Probably the foremost hypothesis of depression is the 5-hydroxytryptamine (5-HT, serotonin) deficiency hypothesis. Accordingly, anomalies in putative 5-HT biomarkers have repeatedly been reported in ...depression patients. However, whether such anomalies in fact reflect deficient central 5-HT neurotransmission remains unresolved. We employed a naturalistic model of 5-HT deficiency, the tryptophan hydroxylase 2 (Tph2) R439H knockin mouse, to address this question. We report that Tph2 knockin mice have reduced basal and stimulated levels of extracellular 5-HT (5-HT(Ext)). Interestingly, cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and fenfluramine-induced plasma prolactin levels are markedly diminished in the Tph2 knockin mice. These data seemingly confirm that low CSF 5-HIAA and fenfluramine-induced plasma prolactin reflects chronic, endogenous central nervous system (CNS) 5-HT deficiency. Moreover, 5-HT(1A) receptor agonist-induced hypothermia is blunted and frontal cortex 5-HT(2A) receptors are increased in the Tph2 knockin mice. These data likewise parallel core findings in depression, but are usually attributed to anomalies in the respective receptors rather than resulting from CNS 5-HT deficiency. Further, 5-HT(2A) receptor function is enhanced in the Tph2 knockin mice. In contrast, 5-HT(1A) receptor levels and G-protein coupling is normal in Tph2 knockin mice, indicating that the blunted hypothermic response relates directly to the low 5-HT(Ext). Thus, we show that not only low CSF 5-HIAA and a blunted fenfluramine-induced prolactin response, but also blunted 5-HT(1A) agonist-induced hypothermia and increased 5-HT(2A) receptor levels are bona fide biomarkers of chronic, endogenous 5-HT deficiency. Potentially, some of these biomarkers could identify patients likely to have 5-HT deficiency. This could have clinical research utility or even guide pharmacotherapy.
To assess the safety profile of iso‐osmolar contrast medium (CM) versus low osmolar CM in cancer patients with an estimated glomerular filtration rate (eGFR) >60 ml/min. In this multicenter, blind ...trial of patients seeking a chest‐abdomen‐pelvis contrast enhanced computed tomography (CT) with iodated CM, participants were centrally randomized to iodixanol or iopromide. Contrast induced nephropathy (CIN) at 24 and/or 72 hr were our primary outcomes. We further considered irreversible CIN, average eGFR percentage variation (%Δ), and adverse events (AEs). Overall, 607 patients were enrolled. Among them, 497 eligible patients were randomized to iodixanol (N: 247) or iopromide (N: 250). No differences emerged by descriptive characteristics. Seven and 3 CIN at 24 hr (p = 0.34) and 8 and 2 CIN at 72 hr (p = 0.11) occurred in the iopromide and iodixanol group, respectively. Within the subgroup of individual patients who developed CIN (N: 17), the event rate was higher in the iopromide arm (p = 0.045). No cases of permanent CIN or significant differences in terms of AEs or GFR %Δ were observed. Our results suggest a more favorable safety profile of iodixanol versus iopromide. Adequately sized trials with similar design are warranted to confirm our findings and clarify the underlying biological mechanisms.
1) This is a multicenter, blind trial of patients seeking a chest‐abdomen‐pelvis CT with iodated CM. 2) Aim of the study was to assess the safety profile of iso‐osmolar contrast medium (CM) versus low osmolar CM in cancer patients with an estimated glomerular filtration rate (eGFR) >60 ml/min. 3) No cases of permanent CIN or significant differences in terms of adverse events were observed.
G Protein Signaling Modulator-3 (GPSM3) is a leukocyte-specific regulator of G protein-coupled receptors (GPCRs), which binds inactivated Gαi·GDP subunits and precludes their reassociation with Gβγ ...subunits. GPSM3 deficiency protects mice from inflammatory arthritis and, in humans, GPSM3 single-nucleotide polymorphisms (SNPs) are inversely associated with the risk of rheumatoid arthritis development; recently, these polymorphisms were linked to one particular SNP (rs204989) that decreases GPSM3 transcript abundance. However, the precise role of GPSM3 in leukocyte biology is unknown. Here, we show that GPSM3 is induced in the human promyelocytic leukemia NB4 cell line following retinoic acid treatment, which differentiates this cell line into a model of neutrophil physiology (NB4*). Reducing GPSM3 expression in NB4* cells, akin to the effect ascribed to the rs204989 C>T transition, disrupts cellular migration toward leukotriene B4 (LTB4) and (to a lesser extent) interleukin-8 (a.k.a. IL-8 or CXCL8), but not migration toward formylated peptides (fMLP). As the chemoattractants LTB4 and CXCL8 are involved in recruitment of neutrophils to the arthritic joint, our results suggest that the arthritis-protective GPSM3 SNP rs204989 may act to decrease neutrophil chemoattractant responsiveness.
