Challenges in treating radioiodine-refractory thyroid cancer: a global perspective with a focus on developing nations in Latin America.

PURPOSE: This article aims to comprehensively analyze the unique challenges in managing patients with metastatic Differentiated Thyroid Cancer (DTC) that develop radioiodine-refractory disease, especially in developing countries in Latin America. We discuss key contentious aspects of their treatment, such as the optimal timing for initiating systemic therapy, the choice of first-line medications, the appropriate timing for requesting molecular interrogation, and the challenges associated with accessing these drugs and molecular panels. METHODS: To illustrate these challenges and enhance understanding, we present five real clinical cases from the authors' experiences. RESULTS: Patients with Differentiated Thyroid Cancer (DTC) generally have an excellent prognosis, with an overall 10-year survival rate exceeding 97%. However, approximately 5% of DTC patients, especially those with distant metastases, may develop radioiodine-refractory disease, reducing survival rates. Access to medications remains difficult and time-consuming, particularly for patients within the public healthcare system. Urgent discussions on drug pricing involving all stakeholders are imperative. To break free from complacency, stakeholders must prioritize patient well-being by advocating for evidence-based drug pricing, increased participation in clinical trials, and streamlined regulatory processes. CONCLUSION: Beyond the recognized need for prospective randomized clinical trials to determine the optimal first-line drug and the timing of molecular testing, this type of manuscript plays a pivotal role in stimulating discussions and disseminating comprehensive knowledge about the challenges associated with treating and monitoring patients with radioiodine-refractory thyroid carcinoma, especially in developing countries.

The role of Zn ions in the interaction between SARS-CoV-2 orf7a protein and BST2/tetherin.

In this paper, we provide evidence that Zn 2 + ions play a role in the SARS-CoV-2 virus strategy to escape the immune response mediated by the BST2-tetherin host protein. This conclusion is based on sequence analysis and molecular dynamics simulations as well as X-ray absorption experiments [1].

Metal Ion Binding in Wild-Type and Mutated Frataxin: A Stability Study.

This work studies the stability of wild-type frataxin and some of its variants found in cancer tissues upon Co2+ binding. Although the physiologically involved metal ion in the frataxin enzymatic activity is Fe2+, as it is customarily done, Co2+ is most often used in experiments because Fe2+ is extremely unstable owing to the fast oxidation reaction Fe2+ → Fe3+. Protein stability is monitored following the conformational changes induced by Co2+ binding as measured by circular dichroism, fluorescence spectroscopy, and melting temperature measurements. The stability ranking among the wild-type frataxin and its variants obtained in this way is confirmed by a detailed comparative analysis of the XAS spectra of the metal-protein complex at the Co K-edge. In particular, a fit to the EXAFS region of the spectrum allows positively identifying the frataxin acidic ridge as the most likely location of the metal-binding sites. Furthermore, we can explain the surprising feature emerging from a detailed analysis of the XANES region of the spectrum, showing that the longer 81-210 frataxin fragment has a smaller propensity for Co2+ binding than the shorter 90-210 one. This fact is explained by the peculiar role of the N-terminal disordered tail in modulating the protein ability to interact with the metal.

Functional capacity, lung function, and muscle strength in patients undergoing hematopoietic stem cell transplantation: A prospective cohort study.

OBJECTIVE/BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a treatment for benign and malignant hematological diseases. These aggressive treatments cause reduced levels of physical activity, decreased lung function, and worse quality of life. Alterations in pulmonary function tests before HSCT are associated with the risk of respiratory failure and early mortality. The objective of this study was to evaluate functional capacity and lung function before and after HSCT and identify the predictors of mortality after 2 years. METHODS: A prospective cohort study was carried out with individuals with oncohematological diseases. The evaluations were carried out in two moments during hospitalization and at hospital discharge. Follow-up was carried out after 48 months. Assessments were carried out on 34 adults, using spirometry, manovacuometry, 6-Minute Walk Test (6MWT), Handgrip Strength Test, and 30-Second Chair Stand Test (30-s CST). RESULTS: There was a statistically significant reduction for the variables in forced vital capacity, forced expiratory volume predicted in the 1st second, Tiffeneau index, handgrip strength, and distance covered (% predicted) on the 6MWT (p < .05). There was a significant difference in the 30-s CST when individuals were compared according to the type of transplant. We found that a 10% reduction in the values of maximum inspiratory pressure (MIP) can predict an increased risk for mortality. CONCLUSIONS: Individuals undergoing HSCT have reduced functional capacity, lung function, and muscle strength during the hospitalization phase. Reduction in the values of MIP increases the risk of nonrelapse mortality.

