EUS-guided radiofrequency ablation of solid pancreatic lesions: An updated review.

Recent years have brought to light newly developed therapeutic modalities for the treatment of premalignant and malignant pancreatic lesions. The role of EUS-guided radiofrequency ablation (EUS-RFA) as a treatment modality for malignant pancreatic lesions is still under evaluation. Several animal studies and human studies have demonstrated the safety and efficacy of EUS-RFA in the management of premalignant and malignant pancreatic lesions. EUS-RFA therapy can potentially ablate these lesions safely and with minimally invasive techniques. In this article, we provide an updated review of the application of EUS-RFA of pancreatic lesions. We also review the clinical efficacy and safety of this technique and future directions.

Breaking Radial Dipole Symmetry in Planar Macrocycles Modulates Edge-to-Edge Packing and Disrupts Cofacial Stacking.

Dipolar interactions are ever-present in supramolecular architectures, though their impact is typically revealed by making dipoles stronger. While it is also possible to assess the role of dipoles by altering their orientations by using synthetic design, doing so without altering the molecular shape is not straightforward. We have now done this by flipping one triazole unit in a rigid macrocycle, tricarb. The macrocycle is composed of three carbazoles (2 Debye) and three triazoles (5 Debye) defining an array of dipoles aligned radially but organized alternately in and out. These dipoles are believed to dictate edge-to-edge tiling and face-to-face stacking. We modified our synthesis to prepare isosteric macrocycles with the orientation of one triazole dipole rotated 40°. The new dipole orientation guides edge-to-edge contacts to reorder the stability of two surface-bound 2D polymorphs. The impact on dipole-enhanced π stacking, however, was unexpected. Our stacking model identified an unchanged set of short-range (3.4 Å) anti-parallel dipole contacts. Despite this situation, the reduction in self-association was attributed to long-range (~6.4 Å) dipolar repulsions between π-stacked macrocycles. This work highlights our ability to control the build-up and symmetry of macrocyclic skeletons by synthetic design, and the work needed to further our understanding of how dipoles control self-assembly.

Endocannabinoid release at ventral hippocampal-amygdala synapses regulates stress-induced behavioral adaptation.

The endocannabinoid (eCB) system is a key modulator of glutamate release within limbic neurocircuitry and thus heavily modulates stress responsivity and adaptation. The ventral hippocampus (vHPC)-basolateral amygdala (BLA) circuit has been implicated in the expression of negative affective states following stress exposure and is modulated by retrograde eCB signaling. However, the mechanisms governing eCB release and the causal relationship between vHPC-BLA eCB signaling and stress-induced behavioral adaptations are not known. Here, we utilized in vivo optogenetic- and biosensor-based approaches to determine the temporal dynamics of activity-dependent and stress-induced eCB release at vHPC-BLA synapses. Furthermore, we demonstrate that genetic deletion of cannabinoid type-1 receptors selectively at vHPC-BLA synapses decreases active stress coping and exacerbates stress-induced avoidance and anhedonia phenotypes. These data establish the in vivo determinants of eCB release at limbic synapses and demonstrate that eCB signaling within vHPC-BLA circuitry serves to counteract adverse behavioral consequences of stress.

Molecular characterization of dissolved organic matter in urban stormwater pond and municipal wastewater discharges transformed by the Florida red tide dinoflagellate Karenia brevis.

