Vitamin D Endocrine System and COVID-19: Treatment with Calcifediol.

The COVID-19 pandemic is the greatest challenge facing modern medicine and public health systems. The viral evolution of SARS-CoV-2, with the emergence of new variants with in-creased infectious potential, is a cause for concern. In addition, vaccination coverage remains in-sufficient worldwide. Therefore, there is a need to develop new therapeutic options, and/or to optimize the repositioning of drugs approved for other indications for COVID-19. This may include the use of calcifediol, the prohormone of the vitamin D endocrine system (VDES) as it may have potential useful effects for the treatment of COVID-19. We review the aspects associating COVID-19 with VDES and the potential use of calcifediol in COVID-19. VDES/VDR stimulation may enhance innate antiviral effector mechanisms, facilitating the induction of antimicrobial peptides/autophagy, with a critical modulatory role in the subsequent host reactive hyperinflammatory phase during COVID-19: By decreasing the cytokine/chemokine storm, regulating the renin-angiotensin-bradykinin system (RAAS), modulating neutrophil activity and maintaining the integrity of the pulmonary epithelial barrier, stimulating epithelial repair, and directly and indirectly decreasing the increased coagulability and prothrombotic tendency associated with severe COVID-19 and its complications. Available evidence suggests that VDES/VDR stimulation, while maintaining optimal serum 25OHD status, in patients with SARS-CoV-2 infection may significantly reduce the risk of acute respiratory distress syndrome (ARDS) and severe COVID-19, with possible beneficial effects on the need for mechanical ventilation and/or intensive care unit (ICU) admission, as well as deaths in the course of the disease. The pharmacokinetic and functional characteristics of calcifediol give it superiority in rapidly optimizing 25OHD levels in COVID-19. A pilot study and several observational intervention studies using high doses of calcifediol (0.532 mg on day 1 and 0.266 mg on days 3, 7, 14, 21, and 28) dramatically decreased the need for ICU admission and the mortality rate. We, therefore, propose to use calcifediol at the doses described for the rapid correction of 25OHD deficiency in all patients in the early stages of COVID-19, in association, if necessary, with the new oral antiviral agents.

Final Overall Survival Analysis of the SOGUG Phase 2 MAJA Study: Maintenance Vinflunine Versus Best Supportive Care After First-Line Chemotherapy in Advanced Urothelial Carcinoma.

INTRODUCTION: The MAJA study compared vinflunine (VFL) plus best supportive care (BSC) maintenance therapy versus BSC alone in advanced urothelial carcinoma responsive to first-line chemotherapy. The primary end point of progression-free survival was achieved. We present the final overall survival (OS) and long-term follow-up safety analyses. PATIENTS AND METHODS: Patients were enrolled, and a subsequent post hoc analysis was performed on the basis of radiologic response or stabilization to first-line cisplatin/gemcitabine (CG) chemotherapy (4-6 cycles), according to Response Evaluation Criteria in Solid Tumors (RECIST). VFL + BSC versus BSC alone were randomly assigned until disease progression. RESULTS: At final analysis, 58 patients (66.7%) had died while 29 (33.3%) had survived; the BSC arm had higher mortality (VFL + BSC, n = 26, 59.1% vs. BSC, n = 32, 74.4%). Median follow-up of surviving patients was 38.8 months (interquartile range, 23.8-61.6). Median OS was 16.7 months (95% confidence interval, 0-34.5) in VFL and 13.2 months (95% confidence interval, 6-20.4) in the BSC groups (hazard ratio, 0.736; 95% confidence interval, 0.44-1.24, P = .182). Post hoc group division did not affect median OS in either study arm. CONCLUSION: Final analysis supported a benefit of VFL in maintenance therapy in patients with disease control after first-line treatment with CG, with no unexpected long-term adverse effects. The study was insufficiently powered to show a significant OS advantage.

Optimization of the Therapeutic Approach to Patients with Sarcoma: Delphi Consensus.

Soft tissue sarcomas (STS) constitute a heterogeneous group of rare solid tumors associated with significant morbidity and mortality. The evaluation and treatment of STS require a multidisciplinary team with extensive experience in the management of these types of tumors. National and international clinical practice guidelines for STS do not always provide answers to a great many situations that specialists have to contend with in their everyday practice. This consensus provides a series of specific recommendations based on available scientific evidence and the experience of a group of experts to assist in decision-making by all the specialists involved in the management of STS.

