Role of Counterions in the Structural Stabilisation of Redox-Active Metal-Organic Frameworks.

The crystal structures of metal-organic frameworks (MOFs) are typically determined by the strong chemical bonds formed between the organic and inorganic building units. However, the latest generation of redox-active frameworks often rely on counterions in the pores to access specific charge states of the components. Here, we model the crystal structures of three layered MOFs based on the redox-active ligand 2,5-dihydroxybenzoquinone (dhbq): Ti2 (Cl2 dhbq)3 , V2 (Cl2 dhbq)3 and Fe2 (Cl2 dhbq)3 with implicit and explicit counterions. Our full-potential first-principles calculations indicate that while the reported hexagonal structure is readily obtained for Ti and V, the Fe framework is stabilised only by the presence of explicit counterions. For high counterion concentrations, we observe the formation of an electride-like pocket in the pore center. An outlook is provided on the implications of solvent and counterion control for engineering the structures and properties of porous solids.

Did anomalous atmospheric circulation favor the spread of COVID-19 in Europe?

The current pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is having negative health, social and economic consequences worldwide. In Europe, the pandemic started to develop strongly at the end of February and beginning of March 2020. Subsequently, it spread over the continent, with special virulence in northern Italy and inland Spain. In this study we show that an unusual persistent anticyclonic situation prevailing in southwestern Europe during February 2020 (i.e. anomalously strong positive phase of the North Atlantic and Arctic Oscillations) could have resulted in favorable conditions, e.g., in terms of air temperature and humidity among other factors, in Italy and Spain for a quicker spread of the virus compared with the rest of the European countries. It seems plausible that the strong atmospheric stability and associated dry conditions that dominated in these regions may have favored the virus propagation, both outdoors and especially indoors, by short-range droplet and aerosol (airborne) transmission, or/and by changing social contact patterns. Later recent atmospheric circulation conditions in Europe (July 2020) and the U.S. (October 2020) seem to support our hypothesis, although further research is needed in order to evaluate other confounding variables. Interestingly, the atmospheric conditions during the Spanish flu pandemic in 1918 seem to have resembled at some stage with the current COVID-19 pandemic.

Prevalence and variables associated with solitary pulmonary nodules in a routine clinic-based population: a cross-sectional study.

OBJECTIVE: To determine the prevalence of solitary pulmonary nodules (SPNs) in chest radiology studies and patient's features associated with malignancy in a non-high-risk clinical population. METHODS: Patients ≥35 years were referred for thoracic imaging in two hospitals (2010-2011). Eight radiologists determined the presence and characteristics of SPN. Selected variables were collected from radiological register and medical records. Observer agreement in the diagnosis of SPN was assessed. RESULTS: 25,529 patients were included: 23,102 (90.5%) underwent chest radiograph and 2,497 (9.5%) a CT. The prevalence of SPN was 2.1% (95% CI 1.9 - 2.3) in radiographs and 17.0% (95% CI 15.5 - 18.5) in CT. In patients undergoing chest radiograph, detection of SPN with an irregular border was more frequent among smokers. In patients who had a CT, larger SPNs appeared to be associated with 60 years of age or over, diagnosis of a respiratory illness, or male gender. In addition, an irregular border was also more common among men. CONCLUSIONS: The prevalence of SPNs detected by both radiograph and CT was lower than that shown in screening studies. Patient characteristics such as age, sex, respiratory disease, or smoking habit were associated with nodule characteristics that are known to be related with malignancy. KEY POINTS: There is a lower SPN prevalence in the clinical population than in screening studies. SPN prevalence is associated with some patient characteristics: sex, age, imaging test. Nodule characteristics related to malignancy were associated with some patient characteristics.

Restoration of hepatic glycogen deposition reduces hyperglycaemia, hyperphagia and gluconeogenic enzymes in a streptozotocin-induced model of diabetes in rats.

