Uveal melanoma, the most common eye malignancy, causes severe visual morbidity and is fatal in approximately 50% of patients. Primary uveal melanoma can be cured by surgery or radiotherapy, but the ...metastatic disease is treatment refractory. To understand comprehensively uveal melanoma genetics, we conducted single-nucleotide polymorphism arrays and whole-genome sequencing on 12 primary uveal melanomas. We observed only approximately 2,000 predicted somatic single-nucleotide variants per tumor and low levels of aneuploidy. We did not observe an ultraviolet radiation DNA damage signature, but identified SF3B1 mutations in three samples and a further 15 mutations in an extension cohort of 105 samples. SF3B1 mutations were associated with good prognosis and were rarely coincident with BAP1 mutations. SF3B1 encodes a component of the spliceosome, and RNA sequencing revealed that SF3B1 mutations were associated with differential alternative splicing of protein coding genes, including ABCC5 and UQCC, and of the long noncoding RNA CRNDE.
Our data show that despite its dismal prognosis, uveal melanoma is a relatively simple genetic disease characterized by recurrent chromosomal losses and gains and a low mutational burden. We show that SF3B1 is recurrently mutated in uveal melanoma, and the mutations are associated with aberrant alternative splicing.
Since the onset of the COVID-19 pandemic, there has been a widespread adoption of mask wearing. With prolonged use of facial masks, an increasing number of new-onset inflammatory facial dermatoses ...have been observed, along with flaring of pre-existing dermatoses. Common dermatoses triggered by facial mask wearing include contact dermatitis, maskne (a subtype of mechanical acne) and mask-induced rosacea. In this report, we present two cases of pemphigus vulgaris, presenting first with a well-defined triangular crusty nose induced by mask wearing during the COVID pandemic.
The objectives were to define the maximum tolerated dose (MTD), safety profile and pharmacokinetics (PKs) of intraperitoneal oxaliplatin delivered by pressurised intraperitoneal aerosol chemotherapy ...(PIPAC) in patients with advanced peritoneal carcinomatosis from gastrointestinal tract cancers.
PIPAC was applied every 4–6 weeks, for 5 cycles, in a phase I dose-escalation study using a 3 + 3 design. The first dose level was 90 mg/m2 with planned increases of 50 mg/m2 per level. Platinum concentration was measured in plasma, tissues and intraperitoneal fluid samples. The trial was registered at ClinicalTrials.gov (NCT03294252).
Ten patients with 33 PIPAC sessions were included. No dose limiting toxicity (DLT) occurred at 90 mg/m2 and two at 140 mg/m2. The MTD was therefore set at 90 mg/m2. Overall treatment included a median number of three PIPAC sessions (range: 1–5) and secondary complete cytoreductive surgery for two patients. Overall safety showed 67 grade I–II and 11 grade III–IV toxicities, usually haematologic, digestive (nausea/vomiting, abdominal pain), and fatigue. Oxaliplatin concentrations were three- to four-fold higher in tissue in contact with aerosol than in muscle without contact. At 140 mg/m2, the plasma oxaliplatin concentration was high with Cmax and area under the curve (AUC)0–48h of 1035 μg/l and 9028 μg h/L, respectively.
The MTD of oxaliplatin during PIPAC is 90 mg/m2. PK data demonstrate a high tumour concentration and a significant systemic absorption.
•The maximal dose of oxaliplatin during intraperitoneal aerosol is 90 mg/m2.•The median number of feasible PIPAC is three.•Some patients with major histological responses underwent a complete resection.•Platin concentrations are three- to four-fold higher in tumour than in muscle.•The systemic absorption of oxaliplatin is high.
