Can the Dose of Belimumab be Reduced in Patients with Systemic Lupus Erythematosus?

OBJECTIVES: The aims of this study were to investigate the prevalence of dose reduction in patients with SLE treated with belimumab (BEL) in Spain, analyze treatment modalities, and determine impact on control of disease activity. METHODS: Retrospective longitudinal and multicentre study of SLE patients treated with BEL. Data on disease activity, treatments and outcomes were recorded before and after reduction (6-12 months), and they were compared. RESULTS: A total of 324 patients were included. The dose was reduced in 29 patients (8.9%). The dosing interval was increased in 9 patients receiving subcutaneous BEL and in 6 patients receiving intravenous BEL. The dose per administration was reduced in 16 patients.Pre-reduction status was remission (2021 DORIS) in 15/26 patients (57.7%) and LLDAS in 23/26 patients (88.5%). After reduction, 2/24 patients (8.3%) and 3/22 patients (13.6%) lost remission at 6 months and 12 months, respectively (not statistically significant [NS]). As for LLDAS, 2/23 patients (8.7%) and 2/21 patients (9.5%) lost their status at 6 and 12 months, respectively (NS). Significantly fewer patients were taking glucocorticoids (GCs) at their 12-month visit, although the median dose of GCs was higher at the 12-month visit (5 [0.62-8.75] vs 2.5 [0-5] at baseline). CONCLUSION: Doses of BEL can be reduced with no relevant changes in disease activity-at least in the short term-in a significant percentage of patients, and most maintain the reduced dose. However, increased clinical or serologic activity may be observed in some patients. Consequently, tighter post-reduction follow-up is advisable.

Chemotherapy toxicity and activity in patients with pancreatic ductal adenocarcinoma and germline BRCA1-2 pathogenic variants (gBRCA1-2pv): a multicenter survey.

BACKGROUND: Germline BRCA1-2 pathogenic variants (gBRCA1-2pv)-related pancreatic ductal adenocarcinoma (PDAC) showed increased sensitivity to DNA cross-linking agents. This study aimed at exploring safety profile, dose intensity, and activity of different chemotherapy regimens in this setting. PATIENTS AND METHODS: gBRCA1-2pv PDAC patients of any age and clinical tumor stage who completed a first course of chemotherapy were eligible. A descriptive analysis of chemotherapy toxicity, dose intensity, response, and survival outcomes was performed. RESULTS: A total of 85 gBRCA1-2pv PDAC patients treated in 21 Italian centers between December 2008 and March 2021were enrolled. Seventy-four patients were assessable for toxicity and dose intensity, 83 for outcome. Dose intensity was as follows: nab-paclitaxel 72%, gemcitabine 76% (AG); cisplatin 75%, nab-paclitaxel 73%, capecitabine 73%, and gemcitabine 65% (PAXG); fluorouracil 35%, irinotecan 58%, and oxaliplatin 64% (FOLFIRINOX). When compared with the literature, grade 3-4 neutropenia, thrombocytopenia, and diarrhea were increased with PAXG, and unmodified with AG and FOLFIRINOX. RECIST responses were numerically higher with the three- (81%) or four-drug (73%) platinum-containing regimens that outperformed AG (41%) and oxaliplatin-based doublets (56%). Carbohydrate antigen 19.9 (CA19.9) reduction >89% at nadir was reported in two-third of metastatic patients treated with triplets and quadruplets, as opposed to 33% and 45% of patients receiving oxaliplatin-based doublets or AG, respectively. All patients receiving AG experienced disease progression, with a median progression-free survival (mPFS) of 6.4 months, while patients treated with platinum-containing triplets or quadruplets had an mPFS >10.8 months. Albeit still immature, data on overall survival seemed to parallel those on PFS. CONCLUSIONS: Our data, as opposed to figures expected from the literature, highlighted that platinum-based regimens provoked an increased toxicity on proliferating cells, when dose intensity was maintained, or an as-expected toxicity, when dose intensity was reduced, while no change in toxicity and dose intensity was evident with AG. Furthermore, an apparently improved outcome of platinum-based triplets or quadruplets over other regimens was observed.

