Certolizumab pegol effectiveness, survival and safety in patients with psoriasis: A multicenter retrospective analysis in daily clinical practice by the Spanish Psoriasis Group.

BACKGROUND: Certolizumab is an Fc-free PEGylated tumor necrosis factor-alpha (TNFα) inhibitor recently approved for the treatment of moderate-to-severe plaque psoriasis, although there is limited real-world evidence on the effectiveness and safety in patients with plaque psoriasis treated with certolizumab. The objective of this article is to determine the effectiveness, drug survival, and safety, including pregnancy, childbirth, and lactation, of certolizumab in moderate-to-severe plaque psoriasis under real-world conditions. METHODS: This is a retrospective, multicenter, observational study performed in 15 hospitals in Spain. It evaluates the effectiveness and safety of certolizumab in plaque psoriasis in the clinical practice setting. RESULTS: A total of 67 patients (73% female) were evaluated with a mean baseline Psoriasis Area Severity Index (PASI) of 8.9. At Week 12, the mean PASI was 2.3 (n = 67), 1.3 (n = 57) at Week 24 and 1.3 at Week 52 (n = 34). Absolute PASI < 3 was achieved in 69, 86, and 92% of patients at Weeks 12, 24, and 52, respectively, as observed. For its part, using the under-response imputation analysis, PASI < 3 at Weeks 12, 24, and 52 were achieved by 69, 73, and 49% of the patients, respectively. A total of 35 patients (52%) had concomitant psoriatic arthritis, and, in 24 of them, Disease Activity in Psoriatic Arthritis Score (DAPSA) was recorded at baseline, with a mean value of 17.9 which decreased to 8.2 at Week 12 (n = 22) and to 3.6 at Week 24 (n = 18). Certolizumab treatment was discontinued in 14 out of 67 patients (21%), due to lack/loss of cutaneous or articular effectiveness (n = 11) or patient decision (n = 2) or adverse event in only one patient who developed active tuberculosis. A lower baseline PASI [hazard ratio (HR): 1.12 (1.02-1.23); P = 0.023] and a more significant reduction in PASI at Week 12 [HR: 1.16 (1.07-1.27); P < 0.001] and Week 52 [HR: 1.47 (1.11-1.96); P = 0.007] was shown to be significantly related with better survival for the entire follow-up period. Fourteen patients were treated during pregnancy and/or lactation without reporting adverse events in either the patient or the newborn. CONCLUSIONS: Certolizumab consistently showed high effectiveness and drug survival rates in this real-life cohort. The safety demonstrated in clinical trials during pregnancy and lactation seems to be confirmed in clinical practice.

Characterizing carbapenemase-producing Escherichia coli isolates from Spain: high genetic heterogeneity and wide geographical spread.

Introduction: Carbapenemase-Producing Escherichia coli (CP-Eco) isolates, though less prevalent than other CP-Enterobacterales, have the capacity to rapidly disseminate antibiotic resistance genes (ARGs) and cause serious difficult-to-treat infections. The aim of this study is phenotypically and genotypically characterizing CP-Eco isolates collected from Spain to better understand their resistance mechanisms and population structure. Methods: Ninety representative isolates received from 2015 to 2020 from 25 provinces and 59 hospitals Spanish hospitals were included. Antibiotic susceptibility was determined according to EUCAST guidelines and whole-genome sequencing was performed. Antibiotic resistance and virulence-associated genes, phylogeny and population structure, and carbapenemase genes-carrying plasmids were analyzed. Results and discussion: The 90 CP-Eco isolates were highly polyclonal, where the most prevalent was ST131, detected in 14 (15.6%) of the isolates. The carbapenemase genes detected were bla OXA-48 (45.6%), bla VIM-1 (23.3%), bla NDM-1 (7.8%), bla KPC-3 (6.7%), and bla NDM-5 (6.7%). Forty (44.4%) were resistant to 6 or more antibiotic groups and the most active antibiotics were colistin (98.9%), plazomicin (92.2%) and cefiderocol (92.2%). Four of the seven cefiderocol-resistant isolates belonged to ST167 and six harbored bla NDM. Five of the plazomicin-resistant isolates harbored rmt. IncL plasmids were the most frequent (45.7%) and eight of these harbored bla VIM-1. bla OXA-48 was found in IncF plasmids in eight isolates. Metallo-ß-lactamases were more frequent in isolates with resistance to six or more antibiotic groups, with their genes often present on the same plasmid/integron. ST131 isolates were associated with sat and pap virulence genes. This study highlights the genetic versatility of CP-Eco and its potential to disseminate ARGs and cause community and nosocomial infections.