Since the late 19th century, exotic ladybirds (Coleoptera: Coccinellidae) have been used extensively for suppressing herbivorous insects of economic importance. In recent decades, the introduction of ...non‐native biological control (BC) agents has been greatly limited due to the awareness of the potential non‐target effects of introductions. Nonetheless, recent episodes of biological invasions of economically important pests have raised the need to carefully consider whether the expected benefits of pest control go beyond the possible environmental risks of introduction. To better understand the factors that contributed to successful BC programs, here we review the literature behind classical and augmentative BC using exotic ladybirds. Additionally, by means of case studies, we discuss the BC efficacy of selected exotic species, e.g., Coccinella septempunctata L., Harmonia axyridis (Pallas), and Hippodamia variegata (Goeze), and their position within the communities of predators in the introduced areas of USA, Canada, and Chile. In Europe, much of the research on exotic ladybirds has been conducted on the undesired impact of H. axyridis. Therefore, we summarize the risk assessment data for this species and review the field research investigating the ecological impact on European aphidophagous predators. According to the BIOCAT database of classical BC programs, 212 ladybird species belonging to 68 genera have been released in about 130 years of BC activity, with 14.6% of introductions having resulted in partial, substantial, or complete control of the target pest. However, because post‐release evaluation of establishment and BC success has not always been conducted, this rate could underestimate the successful cases. Among other factors, ladybird establishment and pest suppression mostly depend on (1) intrinsic factors, i.e., high voracity, synchronized predator‐prey life cycle, and high dispersal ability, and (2) extrinsic factors, i.e., adaptability to the new environment and landscape composition. This review contributes to improved understanding of ladybirds as exotic BC agents.
We analyse and review the current version of the BIOCAT database (CABI) for cases where fully identified exotic ladybird species (Coleoptera: Coccinellidae) were released for classical biological control of herbivorous insects. We discuss the factors promoting ladybird success and non‐target risks of releases by means of case studies relevant for the USA, Canada, Chile, and Europe. Ladybird establishment and pest suppression mostly depend on intrinsic and extrinsic factors. This review contributes to improved understanding of ladybirds as exotic biocontrol agents.
Purpose
The purpose of our study was to assess the concordance of aortic CT angiography (CTA) and FDG-PET/CT in the detection of large-vessel involvement at diagnosis in patients with giant-cell ...arteritis (GCA).
Methods
We created a multicenter cohort of patients with GCA diagnosed between 2010 and 2015, and who underwent both FDG-PET/CT and aortic CTA before or in the first ten days following treatment introduction. Eight vascular segments were studied on each procedure. We calculated concordance between both imaging techniques in a per-patient and a per-segment analysis, using Cohen’s kappa concordance index.
Results
We included 28 patients (21/7 women/men, median age 67 56–82). Nineteen patients had large-vessel involvement on PET/CT and 18 of these patients also presented positive findings on CTA. In a per-segment analysis, a median of 5 1–7 and 3 1–6 vascular territories were involved on positive PET/CT and CTA, respectively (
p
= 0.03). In qualitative analysis, i.e., positivity of the procedure suggesting a large-vessel involvement, the concordance rate between both procedures was 0.85 0.64–1. In quantitative analysis, i.e., per-segment analysis in both procedures, the global concordance rate was 0.64 0.54–0.75. Using FDG-PET/CT as a reference, CTA showed excellent sensitivity (95%) and specificity (100%) in a per-patient analysis. In a per-segment analysis, sensitivity and specificity were 61% and 97.9%, respectively.
Conclusions
CTA and FDG-PET/CT were both able to detect large-vessel involvement in GCA with comparable results in a per-patient analysis. However, PET/CT showed higher performance in a per-segment analysis, especially in the detection of inflammation of the aorta’s branches.
Large-vessel involvement (LVI) in giant cell arteritis (GCA) includes different clinical and imaging patterns that are rarely described separately at diagnosis and whose specific cardiovascular ...outcomes are unknown.
We conducted a nationwide retrospective study and included GCA patients with LVI demonstrated on imaging at diagnosis between 2007 and 2017. We analyzed the prognosis of three different imaging patterns of LVI present at diagnosis, with some of them overlapping but with the first one present in all patients: 1) inflammation of the aorta and/or its branches; 2) dilation of the aorta; and 3) stenosis of the aortic branches. A control group of GCA patients without LVI was constituted.
