Barbosa, Maria Thereza

ABSTRACT Anesthetic technique affects surgical outcomes and oncological prognosis. Recognizing the critical role of surgery in cancer treatment, this narrative review aims to improve anesthesiology practices for cancer patients by evaluating actions that positively influence outcomes. Anesthesiologist experience helps guide technique choice in complex cases. Decisions should be customized based on the type of surgery and patient condition, as different techniques can significantly impact results. The expertise of the entire team at specialized centers further enhances outcomes.

We describe the use of a videolaryngoscope in an unconventional manner, with the provider positioned in front of the patient during intubation. This is called a “face-to-face intubation” technique. During a deep brain stimulation surgery, with the head fixed in a Mayfield frame, the placement of the supraglottic airway was unsuccessful on the induction of general anesthesia due to inadequate formation of a seal. Due to these circumstances, we intubated the patient from the front using the face-to-face intubation technique. We believe that the ability to intubate a patient from the front adds to the anesthesiologist’s airway management skills.

SummaryChronic obesity leads to inflammation, tissue dysfunction, and cellular senescence. It was proposed that cellular senescence during obesity and aging drives inflammation and dysfunction. Consistent with this, clearance of senescent cells increases healthspan in progeroid mice. Here, we show that the protein Deleted in Breast Cancer‐1 (DBC1) regulates cellular senescence during obesity. Deletion of DBC1 protects preadipocytes against cellular senescence and senescence‐driven inflammation. Furthermore, we show protection against cellular senescence in DBC1 KO mice during obesity. Finally, we found that DBC1 participates in the onset of cellular senescence in response to cell damage by mechanism that involves binding and inhibition of HDAC3. We propose that by regulating HDAC3 activity during cellular damage, DBC1 participates in the fate decision that leads to the establishment of cellular senescence and consequently to inflammation and tissue dysfunction during obesity.

Abstract Purpose: Here, we describe a novel interplay between NAD synthesis and degradation involved in pancreatic tumor growth. Experimental Design: We used human pancreatic cancer cells, both in vitro (cell culture experiments) and in vivo (xenograft experiments), to demonstrate the role of NAD synthesis and degradation in tumor cell metabolism and growth. Results: We demonstrated that pharmacologic and genetic targeting of Nampt, the key enzyme in the NAD salvage synthesis pathway, inhibits cell growth and survival of pancreatic cancer cells. These changes were accompanied by a reduction of NAD levels, glycolytic flux, lactate production, mitochondrial function, and levels of ATP. The massive reduction in overall metabolic activity induced by Nampt inhibition was accompanied by a dramatic decrease in pancreatic tumor growth. The results of the mechanistic experiments showed that neither the NAD-dependent enzymes PARP-1 nor SIRT1 play a significant role on the effect of Nampt inhibition on pancreatic cancer cells. However, we identified a role for the NAD degradation pathway mediated by the NADase CD38 on the sensitivity to Nampt inhibition. The responsiveness to Nampt inhibition is modulated by the expression of CD38; low levels of this enzyme decrease the sensitivity to Nampt inhibition. In contrast, its overexpression decreased cell growth in vitro and in vivo, and further increased the sensitivity to Nampt inhibition. Conclusions: Our study demonstrates that NAD metabolism is essential for pancreatic cancer cell survival and proliferation and that targeting NAD synthesis via the Nampt pathway could lead to novel therapeutic treatments for pancreatic cancer. Clin Cancer Res; 20(1); 120–30. ©2013 AACR.

Metabolic syndrome is a growing health problem worldwide. It is therefore imperative to develop new strategies to treat this pathology. In the past years, the manipulation of NAD+ metabolism has emerged as a plausible strategy to ameliorate metabolic syndrome. In particular, an increase in cellular NAD+ levels has beneficial effects, likely because of the activation of sirtuins. Previously, we reported that CD38 is the primary NAD+ase in mammals. Moreover, CD38 knockout mice have higher NAD+ levels and are protected against obesity and metabolic syndrome. Here, we show that CD38 regulates global protein acetylation through changes in NAD+ levels and sirtuin activity. In addition, we characterize two CD38 inhibitors: quercetin and apigenin. We show that pharmacological inhibition of CD38 results in higher intracellular NAD+ levels and that treatment of cell cultures with apigenin decreases global acetylation as well as the acetylation of p53 and RelA-p65. Finally, apigenin administration to obese mice increases NAD+ levels, decreases global protein acetylation, and improves several aspects of glucose and lipid homeostasis. Our results show that CD38 is a novel pharmacological target to treat metabolic diseases via NAD+-dependent pathways.

ABSTRACT Obesity is one of the major health problems of our times. Elucidating the signaling mechanisms by which high‐fat caloric diet induces obesity is critical for the understanding of this condition and for the development of therapeutic strategies for its treatment. Here, we demonstrate a novel role for protein CD38 as a regulator of body weight during a high‐fat diet. CD38 is a ubiquitous enzyme that catalyzes the synthesis of second messengers and has been implicated in the regulation of a wide variety of signaling pathways. We report that CD38‐deficient mice are pro‐tected against high‐fat diet‐induced obesity owing to enhanced energy expenditure. In fact, calorimetric studies indicate that CD38‐deficient animals have a higher metabolic rate compared to control mice. Analysis of the mechanism revealed that this resistance to diet‐induced obesity is mediated at least in part via a NAD‐dependent activation of SIRT‐PGC1α axis, a well‐established cascade, involved in the regulation of mito‐chondrial biogenesis and energy homeostasis. Thus, together these results identify a novel pathway regulating body weight and clearly show that CD38 is a nearly obligatory component of the cellular cascade that led to diet‐induced obesity.—Barbosa, M. T. P., Soares, S. M., Novak, C. M., Sinclair, D., Levine, J. A., Aksoy, P., Chini, E. N. The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet‐induced obesity. FASEB J. 21, 3629–3639 (2007)