The Centre for Data and Knowledge Integration for Health (CIDACS): Linking Health and Social Data in Brazil.

The Centre for Data and Knowledge Integration for Health (CIDACS) was created in 2016 in Salvador, Bahia-Brazil with the objective of integrating data and knowledge aiming to answer scientific questions related to the health of the Brazilian population. This article details our experiences in the establishment and operations of CIDACS, as well as efforts made to obtain high-quality linked data while adhering to security, ethical use and privacy issues. Every effort has been made to conduct operations while implementing appropriate structures, procedures, processes and controls over the original and integrated databases in order to provide adequate datasets to answer relevant research questions. Looking forward, CIDACS is expected to be an important resource for researchers and policymakers interested in enhancing the evidence base pertaining to different aspects of health, in particular when investigating, from a nation-wide perspective, the role of social determinants of health and the effects of social and environmental policies on different health outcomes.

Effect of Brazil's conditional cash transfer programme on tuberculosis incidence.

OBJECTIVE: To evaluate the impact of the Brazilian cash transfer programme (Bolsa Família Programme, BFP) on tuberculosis (TB) incidence in Brazil from 2004 to 2012. DESIGN: We studied tuberculosis surveillance data using a combination of an ecological multiple-group and time-trend design covering 2458 Brazilian municipalities. The main independent variable was BFP coverage and the outcome was the TB incidence rate. All study variables were obtained from national databases. We used fixed-effects negative binomial models for panel data adjusted for selected covariates and a variable representing time. RESULTS: After controlling for covariates, TB incidence rates were significantly reduced in municipalities with high BFP coverage compared with those with low and intermediate coverage (in a model with a time variable incidence rate ratio = 0.96, 95%CI 0.93-0.99). CONCLUSION: This was the first evidence of a statistically significant association between the increase in cash transfer programme coverage and a reduction in TB incidence rate. Our findings provide support for social protection interventions for tackling TB worldwide.

Genomic diversity and immunomodulatory activity of Lactobacillus plantarum isolated from dairy products.

In this study, we aimed to investigate some functional characteristics and the immunomodulatory properties of three strains of Lactobacillus plantarum of dairy origin which, in a previous screening, showed to be candidate probiotics. Genome sequencing and comparative genomics, which confirmed the presence of genes involved in folate and riboflavin production and in the immune response of dendritic cells (DCs), prompted us to investigate the ability of the three strains to accumulate the two vitamins and their immunomodulation properties. The ability of the three strains to release antioxidant components in milk was also investigated. Small amounts of folate and riboflavin were produced by the three strains, while they showed a good antioxidant capacity in milk with FRAP method. The immune response experiments well correlated with the presence of candidate genes influencing in DCs cytokine response to L. plantarum. Specifically, the amounts of secreted cytokins by DCs after stimulation with cells of Lp790, Lp813 and Lp998 resulted pro-inflammatory whereas stimulation with culture supernatants (postbiotics) inhibited the release of interleukin (IL)-12p70 and increased the release of the anti-inflammatory IL-10 cytokine. This study adds further evidence on the importance of L. plantarum in human health. Understanding how probiotics (or postbiotics) work in preclinical models can allow a rational choice of the different strains for clinical and/or commercial use.

A first-principle calculation of the XANES spectrum of Cu(2+) in water.

The progress in high performance computing we are witnessing today offers the possibility of accurate electron density calculations of systems in realistic physico-chemical conditions. In this paper, we present a strategy aimed at performing a first-principle computation of the low energy part of the X-ray Absorption Spectroscopy (XAS) spectrum based on the density functional theory calculation of the electronic potential. To test its effectiveness, we apply the method to the computation of the X-ray absorption near edge structure part of the XAS spectrum in the paradigmatic, but simple case of Cu(2+) in water. In order to keep into account the effect of the metal site structure fluctuations in determining the experimental signal, the theoretical spectrum is evaluated as the average over the computed spectra of a statistically significant number of simulated metal site configurations. The comparison of experimental data with theoretical calculations suggests that Cu(2+) lives preferentially in a square-pyramidal geometry. The remarkable success of this approach in the interpretation of XAS data makes us optimistic about the possibility of extending the computational strategy we have outlined to the more interesting case of molecules of biological relevance bound to transition metal ions.

Predictive factors of malignancy in thyroid nodules with repeatedly nondiagnostic cytology (Bethesda category I): value of ultrasonography.