The human Ether-à-go-go related gene (hERG) potassium channel is responsible for the rapid delayed rectifier potassium current that plays a critical role in the repolarization of cardiomyocytes ...during the cardiac action potential. In humans, inhibition of hERG by drugs can prolong the electrocardiographic QT interval, which, in rare instance, leads to ventricular arrhythmia and sudden cardiac death. As such, several medications that block hERG channels in vitro have been withdrawn from the market due to QT prolongation and arrhythmias. The current FDA guidelines recommend that drug candidates destined for human use be evaluated for potential hERG activity ( www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm074963.pdf ). Here, we employed automated planar patch clamp (APPC), high-throughput fluorescent Tl(+) flux, and moderate-throughput ³Hdofetilide competition binding assays to characterize a panel of 49 drugs for their activities at the hERG channel. Notably, we used the same HEK293-hERG cell line for all assays, facilitating comparisons of hERG potencies across screening platforms. In general, hERG inhibitors were most potent in APPC assays, intermediate potent in ³Hdofetilide binding assays, and least potent in Tl(+) flux assays. Binding affinity constants (pK(i) values) and Tl(+) flux potencies (pEC₅₀ values) correlated well with APPC pEC₅₀ values. Further, the inhibitory potencies of many known hERG inhibitors in APPC matched literature values from manual and/or automated patch clamp systems. We also developed a novel fluorescent Tl(+) flux assays to measure the effects of drugs that modulate hERG trafficking and surface expression.
Complex cystic focal liver lesions (FLLs) found at non-contrast ultrasound (US) may turn out to be malignant. In this prospective, monocentric study we investigated the value of contrast-enhanced US ...(CEUS) in the differential diagnosis of complex cystic FLLs. In the past 3 years, all patients with complex cystic FLLs unclassifiable at US underwent CEUS with low-transmit insonation power. We evaluated 36 consecutive patients with 61 FLLs (1-6/patient, mean = 2). The diameter of the lesions ranged from 1.1 to 7.9 cm (mean = 3.9 cm). Sixteen patients had an extrahepatic malignancy. There were 42 malignant lesions and 19 benign lesions. No lesion had a certain diagnosis at conventional US, whereas 16 FLLs were classified as probable (benign or malignant) and 45 as uncertain. CEUS correctly categorized 95% of the malignant cases. CEUS was not able to differentiate the biliary cystadenoma from its malignant counterpart and misdiagnosed two abscesses. Complete non-enhancement throughout three phases or sustained enhancement in the portal/late phase was exhibited in most benign complex cystic FLLs, except for 1 (of the 3) cystadenomas and in 2 (of the 4) abscesses. On the other hand, all malignant lesions presented a contrast washout with a hypo-enhancing appearance. CEUS may provide added diagnostic value in all complex cystic FLLs found uncertain at conventional US, potentially avoiding the use of more invasive and expensive imaging modalities.
Caveolin-1 (Cav-1) is a scaffolding protein important for regulating receptor signaling cascades by partitioning signaling molecules into membrane microdomains. Disruption of the CAV1 gene has ...recently been identified as a rare structural variant associated with schizophrenia. Although Cav-1 knockout (KO) mice displayed no baseline behavioral disruptions, Cav-1 KO mice, similar to schizophrenic individuals, exhibited increased sensitivity to the psychotomimetic N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). Thus, PCP disruption of prepulse inhibition (PPI) and PCP-induced mouse locomotor activity were both enhanced by genetic deletion of Cav-1. Interestingly, genetic deletion of Cav-1 rendered the atypical antipsychotics clozapine and olanzapine and the 5-HT(2A)-selective antagonist M100907 ineffective at normalizing PCP-induced disruption of PPI. We also discovered that genetic deletion of Cav-1 attenuated 5-HT(2A)-induced c-Fos and egr-1 expression in mouse frontal cortex and also reduced 5-HT(2A)-mediated Ca(2+) mobilization in primary cortical neuronal cultures. The behavioral effects of the 5-HT(2A) agonist (2,5-dimethoxy-4-iodoamphetamine) including head twitch responses and disruption of PPI were also attenuated by genetic deletion of Cav-1, indicating that Cav-1 is required for both inverse agonist (that is, atypical antipsychotic drug) and agonist actions at 5-HT(2A) receptors. This study demonstrates that disruption of the CAV1 gene--a rare structural variant associated with schizophrenia--is not only pro-psychotic but also attenuates atypical antipsychotic drug actions.