Karenia brevis blooms occur almost annually in southwest Florida, imposing significant ecological and human health impacts. Currently, 13 nutrient sources have been identified supporting blooms, including nearshore anthropogenic inputs such as stormwater and wastewater outflows. A 21-day bioassay was performed, where K. brevis cultures were inoculated with water sourced from three stormwater ponds along an age gradient (14, 18, and 34 yrs.) and one municipal wastewater effluent sample, with the aim of identifying biomolecular classes and transformations of dissolved organic matter (DOM) compounds used by K. brevis. All sample types supported K. brevis growth and showed compositional changes in their respective DOM pools. Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR MS) catalogued the molecular composition of DOM and identified specific compound classes that were biodegraded. Results showed that K. brevis utilized species across a wide range of compositions that correspond to amino sugars, humic, and lignin-like biomolecular classes. The municipal wastewater and the youngest stormwater pond (SWP 14) effluent contained the largest pools of labile DOM compounds which were bioavailable to K. brevis, which indicates younger stormwater pond effluents may be as ecologically important as wastewater effluents to blooms. Conversely, generation of DOM compounds of greater complexity and a wide range of aromaticity was observed with the older (SWP 18 and SWP 34) stormwater pond treatments. These data confirm the potential for stormwater ponds and/or wastewater to contribute nutrients which can potentially support K. brevis blooms, revealing the need for improved nutrient retention strategies to protect coastal waters from the potential ill effects of urban effluent.

Nitrogen forms and dissolved organic matter optical properties in bulk rainfall, canopy throughfall, and stormwater in a subtropical urban catchment.

The study of nitrogen (N) transformation in urban ecosystems is crucial in the protection of coastal water bodies because excess N may fuel harmful algae blooms (HABs). The purpose of this investigation was to study and identify the forms and concentrations of N in rainfall, throughfall, and stormwater runoff for 4 storm events in a subtropical urban ecosystem and to use fluorescence spectroscopy to evaluate the optical properties and expected lability of dissolved organic matter (DOM) in the same samples. The rainfall contained both inorganic and organic N pools, and organic N as nearly 50 % of total dissolved N in the rainfall. As water moved through the urban water cycle, from rainfall to stormwater and from rainfall to throughfall, it was enriched in total dissolved N, with most of the enrichment coming from dissolved organic N. Throughfall fluxes of total dissolved N were as high as 0.67 kg ha-1, compared to 0.44 kg ha-1 from rainfall, suggesting that the urban tree canopy can facilitate anthropogenic subsidies of N to the urban water cycle. Through analysis of sample optical properties, we saw that the throughfall presented the highest humification index and the lowest biological index when compared to rainfall, suggesting throughfall likely consists of higher molecular weight compounds of greater recalcitrance. This study highlights the importance of the dissolved organic N fraction of urban rainfall, stormwater, and throughfall and shows how the chemical composition of dissolved organic nutrients can change as rainfall is transformed into throughfall in the urban tree canopy.

Endoscopic Ultrasound-Guided Therapies in Patients with Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine neoplasms (PNETs) are rare but can be associated with significant morbidity and mortality. PNETs can be difficult to diagnose and have a propensity for metastasis before their diagnosis is established. To this end, many PNETs do not become apparent until late in their clinical course. Endoscopic ultrasound (EUS) has become the modality of choice for detecting these lesions due to its high tumor detection rate. Additionally, therapeutic techniques have arisen from EUS which allow for the treatment of PNETs. Overall, EUS has become a powerful diagnostic and therapeutic modality for addressing pancreatic lesions such as PNETs. In this perspective article, we provide an overview of the therapeutic potentials of EUS in the management of PNETs.

Endoscopic management of pancreatic walled-off necrosis.

Pancreatic walled-off necrosis (WON) is a complication of severe pancreatitis. Endoscopic transmural drainage has been recognized as the first-line treatment for pancreatic fluid collections. Endoscopy offers a minimally invasive approach when compared to surgical drainage. Today, endoscopists may choose to use self-expanding metal stents, pigtail stents, or lumen-apposing metal stents to facilitate drainage of fluid collections. Current data suggest that all 3 approaches yield similar outcomes. It was previously thought that drainage should be performed 4 weeks from the initial event of pancreatitis, theoretically allowing the capsule to mature. However, current data show that both early (<4 weeks) and standard (≥4 weeks) endoscopic drainage are comparable. Herein, we provide an up-to-date state-of-the-art review of the indications, techniques, innovations, outcomes, and future perspectives following drainage of pancreatic WON.

Bacterial Involvement in Progression and Metastasis of Adenocarcinoma of the Stomach.

