Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context.

Mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2) is part of the malate-aspartate shuttle, a mechanism by which cells transfer reducing equivalents from the cytosol to the mitochondria. GOT2 is a key component of mutant KRAS (KRAS*)-mediated rewiring of glutamine metabolism in pancreatic ductal adenocarcinoma (PDA). Here, we demonstrate that the loss of GOT2 disturbs redox homeostasis and halts proliferation of PDA cells in vitro. GOT2 knockdown (KD) in PDA cell lines in vitro induced NADH accumulation, decreased Asp and α-ketoglutarate (αKG) production, stalled glycolysis, disrupted the TCA cycle, and impaired proliferation. Oxidizing NADH through chemical or genetic means resolved the redox imbalance induced by GOT2 KD, permitting sustained proliferation. Despite a strong in vitro inhibitory phenotype, loss of GOT2 had no effect on tumor growth in xenograft PDA or autochthonous mouse models. We show that cancer-associated fibroblasts (CAFs), a major component of the pancreatic tumor microenvironment (TME), release the redox active metabolite pyruvate, and culturing GOT2 KD cells in CAF conditioned media (CM) rescued proliferation in vitro. Furthermore, blocking pyruvate import or pyruvate-to-lactate reduction prevented rescue of GOT2 KD in vitro by exogenous pyruvate or CAF CM. However, these interventions failed to sensitize xenografts to GOT2 KD in vivo, demonstrating the remarkable plasticity and differential metabolism deployed by PDA cells in vitro and in vivo. This emphasizes how the environmental context of distinct pre-clinical models impacts both cell-intrinsic metabolic rewiring and metabolic crosstalk with the TME.

IGFBP2 modulates the chemoresistant phenotype in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) patients commonly present with advanced stage disease and demonstrate resistance to therapy, with response rates below 40%. Understanding the molecular mechanisms of resistance is crucial for improvement of clinical outcomes. IGFBP2 is a member of the IGFBP family of proteins that has been reported to modulate both IGF and integrin signaling and is a mediator of cell growth, invasion and resistance in other tumor types. In this study, high IGFBP2 expression was observed in a subset of primary EACs and was found to be significantly higher in patients with shorter disease-free intervals as well as in treatment-resistant EACs as compared to chemonaive EACs. Modulation of IGFBP2 expression in EAC cell lines promoted cell proliferation, migration and invasion, implicating a role in the metastatic potential of these cells. Additionally, knockdown of IGFBP2 sensitized EAC cells to cisplatin in a serum-dependent manner. Further in vitro exploration into this chemosensitization implicated both the AKT and ERK pathways. Silencing of IGFBP2 enhanced IGF1-induced immediate activation of AKT and reduced cisplatin-induced ERK activation. Addition of MEK1/2 (selumetinib or trametinib) or AKT (AKT Inhibitor VIII) inhibitors enhanced siIGFBP2-induced sensitization of EAC cells to cisplatin. These results suggest that targeted inhibition of IGFBP2 alone or together with either the MAPK or PI3K/AKT signaling pathway in IGFBP2-overexpressing EAC tumors may be an effective approach for sensitizing resistant EACs to standard neoadjuvant chemotherapy.

Osteopontin (OPN/SPP1) isoforms collectively enhance tumor cell invasion and dissemination in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is often diagnosed at an advanced stage, thus understanding the molecular basis for EAC invasion and metastasis is critical. Here we report that SPP1/OPN was highly overexpressed in primary EACs and intracellularly localized to tumor cells. We further demonstrate that all known OPN isoforms (OPNa, b, c, 4 and 5) were frequently co-overexpressed in primary EACs. Distinct pro-invasion and dissemination phenotypes of isoform-specific OPNb and OPNc stable transfectants were observed. Expression of OPNb significantly enhanced cell migration and adhesion to laminin. In contrast, OPNc cells showed significantly decreased cell migration yet increased cell detachment. Enhanced invasion, both in vitro and in vivo, was observed for OPNb- but not OPNc-expressing cells. Inhibition of RGD integrins, one family of OPN receptors, attenuated OPNb cell migration, abrogated OPNb cell adhesion and significantly reduced OPNb cell clonogenic survival but did not affect OPNc phenotypes, indicating that OPNb but not OPNc acts through integrin-dependent signaling. Differential expression of vimentin, E-cadherin and ß-catenin in OPN stable cells may account for the variation in cell adhesion and detachment between these isoforms. We conclude that while all OPN isoforms are frequently co-overexpressed in primary EACs, isoforms OPNb and OPNc enhance invasion and dissemination through collective yet distinct mechanisms.