We included 183 patients with LVI and 105 controls without LVI. Altogether, among the 183 patients who all showed inflammation of the aorta and/or its main branches, concomitant aortic dilation and large-vessel stenosis were observed in 27 (15%) and 55 (30%) patients, respectively. During the follow-up period, new cardiovascular events occurred in 49% and 11% of LVI patients and controls, respectively (p < 0.0001). Inflammation of the aorta and/or its branches (HR: 3.42 2.09–5.83, p < 0.0001) and large-artery stenosis (HR: 2.75 1.80–4.15, p < 0.0001) were independent predictive factors of new cardiovascular events. Conversely, the use of an immunosuppressant besides corticosteroids was a protective factor against new cardiovascular events (HR: 0.44 0.29–0.66, p < 0.0001) and the development of aortic dilation (HR: 0.43 0.23–0.77, p = 0.005).
This study suggests different forms of cardiovascular events according to the initial imaging pattern of LVI.
•Large-vessel involvements include aortitis, aorta dilation and vascular stenoses.•These patterns exhibit different outcomes and prognoses.•More cardiovascular events occur in patients with initial large-vessel involvement.•Large-vessel stenosis was associated with the poorest outcomes.•Immunosuppressants might have a protective impact on new cardiovascular events.
Enhanced motivation to take drugs is a central characteristic of addiction, yet the neural underpinning of this maladaptive behavior is still largely unknown. Here, we report a D1-like dopamine ...receptor (DRD1)-mediated long-term potentiation of GABAA-IPSCs (D1-LTPGABA) in the oval bed nucleus of the stria terminalis that was positively correlated with motivation to self-administer cocaine in rats. Likewise, in vivo intra-oval bed nucleus of the stria terminalis DRD1 pharmacological blockade reduced lever pressing for cocaine more effectively in rats showing enhanced motivation toward cocaine. D1-LTPGABA resulted from enhanced function and expression of G-protein-independent DRD1 coupled to c-Src tyrosine kinases and required local release of neurotensin. There was no D1-LTPGABA in rats that self-administered sucrose, in those with limited cocaine self-administration experience, or in those that received cocaine passively (yoked). Therefore, our study reveals a novel neurophysiological mechanism contributing to individual motivation to self-administer cocaine, a critical psychobiological element of compulsive drug use and addiction.
The enthesis, which attaches the tendon to the bone, naturally disappears with aging, thus limiting joint mobility. Surgery is frequently needed but the clinical outcome is often poor due to the ...decreased natural healing capacity of the elderly. This study explored the benefits of a treatment based on injecting chondrocyte and mesenchymal stem cells (MSC) in a new rat model of degenerative enthesis repair.
The Achilles' tendon was cut and the enthesis destroyed. The damage was repaired by classical surgery without cell injection (group G1, n = 52) and with chondrocyte (group G2, n = 51) or MSC injection (group G3, n = 39). The healing rate was determined macroscopically 15, 30 and 45 days later. The production and organization of a new enthesis was assessed by histological scoring of collagen II immunostaining, glycoaminoglycan production and the presence of columnar chondrocytes. The biomechanical load required to rupture the bone-tendon junction was determined.
The spontaneous healing rate in the G1 control group was 40%, close to those observed in humans. Cell injection significantly improved healing (69%, p = 0.0028 for G2 and p = 0.006 for G3) and the load-to-failure after 45 days (p<0.05) over controls. A new enthesis was clearly produced in cell-injected G2 and G3 rats, but not in the controls. Only the MSC-injected G3 rats had an organized enthesis with columnar chondrocytes as in a native enthesis 45 days after surgery.
Cell therapy is an efficient procedure for reconstructing degenerative entheses. MSC treatment produced better organ regeneration than chondrocyte treatment. The morphological and biomechanical properties were similar to those of a native enthesis.
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