Unveiling Non-Covalent Interactions in Novel Cooperative Photoredox Systems for Efficient Alkene Oxidation in Water.

A new cooperative photoredox catalytic system, [RuII(trpy)(bpy)(H2O)][3,3'-Co(8,9,12-Cl3-1,2-C2B9H8)2]2, 5, has been synthesized and fully characterized for the first time. In this system, the photoredox catalyst [3,3'-Co(8,9,12-Cl3-1,2-C2B9H8)2]-[Cl6-1]-, a metallacarborane, and the oxidation catalyst [RuII(trpy)(bpy)(H2O)]2+, 2 are linked by non-covalent interactions. This compound, along with the one previously synthesized by us, [RuII(trpy)(bpy)(H2O)][(3,3'-Co(1,2-C2B9H11)2]2, 4, are the only examples of cooperative molecular photocatalysts in which the catalyst and photosensitizer are not linked by covalent bonds. Both cooperative systems have proven to be efficient photocatalysts for the oxidation of alkenes in water through Proton Coupled Electron Transfer processes (PCETs). Using 0.05 mol% of catalyst 4, total conversion values were achieved after 15 min with moderate selectivity for the corresponding epoxides, which decreases with reaction time, along with the TON values. However, with 0.005 mol% of catalyst, the conversion values are lower, but the selectivity and TON values are higher. This occurs simultaneously with an increase in the amount of the corresponding diol for most of the substrates studied. Photocatalyst 4 acts as a photocatalyst in both the epoxidation of alkenes and their hydroxylation in aqueous medium. The hybrid system 5 shows generally higher conversion values at low loads compared to those obtained with 4 for most of the substrates studied. However, the selectivity values for the corresponding epoxides are lower even after 15 min of reaction. This is likely due to the enhanced oxidizing capacity of CoIV in catalyst 5, resulting from the presence of more electron-withdrawing substituents on the metallacarborane platform.

Enhanced selectivity towards melanoma cells with zinc(II)-Schiff bases containing imidazole derivatives.

Zinc(II)-complexes with the general formula [Zn(L)2] containing 8-hydroxyquinoline Schiff bases functionalized with 1-(3-aminopropyl)imidazole or 1-(3-aminopropyl)-2-methyl-1H-imidazole on 2-position and their respective ligands (HL1 or HL2) were synthesized and characterized by NMR, UV-Vis, FTIR and CD spectroscopies as well as ESI-MS spectrometry. Single crystals of HL2 and [Zn(L1)2]n were analysed by SC-XRD. [Zn(L1)2]n shows a 1D polymeric chain structure of alternating Zn(II) cations and bridging Schiff base ligands, in contrast to previously reported monomeric structures of analogous complexes. DFT calculations were performed to rationalize the polymeric X-ray structure of Zn(L1)2. Results showed that the ligands can bind as bi- or tridentate to Zn(II) and there is the possibility of a dynamic behavior for the complexes in solution. Both ligands and complexes present limited stability in aqueous media, however, in the presence of bovine serum albumin the complexes are stable. Molecular docking simulations and circular dichroism spectroscopic studies suggest binding to this protein in close proximity to the Trp213 residue. Biological studies on a panel of cancer cells revealed that the Zn(II)-complexes have a lower impact on cell viability than cisplatin, except for triple-negative breast cancer cells in which they were comparable. Notwithstanding, they display much higher selectivity towards cancer cells vs. normal cells, than cisplatin. They induce the generation of ROS and DNA double-strand breaks, primarily through apoptosis as the mode of cell death. Overall, the novel Zn(II)-complexes demonstrate improved induction of apoptosis and higher selectivity, particularly for melanoma cells, compared to previously reported analogues, making them promising candidates for clinical application.

Comorbidities and Complications in People Admitted for Leprosy in Spain, 1997-2021.

