months (mo) after last R-based therapy or unwilling/unfit to receive chemotherapy were randomized 2:1 to receive C+R or P+R. C 60 mg/P was given i.v. on days 1, 8, and 15 (28-day cycle); R 375 mg/m2 was given i.v. on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint: centrally assessed progression-free survival (PFS). Secondary endpoints: objective response rate (ORR), duration of response, complete response rate (CRR), overall survival (OS), and treatment-emergent adverse events (TEAEs). The data cut-off date was August 31, 2020. Results: 307 pts were randomized to C+R and 151 to P+R. FL was the most common lymphoma histology subtype (60.0%), followed by marginal zone (MZL, 20.7%), small lymphocytic (SLL, 10.9%), and lymphoplasmacytic/Waldenström macroglobulinemia (LPL/WM, 8.3%). Median age was 63 years (range 28-91). With a median follow-up of 19.2 mo, the primary study endpoint was met: C+R significantly reduced the risk of disease progression/death vs P+R (hazard ratio [HR] 0.52 [95% CI 0.39, 0.69]; 1-sided p = 0.000002); median PFS was 21.5 mo (95% CI 17.8, 33.0) vs 13.8 mo (95% CI 10.2, 17.5), respectively. Reductions in risk of progression/death were seen across all histology subtypes (HR [95% CI]): FL 0.580 [0.404, 0.833]; MZL 0.475 [0.245, 0.923]; SLL 0.243 [0.111, 0.530]; LPL/WM 0.443 [0.160, 1.231]. ORRs were 80.8% (CRR 33.9%) for C+R and 47.7% (CRR 14.6%) for P+R. Higher ORRs and CRRs were seen across all iNHL subtypes with C+R treatment. Median OS was not estimable. Most common TEAEs (all grades [G]/G3+) in pts receiving C+R were hyperglycemia (69.4%/56.4%), hypertension (49.2%/39.7% [all G3]), and diarrhea (33.6%/4.9% [all G3]). For pts receiving P+R, hyperglycemia (23.3%/8.2% [all G3]), hypertension (19.2%/8.9% [all G3]), neutropenia (16.4%/12.3%), and upper respiratory tract infection (16.4%/0%) were the most common TEAEs. Serious adverse events were higher with C+R (47.2%) vs P+R (18.5%). G5 TEAEs occurred in 6 pts (2.0%) receiving C+R (1 [0.3%] deemed treatment-related; pneumonitis) and 1 (0.7%) receiving P+R. Conclusions: C+R demonstrated broad and superior efficacy vs P+R in pts with relapsed iNHL. The safety profile of C+R was manageable and consistent with C and R as monotherapy. Copanlisib is the first PI3K inhibitor to be safely combined with R in relapsed iNHL, representing a potential new therapy option for relapsed iNHL across all subtypes

Abstract CT001: CHRONOS-3: Randomized Phase III study of copanlisib plus rituximab vs rituximab/placebo in relapsed indolent non-Hodgkin lymphoma (iNHL)

Introduction: Rituximab (R)-based therapies are standard for patients (pts) with relapsed advanced iNHL. Copanlisib (C) is a PI3K inhibitor approved as monotherapy for relapsed follicular lymphoma (FL) in pts who have had ≥2 prior systemic therapies. We report primary data from the Phase III CHRONOS-3 study of treatment with C+R vs placebo (P)+R in relapsed iNHL (NCT02367040). Methods: Pts with relapsed iNHL who were progression-free and treatment-free for ≥12 months (mo) after last R-based therapy or unwilling/unfit to receive chemotherapy were randomized 2:1 to receive C+R or P+R. C 60 mg/P was given i.v. on days 1, 8, and 15 (28-day cycle); R 375 mg/m2 was given i.v. on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint: centrally assessed progression-free survival (PFS). Secondary endpoints: objective response rate (ORR), duration of response, complete response rate (CRR), overall survival (OS), and treatment-emergent adverse events (TEAEs). The data cut-off date was August 31, 2020. Results: 307 pts were randomized to C+R and 151 to P+R. FL was the most common lymphoma histology subtype (60.0%), followed by marginal zone (MZL, 20.7%), small lymphocytic (SLL, 10.9%), and lymphoplasmacytic/Waldenström macroglobulinemia (LPL/WM, 8.3%). Median age was 63 years (range 28-91). With a median follow-up of 19.2 mo, the primary study endpoint was met: C+R significantly reduced the risk of disease progression/death vs P+R (hazard ratio [HR] 0.52 [95% CI 0.39, 0.69]; 1-sided p=0.000002); median PFS was 21.5 mo (95% CI 17.8, 33.0) vs 13.8 mo (95% CI 10.2, 17.5), respectively. Reductions in risk of progression/death were seen across all histology subtypes (HR [95% CI]): FL 0.580 [0.404, 0.833]; MZL 0.475 [0.245, 0.923]; SLL 0.243 [0.111, 0.530]; LPL/WM 0.443 [0.160, 1.231]. ORRs were 80.8% (CRR 33.9%) for C+R and 47.7% (CRR 14.6%) for P+R. Higher ORRs and CRRs were seen across all iNHL subtypes with C+R treatment. Median OS was not estimable. Most common TEAEs (all grades [G]/G3+) in pts receiving C+R were hyperglycemia (69.4%/56.4%), hypertension (49.2%/39.7% [all G3]), and diarrhea (33.6%/4.9% [all G3]). For pts receiving P+R, hyperglycemia (23.3%/8.2% [all G3]), hypertension (19.2%/8.9% [all G3]), neutropenia (16.4%/12.3%), and upper respiratory tract infection (16.4%/0%) were the most common TEAEs. Serious adverse events were higher with C+R (47.2%) vs P+R (18.5%). G5 TEAEs occurred in 6 pts (2.0%) receiving C+R (1 [0.3%] deemed treatment-related; pneumonitis) and 1 (0.7%) receiving P+R. Conclusions: C+R demonstrated broad and superior efficacy vs P+R in pts with relapsed iNHL. The safety profile of C+R was manageable and consistent with C and R as monotherapy. Copanlisib is the first PI3K inhibitor to be safely combined with R in relapsed iNHL, representing a potential new therapy option for relapsed iNHL across all subtypes

Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH

Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH