A review of functional pancreatic neuroendocrine tumors: Exploring the molecular pathogenesis, diagnosis and treatment.

Pancreatic neuroendocrine tumors (PanNETs) are a rare subtype of pancreatic cancer and can be divided into functional (30-40%) and nonfunctional subtypes. The different subtypes of functional PanNETs (F-PanNETs) have a variety of classical presentations that raise suspicion for an underlying PanNET. It is estimated that 90% of PanNETs are sporadic, and the PI3K-Akt-mTOR and ATRX/DAXX signaling pathways have been recognized as key genetic pathways implicated in the pathogenesis. The other 10% of PanNETs may occur in the context of familial cancer syndromes such as MEN1. Chromogranin A is the most useful biomarker currently; however, several studies have shown limitations with its use, especially its prognostic value. Synaptophysin is a novel biomarker which has shown promising preliminary results however its use clinically has yet to be established. Blood tests assessing hormone levels, cross-sectional imaging, and endoscopic ultrasound remain at the core of establishing a diagnosis of F-PanNET. The treatment options for F-PanNETs include surgical methods such as enucleation, systemic therapies like chemotherapy and novel targeted therapies such as everolimus. The prognosis for F-PanNETs is more favorable than for nonfunctional PanNETs, however metastatic disease is associated with poor survival outcomes. Researchers should also focus their efforts on identifying novel pathways implicated in the pathogenesis of F-PanNETs in order to develop new targeted therapies that may reduce the need for surgical intervention and on the establishment of novel biomarkers that may reduce the need for invasive testing and allow for earlier detection of F-PanNETs.

SARS-CoV-2 spike and nucleocapsid proteins fail to activate human dendritic cells or γδ T cells.

γδ T cells are thought to contribute to immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the mechanisms by which they are activated by the virus are unknown. Using flow cytometry, we investigated if the two most abundant viral structural proteins, spike and nucleocapsid, can activate human γδ T cell subsets, directly or in the presence of dendritic cells (DC). Both proteins failed to induce interferon-γ production by Vδ1 or Vδ2 T cells within fresh mononuclear cells or lines of expanded γδ T cells generated from healthy donors, but the same proteins stimulated CD3+ cells from COVID-19 patients. The nucleocapsid protein stimulated interleukin-12 production by DC and downstream interferon-γ production by co-cultured Vδ1 and Vδ2 T cells, but protease digestion and use of an alternative nucleocapsid preparation indicated that this activity was due to contaminating non-protein material. Thus, SARS-CoV-2 spike and nucleocapsid proteins do not have stimulatory activity for DC or γδ T cells. We propose that γδ T cell activation in COVID-19 patients is mediated by immune recognition of viral RNA or other structural proteins by γδ T cells, or by other immune cells, such as DC, that produce γδ T cell-stimulatory ligands or cytokines.

Making sense of theory of mind and paranoia: the psychometric properties and reasoning requirements of a false belief sequencing task.

INTRODUCTION. This study used Item-Response Theory (IRT) to model the psychometric properties of a false belief picture sequencing task. Consistent with the mental time travel hypothesis of paranoia, we anticipated that performance on this deductive theory of mind (ToM) task would not be associated with the presence of persecutory delusions but would be related to other clinical, cognitive, and demographic factors. METHOD. A large (N=237) and diverse clinical and nonclinical sample differing in levels of depression and paranoid ideation performed 2 ToM tasks: the false belief sequencing task and a ToM stories task that was used to assess the validity of the false belief sequencing task as a measure of ToM. RESULTS. A unidimensional IRT model was found to fit the data well. Latent ToM ability as measured by the false belief sequencing task was negatively related with age and positively with IQ. In contrast to the ToM stories measure, there was no association between clinical diagnosis or symptoms and false belief picture sequencing after controlling for age and IQ. CONCLUSIONS. In line with mental time travel hypothesis of paranoia (Corcoran, 2010 ), performance on this deductive nonverbal ToM task is not related to the presence of paranoid symptoms. This measure is best suited for assessing ToM functioning where participants' performance falls just short of the average latent ToM ability. Furthermore, it is sensitive to the effects of increasing age and decreasing IQ.

Paranoid delusions in schizophrenia spectrum disorders and depression: the transdiagnostic role of expectations of negative events and negative self-esteem.

We aimed to identify transdiagnostic psychological processes associated with persecutory delusions. Sixty-eight schizophrenia patients, 47 depressed patients, and 33 controls were assessed for paranoia, positive and negative self-esteem, estimations of the frequency of negative, neutral, and positive events occurring to the self in the past and in the future and similar estimates for events affecting others in the future. Negative self-esteem and expectations of negative events were strongly associated with paranoia in all groups. Currently deluded patients were asked to rate whether their persecution was deserved on an analogue scale. Mean deservedness scores were higher in deluded-depressed patients than deluded-schizophrenia patients, but patients in both groups used the full range of scores. The findings indicate that negative self-esteem and negative expectations independently contribute to paranoia, but do not support a simple categorical distinction between poor-me (persecution undeserved) and bad-me (persecution deserved) patients.

Deception and false belief in paranoia: modelling theory of mind stories.

BACKGROUND: This study used Item Response Theory (IRT) to model the psychometric properties of a Theory of Mind (ToM) stories task. The study also aimed to determine whether the ability to understand states of false belief in others and the ability to understand another's intention to deceive are separable skills, and to establish which is more sensitive to the presence of paranoia. METHOD: A large and diverse clinical and nonclinical sample differing in levels of depression and paranoid ideation performed a ToM stories task measuring false belief and deception at first and second order. RESULTS: A three-factor IRT model was found to best fit the data, consisting of first- and second-order deception factors and a single false-belief factor. The first-order deception and false-belief factors had good measurement properties at low trait levels, appropriate for samples with reduced ToM ability. First-order deception and false beliefs were both sensitive to paranoid ideation with IQ predicting performance on false belief items. CONCLUSIONS: Separable abilities were found to underlie performance on verbal ToM tasks. However, paranoia was associated with impaired performance on both false belief and deception understanding with clear impairment at the simplest level of mental state attribution.

Reasoning under uncertainty: heuristic judgments in patients with persecutory delusions or depression.

OBJECTIVE: The substantial literature examining social reasoning in people with delusions has, to date, neglected the commonest form of decision making in daily life. We address this imbalance by reporting here the findings of the first study to explore heuristic reasoning in people with persecutory delusions. METHOD: People with active or remitted paranoid delusions, depressed and healthy adults performed two novel heuristic reasoning tasks that varied in emotional valence. RESULTS: The findings indicated that people with persecutory delusions displayed biases during heuristic reasoning that were most obvious when reasoning about threatening and positive material. Clear similarities existed between the currently paranoid group and the depressed group in terms of their reasoning about the likelihood of events happening to them, with both groups tending to believe that pleasant things would not happen to them. However, only the currently paranoid group showed an increased tendency to view other people as threatening. CONCLUSION: This study has initiated the exploration of heuristic reasoning in paranoia and depression. The findings have therapeutic utility and future work could focus on the differentiation of paranoia and depression at a cognitive level.