This study aims to describe the epidemiological and clinical characteristics and trends of these admissions in Spain. This retrospective study drew data from the Hospital Discharge Records Database of the Spanish National Health System. We used the diagnostic codes for leprosy from the International Classification of Diseases, ninth and tenth revisions, to retrieve leprosy admissions from 1997 to 2021. There were 1387 hospitalizations for leprosy The number of annual cases decreased gradually, from 341 cases in 1997-2001 to 232 in 2017-2021 (p < 0.001). Patients' median age increased, from 65 years in 1997-2001 to 76 years in 2017-2021 (p < 0.001), as did the prevalence of some comorbidities, such as hypertension (15% in 1997-2001 to 27.6% in 2017-2021; p < 0.001). The mortality rate (6%) and the frequency of leprosy complications remained stable. After Spain (79.1%), the most common country of origin was Paraguay (4.4%). Admissions decreased significantly in Andalusia, from 42% in 1997-2001 to 10.8% in 2017-2021 (p < 0.001), and in the Canary Islands, from 7.9% in 1997-2001 to 2.6% in 2017-2021 (p = 0.001), whereas they increased in Madrid, from 5.9% in 1997-2001 to 12.1% in 2017-2021 (p = 0.005). Overall, leprosy admissions in Spain have declined, even in the regions with the highest prevalence. Patients admitted for leprosy have become older and sicker.

Safety and effectiveness of isavuconazole in real-life non-neutropenic patients.

OBJECTIVES: Information is scarce on clinical experiences with non-neutropenic patients with invasive fungal infection (IFI) receiving isavuconazole. We aimed to report the safety and effectiveness of this drug as a first-line treatment or rescue in real life. METHODS: A retrospective, observational multicentric study of non-neutropenic patients who received isavuconazole as an IFI treatment at 12 different university hospitals (January 2018-2022). All patients met criteria for proven, probable or possible IFI according to EORTC-MSG. RESULTS: A total of 238 IFIs were treated with isavuconazole during the study period. Combination therapy was administered in 27.7% of cases. The primary IFI was aspergillosis (217, 91.2%). Other IFIs treated with isavuconazole were candidemia (n = 10), mucormycosis (n = 8), histoplasmosis (n = 2), cryptococcosis (n = 2), and others (n = 4). Median time of isavuconazole treatment was 29 days. Only 5.9% (n = 14) of cases developed toxicity, mainly hepatic-related (10 patients, 4.2%). Nine patients (3.8%) had treatment withdrawn. Successful clinical response at 12 weeks was documented in 50.5% of patients. CONCLUSION: Isavuconazole is an adequate treatment for non-neutropenic patients with IFIs. Toxicity rates were low and its effectiveness was comparable to other antifungal therapies previously reported.

Top-50 cited articles on cysticercosis and neurocysticercosis.

BACKGROUND: Identifying the most highly cited papers in a given field can help researchers and professionals understand the milestones and research areas that are generating the most impact. This study aimed to identify and describe the 50 most frequently cited manuscripts on cysticercosis and neurocysticercosis. METHODS: We identified the 50 most cited papers (articles and reviews) on cysticercosis and neurocysticercosis from the MEDLINE database and indexed in Web of Science-Core Collection, analyzing their bibliographic and content characteristics. RESULTS: The most cited documents comprised 29 (58%) original articles and 21 (42%) reviews, the bulk of which were narrative reviews (n = 17), with a negligible presence of other types of reviews with high-level scientific evidence. Six journals published 42% of the articles. In addition to the USA, Mexico and Peru were prominent countries of origin among leading researchers. The main research topics were the central nervous system and epilepsy on the one hand, and diagnostic and therapeutic approaches on the other. CONCLUSION: Our findings shed light on the dissemination of knowledge about cysticercosis and neurocysticercosis in recent decades, identifying the most highly cited contributions that have driven research in the field.

Paraptotic Cell Death as an Unprecedented Mode of Action Observed for New Bipyridine-Silver(I) Compounds Bearing Phosphane Coligands.