The role of nanostructure in the wetting behavior of mixed-monolayer-protected metal nanoparticles.

Self-assembled monolayer-protected nanoparticles are promising candidates for applications, such as sensing and drug delivery, in which the molecular ligands' interactions with the surrounding environment play a crucial role. We recently showed that, when gold nanoparticles are coated with a binary mixture of immiscible ligands, ordered ribbon-like domains of alternating composition spontaneously form and that their width is comparable with the size of a single solvent molecule. It is usually assumed that nanoparticles' solubility depends solely on the core size and on the molecular composition of the ligand shell. Here, we show that this is not always the case. We find that the ligand shell morphology affects the solubility of these nanoparticles almost as much as the molecular composition. A possible explanation is offered through a molecular dynamics analysis of the surface energy of monolayers differing only in their domain structure. We find that the surface free energy of such model systems can vary significantly as a function of ordering, even at fixed composition. This combined experimental and theoretical study provides a unique insight into wetting phenomena at the nano- and subnanometer scale.

The Atlantic-Mediterranean transition: discordant genetic patterns in two seabream species, Diplodus puntazzo (Cetti) and Diplodus sargus (L.).

Sparids are a group of demersal perciform fish of high commercial value, which have experienced an extensive radiation, particularly in the Mediterranean, where they occupy a variety of different niches. The present study focuses on two species: Diplodus sargus and D. puntazzo, presenting a wide distribution from the Mediterranean to the eastern Atlantic coasts. They display similar ecological behaviour and are evolutionary closely related. Both are highly appreciated in fisheries and D. puntazzo is currently under domestication process. However, little is know on their population structure and it is an open question whether any genetic differentiation exists at the geographic level. To address this issue we examined sequence variation of a portion of the mitochondrial DNA (mtDNA) control region in population samples of each of the two species collected over a wide geographic range. In addition to the mtDNA, analysis of nuclear loci (allozymes) was included in the study to compare patterns revealed by nuclear and mitochondrial markers. The studied samples covered an area from the eastern Mediterranean to the Portuguese coasts immediately outside the Gibraltar Strait. The two species revealed a level of sequence polymorphism remarkably different for the control region with the D. puntazzo and D. sargus showing 111 and 28 haplotypes, respectively. Such a difference was not detected with allozyme markers. The two species also showed large differences in their population structure. While D. puntazzo presented a marked genetic divergence between the Atlantic and Mediterranean samples, D. sargus showed little intraspecific differentiation. These results were supported using both mtDNA and allozyme markers, and were interpreted as the consequence of differences in the history of the two species such as fluctuations in the effective population size due to bottlenecks and expansions, possibly combined with present-day differences in levels of gene flow.

Discord in the family Sparidae (Teleostei): divergent phylogeographical patterns across the Atlantic-Mediterranean divide.

The Strait of Gibraltar has been proposed to be the divide between two marine biogeographical regions, the Mediterranean Sea and the Northeast Atlantic. Intraspecific studies have shown, for several of the examined species, a reduction of gene flow between the two basins. The present study examines genetic variation at nuclear and mitochondrial loci in five marine teleost species belonging to the family Sparidae. Four samples for each species were analysed spanning the Northeast Atlantic and the Mediterranean. For all individuals 17 allozyme loci were scored and a combined single strand conformation polymorphism-sequencing approach was used to survey approximately 190 bp of the mitochondrial DNA (mtDNA) D-loop region. All five species share similar biological features. For three species, namely Lithognathus mormyrus, Spondyliosoma cantharus, and Dentex dentex, large mtDNA divergence was observed between Atlantic and Mediterranean samples. Little or no mtDNA differentiation was found in the other two species, Pagrus pagrus and Pagellus bogaraveo. Allozyme data revealed strong differentiation when comparing Atlantic and Mediterranean samples of L. mormyrus and D. dentex, moderate for P. pagrus, and no differentiation for P. bogaraveo and S. cantharus. These results provide evidence for a sharp phylogeographical break (sensu Avise) between the Atlantic and the Mediterranean for two (or possibly three) sparid species of the five investigated. At the same time, the obtained results for the other two species raise the question on which ecological/historical factors might have caused the observed discrepancy in the geographical distribution of genetic variation among otherwise biologically similar species.

