Patients with acute upper gastrointestinal bleeding were assigned to receive endoscopy within 6 hours or between 6 and 24 hours after gastroenterologic consultation. Mortality at 30 days was 8.9% in ...the former group and 6.6% in the latter group; earlier endoscopy did not lower mortality.
Employing inducible genetically engineered and orthotopic mouse models, we demonstrate a key role for transcriptional regulator Yap in maintenance of Kras-mutant pancreatic tumors. Integrated ...transcriptional and metabolomics analysis reveals that Yap transcribes Myc and cooperates with Myc to maintain global transcription of metabolic genes. Yap loss triggers acute metabolic stress, which causes tumor regression while inducing epigenetic reprogramming and Sox2 upregulation in a subset of pancreatic neoplastic cells. Sox2 restores Myc expression and metabolic homeostasis in Yap-deficient neoplastic ductal cells, which gradually re-differentiate into acinar-like cells, partially restoring pancreatic parenchyma in vivo. Both the short-term and long-term effects of Yap loss in inducing cell death and re-differentiation, respectively, are blunted in advanced, poorly differentiated p53-mutant pancreatic tumors. Collectively, these findings reveal a highly dynamic and interdependent metabolic, transcriptional, and epigenetic regulatory network governed by Yap, Myc, Sox2, and p53 that dictates pancreatic tumor metabolism, growth, survival, and differentiation.
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•Yap maintains the global metabolic transcriptional program in conjunction with Myc•Yap ablation triggers metabolic crisis and regresses early-stage pancreatic tumors•Yap ablation de-represses Sox2 and acinar lineage genes via DNA demethylation•Sox2 restores Myc and metabolic homeostasis in Yap-null pancreatic tumor cells
Murakami et al. demonstrate the stage-dependent requirement for Yap in PDAC maintenance. Yap knockout causes tumor regression and regeneration of pancreatic parenchyma in early-stage PDAC but only temporarily halts tumor growth in advanced p53 mutant PDAC tumors due to de-repression of Sox2, which substitutes for Yap in maintaining metabolic homeostasis.
Type 2 diabetes mellitus is a risk factor for incident heart failure and increases the risk of morbidity and mortality in patients with established disease. Secular trends in the prevalence of ...diabetes mellitus and heart failure forecast a growing burden of disease and underscore the need for effective therapeutic strategies. Recent clinical trials have demonstrated the shared pathophysiology between diabetes mellitus and heart failure, the synergistic effect of managing both conditions, and the potential for diabetes mellitus therapies to modulate the risk of heart failure outcomes. This scientific statement on diabetes mellitus and heart failure summarizes the epidemiology, pathophysiology, and impact of diabetes mellitus and its control on outcomes in heart failure; reviews the approach to pharmacological therapy and lifestyle modification in patients with diabetes mellitus and heart failure; highlights the value of multidisciplinary interventions to improve clinical outcomes in this population; and outlines priorities for future research.
Rationale
Male rats escalate methamphetamine (meth) intake during long-access meth self-administration, show enhanced reinstatement of meth-seeking, and exhibit meth-induced memory impairments. ...However, the impact of long-access daily meth self-administration on reinstatement and cognitive dysfunction has not been assessed in females, even though clinical studies on meth addiction have shown differences between men and women.
Objectives
This study determined whether male and freely cycling female rats: (1) escalate meth intake in a 6-h daily-access period relative to 1-h access; (2) show different sensitivity to meth primed reinstatement after short- and long-access conditions; and (3) show deficits in novel object and object in place recognition memory.
Methods
Male and female Long–Evans rats self-administered meth in limited (1-h/day) or extended (6-h/day) daily access sessions. After 21 days, meth access was discontinued, and rats entered an abstinence period. On the seventh and 14th days of abstinence, rats were assessed for recognition memory using tests for: (a) novel object recognition memory and (b) object-in-place memory. Rats were tested for reinstatement of meth-seeking following extinction of responding.
Results
Female rats self-administered more meth and escalated intake faster than males during extended, but not limited, daily access. Both males and females in the extended, but not limited, access groups showed memory deficits on both tasks. Female rats showed greater reinstatement to meth-seeking with lower doses of meth priming injections than males.
Conclusions
Relative to males, females were equally susceptible to meth-induced memory deficits but exhibited higher meth intake and greater relapse to meth-seeking.