In this work, we investigated the anticancer activity of several novel silver(I) 2,2'-bipyridine complexes containing either triphenylphosphane (PPh3) or 1,2-bis(diphenylphosphino)ethane (dppe) ligands. All compounds were characterized by diverse analytical methods including ESI-MS spectrometry; NMR, UV-vis, and FTIR spectroscopies; and elemental analysis. Moreover, several compounds were also studied by X-ray single-crystal diffraction. Subsequently, the compounds were investigated for their anticancer activity against drug-resistant and -sensitive cancer cells. Noteworthily, neither carboplatin and oxaliplatin resistance nor p53 deletion impacted on their anticancer efficacy. MES-OV cells displayed exceptional hypersensitivity to the dppe-containing drugs. This effect was not based on thioredoxin reductase inhibition, enhanced drug uptake, or apoptosis induction. In contrast, dppe silver drugs induced paraptosis, a novel recently described form of programmed cell death. Together with the good tumor specificity of this compound's class, this work suggests that dppe-containing silver complexes could be interesting drug candidates for the treatment of resistant ovarian cancer.

Complement receptor 3 is required for maximum in vitro trogocytic killing of the parasite Trichomonas vaginalis by human neutrophil-like cells.

Trichomonas vaginalis (Tv) is a parasite that causes trichomoniasis, a prevalent sexually-transmitted infection. Neutrophils are found at the site of infection, and can rapidly kill the parasite in vitro, using trogocytosis. However, the specific molecular players in neutrophil killing of Tv are unknown. Here, we show that complement proteins play a role in Tv killing by human neutrophil-like cells (NLCs). Using CRISPR/Cas9, we generated NLCs deficient in each of three complement receptors (CRs) known to be expressed on human neutrophils: CR1, CR3, and CR4. Using in vitro trogocytosis assays, we found that CR3, but not CR1 or CR4 is required for maximum trogocytosis of the parasite by NLCs, with NLCs lacking CR3 demonstrating ~40% reduction in trogocytosis, on average. We also observed a reduction in NLC killing of Tv in CR3 knockout, but not CR1 or CR4 knockout NLCs. On average, NLCs lacking CR3 had ~50% reduction in killing activity. We also used a parallel approach of pre-incubating NLCs with blocking antibodies against CR3, which similarly reduced NLC killing of parasites. These data support a model in which Tv is opsonized by the complement protein iC3b, and bound by neutrophil CR3 receptor, to facilitate trogocytic killing of the parasite.

Benthic foraminifera in Gulf of Mexico show temporal and spatial dynamics of microplastics.

Microplastics have accumulated in the environment since plastic production began, with present-day observations that range from marine trenches to mountains. However, research on microplastics has only recently begun so it is unclear how they have changed over time in many oceanic regions. Our study addressed this gap by quantifying the temporal and spatial dynamics of microplastics in two deep-water regions of the Gulf of Mexico (GOM). We isolated agglutinated foraminifera from sediment cores and assessed microplastics that were incorporated into their tests. Our results indicated that microplastics were incorporated by agglutinated foraminifera after plastic production began. Microplastics were higher at deep-water sites and closer to the Mississippi River. This study confirms the presence of microplastic incorporation into agglutinated foraminifera tests and investigates microplastics in deep-water sediments in the GOM. Additional work is needed to fully identify the distribution of microplastics across the GOM and other oceanic basins.

Enhancing Photoredox Catalysis in Aqueous Environments: Ruthenium Aqua Complex Derivatization of Graphene Oxide and Graphite Rods for Efficient Visible-Light-Driven Hybrid Catalysts.

A ruthenium aqua photoredox catalyst has been successfully heterogeneneized on graphene oxide (GO@trans-fac-3) and graphite rods (GR@trans-fac-3) for the first time and have proven to be sustainable and easily reusable systems for the photooxidation of alcohols in water, in mild and green conditions. We report here the synthesis and total characterization of two Ru(II)-polypyridyl complexes, the chlorido trans-fac-[RuCl(bpea-pyrene)(bpy)](PF6) (trans-fac-2) and the aqua trans-fac-[Ru(bpea-pyrene)(bpy)OH2](PF6)2 (trans-fac-3), both containing the N-tridentate, 1-[bis(pyridine-2-ylmethyl)amino]methylpyrene (bpea-pyrene), and 2,2'-bipyridine (bpy) ligands. In both complexes, only a single isomer, the trans-fac, has been detected in solution and in the solid state. The aqua complex trans-fac-3 displays bielectronic redox processes in water, assigned to the Ru(IV/II) couple. The trans-fac-3 complex has been heterogenized on different types of supports, (i) on graphene oxide (GO) through π-stacking interactions between the pyrene group of the bpea-pyrene ligand and the GO and (ii) both on glassy carbon electrodes (GC) and on graphite rods (GR) through oxidative electropolymerization of the pyrene group, which yield stable heterogeneous photoredox catalysts. GO@trans-fac-3- and GR/poly trans-fac-3-modified electrodes were fully characterized by spectroscopic and electrochemical methods. Trans-fac-3 and GO@trans-fac-3 photocatalysts (without a photosensitizer) showed good catalytic efficiency in the photooxidation of alcohols in water under mild conditions and using visible light. Both photocatalysts display high selectivity values (>99%) even for primary alcohols in accordance with the presence of two-electron transfer processes (2e-/2H+). GO@trans-fac-3 keeps intact its homogeneous catalytic properties but shows an enhancement in yields. GO@trans-fac-3 can be easily recycled by filtration and reused for up to five runs without any significant loss of catalytic activity. Graphite rods (GR@trans-fac-3) were also evaluated as heterogeneous photoredox catalysts showing high turnover numbers (TON) and selectivity values.

