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Peptide receptor radionuclide therapy (PRRT) of metastatic neuroendocrine tumors (NET) can be successfully repeated but may eventually be dose-limited. Since 177Lu-DOTATATE dose limitation may come from hematological rather than renal function, hematological peripheral blood stem cell backup might be desirable. Here, we report our initial experience of peripheral blood stem-cell collection (PBSC) in patients with treatment-related cytopenia and therefore high risk of bone-marrow failure. Five patients with diffuse bone-marrow infiltration of NET and relevant myelosuppression (≥grade 2) received PBSC before one PRRT cycle with 177Lu-DOTATATE (7.6 ± 0.8 GBq/cycle). Standard stem-cell mobilization with Granulocyte-colony stimulating factor (G-CSF) was applied, and successful PBSC was defined as a collection of >2 × 106/kg CD34+ cells. In case of initial failure, Plerixafor was administered in addition to G-CSF prior to apheresis. PBSC was successfully performed in all patients with no adverse events. Median cumulative activity was 44.8 GBq (range, 21.3–62.4). Three patients had been previously treated with PRRT, two of which needed the addition of Plerixafor for stem-cell mobilization. Only one of five patients required autologous peripheral blood stem-cell transplantation during the median follow up time of 28 months. PBSC collection seems to be feasible in NET with bone-marrow involvement and might be worth considering as a backup strategy prior to PRRT, in order to overcome dose-limiting bone-marrow toxicity.
Gaining detailed knowledge about sex-related immunoregulation remains a crucial prerequisite for the development of adequate disease models and therapeutic strategies enabling personalized medicine. Here, the key parameter of the production of cytokines mediating disease resolution was investigated. Among these cytokines, STAT3-activating interleukin (IL)-22 is principally associated with recovery from tissue injury. By investigating paradigmatic acetaminophen-induced liver injury, we demonstrated that IL-22 expression is enhanced in female mice. Increased female IL-22 was confirmed at a cellular level using murine splenocytes stimulated by lipopolysaccharide or αCD3/CD28 to model innate or adaptive immunoactivation. Interestingly, testosterone or dihydrotestosterone reduced IL-22 production by female but not by male splenocytes. Mechanistic studies on PMA/PHA-stimulated T-cell-lymphoma EL-4 cells verified the capability of testosterone/dihydrotestosterone to reduce IL-22 production. Moreover, we demonstrated by chromatin immunoprecipitation that testosterone impairs binding of the aryl hydrocarbon receptor to xenobiotic responsive elements within the murine IL-22 promoter. Overall, female mice undergoing acute liver injury and cultured female splenocytes upon inflammatory activation display increased IL-22. This observation is likely related to the immunosuppressive effects of androgens in males. The data presented concur with more pronounced immunological alertness demonstrable in females, which may relate to the sex-specific course of some immunological disorders.
Chronic rhinosinusitis (CRS) is often treated by functional endoscopic paranasal sinus surgery, which improves endoscopic parameters and quality of life, while olfactory function was suggested as a further criterion of treatment success. In a prospective cohort study, 37 parameters from four categories were recorded from 60 men and 98 women before and four months after endoscopic sinus surgery, including endoscopic measures of nasal anatomy/pathology, assessments of olfactory function, quality of life, and socio-demographic or concomitant conditions. Parameters containing relevant information about changes associated with surgery were examined using unsupervised and supervised methods, including machine-learning techniques for feature selection. The analyzed cohort included 52 men and 38 women. Changes in the endoscopic Lildholdt score allowed separation of baseline from postoperative data with a cross-validated accuracy of 85%. Further relevant information included primary nasal symptoms from SNOT-20 assessments, and self-assessments of olfactory function. Overall improvement in these relevant parameters was observed in 95% of patients. A ranked list of criteria was developed as a proposal to assess the outcome of functional endoscopic sinus surgery in CRS patients with nasal polyposis. Three different facets were captured, including the Lildholdt score as an endoscopic measure and, in addition, disease-specific quality of life and subjectively perceived olfactory function.
The family of phytochrome photoreceptors contains proteins with different domain architectures and spectral properties. Knotless phytochromes are one of the three main subgroups classified by their distinct lack of the PAS domain in their photosensory core module, which is in contrast to the canonical PAS-GAF-PHY array. Despite intensive research on the ultrafast photodynamics of phytochromes, little is known about the primary kinetics in knotless phytochromes. Here, we present the ultrafast Pr ⇆ Pfr photodynamics of SynCph2, the best-known knotless phytochrome. Our results show that the excited state lifetime of Pr* (~200 ps) is similar to bacteriophytochromes, but much longer than in most canonical phytochromes. We assign the slow Pr* kinetics to relaxation processes of the chromophore-binding pocket that controls the bilin chromophore’s isomerization step. The Pfr photoconversion dynamics starts with a faster excited state relaxation than in canonical phytochromes, but, despite the differences in the respective domain architectures, proceeds via similar ground state intermediate steps up to Meta-F. Based on our observations, we propose that the kinetic features and overall dynamics of the ultrafast photoreaction are determined to a great extent by the geometrical context (i.e., available space and flexibility) within the binding pocket, while the general reaction steps following the photoexcitation are most likely conserved among the red/far-red phytochromes.