SEOM clinical guidelines for the management of adult soft tissue sarcomas.

Soft tissue sarcomas are uncommon tumors of mesenchimal cell origin. Criteria for suspicion is a soft tissue mass that is increasing in size, and has a size greater than 5 cm or is located under the deep fascia. Diagnosis and management of these patients should preferably be performed by a specialist multidisciplinary team in a referral center. Assessment of a patient with a suspect of sarcoma should include magnetic resonance and biopsy performed prior to surgery. Primary local therapy for patients with localized sarcoma is based on wide surgical resection with a tumor-free tissue margin, in association in most cases with radiotherapy. Adjuvant chemotherapy constitutes an option that could be considered in high-risk sarcomas of the extremities. When metastasis are present, surgery of pulmonary lesions, in some selected patients, and chemotherapy are current available options.

Cyclometallation of amino-imines on palladium complexes. The effect of the solvent on the experimental and calculated mechanism.

The ortho-metallation reaction of chloro and acetato complexes of palladium(ii) having 5- and 6-membered kappa(2)-(N(amino),N(imino)) chelate ligands, [Pd(Me(2)NCH(2)(CH(2))(n)NCH(4-ClC(6)H(4)))(X)(2)] (X = AcO, Cl; n = 1, 2), in methanol solution has been carried out. The results are a good indicator of the distinct nature of the transition state involved in the processes where acetic acid has been used as a solvent. The presence of Brønsted bases, contrary to what has been reported for Pt(II) analogue compounds, does not affect this process, which indicates the "coordinated" nature of the leaving [H(+)] species. The characterization of the solution chemistry of the process in methanol has been fully achieved and the structure determination of one of the final cyclometallated complexes, [Pd(Me(2)NCH(2)(CH(2))(n)NCH(2-C,4-ClC(5)H(3)))Cl], has been carried out. The experimental temperature and pressure dependent kinetico-mechanistic parameters involved in the process have been determined and the results agree with the previously established experimental trends where important differences were observed in the presence of acidic or protonatable ligands on the palladium centre. From a DFT calculation perspective, we have carried out a systematic mechanistic study of the reaction of the simpler system N-methylbenzylimine with palladium(ii) acetate in acetic acid and acidic media to account for the experimental differences observed. The calculations indicate that neither the accepted classical 6-membered transition state mechanism nor an alternative 4-membered type justify the acceleration observed in strong acid. Only when coordination of three protonated acetato ligands on the Pd(II) square-planar complex is considered, i.e. [Pd(HAcO)(3)(kappa(1)-N(imino))](2+), can the observed acceleration of the Pd(II)-C bond formation in protic media be accounted for. The results suggest an alternative and accessible way to accelerate the reaction in such acidic media, even though more complex paths may be plausible. Both the presence of a high concentration of Lewis base in the medium and a protonatable nature of the ligands used are key factors to be considered in order to account for the experimental results reported in the literature.

New approach to the stereoselective synthesis of tertiary methyl ethers.

The Lewis acid-mediated addition of titanium enolates from 1 to dimethyl ketals of aliphatic methyl ketones followed by removal of the chiral auxiliary furnishes enantiomerically pure derivatives containing a tertiary methyl ether and a contiguous stereocenter in a straightforward manner.

Stereocontrolled synthesis of highly functionalized quaternary carbon centers: a route to alpha-substituted serines.

Three in a row! Highly functionalized quaternary amino polyols with three consecutive asymmetric carbon centers have been prepared through tandem hydroboration of allene 1 and addition to an aldehyde (see scheme; Cy = cyclohexyl, TBDPS = tert-butyldiphenylsilyl, Ts = 4-toluenesulfonyl). This one-pot process provides access to advanced intermediates for the enantioselective synthesis of alpha-substituted serines.

2D copper(II) complex built from N-methyl-1,3-diamino-2-propanolate and azide ligands: structure, magnetic, and DFT studies.