One possible result of fine-needle aspiration (FNA) of thyroid nodules is "nondiagnostic" cytology. Consensus exists in these cases to repeat FNA guided by ultrasonography (US), but the result obtained may continue to be nondiagnostic. The objective of this study was to evaluate predictive factors of malignancy (including US) in nodules with indication for FNA whose cytology result was classified as "nondiagnostic" on 2 occasions. The sample consisted of 158 patients with thyroid nodules >5 mm with indication for FNA whose material obtained by US-guided FNA was classified as nondiagnostic on 2 occasions according to the criteria of the Bethesda classification. Papillary thyroid carcinoma (PTC) was confirmed by histology in 23/158 cases (14.5%). Sex, age, family history of PTC, palpation, number of nodules, serum TSH, or circulating antithyroperoxidase antibodies were not predictors of malignancy. Only US predicted risk of malignancy. US showed a sensitivity of 65.2% and a specificity of 90.4%. When US indicated the nodule to be "suspicious for malignancy", histology confirmed PTC in 15/28 cases (positive predictive value 53.4%). When the nodule showed no suspicious US features, histology detected malignancy in only 8/130 cases (negative predictive value 94%). The diagnostic accuracy of the US was 89.5%. The present results suggest that, in cases of patients with thyroid nodules and repeatedly nondiagnostic cytology, ultrasonographic findings represent an excellent parameter for the selection of those who could be followed up by periodic US and those who should be referred for thyroidectomy because of the risk of malignancy.

MDR-1 polymorphisms (G2677T and C3435T) in B-chronic lymphocytic leukemia: an impact on susceptibility and prognosis.

Patients with B-chronic lymphocytic leukemia present diverse clinical features, genetic abnormalities, variable response to treatment, and heterogeneous prognosis. Novel biological markers such as IgVH mutation, CD38, and ZAP-70 expression have shown to offer important prognostic information. An altered expression of the multidrug resistance 1 may represent an additional prognostic marker. Aim of our study was to evaluate two MDR-1 gene polymorphisms: G2677T polymorphism in exon 21 and C3435T polymorphism in exon 26, to evidence if polymorphisms influence the risk of development of B-CLL and whether genomic polymorphisms provide prognostic information on the clinical progression of the disease. A total of 125 patients with B-CLL and 125 healthy subjects were enrolled in this study. The mutant homozygous 2677 TT genotype was found to be associated with the occurrence of B-CLL and higher T allele frequency in patients with B-CLL when compared with controls was observed (P=0.009). When comparing the prognostic patients' characteristics, patients with 2677 GT genotype were statistically linked to the unmutated IgVH genes (r=0.209, P=0.01). Moreover, the same genotype was correlated with lymphocyte number (r=0.269, P=0.02). Finally for the 2677GT polymorphism, the heterozygous status was associated with higher hemoglobin levels (r=0.247, P=0.005). As far the C3435T MDR1 polymorphism, we were not able to identify any significant correlation with IgVH gene status or other variables. In conclusion, MDR1 gene polymorphism could be a factor predisposing to LLC. Moreover, our findings support the possibility of considering these genomic polymorphisms as prognostic markers in patients with B-CLL.

Human prostatic urethra expresses vitamin D receptor and responds to vitamin D receptor ligation.

BACKGROUND: Chronic inflammation is now considered a determinant of benign prostatic hyperplasia (BPH), promoting, together with the hormonal milieu, prostate overgrowth and lower urinary tract symptoms (LUTS). Prostatic urethra actively participates in determining progression of LUTS associated with BPH. AIM: To investigate the expression of the vitamin D receptor (VDR) and the ability of the VDR agonist elocalcitol to reduce inflammatory responses in human prostatic urethra (hPU) cells. MATERIALS AND METHODS: Human prostatic urethra, prostate and bladder neck were obtained from patients affected by BPH. Immunohistochemical studies for VDR expression were performed in tissue samples, from which primary cell cultures were also derived. In hPU cells, proliferation and chemiotaxis were studied, along with Rho kinase (ROCK) activity (MYPT-1 phosphorylation) by western blot. Quantitative RT-PCR was performed for VDR, cyclooxygenase (COX-2), and interleukin (IL)-8 expression. RESULTS: Urethra displays higher VDR expression compared to prostate and bladder neck tissues. The VDR agonist elocalcitol partially reverts COX-2 and IL-8 mRNA upregulation induced by a pro-inflammatory cytokine mixture (IL-17, interferon-γ, tumor necrosis factor-α) and inhibits cell migration in urethral cells. Elocalcitol prevents activation of ROCK, as previously demonstrated in bladder and prostate cell cultures. CONCLUSIONS: Our results suggest that prostatic urethra is, within the lower urinary tract, a novel target for VDR agonists, as shown by the capacity of elocalcitol to inhibit ROCK activity and to limit inflammatory responses in human primary urethra cells.