The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Most SARS-CoV-2 infections are mild or even asymptomatic. However, a small fraction of infected individuals develops severe, life-threatening disease, which is caused by an uncontrolled immune response resulting in hyperinflammation. However, the factors predisposing individuals to severe disease remain poorly understood. Here, we show that levels of CD47, which is known to mediate immune escape in cancer and virus-infected cells, are elevated in SARS-CoV-2-infected Caco-2 cells, Calu-3 cells, and air−liquid interface cultures of primary human bronchial epithelial cells. Moreover, SARS-CoV-2 infection increases SIRPalpha levels, the binding partner of CD47, on primary human monocytes. Systematic literature searches further indicated that known risk factors such as older age and diabetes are associated with increased CD47 levels. High CD47 levels contribute to vascular disease, vasoconstriction, and hypertension, conditions that may predispose SARS-CoV-2-infected individuals to COVID-19-related complications such as pulmonary hypertension, lung fibrosis, myocardial injury, stroke, and acute kidney injury. Hence, age-related and virus-induced CD47 expression is a candidate mechanism potentially contributing to severe COVID-19, as well as a therapeutic target, which may be addressed by antibodies and small molecules. Further research will be needed to investigate the potential involvement of CD47 and SIRPalpha in COVID-19 pathology. Our data should encourage other research groups to consider the potential relevance of the CD47/ SIRPalpha axis in their COVID-19 research.
Deformation in the upper mantle is localized in shear zones. In order to localize strain, weakening has to occur, which can be achieved by a reduction in grain size. In order for grains to remain small and preserve shear zones, phases have to mix. Phase mixing leads to dragging or pinning of grain boundaries which slows down or halts grain growth. Multiple phase mixing processes have been suggested to be important during shear zone evolution. The importance of a phase mixing process depends on the geodynamic setting. This study presents detailed microstructural analysis of spinel bearing shear zones from the Erro-Tobbio peridotite (Italy) that formed during pre-alpine rifting. The first stage of deformation occurred under melt-free conditions, during which clinopyroxene and olivine porphyroclasts dynamically recrystallized. With ongoing extension, silica-undersaturated melt percolated through the shear zones and reacted with the clinopyroxene neoblasts, forming olivine–clinopyroxene layers. Furthermore, the melt reacted with orthopyroxene porphyroclasts, forming fine-grained polymineralic layers (ultramylonites) adjacent to the porphyroclasts. Strain rates in these layers are estimated to be about an order of magnitude faster than within the olivine-rich matrix. This study demonstrates the importance of melt-rock reactions for grain size reduction, phase mixing and strain localization in these shear zones.
A high incidence of thromboembolic events associated with high mortality has been reported in severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections with respiratory failure. The present study characterized post-transcriptional gene regulation by global microRNA (miRNA) expression in relation to activated coagulation and inflammation in 21 critically ill SARS-CoV-2 patients. The cohort consisted of patients with moderate respiratory failure (n = 11) and severe respiratory failure (n = 10) at an acute stage (day 0–3) and in the later course of the disease (>7 days). All patients needed supplemental oxygen and severe patients were defined by the requirement of positive pressure ventilation (intubation). Levels of D-dimers, activated partial thromboplastin time (aPTT), C-reactive protein (CRP), and interleukin (IL)-6 were significantly higher in patients with severe compared with moderate respiratory failure. Concurrently, next generation sequencing (NGS) analysis demonstrated increased dysregulation of miRNA expression with progression of disease severity connected to extreme downregulation of miR-320a, miR-320b and miR-320c. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed involvement in the Hippo signaling pathway, the transforming growth factor (TGF)-β signaling pathway and in the regulation of adherens junctions. The expression of all miR-320 family members was significantly correlated with CRP, IL-6, and D-dimer levels. In conclusion, our analysis underlines the importance of thromboembolic processes in patients with respiratory failure and emphasizes miRNA-320s as potential biomarkers for severe progressive SARS-CoV-2 infection.