The synthesis, structural characterization, and magnetic behavior of a new 2D copper(II) compound with formula {[Cu2(mu-O2CMe)(mu-MedapO)(mu1,1-N3)2]n (CH3OH)n} 1, in which MedapOH is N-methyl-1,3-diamino-2-propanol is reported herein. 1 crystallizes in the triclinic system, space group P1, with unit cell parameters a = 6.688(5) A, b = 10.591(6) A, c = 12.100(7) A, alpha = 113.01(3) degrees, beta = 105.08(4) degrees, gamma = 93.93(3) degrees, Z = 2. The structure of 1 consists of neutral alternate 1D chains formed by the sequence of [Cu(1)-(mu1,1-N3)2-Cu(1)-(MedapO/acetate)-Cu(2)-(mu1,1-N3)2-Cu2)]. Each dinuclear [Cu(1)-Cu(2)] unit interacts with similar dinuclear units of neighbor chains in basis to large Cu-N(azido) distances to give a 2D arrangement. The magnetic behavior of 1 has been checked giving a net ferromagnetic coupling. The fit of the chiM versus T data as dinuclear compound affords a J value of 53.0 cm(-1) as a consequence of the orbital countercomplementarity phenomenon. The exchange pathways have been justified by density functional calculations.

trans-Dichloridobis(triphenyl-phosphine)palladium(II).

The title compound, [PdCl(2){P(C(6)H(5))(3)}(2)], has a slightly distorted square-planar geometry, with the chloride ligands coordinated in a trans configuration. The Pd atom is located on a centre of inversion.

Synthesis and characterization of metallomacrocyclic palladium(II) complexes with new hybrid pyrazole ligands. Diffusion NMR studies and theoretical calculations.

Three new 3,5-dimethylpyrazolic hybrid ligands N1-substituted by polyether chains and phenyl groups have been synthesized: 1,2-bis[4-(3,5-dimethyl-1H-pyrazol-1-yl)-2-oxabutyl]benzene (L1), 1,3-bis[4-(3,5-dimethyl-1H-pyrazol-1-yl)-2-oxabutyl]benzene (L2), and 1,4-bis[4-(3,5-dimethyl-1H-pyrazol-1-yl)-2-oxabutyl]benzene (L3). The reaction of these ligands with [PdCl(2)(CH(3)CN)(2)] gives two kinds of complexes, monomer or dimer, depending on the solvent. Monomeric chelated complexes [PdCl(2)(L)] [L = L1 (1), L2 (2), L3 (3)] are obtained when the solvent of the reaction is acetonitrile, whereas when the reaction takes place in tetrahydrofuran binuclear compounds [PdCl(2)(L)](2) [L = L1 (4), L2 (5), L3 (6)] are formed. The solid-state structures for 1 and 4 were determined by single-crystal X-ray diffraction methods. All of the palladium(II) complexes 1-6 were isolated and fully characterized. Diffusion NMR studies have been performed to characterize monomeric and dimeric species in solution. Dimeric compounds present complex (1)H NMR spectra, especially 4. Theoretical calculations on this molecule suggest that it is due to the coexistence of different conformers that do not interconvert to each other at room temperature. Finally, it has been observed that dimers are converted into the corresponding monomers in an acetonitrile reflux, thus indicating that the latter are thermodynamically more stable than dimers.

N,N-Dialkyl-2-iodoanilines: a versatile source for the synthesis of Pd(ii) complexes. Synthesis of novel OCP- and CCN-pincer palladium complexes.

The reactivity of a series of N,N-dimethyl-2-iodoanilines bearing different chelating "arms" at the 3-position with Pd(2)(dba)(3) has been explored. 3-[(Diphenylphosphino)methyl]-2-iodo-N,N-dimethylaniline reacted with Pd(2)(dba)(3) and PPh(3) under aerobic conditions to give the OCP-pincer complex , which was formed by sequential C(sp(3))-H activation/oxidation at the alpha-position of the aniline N atom. On the other hand, under similar reaction conditions, 3-[2-(dimethylamino)ethyl]-2-iodo-N,N-dimethylaniline afforded the CCN-pincer complex , after a second C-H activation process at the formyl group of the initially formed OCN-pincer complex. In contrast, 2-iodo-3-(1H-1,2,4-triazol-1-ylmethyl)-N,N-dimethylaniline and 2-iodo-3-(pyrazol-1-ylmethyl)-N,N-dimethylaniline reacted with Pd(2)(dba)(3) and PPh(3), respectively, to give the 6-membered azapalladacycles and , in which the aniline nitrogen is merely a spectator substituent. Finally, treatment of iodide complex with Tl(TfO) afforded the CN-bidentate cationic complex. Solid-state structures of palladium complexes, and CH(2)Cl(2).3CH(3)OH.5H(2)O were determined by X-ray analysis.