Self-efficacy as a relevant construct in understanding sexual response and dysfunction.

While self-efficacy has been widely used to explain and treat various biobehavioral responses, few investigations have examined this concept in the context of sexual response and dysfunction. In this study, the authors constructed a measure of sexual self-efficacy, investigated whether it differentiated men with and without sexual dysfunction, and determined the utility of this construct by exploring its relation to other variables known to be related to erectile dysfunction in a sample of 60 men with erectile dysfunction and 14 functional men visiting a urology clinic. The sexual self-efficacy index differentiated men with and without erectile dysfunction, and general linear modeling showed that the index did indeed relate to other variables known to affect sexual and emotional response during a partnered sexual experience. These findings suggest that, as a unifying construct that predicts cognitive, affective, motivational, and behavioral responses, sexual self-efficacy has the potential to play an important role in the assessment of effective treatments for sexual problems.

Role of attribution in affective responses to a partnered sexual situation among sexually dysfunctional men.

UNLABELLED: Study Type - Therapy (qualitative) Level of Evidence 4 What's known on the subject? and What does the study add? Sexually dysfunctional men report higher negative affect and lower positive affect than sexually functional men. Furthermore, men with sexual problems tend to make internal, self-blaming, attributions for negative sexual events, which can result in a diminished sense of self-efficacy and cause men to expect similar negative outcomes across future sexual situations. This pattern may sustain and actually intensify the sexual problem. This study shows that causal attributions for dysfunctional response influence emotional response to a partnered sexual situation. Specifically, sexually dysfunctional men who attribute their problem to a medical condition do better emotionally than those who attribute the problem to unknown or psychological factors - and this attribution process is a more powerful and reliable predictor of emotional response than the man's actual diagnosed somatic risk for a sexual problem. Furthermore, the study strongly suggests that those men who attribute their problem to a physical/medical issue are able to 'externalize' it - needing to assume less responsibility for and/or control over it, thereby reducing their psychological burden. These findings indicate not only that communication between physician and patient regarding the aetiology of a sexual problem may be critically important but also that, at least for some patients, pharmacological treatment should be combined with strategies that promote the development of internal positive self-serving attributions surrounding sexual activity. OBJECTIVE: To investigate factors that influence sexually dysfunctional men's emotional response within a partnered sexual situation, and, most specifically, whether they attribute their dysfunctional response to a specific biomedical cause vs a psychological or unknown cause. PATIENTS AND METHODS: Based on a sample of 59 sexually dysfunctional men visiting a urology clinic, linear regression was used to determine the relationship between patients' attributions and five global affective factors derived through principal components analysis: apprehension, insecure, arousable, affection, and pleasant. Two other covariates were included: actual (diagnosed) somatic risk as determined by the patient's medical history and clinician's notes, and the patient's self-reported importance of sexual intimacy. RESULTS: Attribution (biomedical vs psychological/unknown) had significant effects on three psycho-affective factors (insecure, arousable, affection); men who attributed their problem to a biomedical cause had higher positive affect and lower insecurity. Diagnosed somatic risk was significant for insecure and marginally for affection. Importance of sex was significant on four psycho-affective variables (insecure, arousable, pleasant, affection), with higher endorsement associated with higher insecurity and lower positive affect. CONCLUSIONS: Men who can attribute their sexual dysfunction to a medical condition do much better emotionally (higher positive affect and lower negative affect) than those who attribute the problem to unknown or psychological factors - and this factor is more predictive of their emotionality than the patient's actual somatic risk for sexual dysfunction. As demonstrated in a previous analysis, higher ratings of the importance of sex independently predicted stronger negative affect for men experiencing sexual problems.

Discharge planning process: applying a model for evidence-based practice.

Discharge planning is an integral but ill-defined process in most acute care settings. The time available to a healthcare team to adequately prepare patients for discharge has virtually evaporated with decreasing lengths of hospital stay. A research utilization (RU) team at a tertiary care teaching institution reviewed the literature from 1990 to 2002 in search of a research-based practice regarding staff nurses' roles in the discharge process. Review of the literature revealed varied discharge planning processes using staff nurses, advanced practice nurses, or case managers specifically prepared to implement the discharge planning process. Insufficient evidence was found to support a change from the current staff nurse practice.