AIMS/HYPOTHESIS: Glycogen deposition is impaired in diabetes, thus contributing to the development of hyperglycaemia. Several glucose-lowering strategies have attempted to increase liver glycogen deposition by modulating targets, which eventually trigger the activation of liver glycogen synthase (LGS). However, these targets also alter several other biological processes, and therefore their therapeutic use may be limited. Here we tested the approach of directly activating LGS and evaluated the potential of this strategy as a possible treatment for diabetes. METHODS: In this study, we examined the efficacy of directly overproducing a constitutively active form of LGS in the liver to ameliorate streptozotocin-induced diabetes in rats. RESULTS: Activated mutant LGS overproduction in the liver of streptozotocin-induced diabetic rats normalised liver glycogen content, despite low levels of glucokinase and circulating insulin. Moreover, this overproduction led to a decrease in food intake and in the production of the main gluconeogenic enzymes, glucose-6-phosphatase, fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase. The resulting combined effect was a reduction in hyperglycaemia. CONCLUSIONS/INTERPRETATION: The restoration of liver glycogen ameliorated diabetes and therefore is considered a potential strategy for the treatment of this disease.

[High retention of (99m)Tc-MIBI in delayed phase as a pitfall in the combined parathyroid-thyroid scintigraphy]. / Intensa retención de (99m)Tc-MIBI en la fase tardía como causa de error diagnóstico en la gammagrafía combinada paratiroides-tiroides.

Dual phase parathyroid scintigraphy with (99m)Tc-sestaMIBI is a very sensitive technique in the preoperative localization and diagnosis of parathyroid adenoma. However, pitfalls have been reported in patients with thyroid nodules with MIBI uptake or with previous thyroid surgery. To solve this problem, a thyroid scintigraphy with (99m)Tc-pertechnetate is usually performed following the parathyroid study. Occasionally, as in our patient the parathyroid lesion may show high MIBI uptake and delayed washout that interfere with the subsequent thyroid scintigraphy giving the false appearance of a pertechnetate avid lesion. This has been called the «shine through¼ effect. To avoid it, the parathyroid and thyroid scintigraphies can be performed on separate days. We have also found it useful to compare our results with that of ultrasound and fine needle aspiration puncture with measurement of the parathyroid hormone (PTH) and thyroglobulin in the aspirated material.

[MRI visualization of venous drainage helps determine the origin of pelvic masses.]. / Visualización por resonancia magnética del drenaje venoso en las masas pélvicas: una ayuda para filiar su origen.

OBJECTIVE: To evaluate the usefulness of detecting at MRI an ovarian vascular pedicle or prominent vessels between the uterus and large tumors for determining whether masses originate in the ovary or uterus. MATERIAL AND METHODS: We reviewed MRI studies from 80 patients with histologically confirmed pelvic masses greater than 7cm in diameter. We evaluated the presence of gonadal veins draining the tumors and the presence of vessels between the surface of the lesion and the uterus. RESULTS: We detected gonadal veins draining the pelvic masses in 36 of the 43 tumors originating in the ovaries (84%); we detected vessels between the uterus and the pelvic mass in 30 of the 37 tumors that originated in the uterus (81%). The sensitivity, specificity, and positive and negative predictive values for the presence of gonadal veins draining the lesion were 84%, 95%, 95%, and 83%, respectively, for ovarian masses, and 81%, 91%, 88%, and 85%, respectively, for vessels between the uterus and the mass in subserous myomas. CONCLUSION: Evaluating the venous drainage of pelvic tumors is very useful in cases in which it is not easy to establish the origin of the tumor.

The fate of pancreatic tumor cell lines following p16 overexpression depends on the modulation of CDK2 activity.

Restitution of lost tumor-suppressor activities may be a promising strategy to target specifically cancer cells. However, the action of ectopically expressed tumor-suppressor genes depends on genetic background of tumoral cells. Ectopic expression of p16(INK4a) induces either cell cycle arrest or apoptosis in different pancreatic cancer cell lines. We examined the molecular mechanisms mediating these two different cellular responses to p16 overexpression. Ectopic expression of p16 leads to G1 arrest in NP-9 cells by redistributing p21/p27 CKIs and inhibiting cyclin-dependent kinase CDK2 activity. In contrast, in NP-18 cells cyclin E (CycE)/CDK2 activity is significantly higher and is not downregulated by p16-mediated redistribution of p21/p27. Moreover, inhibition of CDK4 activity with fascaplysine, which does not affect CycE/CDK2 activity, reduces pocket protein phosphorylation in both cell lines, but fails to induce growth arrest. Like overexpression of p16, fascaplysine induces apoptosis in NP-18 cells, suggesting that inhibition of D-type cyclin/CDK activity in cells with high levels of CycE/CDK2 activity activates an apoptotic pathway. Inhibition of CycE/CDK2 activity via ectopic expression of p21 in NP-18 cells overexpressing p16 induces growth arrest and prevents p16-mediated apoptosis. Accordingly, silencing of p21 expression by using small interfering RNA switches the fate of p16-expressing NP-9 cells from cell cycle arrest to apoptosis. Our data suggest that, after CDK4/6 inactivation, the fate of pancreatic tumor cells depends on the ability to modulate CDK2 activity.