Background: To test the effect of urological primary cancers (bladder, kidney, testis, upper tract, penile, urethral) on overall mortality (OM) after secondary prostate cancer (PCa). Methods: Within the Surveillance, Epidemiology and End Results (SEER) database, patients with urological primary cancers and concomitant secondary PCa (diagnosed 2004-2016) were identified and were matched in 1:4 fashion with primary PCa controls. OM was compared between secondary and primary PCa patients and stratified according to primary urological cancer type, as well as to time interval between primary urological cancer versus secondary PCa diagnoses. Results: We identified 5,987 patients with primary urological and secondary PCa (bladder, n = 3,287; kidney, n = 2,127; testis, n = 391; upper tract, n = 125; penile, n = 47; urethral, n = 10) versus 531,732 primary PCa patients. Except for small proportions of Gleason grade group and age at diagnosis, PCa characteristics between secondary and primary PCa were comparable. Conversely, proportions of secondary PCa patients which received radical prostatectomy were smaller (29.0 vs. 33.5%), while no local treatment rates were higher (34.2 vs. 26.3%). After 1:4 matching, secondary PCa patients exhibited worse OM than primary PCa patients, except for primary testis cancer. Here, no OM differences were recorded. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis. Conclusions: After detailed matching for PCa characteristics, secondary PCa patients exhibit worse survival, except for testis cancer patients. The survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary urological cancer diagnosis.
Pseudocetherinae (Hemiptera: Reduviidae) revisited: phylogeny and taxonomy of the lobe-headed bugs
(2022)
The concept of the previously monogeneric subfamily Pseudocetherinae (Hemiptera: Heteroptera: Reduviidae) is revised and expanded. We here transfer Gerbelius Distant, 1903, Kayanocoris Miller, 1954, Microvarus Jeannel, 1917, Paragerbelius Miller, 1958, and Voconia Stål, 1866 from Reduviinae to Pseudocetherinae and treat Kayanocoris, Microvarus, Paragerbelius, and Pseudocethera Villiers, 1963 as junior synonyms of Voconia, resulting in new combinations for Voconia conradti (Jeannel, 1917) comb. nov., V. ifana (Villiers, 1963) comb. nov., V. monodi (Villiers, 1963) comb. nov., V. motoensis (Schouteden, 1929) comb. nov., V. ornata (Distant, 1903) comb. nov., V. schoutedeni (Villiers, 1964) comb. nov., V. typica (Miller, 1958) comb. nov., and V. wegneri (Miller, 1954) comb. nov. We also describe 23 new species of Voconia: V. bakeri sp. nov., V. bracata sp. nov., V. brachycephala sp. nov., V. chrysoptera sp. nov., V. coronata sp. nov., V. decorata sp. nov., V. dolichocephala sp. nov., V. fasciata sp. nov., V. grandioculata sp. nov., V. hemera sp. nov., V. isosceles sp. nov., V. laosensis sp. nov., V. lasiosoma sp. nov., V. lirophleps sp. nov., V. loki sp. nov., V. mexicana sp. nov., V. minima sp. nov., V. nyx sp. nov., V. smithae sp. nov., V. tridens sp. nov., V. trinidadensis sp. nov., V. tuberculata sp. nov., and V. vittata sp. nov. Lectotypes are designated for Gerbelius confluens Distant, 1903, G. typicus Distant, 1903, V. conradti comb. nov., V. ornata comb. nov., and V. pallidipes Stål, 1866. A revised diagnosis and description of Pseudocetherinae are provided along with photographs of the species and of the male genitalia of 13 pseudocetherine and five closely related reduviine species. An identification key to the two genera of Pseudocetherinae as well as a key to species of Voconia are presented. A phylogenetic hypothesis is proposed for the relationships of Pseudocetherinae using parsimony analyses of 77 morphological characters.
A new whitefly genus, Rudisculptus gen. nov. is described for its type species Rudisculptus caudalis gen. et sp. nov. feeding on Orophea katschallica Kurz (Annonaceae) from the Andaman Islands, India. Rudisculptus gen. nov. is similar to the New World genus, Aleuropleurocelus Drews & Sampson, 1956 and an Old World genus, Tetralicia Harrison, 1917 in pupal morphology, but differs in having the first abdominal setae, thoracic tracheal pores, caudal furrow, differentiated cephalothorax in slide mounts, the lingula excluded beyond the vasiform orifice. The new genus also differs from an Old World genus, Regiominutus Dubey, 2021 in habitus, pattern of wax secretion, shape, size, cuticle colour, raised lateral margin, extension of segment sutures and the lingula reaching outside the margin of the vasiform orifice, and in having the thoracic tracheal folds. Orophea katschallica is recorded as a new host plant for the whiteflies. Images of puparial habitus and types, line drawings and scanning electron microscope (SEM) microphotographs are provided.