[Occupational exposure to airborne fungi and bacteria in a household recycled container sorting plant ]. / Exposición laboral a hongos y bacterias ambientales en una planta de selección de residuos de envases.

Several studies have showed an association between the work in waste treatment plants and occupational health problems such as irritation of skin, eyes and mucous membranes, pulmonary diseases, gastrointestinal problems and symptoms of organic dust toxic syndrome (ODTS). These symptoms have been related to bioaerosol exposure. The aim of this study was to investigate the occupational exposure to biological agents in a plant sorting source-separated packages (plastics materials, ferric and non-ferric metals) household waste. Airborne samples were collected with M Air T Millipore sampler. The concentration of total fungi and bacteria and gram-negative bacteria were determined and the most abundant genera were identified. The results shown that the predominant airborne microorganisms were fungi, with counts greater than 12,000 cfu/m(3) and gram-negative bacteria, with a environmental concentration between 1,395 and 5,280 cfu/m(3). In both cases, these concentrations were higher than levels obtained outside of the sorting plant. Among the fungi, the predominant genera were Penicillium and Cladosporium, whereas the predominant genera of gram-negative bacteria were Escherichia, Enterobacter, Klebsiella and Serratia. The present study shows that the workers at sorting source-separated packages (plastics materials, ferric and non-ferric metals) domestic waste plant may be exposed to airborne biological agents, especially fungi and gram-negative bacteria.

Synthesis, structure, redox properties, and catalytic activity of new ruthenium complexes containing neutral or anionic and facial or meridional ligands: an evaluation of electronic and geometrical effects.

The synthesis of a family of new Ru complexes containing meridional or facial tridentate ligands with the general formula [Ru(II)(T)(D)(X)](n+) [T = 2,2':6',2' '-terpyridine or tripyrazolylmethane; D = 4,4'-dibenzyl-4,4',5,5'-tetrahydro-2,2'-bioxazole (S,S-box-C) or 2-[((1'S)-1'-(hydroxymethyl)-2'-phenyl)ethylcarboxamide]-(4S)-4-benzyl-4,5-dihydrooxazole (S,S-box-O); X = Cl, H(2)O, MeCN or pyridine] has been described. All complexes have been spectroscopically characterized in solution through (1)H NMR and UV-vis techniques. Furthermore, all of the chloro complexes presented here have also been characterized in the solid state through monocrystal X-ray diffraction analysis. The oxazolinic S,S-box-C ligands undergo a Ru-assisted hydrolysis reaction generating the corresponding amidate anionic oxazolinic ligands S,S-box-O, which are also strongly attached to the metal center and produce a strong sigma-donation effect over the Ru metal center. The redox properties of all complexes have also been studied by means of cyclic voltammetry, strongly reflecting the nature of the ligands; both effects, geometrical (facial vs meridional) and electronic (neutral vs anionic), can be unveiled and rationalized. Finally, the reactivity of the Ru-OH(2) complexes has been tested with regard to the epoxidation of trans-stilbene, and it has been shown that, in this particular case, the reactivity is practically not dependent on the redox potentials of the catalyst but, in sharp contrast, it is strongly dependent on the geometry of the tridentate ligands.

A comparative study of the structures and reactivity of cyclometallated platinum compounds of N-benzylidenebenzylamines and cycloplatination of a primary amine.