Pancreatic ductal adenocarcinoma (PDAC) represents a challenge for a multidisciplinary oncology team. Diagnosis of PDAC remains challenging due to overlapping imaging features with benign lesions, ...notwithstanding great advances with computed tomography (CT) and magnetic resonance imaging (MRI). The term "Radiomics" has recently been introduced to define a mathematical process to extract countless quantitative features from medical images (including each diagnostic technique) with high throughput computing for diagnosis and prediction. This article is an updated overview of the imaging techniques to be employed during detection and characterization of pancreatic cancer diagnostic workup. Particularly, the limitations and advantages of the different imaging techniques are discussed, with a particular focus on functional imaging. This overview is the result of a self-study without protocol and registration number. Articles published in the English language from January 2000 to January 2021 were included. We analyzed 15 papers on radiomics. The possibility of functional imaging, such as CT, MRI, and radiomics has revolutionized pancreatic imaging, improving the detection and characterization of the lesions and allowing a prognosis related to radiological features, favoring the process of personalized medicine.
G protein signaling modulator 3 (GPSM3) is a regulator of G protein-coupled receptor signaling, with expression restricted to leukocytes and lymphoid organs. Previous genome-wide association studies ...have highlighted single-nucleotide polymorphisms (SNPs; rs204989 and rs204991) in a region upstream of the GPSM3 transcription start site as being inversely correlated to the prevalence of rheumatoid arthritis (RA)-this association is supported by the protection afforded to Gpsm3-deficient mice in models of inflammatory arthritis. Here, we assessed the functional consequences of these polymorphisms. We collected biospecimens from 50 volunteers with RA diagnoses, 50 RA-free volunteers matched to the aforementioned group and 100 unmatched healthy young volunteers. We genotyped these individuals for GPSM3 (rs204989, rs204991), CCL21 (rs2812378) and HLA gene region (rs6457620) polymorphisms, and found no significant differences in minor allele frequencies between the RA and disease-free cohorts. However, we identified that individuals homozygous for SNPs rs204989 and rs204991 had decreased GPSM3 transcript abundance relative to individuals homozygous for the major allele. In vitro promoter activity studies suggest that SNP rs204989 is the primary cause of this decrease in transcript levels. Knockdown of GPSM3 in THP-1 cells, a human monocytic cell line, was found to disrupt ex vivo migration to the chemokine MCP-1.
Purpose
The superficial temporal artery (STA) is one of the terminal branches of the external carotid artery; STA pseudoaneurysms are uncommon vascular lesion, generally subsequent to blunt or ...penetrating trauma that could represent a trick for radiologist, especially when the only anamnestic information is “palpable superficial swelling”. In this article, we describe our ultrasonographic experience about STA pseudoaneurysm reporting several cases with different etiopatogenesis.
Methods
Between January 2004 and March 2015 six patients (4F and 2M; aged 15–55 years, mean 36 year) presented at our department with superficial palpable swelling in temporal region (four with trauma history, two with iatrogenic cause) underwent to ultrasonographic study to assess the presence of STA pseudoaneurysm. Ultrasonographic findings suggestive of pseudoaneurysm was a well-defined, pulsatile, anechoic mass in B-mode, a swirling or disorganized pattern of blood flow in the lesion with demonstration of direct communication between arterial lumen and pseudoaneurysm at colour-Doppler and a typical to-and-fro waveform on pseudoaneurysm neck at pulsed-Doppler.
Results
B-mode proves the presence of anechoic mass in five on six patients. Colour-Doppler demonstrates the presence of flow inside the lesion in five patients and a direct communication in all patients. To-and-fro typical waveform has been demonstrated in five patients. Ultrasound made diagnosis in all patients with a sensibility and specificity of 100 %.
Conclusion
US is the imaging modality of choice, since it can provide detailed information about vascular anatomy without incurring the risks of invasive methods like angiography or radiation.
In patients with recurrent ovarian cancer, the choice of second-line therapy is complex. Several factors have to be considered, such as platinum-free interval (PFI), residual toxicity from the ...previous treatments, BRCA1/2 gene mutation status. Trebectedin is a minor groove DNA binder derived from a marine organism that has shown efficacy in different settings in ovarian cancer therapy. It has been approved in the treatment of partially platinum sensitive (PPS) (PFI between 6 and 12 months) relapsed ovarian cancer according to the statistically significant progression-free survival (7.3 versus 5.8 months) and overall survival (22.2 versus 18.9 months) benefit compared with single-agent pegylated liposomal doxorubicin (PLD) in the OVA 301 phase III trial. This drug has been shown to prolong the time to first subsequent treatment and improve the efficacy of further platinum-based chemotherapy. The role of trabectedin/PLD followed by platinum combination compared with the reverse sequence in PPS is actually in evaluation in the INOVATYON phase III study, which will clarify the best sequence to be adopted in this setting. Trabectedin has been shown to be active in patient carriers of BRCA mutations, probably for its mechanism of action directly affecting DNA and it is actually tested as a single agent in some phase III trials in BRCA mutated and BRCAness ovarian cancer patients. Trabectedin is also active on the immune system. There is, therefore, the rational for new trials of a combination with immune checkpoint inhibitors.
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