Lineage plasticity has been proposed as a major source of intratumoral heterogeneity and therapeutic resistance. Here, by employing an inducible genetic engineered mouse model, we illustrate that ...lineage plasticity enables advanced Pancreatic Ductal Adenocarcinoma (PDAC) tumors to develop spontaneous relapse following elimination of the central oncogenic driver - Yap. Transcriptomic and immunohistochemistry analysis of a large panel of PDAC tumors reveals that within high-grade tumors, small niches of PDAC cells gradually evolve to re-activate pluripotent transcription factors (PTFs), which lessen their dependency on Yap. Comprehensive Cut&Tag analysis demonstrate that although acquisition of PTF expression is coupled with the process of epithelial-to-mesenchymal transition (EMT), PTFs form a core transcriptional regulatory circuitry (CRC) with Jun to overcome Yap dependency, which is distinct from the classic TGFb-induced EMT-TF network. A chemical-genetic screen and follow-up functional studies establish Brd4 as an epigenetic gatekeeper for the PTF-Jun CRC, and strong synergy between BET and Yap inhibitors in blocking PDAC growth.
Although innate immunity is linked to metabolic health, the effect of leptin signaling in cells from the innate immune system on glucose homeostasis has not been thoroughly investigated. We generated ...two mouse models using Cre-lox methodology to determine the effect of myeloid cell-specific leptin receptor (Lepr) reconstitution and Lepr knockdown on in vivo glucose metabolism. Male mice with myeloid cell-specific Lepr reconstitution (Lyz2Cre
Lepr
) had better glycemic control as they aged compared to male mice with whole-body transcriptional blockade of Lepr (Lyz2Cre
Lepr
). In contrast, Lyz2Cre
Lepr
females only had a trend for diminished hyperglycemia after a prolonged fast. During glucose tolerance tests, Lyz2Cre
Lepr
males had a mildly improved plasma glucose profile compared to Cre
controls while Lyz2Cre
Lepr
females had a similar glucose excursion to their Cre
controls. Myeloid cell-specific Lepr knockdown (Lyz2Cre
Lepr
) did not significantly alter body weight, blood glucose, insulin sensitivity, or glucose tolerance in males or females. Expression of the cytokine interleukin 10 (anti-inflammatory) tended to be higher in adipose tissue of male Lyz2Cre
Lepr
mice (p = 0.0774) while interleukin 6 (pro-inflammatory) was lower in male Lyz2Cre
Lepr
mice (p < 0.05) vs. their respective controls. In conclusion, reconstitution of Lepr in cells of myeloid lineage has beneficial effects on glucose metabolism in male mice.
Patients with cardiogenic shock were assigned to receive milrinone or dobutamine for inotropic support. There was no significant difference between the two groups in the composite primary outcome of ...in-hospital death from any cause or cardiovascular or renal events.
Disruption of the cellular pathway modulating endogenous 24-h rhythms, referred to as "the circadian clock", has been recently proven to be associated with cancer risk, development, and progression. ...This pathway operates through a complex network of transcription-translation feedback loops generated by a set of interplaying proteins. The expression of core circadian clock genes is frequently dysregulated in human tumors; however, the specific effects and underlying mechanisms seem to vary depending on the cancer types and are not fully understood. In addition, specific oncogenes may differentially induce the dysregulation of the circadian clock in tumors. Pharmacological modulation of clock components has been shown to result in specific lethality in certain types of cancer cells, and thus holds great promise as a novel anti-cancer therapeutic approach. Here we present an overview of the rationale and current evidence for targeting the clock in cancer treatment.
Abstract
Background
It is unknown whether there is an advantage to using the wet-suction or slow-pull technique during endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) with new-generation ...needles. We aimed to compare the performance of each technique in EUS-FNB.
Methods
This was a multicenter, randomized, single-blind, crossover trial including patients with solid lesions of ≥ 1 cm. Four needle passes with 22 G fork-tip or Franseen-type needles were performed, alternating the wet-suction and slow-pull techniques in a randomized order. The primary outcome was the histological yield (samples containing an intact piece of tissue of at least 550 μm). Secondary end points were sample quality (tissue integrity and blood contamination), diagnostic accuracy, and adequate tumor fraction.
Results
Overall, 210 patients with 146 pancreatic and 64 nonpancreatic lesions were analyzed. A tissue core was retrieved in 150 (71.4 %) and 129 (61.4 %) cases using the wet-suction and the slow-pull techniques, respectively (
P
= 0.03). The mean tissue integrity score was higher using wet suction (
P
= 0.02), as was the blood contamination of samples (
P
< 0.001). In the two subgroups of pancreatic and nonpancreatic lesions, tissue core rate and tissue integrity score were not statistically different using the two techniques, but blood contamination was higher with wet suction. Diagnostic accuracy and tumor fraction did not differ between the two techniques.
Conclusion
Overall, the wet-suction technique in EUS-FNB resulted in a higher tissue core procurement rate compared with the slow-pull method. Diagnostic accuracy and the rate of samples with adequate tumor fraction were similar between the two techniques.
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