Modulation of drug cytotoxicity by reintroduction of wild-type p53 gene (Ad5CMV-p53) in human pancreatic cancer.

Chemotherapy does not significantly improve prognosis in pancreatic cancer. New therapeutical approaches involving p53 gene replacement appear to be very encouraging due to the key role of p53 in the cell response to DNA damage. Here, we have evaluated the effectiveness of combining wild-type p53 (wt-p53) gene reintroduction (Ad5CMV-p53) and exposure to two genotoxic drugs, gemcitabine and cisplatin, in several human pancreatic cell lines. The efficiency of the combinations was clearly dependent upon timing, as assessed by cell survival determinations. Although wt-p53 transduction before drug treatment induced chemoresistance, p53 transduction in cells treated previously with gemcitabine increased cytotoxicity. Cell cycle profiles showed significant decreases in the percentage of cells in the S phase as a consequence of arrests provoked by the expression of exogenous p53, reducing the number of cells susceptible to the drug. The sensitivity of cells to cisplatin, which has a lower degree of S-phase specificity, was not modified as much by p53 gene replacement. In contrast, the recognition of the previous drug-induced DNA damage by the newly expressed wt-p53 elicited increases in sub-G1 populations, consistent with the annexin determinations and bax/bcl-2 ratios observed. Experiments on subcutaneous pancreatic xenografts corroborated the effectiveness of this approach in vivo. Thus, the combination of p53 transduction and chemotherapy, under a correct schedule of administration, appears to be a very promising therapy for human pancreatic cancer.

Adenovirus-mediated wt-p16 reintroduction induces cell cycle arrest or apoptosis in pancreatic cancer.

Pancreatic cancer has long carried poor prognosis. The development of new therapeutic approaches is particularly urgent. Inactivation of the tumor-suppressor gene p16(INK4a/CDKN2), a specific inhibitor of the cyclin-dependent kinases CDK4 and CDK6, is the most common genetic alteration in human pancreatic cancer, making it an ideal target for gene replacement. Here we transfected tumor cells using a recombinant adenovirus containing the wt-p16 cDNA (Ad5RSV-p16). The overexpression of p16 decreased cell proliferation in all four human pancreatic tumor cell lines (NP-9, NP-18, NP-29, and NP-31). However, G1 arrest and senescence were observed in only three. In contrast, the fourth (NP-18) showed a significant increase in apoptosis. This differential behavior may be related to the differences found in the expression level of E2F-1. Experiments on subcutaneous pancreatic xenografts demonstrated the effectiveness of p16 in the inhibition of pancreatic tumor growth in vivo. Taken together, our results indicate that approaches involving p16 replacement are promising in pancreatic cancer treatment.

Sodium tungstate modulates ATM function upon DNA damage.

Both radiotherapy and most effective chemotherapeutic agents induce different types of DNA damage. Here we show that tungstate modulates cell response to DNA damaging agents. Cells treated with tungstate were more sensitive to etoposide, phleomycin and ionizing radiation (IR), all of which induce DNA double-strand breaks (DSBs). Tungstate also modulated the activation of the central DSB signalling kinase, ATM, in response to these agents. These effects required the functionality of the Mre11-Nbs1-Rad50 (MRN) complex and were mimicked by the inhibition of PP2A phosphatase. Therefore, tungstate may have adjuvant activity when combined with DNA-damaging agents in the treatment of several malignancies.

Genotype-phenotype relationships in a mouse model for human small-cell lung cancer.