Novel family of [RuCp(N,N)(P)]+ compounds with simultaneous anticancer and antibacterial activity: Biological evaluation and solution chemistry studies.

A family of ten novel ruthenium(II)-cyclopentadienyl organometallics of general formula [Ru(η5-C5H5)(N,N)(PPh2(C6H4COOR)][CF3SO3] (1-10) in which (N,N) = 4,4'-R'-2,2'-bipyridyl (R = -H or -CH2CH2OH; R' = -H, -CH3, -OCH3, -CH2OH, and -CH2-biotin) was prepared from [Ru(η5-C5H5)(PPh2(C6H4COOH))2Cl]. All compounds were fully characterized by means of several spectroscopic and analytical techniques, and the molecular structures of [Ru(η5-C5H5)(PPh2(C6H4COOH))2Cl], 1, 3 and 4 have been additionally studied by single-crystal X-ray diffraction. The anticancer activity of all compounds was evaluated in sensitive and multidrug-resistant counterpart cell lines from human colorectal cancer (Colo 205 and Colo 320) and non-small cell lung cancer NSCLC (A549, NCI-H460 versus NCI-H460/R) as well. Notably, compounds 6 and 7 (R CH2CH2OH and (N,N) = bipy or Me2bipy, respectively) showed antiproliferative effect against both cell lines with high intrinsic selectivity towards cancer cells. The antibacterial activity of all compounds was also evaluated against both Gram negative and Gram positive strains, and some compounds in the series showed potent antibacterial activity against Staphylococcus aureus strains, including the methicillin-resistant MRSA strains. Solution speciation studies revealed that the complexes bearing the PPh2(C6H4COO-) ligand are neutral at physiological pH (7.4) in contrast with their ethylene glycol derivatives that have a permanent positive charge. While all compounds are lipophilic, the difference in the distribution coefficient for neutral and charged complexes is around one order of magnitude. Complexes 6 and 7 exhibited excellent biological activity and were selected for further studies. Spectrofluorometric methods were used to investigate their interaction with biomolecules such as human serum albumin (HSA) and calf thymus DNA (ct-DNA). For these complexes, binding site II of HSA is a possible binding pocket through non-covalent interactions. The release of ethidium from the DNA adduct by the charged complexes proves their interaction with DNA in contrast to the neutral ones. In conclusion, Ru(II)-cyclopentadienyl complexes with 2,2'-bipyridyl-derivatives and an ethylene glycol moiety tethered to the phenylphosphane co-ligand are very promising from a therapeutic perspective, in particular complexes 6 and 7 that display remarkable antibacterial activity with a high anti-proliferative effect against colon and non-small cell lung cancers, both clinically challenging neoplasias in need of effective solutions.

Multicenter Retrospective Andalusian Study of the Use of Sonidegib for the Treatment of Local Advanced Basal Cell Carcinoma in Real Clinical Practice.