Gastric cancer metastasis is a process in which the tumor microenvironment may carry significant influence. Helicobacter pylori (H. pylori) infection is well-established as a contributor to gastric carcinoma. However, the role that these bacteria and others may play in gastric carcinoma metastasis is a current focus of study. A review of the literature was conducted to elucidate the process by which gastric adenocarcinoma metastasizes, including its ability to utilize both the lymphatic system and the venous system to disseminate. Studies that investigate the tumor microenvironment at both the primary and secondary sites were assessed in detail. H. pylori and Mycoplasma hyorhinis (M. hyorhinis) were found to be important drivers of the pathogenesis of gastric adenocarcinoma by modifying various steps in cell metastasis, including epithelial-mesenchymal transition, cell migration, and cell invasion. H. pylori is also a known driver of MALT lymphoma, which is often reversible simply with the eradication of infection. M. hyorhinis has been implicated in gastric neoplasia via ß-catenin stabilization and subsequent activation of the WNT-signaling pathway, promoting gastric cancer cell motility and inciting cancer progression. Fusobacterium nucleatum (F. nucleatum) and its association with worse prognosis in diffuse-type gastric adenocarcinoma are also reviewed. Recognition of the roles that bacteria play within the metastatic cascade is vital in gastrointestinal adenocarcinoma treatment and potential reoccurrence. Further investigation is needed to establish potential treatment for metastatic gastric carcinoma by targeting the tumor microenvironment.

2-Arachidonoylglycerol-mediated endocannabinoid signaling modulates mechanical hypersensitivity associated with alcohol withdrawal in mice.

BACKGROUND: Alcohol use disorder (AUD) commonly occurs in patients with chronic pain, and a major barrier to achieving abstinence and preventing relapse is the emergence of hyperalgesia during alcohol withdrawal. Elucidating novel therapeutic approaches to target hyperalgesia associated with alcohol withdrawal could have important implications for treating AUD. Here, we examined the role of 2-arachidonoylglycerol (2-AG)-mediated endocannabinoid (eCB) signaling in the regulation of hyperalgesia associated with alcohol withdrawal in mice. We tested the hypothesis that pharmacological augmentation of 2-AG signaling could reduce hyperalgesia during withdrawal. METHODS: Male and female C57BL/6J mice were tested during withdrawal from a continuous access two-bottle choice (2BC) paradigm to investigate how eCB signaling modulates mechanical and thermal sensitivity during withdrawal. Mice were pretreated with the monoacylglycerol lipase (MAGL) inhibitor JZL184 to elevate levels of 2-AG. Rimonabant or AM630 were given to block CB1 and CB2 receptor activity, respectively. DO34 was given to reduce 2-AG by inhibiting the 2-AG synthetic enzyme diacylglycerol lipase (DAGL). RESULTS: After 72 h of withdrawal, male and female mice exhibited increased mechanical, but not thermal, hypersensitivity, which normalized by 7 days. This effect was reversed by pretreatment with JZL184. The effects of JZL184 were prevented by coadministration of either the CB1 or the CB2 antagonist. DO34, Rimonabant, and AM630 exacerbated mechanical hypersensitivity during alcohol withdrawal, causing an earlier onset and persistent hypersensitivity even 1 week into withdrawal. CONCLUSIONS: Our findings demonstrate the critical role of 2-AG signaling in the bidirectional regulation of mechanical sensitivity during alcohol withdrawal, with enhancement of 2-AG levels reducing sensitivity, and inhibition of 2-AG signaling exacerbating sensitivity. These data suggest that 2-AG augmentation represents a novel approach to the treatment of alcohol withdrawal-associated hyperalgesia and AUD in patients with comorbid pain disorders.

The Endocannabinoid 2-Arachidonoylglycerol Bidirectionally Modulates Acute and Protracted Effects of Predator Odor Exposure.