Lung tumors are usually classified into small-cell lung cancer (SCLC) or non-SCLC (NSCLC) depending on their pathological and histological characteristics. SCLC is defined not only by its characteristic neuroendocrine differentiation, aggressiveness, and metastatic potential, but also by a specific set of genetic aberrations, including the loss of the tumor suppressor genes p53 and Rb1 and the amplification of any member of the Myc family of oncogenes. We have previously described a mouse model of SCLC by somatic conditional disruption of Trp53 and Rb1 genes that closely resembles the human condition. Based on the possibility to study early tumor lesions and to culture and subclone progressed tumors and metastases, we discuss here a strategy to define genotype-phenotype relationships that can explain the underlying biology of lung neuroendocrine tumors. We have found that tumors may be constituted by genetically variant cell populations, which might represent different progression stages. Interestingly, we observed L-myc amplification and Ascl-1 expression in those populations showing neuroendocrine differentiation. Non-neuroendocrine cell populations from the same tumors did not show L-myc amplification nor Ascl-1 expression. We propose that this genetic divergence can play a relevant role in the definition of some phenotypic characteristics like metastasis potential or chemoresistance.

Treatment based on a combination of the CYP2B1/cyclophosphamide system and p53 delivery enhances tumour regression in human pancreatic cancer.

BACKGROUND: Strategies based on the introduction of pro-drug activating enzymes or the restoration of tumour suppressor genes have been proposed as encouraging methods to improve the efficiency of treatments in pancreatic cancer. The in situ bioactivation of cyclophosphamide by cytochrome p450-2B1 and subsequent p53 delivery were examined. MATERIALS AND METHODS: NP-18 cell line derived from a human pancreatic adenocarcinoma was treated in vitro with a combination of the Adenovirus-CYP2B1/cyclophosphamide and adenoviral-mediated wt-p53 reintroduction. Cell viability and cytometric cell cycle profiles were analyzed to evaluate the sensitivity of NP-18 cells to this treatment. The efficiency of this combination was assessed in an in vivo model consisting of xenografts into the subcutaneous tissue of Balb/c mice by tumour growth, histological analysis and cell cycle determinations. RESULTS: Ad-CYP2B1/cyclophosphamide or Ad-p53 treatments led to a marked decrease in cell viability of NP-18 cells. Combination of both treatments elicited a higher loss of cell viability and marked increases in sub-G1 population in cell cycle profiles. Animals treated with the combination strategy showed a quick reduction of tumour volumes due to the bioactivation of cyclophosphamide by CYP2B1 and sustained growth inhibition throughout the period evaluated after p53 delivery. Only this group of animals presented statistically significant differences with respect to control and cyclophosphamide-treated groups (P < 0.05). CONCLUSIONS: These results indicate that in situ bioactivation of cyclophosphamide by CYP2B1 and the recognition of the damaged DNA by p53 increase tumour regressions and may be a promising therapy for solid tumour therapy in man.

Expression profiles of a human pancreatic cancer cell line upon induction of apoptosis search for modulators in cancer therapy.

We analyzed the differential gene expression in the pancreatic cancer cell line NP-18 upon induction of apoptosis caused by cyclin-dependent kinase inhibition triggered by either overexpression of the tumor suppressor gene p16(INK4A)using an adenoviral construction or incubation with the chemical inhibitors, roscovitine or olomoucine. Screening was performed using cDNA arrays from Clontech that allowed the determination of the expression of 1,176 genes specifically related with cancer. The analysis was carried out using the Atlas Image 2.01 (Clontech) and GeneSpring 4.2 (Silicon Genetics) softwares. Among the differentially expressed genes, we chose for further validation histone deacetylase 1 (HDAC1), von Hippel Lindau and decorin as upregulated genes, and Sp1, hypoxia-inducible factor-1 alpha and DNA primase as downregulated genes. The changes in the expression of these genes to mRNA were validated by quantitative RT-PCR and the final translation into protein by Western blot analysis. Inhibition of HDAC activity, Sp1 binding and DNA primase expression led to an increase in the level of apoptosis, both in parental cells and in doxorubicin-resistant cells. Therefore, these proteins could constitute possible targets to develop modulators in cancer chemotherapy that would increase or restore apoptosis.