Chronic inflammation in the pathogenesis of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a common disorder affecting 50-80% of the aged male population. Androgens and age have been traditionally considered the main determinants of prostate enlargement, but in the last years a potentially important role of chronic inflammation in BPH pathogenesis has emerged. Bacterial and non-infectious chronic prostatitis could represent inciting factors leading to tissue hyperproliferation, possibly via the recently demonstrated antigen-presenting capacity of prostatic stromal cells, enabling them to induce and sustain intraglandular immune responses. The prostate growth-promoting chemokine IL-8 could represent a direct link between chronic prostate inflammation and autocrine/paracrine stromal cell proliferation, in agreement with its marked secretion induced in BPH stromal cells by a combination of Th1 and Th17 cell-derived inflammatory cytokines. BPH stromal cells express the vitamin D receptor (VDR), which is up-regulated by exposure to inflammatory stimuli. The non-hypercalcaemic VDR agonist elocalcitol, shown to arrest BPH development by decreasing the intra-prostatic androgen signalling without directly interfering with systemic androgen action, exerts immunoregulatory and anti-inflammatory properties in different prostatic pathology characterized by growth and inflammation. The mechanism of action of VDR agonists supports an important role of chronic inflammation in BPH pathogenesis and strengthens the concept of these agents as a therapeutic option for pharmacological treatment of BPH.

Soluble CD138 serum levels are not associated with other poor prognostic markers in patients with B-chronic lymphocytic leukaemia.

The clinical course of CLL is highly variable, and survival from the time of diagnosis of CLL can range from months to decades. Novel biological markers such as IgVH mutation, CD38, and ZAP-70 expression have shown to offer important prognostic informations. Few reports deal with the sCD138 levels and bad prognostic factors in patients with CLL, and contrasting data are reported in literature. In our study, we evaluated the serum level of sCD138 in patients with B-CLL and its relationship with other prognostic markers. There was a significant association between advanced Rai stage and serum sCD138 levels in CLL subjects. Patients with Rai stage III-IV had significantly higher levels of sCD138 with respect to controls (48.85±34 ng/ml vs. 31.1±19.34 ng/ml; P<0.05). We were unable to demonstrate a significant association between sCD138 serum levels and IgVH gene status, ZAP-70 expression, CD38 expression, beta-2 microglobulin, absolute peripheral blood lymphocytosis, haemoglobin or LDH levels. Our finding that high sCD138 serum levels correlates with advanced stages in patients with B-CLL is consistent with the possibility molecule can identify patients with high tumour burden, but the lack of correlation between sCD138 serum levels and markers such the mutation status of IgVH, ZAP-70, and CD38 suggests that sCD138 levels only reflect the clinical stage of disease than the clinical course or progression.

Evaluation of circulating endothelial cells, VEGF and VEGFR2 serum levels in patients with chronic myeloproliferative diseases.

Authors evaluated some markers of angiogenetic activity in patients with chronic myeloproliferative diseases (CMDs). In this study by using a cytofluorimetric analysis we evaluated circulating endothelial progenitor cells (EPCs) in patients with chronic myeloproliferative disease. Moreover, in the same group of subjects, we evaluated serum levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR2). In our patients, we have found an increase in the number of endothelial progenitor cells in primary myelofibrosis (PMF) and polycythaemia vera (PV) patients, while an increase of circulating endothelial cells (CECs) was found in all patients with CMD. Moreover, we found higher serum levels of VEGF with respect to control subjects in every group of patients with CMD, and a not significant reduction of VEGFR2 levels in essential thrombocythaemia (ET) patients. A correlation was also found in PV patients between VEGF levels and erythrocyte number and in PMF subjects with the count of white cells. Our data suggest that some markers of angiogenesis are activated in CMD patients and angiogenesis may have a role in the pathophysiology of chronic myeloproliferative disorders.

Studying the Cu binding sites in the PrP N-terminal region: a test case for ab initio simulations.

First principle ab initio molecular dynamics simulations of the Car-Parrinello type have proved to be of invaluable help in understanding the microscopic mechanisms of chemical bonding both in solid state physics and in structural biophysics. In this work we present as a test case a study of the Cu coordination mode at the Prion Protein binding sites localized in the N-terminal octarepeat region. Using medium size PC-clusters, we are able to deal with systems with up to about 350 atoms and 10(3) electrons for as long as approximately 2 ps. With a foreseeable forthcoming scaling up of the available CPU times by a factor 10(3), one can hope to be soon able to simulate systems of biological interest of realistic size and for physical times of the order of the nanosecond.