Messinian salinity crisis and the origin of freshwater lifestyle in western Mediterranean gobies.

The present paper reports on a molecular study based on 12S rRNA and 16S rRNA mitochondrial genes partly sequenced in 13 species of western Mediterranean gobies, three of which are strictly freshwater-dwelling. A total of 867 bp were aligned and used for the phylogenetic reconstruction. Two major lineages were identified, one clustering the sand gobies in a monophyletic clade. Relationships among taxa based on sequence analysis only partly match those based on morphological criteria, suggesting that the latter are somehow insufficient to correctly establish phylogenetic relationships within this family. The results provide evidence for a multiple independent evolution of the freshwater lifestyle in Knipowitschia and Padogobius lineages. On the basis of the present results, it is uncertain whether the freshwater preference within the genus Padogobius originated twice independently in P. nigricans and P. martensii or only once in their common ancestor. Estimation of the ages of the two major lineages of this group of fish with a molecular clock (in combination with the construction of a linearized tree) suggests that they are much older (at least 40 Myr) than previously thought. Thus, there should be no correlation between their diversification and the Miocene-Pliocene geological events, including the so-called Messinian salinity crisis, which occurred about 10 MYA and is believed to have played a role in their evolution. Alternatively, these gobies would have an evolutionary rate at least fourfold faster than those of other vertebrates.

Molecular phylogeny of grey mullets based on mitochondrial DNA sequence analysis: evidence of a differential rate of evolution at the intrafamily level.

The phylogeny of the grey mullets is considered problematic both at the intra- and interfamily level. Such a difficulty arises from the highly homogeneous morphology displayed by this group of fish and, consequently, from the paucity of the key morphological characters suitable to address their phylogeny and evolution. In the present work, we have approached the phylogenetic and evolutionary relationships of seven species of Mugilidae, six of which from the Mediterranean Sea, on the basis of the DNA sequences of two mitochondrial genes (cytochrome b and 12S rRNA). Despite the morphological homogeneity exhibited by the taxa considered, the two species of the genus Mugil (M. cephalus and M. curema) showed a remarkable genetic divergence compared to all the other members of the family. The relative rate test revealed a significantly higher rate of evolution along the Mugil lineage.

Optimization of single-strand conformation polymorphism and sequence analysis of the mitochondrial control region in Pagellus bogaraveo (Sparidae, Teleostei): rationalized tools in fish population biology.

We report the isolation and sequencing of 400-550 base pairs (bp) of the mitochondrial DNA (mtDNA) control region of eight species of Sparidae (Perciformes, Teleostei). This sequence information allowed us to design specific primers to one of these species (Pagellus bogaraveo). The new set of primers was used to test a rationalized approach to study the mtDNA nucleotide variability at the intraspecific level. The single-strand conformation polymorphism (SSCP) technique was applied to detect sequence variation in two non-overlapping fragments of the control region of 32 individuals of P. bogaraveo. To assess the sensitivity of the method, the nucleotide sequence of the analysed region was determined for all the specimens. The results showed that, for one of the two fragments, SSCP analysis was able to detect 100% of the underlying genetic variability. In sharp contrast, nucleotide variation of the second DNA fragment was completely unresolved by SSCP under different experimental conditions. This suggests that the resolution power of SSCP is crucially dependent on the nature of the fragment subjected to the analysis; therefore, a preliminary test of the sensitivity of the method should be performed on each specific DNA fragment before starting a large-scale survey. A rationalized approach, combining the SSCP technique and a simplified sequencing procedure, is proposed for studying intraspecific polymorphism at the mtDNA control region in fish.