BACKGROUND: Stress-related disorders are among the most prevalent psychiatric disorders, characterized by excess fear and enhanced avoidance of trauma triggers. Elucidating the mechanisms regulating temporally distinct aspects of innate and conditioned fear responses could facilitate novel therapeutic development for stress-related disorders. One potential target that has recently emerged is the endocannabinoid system, which has been reported to mediate the physiological response to stress and represents an important substrate underlying individual differences in stress susceptibility. METHODS: Here, we exposed male and female CD-1 mice to an innate predator stressor, 2MT (2-methyl-2-thiazoline), to investigate the ability of endocannabinoid signaling to modulate temporally distinct innate and conditioned fear behaviors. RESULTS: We found that 2MT exposure increased amygdala 2-AG (2-arachidonoylglycerol) content and selectively increased excitability in central, but not basolateral, amygdala neurons. We also found that pharmacological 2-AG augmentation during stress exposure exacerbated both acute freezing responses and central amygdala hyperexcitability via cannabinoid receptor type 1- and type 2-dependent mechanisms. Finally, 2-AG augmentation during stress exposure reduced long-term contextual conditioned freezing, and 2-AG augmentation 24 hours after stress exposure reduced conditioned avoidance behavior. CONCLUSIONS: Our findings demonstrate a bidirectional effect of 2-AG augmentation on innate and conditioned fear behavior, with enhancement of 2-AG levels during stress promoting innate fear responses but ultimately resulting in long-term conditioned fear reduction. These data could reconcile contradictory data on the role of 2-AG in the regulation of innate and conditioned fear-related behavioral responses.

Bacterial Involvement in Progression and Metastasis of Colorectal Neoplasia.

While the gut microbiome is composed of numerous bacteria, specific bacteria within the gut may play a significant role in carcinogenesis, progression, and metastasis of colorectal carcinoma (CRC). Certain microbial species are known to be associated with specific cancers; however, the interrelationship between bacteria and metastasis is still enigmatic. Mounting evidence suggests that bacteria participate in cancer organotropism during solid tumor metastasis. A critical review of the literature was conducted to better characterize what is known about bacteria populating a distant site and whether a tumor depends upon the same microenvironment during or after metastasis. The processes of carcinogenesis, tumor growth and metastatic spread in the setting of bacterial infection were examined in detail. The literature was scrutinized to discover the role of the lymphatic and venous systems in tumor metastasis and how microbes affect these processes. Some bacteria have a potent ability to enhance epithelial-mesenchymal transition, a critical step in the metastatic cascade. Bacteria also can modify the microenvironment and the local immune profile at a metastatic site. Early targeted antibiotic therapy should be further investigated as a measure to prevent metastatic spread in the setting of bacterial infection.

Parenting Stress in Non-Offending Caregivers of Sexually Abused Children.

The non-offending caregiver (NOC) population is under studied despite their role in the recovery of child victim-survivors of sexual abuse. Research suggests that NOCs experience significant distress following a child's disclosure of sexual abuse. Trauma has been demonstrated to negatively impact the caregiver-child relationship. This study informs about common NOC stress reactions in response to child sexual abuse (CSA) disclosures and has clinical implications for treating families affected by CSA. Participants included 66 NOCs (age 23-66, M = 41.09, SD = 10.26) who participated in clinical intakes at a CSA treatment program and completed a self-report measure of parenting stress. Depending on the child's age, NOCs were administered either the Parenting Stress Index-fourth edition, Short Form (PSI-4-SF) or the Stress Index for Parents of Adolescents (SIPA). NOCs reported higher than average parenting stress. Statistically significant differences between the clinical and normative samples were found on all PSI-4-SF domains and on majority of SIPA domains. High to Clinically Significant scores were reported by 42% of NOCs for Parent-Child Dysfunctional Interaction. Stress related to their child's social withdrawal was reported by 56% of NOCs. This study provides comparison data for evaluations of NOCs. NOCs may require treatment and family-based approaches are implicated.

Targeting diacylglycerol lipase reduces alcohol consumption in preclinical models.