The reaction of cis-[PtCl(2)(dmso)2] with ligands 4-ClC(6)H(4)CHNCH(2)C(6)H(5) (1a) and 4-ClC(6)H(4)CHNCH(2)(4-ClC(6)H(4)) (1b) in the presence of sodium acetate and using either methanol or toluene as solvent produced the corresponding five-membered endo-metallacycles [PtCl{(4-ClC(6)H(3))CHNCH(2)C(6)H(5)}{SOMe(2)}] (2a) and [PtCl{(4-ClC(6)H(3))CHNCH(2)(4'-ClC(6)H(4))}{SOMe(2)}] (2b). An analogous reaction for ligands 2,6-Cl(2)C(6)H(3)CHNCH(2)C(6)H(5) (1c) and 2,6-Cl(2)C(6)H(3)CHNCH(2)(4-ClC(6)H(4)) (1d) produced five-membered exo-metallacycles [PtCl{(2,6-Cl(2)C(6)H(3))CHNCH(2)C(6)H(4)}{SOMe(2)}] (2c) and [PtCl{(2,6-Cl(2)C(6)H(3))CHNCH(2)(4'-ClC(6)H(3))}{SOMe(2)}] (2d) when the reaction was carried out in methanol and seven-membered endo-platinacycles [PtCl{(MeC(6)H(3))ClC(6)H(3)CHNCH(2)C(6)H(4)}{SOMe(2)}] (3c) and [PtCl{(MeC(6)H(3))ClC(6)H(3)CHNCH(2)(4'-ClC(6)H(3))}{SOMe(2)}] (3d) when toluene was used as a solvent. The reaction of 2,4,6-(CH(3))(3)C(6)H(2)CHNCH(2)(4-ClC(6)H(4)) (1e) produced in both solvents an exo-platinacycle [PtCl{(2,4,6-(CH(3))(3)C(6)H(2))CHNCH(2)(4'-ClC(6)H(3))}{SO(CH(3))(2)}] (2e). Cyclometallation of 4-chlorobenzylamine was also achieved to produce compound [PtCl{(4-ClC(6)H(3))CH(2)NH(2)}{SOMe(2)}] (2g). The reactions of endo- and exo-metallacycles with phosphines evidenced the higher lability of the Pt-N bond in exo-metallacycles while a comparative analysis of the crystal structures points out a certain degree of aromaticity in the endo-metallacycle.

Synthesis and structure-activity relationships of new benzodioxinic lactones as potential anticancer drugs.

A set of disubstituted tetracyclic lactones has been synthesized and tested for potential antitumor activity. Several of them possess a noticeable cytotoxicity against L1210 and HT-29 colon cells in vitro. Relationships between chain nature and biological properties were sought. Lactones with a pentyl or hexyl substituent at C-11 are the most active ones. The introduction of a functional group at the side chain of C-11 modified the potency; carboxylic acid and primary amine decreased the cytotoxicity, whereas a cyano group increased the activity. An extensive structure-activity relationship study of these derivatives, including carbon homologues and bioisosteres has been performed. The synthesis and cytotoxicity of these compounds are discussed. Two lactones are recognized as potential lead compounds.

Influence of the position of substituents in the cytotoxic activity of trans platinum complexes with hydroxymethyl pyridines.

The synthesis and chemical characterization of two trans platinum complexes, (1) trans-[PtCl(2)NH(3)(2-hydroxymethylpyridine)] and (2) trans-[PtCl(2)NH(3)(3-hydroxymethylpyridine)], are described. The structures and chemical behaviour of these compounds have been compared to those of their isomer (3) trans-[PtCl(2)NH(3)(4-hydroxymethylpyridine)] previously studied. X-ray structures of all of them were solved and some interesting differences were found. The values of the dihedral angle (85 degrees , 57 degrees and 42 degrees for 1, 2 and 3, respectively) demonstrate how important is the position of substituent from a structural point of view. Studies of circular dichroism (CD), electrophoretic mobility (EM) in agarose gel and atomic force microscopy (AFM) showed differences in the modifications caused by the three complexes on DNA. Studies of antiproliferative activity of complexes 1 and 2 against cell tumour lines (HL-60) and apoptosis assays have also been carried out, showing that 1 as well as 2 are far less active than the previously described complex 3 (IC(50)=19; 19 and 3 microM, respectively). This fact probes that slight modifications on the drug's design may generate significant differences in the final antitumour activity by modifying the DNA-drug adducts, performance of resistance mechanisms and all the factors that play a fundamental role in Pt complexes' cytotoxicity.