INTRODUCTION: Locally advanced basal cell carcinoma (LA-BCC) is defined as that BCC in which there is radiological confirmation of invasion of certain neighboring structures in depth and also, usually, a BCC that is of a sufficient size and invasion (although there is no radiological demonstration of deep invasion) in which surgery and radiotherapy are not adequate, are insufficient or are contraindicated to achieve the cure of the tumor, either due to characteristics of the tumor itself or of the patient. Sonidegib is indicated for the treatment of adult patients with locally advanced basal cell carcinoma that is not amenable to curative surgery or radiotherapy. MATERIAL AND METHODS: This is a retrospective, multicenter and descriptive study in nine centers in Andalusia, Spain. Patients treated with sonidegib for >3 months for locally advanced BCC were included from 1 January 2021 to 1 January 2023. Epidemiological, efficacy and safety data were collected. RESULTS: In the present study, a total of 38 patients were included, with a median age of 76.23 years (range 40-101). Prior treatment was surgery (31.57%; n = 25), radiotherapy (15.78%; n = 6), vismodegib (31.57%; n = 12). Eleven patients had not received prior treatment. LA-BCC were located in the cephalic pole, face or scalp. There was a total response in 9/38 patients (23.7%), partial response in 25/38 patients (65.8%) and no response in 4 patients (10.52%). In 6/34 patients, the dose was reduced to 200 mg every other day until it was discontinued due to adverse effects. The main adverse effects reported were dysgeusia (n = 8), asthenia (n = 8), = 6), muscle spasms (n = 6), alopecia (n = 4) and gastrointestinal intolerance (n = 4). DISCUSSION: Sonidegib is the second iHh authorized for the treatment of adult patients with locally advanced BCC who are not amenable to curative surgery or radiotherapy, based on the results of the phase II clinical trial, BOLT. Sonidegib shows good effectiveness and an acceptable safety profile in routine clinical practice in the sample presented.

Effectiveness and safety of tildrakizumab for the treatment of psoriasis in real-world settings at 24 weeks: A retrospective, observational, multicentre study by the Spanish Psoriasis Group.

BACKGROUND: Tildrakizumab is a humanized, IgG1/κ antibody that interacts with the p19 subunit of interleukin 23. It is approved for the treatment of moderate-to-severe plaque psoriasis. Real-world evidence on the effectiveness and safety of tildrakizumab is limited. OBJECTIVES: To assess the effectiveness and safety of tildrakizumab at 24 weeks in patients with moderate-to-severe plaque psoriasis in routine clinical practice. METHODS: Retrospective, observational, multicentre study including adult patients with moderate-to-severe plaque psoriasis treated with tildrakizumab under real-life conditions. Patient data were extracted from anonymized electronic medical records. Statistical analysis was performed using SPSS22. RESULTS: A total of 190 patients were included. About 53.9% were men with a mean age of 51.45 (SD 3.9) and a mean BMI of 29.13 (SD 6.21). About 79.8% (132 out of 190) of patients had previously received biological therapy (BT) and 17.3% (33 out of 191) had psoriatic arthritis. Baseline PASI was 10.7 (SD 6.53). Up to 109 patients reached Week 24 and at this point mean baseline PASI decreased to 1.7 (SD 4.8), representing an 88.79% mean PASI reduction. At 6 months, 87.1% and 40.3% of the treated patients achieved PASI ≤3 and ≤1, respectively. At Week 24 mean BSA decreased from 13.2 (SD 10.07) to 1.6 (SD 4.40) and mean DLQI went from 12.5 (SD 7.12) to 1.2 (SD 3.27). Multivariate analysis showed no differences when effectiveness was correlated with gender, obesity, psoriatic arthritis or prior exposure to BT. The rate of adverse events (AE) was 5.9% (11 out of 190), where infections were the most frequent AE (4 out of 11). One patient suffered a haemorrhagic ictus and one patient died due to causes unrelated to the study. CONCLUSION: Tildrakizumab was effective and safe in a large cohort of patients with moderate-to-severe plaque psoriasis treated in a routine clinical setting.

Fighting Multidrug Resistance with Ruthenium-Cyclopentadienyl Compounds: Unveiling the Mechanism of P-gp Inhibition.

The search for more effective and selective drugs to overcome cancer multidrug resistance is urgent. As such, a new series of ruthenium-cyclopentadienyl ("RuCp") compounds with the general formula [Ru(η5-C5H4R)(4,4'-R'-2,2'-bipy)(PPh3)] were prepared and fully characterized. All compounds were evaluated toward non-small cell lung cancer cells with different degrees of cisplatin sensitivity (A549, NCI-H2228, Calu-3, and NCI-H1975), showing better cytotoxicity than the first-line chemotherapeutic drug cisplatin. Compounds 2 and 3 (R' = -OCH3; R = CHO (2) or CH2OH (3)) further inhibited the activity of P-gp and MRP1 efflux pumps by impairing their catalytic activity. Molecular docking calculations identified the R-site P-gp pocket as the preferred one, which was further validated using site-directed mutagenesis experiments in P-gp. Altogether, our results unveil the first direct evidence of the interaction between P-gp and "RuCp" compounds in the modulation of P-gp activity and establish them as valuable candidates to circumvent cancer MDR.