Alcohol use disorder (AUD) is associated with substantial morbidity, mortality, and societal cost, and pharmacological treatment options for AUD are limited. The endogenous cannabinoid (eCB) signaling system is critically involved in reward processing and alcohol intake is positively correlated with release of the eCB ligand 2-Arachidonoylglycerol (2-AG) within reward neurocircuitry. Here we show that genetic and pharmacological inhibition of diacylglycerol lipase (DAGL), the rate limiting enzyme in the synthesis of 2-AG, reduces alcohol consumption in a variety of preclinical models ranging from a voluntary free-access model to aversion resistant-drinking and dependence-like drinking induced via chronic intermittent ethanol vapor exposure in mice. DAGL inhibition during either chronic alcohol consumption or protracted withdrawal was devoid of anxiogenic and depressive-like behavioral effects. Lastly, DAGL inhibition also prevented ethanol-induced suppression of GABAergic transmission onto midbrain dopamine neurons, providing mechanistic insight into how DAGL inhibition could affect alcohol reward. These data suggest reducing 2-AG signaling via inhibition of DAGL could represent an effective approach to reduce alcohol consumption across the spectrum of AUD severity.

Cyclooxygenase-2 inhibition prevents stress induced amygdala activation and anxiety-like behavior.

Stress is a major risk factor for the development and exacerbation of mood and anxiety disorders, and recent studies have suggested inflammatory contributions to the pathogenesis of depression. Interestingly, pharmacological inhibition of cyclooxygenase-2 (COX-2) has shown promise in the treatment of affective disorders in small scale clinical studies; however, the mechanisms by which COX-2 inhibition affects behavioral domains relevant to affective disorders are not well understood. Here, we examined the effects of pharmacological inhibition of COX-2 with the highly selective inhibitor Lumiracoxib (LMX) on anxiety-like behavior and in vivo basolateral amygdala (BLA) neural activity in response to acute restraint stress exposure. In male mice, pretreatment with LMX prevented the increase in BLA calcium transients induced by restraint stress and prevented anxiogenic behavior seen after restraint stress exposure. Specifically, acute injection of LMX 5 mg kg-1 reduced anxiety-like behavior in the light-dark box (LD) and elevated-zero maze (EZM). In addition, in vivo fiber photometry studies showed that acute stress increased calcium transients and the predicted action potential frequency of BLA neurons, which was also normalized by acute LMX pretreatment. These findings indicate pharmacological inhibition of COX-2 can prevent acute stress-induced increase in BLA cellular activity and anxiety-like behavior and provides insights into the neural mechanisms by which COX-2 inhibition could affect anxiety domain symptoms in patients with affective disorders.

Characterization of a multicenter pediatric-hydrocephalus shunt biobank.

BACKGROUND: Pediatric hydrocephalus is a devastating and costly disease. The mainstay of treatment is still surgical shunting of cerebrospinal fluid (CSF). These shunts fail at a high rate and impose a significant burden on patients, their families and society. The relationship between clinical decision making and shunt failure is poorly understood and multifaceted, but catheter occlusion remains the most frequent cause of shunt complications. In order to investigate factors that affect shunt failure, we have established the Wayne State University (WSU) shunt biobank. METHODS: To date, four hospital centers have contributed various components of failed shunts and CSF from patients diagnosed with hydrocephalus before adulthood. The hardware samples are transported in paraformaldehyde and transferred to phosphate-buffered saline with sodium azide upon deposit into the biobank. Once in the bank, they are then available for study. Informed consent is obtained by the local center before corresponding clinical data are entered into a REDCap database. Data such as hydrocephalus etiology and details of shunt revision history. All data are entered under a coded identifier. RESULTS: 293 shunt samples were collected from 228 pediatric patients starting from May 2015 to September 2019. We saw a significant difference in the number of revisions per patient between centers (Kruskal-Wallis H test, p value < 0.001). The leading etiology at all centers was post-hemorrhagic hydrocephalus, a fisher's exact test showed there to be statistically significant differences in etiology between center (p = 0.01). Regression showed age (p < 0.01), race (p = 0.038) and hospital-center (p < 0.001) to explain significant variance in the number of revisions. Our model accounted for 31.9% of the variance in revisions. Generalized linear modeling showed hydrocephalus etiology (p < 0.001), age (p < 0.001), weight and physician (p < 0.001) to impact the number of ventricular obstructions. CONCLUSION: The retrospective analysis identified that differences exist between currently enrolled centers, although further work is needed before clinically actionable recommendations can be made. Moreover, the variables collected from this chart review explain a meaningful amount of variance in the number of revision surgeries. Future work will expand on the contribution of different site-specific and patient-specific factors to identify potential cause and effect relationships.