Exposición laboral a hongos y bacterias ambientales en una planta de selección de residuos de envases / Occupational exposure to airborne fungi and bacteria in a sorting source-separated packages household waste plant

Distintos estudios han mostrado una asociación entre la actividad laboral enplantas de tratamiento de residuos y la aparición de distintos síntomas en lostrabajadores, como irritación de piel, ojos y membranas mucosas, trastornosgastrointestinales y respiratorios, y el síndrome tóxico por polvo orgánico.Estos síntomas se han asociado con la exposición a bioaerosoles.El objetivo de este trabajo es determinar la exposición laboral a agentesbiológicos en una planta de selección de envases procedentes exclusivamentede la recogida selectiva de residuos sólidos urbanos.Las muestras ambientales se obtuvieron por el método de impactación enplaca con el equipo M Air T de Millipore. Se determinó la concentración dehongos totales, bacterias totales y bacterias gramnegativas y, en cada caso,se identificaron los géneros fúngicos y bacterianos obtenidos.Los microorganismos mayoritarios han sido los hongos, con recuentossuperiores a 12.000 ufc/m3, y las bacterias gramnegativas, que se handeterminado en concentraciones ambientales entre 1.395 y 5.280 ufc/m3.En ambos casos, estas concentraciones han sido muy superiores a lashalladas en la muestra de referencia obtenida en el exterior de la planta.Entre los hongos, los géneros mayoritarios han sido Penicillium yCladosporium, mientras que entre las bacterias gramnegativas se identificaronlos géneros Escherichia, Enterobacter, Klebsiella y Serratia.En conclusión, los trabajadores de una planta de selección de envasesprocedentes de la recogida selectiva de residuos sólidos urbanos puedenestar expuestos a agentes biológicos, especialmente en forma de hongos ybacterias gramnegativas(AU)

Several studies have showed an association between the work in wastetreatment plants and occupational health problems such as irritation of skin,eyes and mucous membranes, pulmonary diseases, gastrointestinal problemsand symptoms of organic dust toxic syndrome (ODTS). These symptoms havebeen related to bioaerosol exposure.The aim of this study was to investigate the occupational exposure tobiological agents in a plant sorting source-separated packages (plasticsmaterials, ferric and non-ferric metals) household waste.Airborne samples were colleted with M Air T Millipore sampler.The concentration of total fungi and bacteria and gram-negative bacteria weredetermined and the most abundant genera were identified.The results shown that the predominant airborne microorganisms were fungi,with counts greater than 12,000 cfu/m3 and gram-negative bacteria, with aenvironmental concentration between 1,395 and 5,280 cfu/m3. In both cases,these concentrations were higher than levels obtained outside of the sortingplant.Among the fungi, the predominant genera were Penicillium and Cladosporium,whereas the predominant genera of gram-negative bacteria were Escherichia,Enterobacter, Klebsiella and Serratia.The present study shows that the workers at sorting source-separatedpackages (plastics materials, ferric and non-ferric metals) domestic wasteplant may be exposed to airborne biological agents, especially fungi andgram-negative bacteria(AU)

Crystal structure and DNA interaction of the facial-type rac-tris[2-(aminomethyl)benzimidazole]cobalt(III) complex.

rac-[Co(ambi)3]Cl3.3H2O corresponds to a tris-chelate complex bearing 2-(aminomethyl)benzimidazole (ambi) ligands bound to the Co(III) ion in a facial-type fashion. The high metal q/r ratio and electronic delocalization between coordination heterocyclic functionalities can provide powerful tools to minimize DNA condensation, which arises from the neutralization of the negatively charged sugar phosphate backbone in the presence of multivalent [Co(ambi)3]3+.

A singular noninterpenetrating coordination polymer with the Pt3O4 structure containing naked [Na+]4 units.

The homoleptic low-spin complex [Fe(L)3]2+ where L is the bisbidentate ligand 1,10-phenanthroline-5,6-dione, coordinates Na+ ions via exo-oriented dione groups defining a three-dimensional cationic network {[Fe(L)3]4Na3}11+}n with Pt3O4 topology. The large volume generated by the network is filled with 11 perchlorate ions, 7 "NaClO4" ionic pairs, and 9 H2O molecules. Singular [Na+]4 units, in which the Na+ ions are practically uncoordinated, are formed.

Unprecedented intermolecular C-H bond activation of a solvent toluene molecule leading to a seven-membered platinacycle.

A novel platinum-mediated process involving intermolecular activation of a C(aryl)-H bond of toluene, intramolecular activation of an imine C(aryl)-Cl bond and formation of a C-C bond is reported.