Cu(II) and Zn(II) Complexes of New 8-Hydroxyquinoline Schiff Bases: Investigating Their Structure, Solution Speciation, and Anticancer Potential.

We report the synthesis and characterization of three novel Schiff bases (L1-L3) derived from the condensation of 2-carbaldehyde-8-hydroxyquinoline with amines containing morpholine or piperidine moieties. These were reacted with CuCl2 and ZnCl2 yielding six new coordination compounds, with the general formula ML2, where M = Cu(II) or Zn(II) and L = L1-L3, which were all characterized by analytical, spectroscopic (Fourier transform infrared (FTIR), UV-visible absorption, nuclear magnetic resonance (NMR), or electron paramagnetic resonance (EPR)), and mass spectrometric techniques, as well as by single-crystal X-ray diffraction. In the solid state, two Cu(II) complexes, with L1 and L2, are obtained as dinuclear compounds, with relatively short Cu-Cu distances (3.146 and 3.171 Å for Cu2(L1)4 and Cu2(L2)4, respectively). The free ligands show moderate lipophilicity, while their complexes are more lipophilic. The pKa values of L1-L3 and formation constants of the complex (for ML and ML2) species were determined by spectrophotometric titrations, with the Cu(II) complexes showing higher stability than the Zn(II) complexes. EPR indicated the presence of several species in solution as pH varied and binding modes were proposed. The binding of the complexes to bovine serum albumin (BSA) was evaluated by fluorescence and circular dichroism (CD) spectroscopies. All complexes bind BSA, and as demonstrated by CD, the process takes several hours to reach equilibrium. The antiproliferative activity was evaluated in malignant melanoma cells (A375) and in noncancerous keratinocytes (HaCaT). All complexes display significant cytotoxicity (IC50 < 10 µM) but modest selectivity. The complexes show higher activity than the free ligands, the Cu(II) complexes being more active than the Zn(II) complexes, and approximately twice more cytotoxic than cisplatin. A Guava ViaCount assay corroborated the antiproliferative activity.

Breakthrough invasive fungal infection among patients with haematologic malignancies: A national, prospective, and multicentre study.

OBJECTIVES: We describe the current epidemiology, causes, and outcomes of breakthrough invasive fungal infections (BtIFI) in patients with haematologic malignancies. METHODS: BtIFI in patients with ≥ 7 days of prior antifungals were prospectively diagnosed (36 months across 13 Spanish hospitals) according to revised EORTC/MSG definitions. RESULTS: 121 episodes of BtIFI were documented, of which 41 (33.9%) were proven; 53 (43.8%), probable; and 27 (22.3%), possible. The most frequent prior antifungals included posaconazole (32.2%), echinocandins (28.9%) and fluconazole (24.8%)-mainly for primary prophylaxis (81%). The most common haematologic malignancy was acute leukaemia (64.5%), and 59 (48.8%) patients had undergone a hematopoietic stem-cell transplantation. Invasive aspergillosis, principally caused by non-fumigatus Aspergillus, was the most frequent BtIFI with 55 (45.5%) episodes recorded, followed by candidemia (23, 19%), mucormycosis (7, 5.8%), other moulds (6, 5%) and other yeasts (5, 4.1%). Azole resistance/non-susceptibility was commonly found. Prior antifungal therapy widely determined BtIFI epidemiology. The most common cause of BtIFI in proven and probable cases was the lack of activity of the prior antifungal (63, 67.0%). At diagnosis, antifungal therapy was mostly changed (90.9%), mainly to liposomal amphotericin-B (48.8%). Overall, 100-day mortality was 47.1%; BtIFI was either the cause or an essential contributing factor to death in 61.4% of cases. CONCLUSIONS: BtIFI are mainly caused by non-fumigatus Aspergillus, non-albicans Candida, Mucorales and other rare species of mould and yeast. Prior antifungals determine the epidemiology of BtIFI. The exceedingly high mortality due to BtIFI warrants an aggressive diagnostic approach and early initiation of broad-spectrum antifungals different than those previously used.