Manipulating dendritic cells to induce regulatory T cells.

Dendritic cells (DCs) induce and regulate T-cell responses, and tolerogenic DCs can promote the development of regulatory T cells with suppressive activity. The possibility of manipulating DCs using different pharmacological or biological agents, enabling them to exert tolerogenic activities, could be exploited to better control a variety of chronic inflammatory conditions, from autoimmune diseases to allograft rejection.

Modeling the dynamics of the solvated SL1 domain of HIV-1 genomic RNA.

A mode-coupling solution of the Smoluchowski diffusion equation (MCD theory), designed to describe the dynamics of wobbling macromolecules in water, is applied to a macromolecular bead model including water beads in the nearest layers. The necessary statistical averages are evaluated by time averaging along a molecular dynamics (MD) trajectory where both solute and water are introduced as atomistic models. The cross peaks in (1)H nuclear Overhauser effect spectroscopy (NOESY) NMR spectra that are routinely measured to determine biological structures are here calculated for the mutated 23 nucleotides stem-loop fragment of the SL1 domain in the HIV-1(Lai) genomic RNA. The calculations are in acceptable agreement with experiments without requiring any screening of the hydrodynamic interactions. The screening of hydrodynamics was necessary in previous MCD calculations obtained by using the same full atomistic MD trajectory, but a nonsolvated frictional model.

Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains.

Interleukin (Il)-12 is a heterodimeric cytokine composed of 35 and 40 kD chains that plays a key role in the induction of Th1 cells, a T cell subset involved in many autoimmune diseases. We report here the cDNA sequence encoding the IL-12 p40 subunit from the autoimmune-prone non-obese diabetic (NOD) mouse, which spontaneously develops type 1 diabetes. Compared with the C57BL/6 sequence, there are two base changes that lead to amino acid replacements. Other autoimmune-prone strains, but not the diabetes-resistant NOR strain, share the same allele as NOD. We found both trans- and cis- allele-dependent effects on levels of basal and induced IL-12p40 expression. Furthermore, we show that one of these changes results in a structural change in the p40 molecule, as evidenced by the failure of a monoclonal antibody to bind NOD IL-12. These findings have implications for the predisposition to autoimmune responses in NOD and other autoimmune-prone mouse strains.

IL-12 administration reveals diabetogenic T cells in genetically resistant I-Ealpha-transgenic nonobese diabetic mice: resistance to autoimmune diabetes is associated with binding of Ealpha-derived peptides to the I-A(g7) molecule.

Nonobese diabetic (NOD) and NOD-DRalpha transgenic (tg) mice, expressing Aalpha(d):Abeta(g7) and Aalpha(d):Abeta(g7) plus DRalpha:Ebeta(g7) class II molecules, respectively, both develop insulin-dependent diabetes mellitus (IDDM), whereas NOD-Ealpha tg mice expressing Aalpha(d):Abeta(g7) plus Ealpha:Ebeta(g7) are protected. We show that IL-12 administration induces rapid IDDM onset in NOD-DRalpha but fails to provoke insulitis and diabetes in NOD-Ealpha tg mice. Nevertheless, T cells from IL-12-treated NOD-Ealpha tg mice secrete IFN-gamma and transfer IDDM to NOD-SCID and NOD-Ealpha-SCID recipients, demonstrating the presence of peripheral diabetogenic Th1 cells in the protected mice. Surprisingly, regulatory cells were undetectable. Moreover, Ealpha:Ebeta(g7) could substitute for DRalpha:Ebeta(g7) in Ag presentation, arguing against mechanisms of protection involving capture of diabetogenic I-A(g7)-restricted epitopes by Ealpha:Ebeta(g7)molecules. Interestingly, the expression of naturally processed epitopes derived from DRalpha- and Ealpha-chains bound to I-A(g7) is different in the two strains of tg mice, and the difference is enhanced by IL-12 administration. I-A(g7) molecules from both NOD-DRalpha and NOD-Ealpha tg mice present the conserved DRalpha/Ealpha 52-68 sequence, at high and low levels, respectively. In addition, only IDDM-resistant NOD-Ealpha tg mice possess APCs bearing Ealpha65-77/I-A(g7) complexes, which tolerize the specific T cells. This is associated with the selective inhibition of the response to insulinoma-associated protein 2 (IA-2), an autoantigen in IDDM. Our results support protective mechanisms based on I-A(g7) blockade by peptides unique to the Ealpha-chain, such as Ealpha65-77 and/or tolerance of diabetogenic T cells cross-reactive with Ealpha-peptide/I-A(g7) complexes.