Aspects of Prostaglandin Glycerol Ester Biology.

The Cyclooxygenase enzymes (COX-1 and COX-2) incorporate 2 molecules of O2 into arachidonic acid (AA), resulting in an array of bioactive prostaglandins. However, much work has been done showing that COX-2 will perform this reaction on several different AA-containing molecules, most importantly, the endocannabinoid 2-arachidonoylglycerol (2-AG). The products of 2-AG oxygenation, prostaglandin glycerol esters (PG-Gs), are analogous to canonical prostaglandins. This chapter reviews the literature detailing the production, metabolism, and bioactivity of these compounds, as well as their detection in intact animals.

Cyclooxygenase-2 inhibition reduces anxiety-like behavior and normalizes enhanced amygdala glutamatergic transmission following chronic oral corticosterone treatment.

Chronic stress increases the probability of receiving an anxiety, depression, or chronic illness diagnosis. Pharmacological interventions that reduce the behavioral and physiological effects of chronic stress in animal models may represent novel approaches for the treatment of stress-related psychiatric disorders. Here, we examined the effects of cyclooxygenase-2 (COX-2) inhibition on anxiety-like behaviors and amygdala glutamatergic signaling after chronic non-invasive oral corticosterone (CORT) administration in mice. Treatment with the highly selective COX-2 inhibitor Lumiracoxib (LMX) reversed anxiety-like behavior induced by chronic CORT. Specifically, acute and repeated administration of LMX 5 mg kg-1 reduced chronic CORT-induced anxiety-like behavior measured using the elevated-plus maze, elevated-zero maze, and light-dark box tests. In contrast, LMX did not affect anxiety-like behaviors in naïve mice. Ex vivo electrophysiology studies revealed that repeated LMX treatment normalized chronic CORT-induced increases in spontaneous excitatory glutamatergic currents recorded from anterior, but not posterior, basolateral amygdala neurons. These data indicate COX-2 inhibition can reverse chronic CORT-induced increases in anxiety-like behaviors and amygdala glutamatergic signaling, and support further clinical investigation of selective COX-2 inhibitors for the treatment of affective and stress-related psychiatric disorders.

The association between endogenous opioid function and morphine responsiveness: a moderating role for endocannabinoids.

We sought to replicate previous findings that low endogenous opioid (EO) function predicts greater morphine analgesia and extended these findings by examining whether circulating endocannabinoids and related lipids moderate EO-related predictive effects. Individuals with chronic low-back pain (n = 46) provided blood samples for endocannabinoid analyses, then underwent separate identical laboratory sessions under 3 drug conditions: saline placebo, intravenous (i.v.) naloxone (opioid antagonist; 12-mg total), and i.v. morphine (0.09-mg/kg total). During each session, participants rated low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects 4 times in sequence after incremental drug dosing. Mean morphine effects (morphine-placebo difference) and opioid blockade effects (naloxone-placebo difference; to index EO function) for each primary outcome (low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects) were derived by averaging across the 4 incremental doses. The association between EO function and morphine-induced back pain relief was significantly moderated by endocannabinoids [2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)]. Lower EO function predicted greater morphine analgesia only for those with relatively lower endocannabinoids. Endocannabinoids also significantly moderated EO effects on morphine-related changes in visual analog scale-evoked pain intensity (2-AG), drug liking (AEA and 2-AG), and desire to take again (AEA and 2-AG). In the absence of significant interactions, lower EO function predicted significantly greater morphine analgesia (as in past work) and euphoria. Results indicate that EO effects on analgesic and subjective responses to opioid medications are greatest when endocannabinoid levels are low. These findings may help guide development of mechanism-based predictors for personalized pain medicine algorithms.