Global research on cysticercosis and neurocysticercosis: A bibliometric analysis.

Background: Cysticercosis is a parasitic infection caused by the larval stage Taenia solium. As a neglected tropical disease that is also difficult to diagnose, cysticercosis constitutes an important public health and research challenge. To characterize the development of research on cysticercosis and neurocysticercosis, considering the level of scientific evidence provided and the contribution of different countries to research, according to their endemic nature and their income level. Methods: Indexed publications on cysticercosis and neurocysticercosis were retrieved from the MEDLINE database, and the evolution of scientific production and the topic areas addressed in the body of research were analyzed. Results: A total of 7,860 papers published between 1928 and 2021 were analyzed. The volume of annual publications increased over time, standing at over 200 documents/year since 2010. Case studies constitute the main study design (27.4% of the documents with available information, n = 2,155), with fewer studies that provide the highest levels of scientific evidence, such as clinical studies (1.9%, n = 149) or systematic reviews (0.8%, n = 63). The most productive journals belong to the Parasitology and Tropical Medicine categories. Although the USA is the most productive country (n = 2,292), countries where Tenia solium is endemic, such as India (n = 1,749), Brazil (n = 941) and Peru (n = 898) also stand out, as does Mexico (n = 1,414). However, other endemic countries in Latin America and sub-Saharan Africa show little participation in the research. The level of international collaboration by country is very uneven, with some countries presenting very low values, such as India (9.9% of documents in international collaboration) or Brazil (18.7%); while there is evidence of intense international collaboration in countries like Peru (91.3%), Tanzania (88.2%) or Kenya (93.1%). Research output has coalesced in three thematic clusters: basic research in animals; parasitism, animal health, and zoonoses; and the diagnosis and therapeutic approach in diseases associated with cysticercosis and neurocysticercosis. Conclusions: The generation of knowledge on cysticercosis presents different features from other areas of research, such as the outstanding contribution of only some endemic countries; and the relevance of comprehensive approaches to research (animal and human health). Studies that provide higher levels of scientific evidence should be promoted, as should research in endemic areas.

Criteria used to define tumor necrosis factor-alpha inhibitors failure in patients with moderate-to-severe psoriasis: a systematic literature review.

BACKGROUND: Determining tumor necrosis factor-alpha inhibitors (anti-TNF-α) failure is still a challenge in the management of moderate-to-severe psoriasis. Thus, our comprehensive systematic literature review aimed to gather information on the criteria used to define anti-TNF-α failure. We also aimed to discover the main reasons for anti-TNF-α failure and define subsequently administered treatments. MATERIALS AND METHODS: We conducted a systematic review following review and reporting guidelines (Cochrane and PRISMA). International (Medline/PubMed and Cochrane Library) and Spanish databases (MEDES, IBECS), and gray literature were consulted to identify publications issued until April 2021 in English or Spanish. RESULTS: Our search yielded 58 publications. Of these, 37 (63.8%) described the criteria used to define anti-TNF-α primary or secondary failure. Criteria varied across studies, although around 60% considered Psoriasis Area and Severity Index (PASI)-50 criteria. Nineteen (32.8%) reported the reasons for treatment failure, including the lack or loss of efficacy and safety-related problems, mainly infections. Finally, 29 (50%) publications outlined the treatments administered after anti-TNF-α: 62.5% reported a switch to another anti-TNF-α and 37.5% to interleukin (IL)-inhibitors.Our findings suggest a need to standardize the management of anti-TNF-α failure and reflect the incorporation of new targets, such as IL-inhibitors, in the treatment sequence.KEY MESSAGESIn the treatment of psoriasis, the primary and secondary anti-TNF-α failure criteria differ widely in the scientific literature.The strictest efficacy criteria for defining anti-TNF-α failure, or those recommended by guidelines such as PASI75, were underused both in clinical trials and observational studies.Most studies failed to consider patient-reported outcomes in assessing psoriasis treatment efficacy, which contrasts with recent recommendations on the inclusion of patient-reported HRQoL as a supporting criterion when considering clinical outcomes.