Adjuvant Gemcitabine Versus Neoadjuvant/Adjuvant FOLFIRINOX in Resectable Pancreatic Cancer: The Randomized Multicenter Phase II NEPAFOX Trial.

BACKGROUND: Although addition of adjuvant chemotherapy is the current standard, the prognosis of pancreatic cancers still remains poor. The NEPAFOX trial evaluated perioperative treatment with FOLFIRINOX in resectable pancreatic cancer. PATIENTS AND METHODS: This multicenter phase II trial randomized patients with resectable or borderline resectable pancreatic cancer without metastases into arm (A,) upfront surgery plus adjuvant gemcitabine, or arm (B,) perioperative FOLFIRINOX. The primary endpoint was overall survival (OS). RESULTS: Owing to poor accrual, recruitment was prematurely stopped after randomization of 40 of the planned 126 patients (A: 21, B: 19). Overall, approximately three-quarters were classified as primarily resectable (A: 16, B: 15), and the remaining patients were classified as borderline resectable (A: 5, B: 4). Of the 12 evaluable patients, 3 achieved partial response under neoadjuvant FOLFIRINOX. Of the 21 patients in arm A and 19 patients in arm B, 17 and 7 underwent curative surgery, and R0-resection was achieved in 77% and 71%, respectively. Perioperative morbidity occurred in 72% in arm A and 46% in arm B, whereas non-surgical toxicity was comparable in both arms. Median RFS/PFS was almost doubled in arm B (14.1 months) compared with arm A (8.4 months) in the population with surgical resection, whereas median OS was comparable between both arms. CONCLUSIONS: Although the analysis was only descriptive owing to small patient numbers, no safety issues regarding surgical complications were observed in the perioperative FOLFIRINOX arm. Thus, considering the small number of patients, perioperative treatment approach appears feasible and potentially effective in well-selected cohorts of patients. In pancreatic cancer, patient selection before initiation of neoadjuvant therapy appears to be critical.

Long-term outcome of permanent tracheostomy management in two brachycephalic dogs using a commercial and a three-dimensional-printed silicone stent.

OBJECTIVE: To report the long-term outcome of utilization of a silicone stent to support the management of a permanent tracheostomy. STUDY DESIGN: Short case series. ANIMALS: Two client-owned brachycephalic dogs. METHODS: Two brachycephalic dogs with stage III laryngeal collapse underwent permanent tracheostomy. After the tracheostomy had healed, a silicone stent was inserted to support the stoma and facilitate home care. One dog wore a commercially available silicone stent for the follow-up period of 2 years. For the dog in Case 2, a 3D-printed, medical-grade silicone stent with an increased length was designed, as the dog had developed skin sores from the commercial device. RESULTS: Both dogs tolerated the silicone stent well. Stent care was managed by the owners without need for assistance. They reported that the silicone stent facilitated cleaning of the stoma surroundings and that they felt an increased confidence in airway patency, as the device prevented the tracheal stoma from collapsing. In Case 1, tracheoscopy 1 year after first stent insertion revealed minimal visible changes to the tracheal stoma. In Case 2, the 3D printed silicone stent led to a remission of skin sores and the dog wore the device comfortably until succumbing to an unrelated disease 13 months later. CONCLUSION: The insertion of a silicone stent is a simple and cost-effective method to improve home care of dogs with permanent tracheostomy. Larger dogs, as in Case 2, may benefit from custom-designed 3D-printed stents.

Coronary Artery Surgery: Past, Present, and Future.

Coronary artery bypass grafting (CABG) is the most commonly performed and studied major cardiac operation worldwide. An understanding of the evolution of CABG, including the early days of cardiac surgery, the first bypass operation, continuous improvements in techniques, and streamlining of the operation, is important to inform current trends and future innovations. This article will examine how CABG evolved (from techniques to conduits), describe current trends in the field, and explore what lies on the horizon for the future of CABG.

Economic activity and suicides: Causal evidence from macroeconomic shocks in England and Wales.

The relationship between economic activity and suicides has been the subject of much scrutiny, but the focus in the extant literature has been almost exclusively on estimating associations rather than causal effects. In this paper, using data from England and Wales between January 1, 1997 and December 31, 2017, we propose a plausible set of assumptions to estimate the causal impacts of well-known macroeconomic variables on the daily suicide rate. Our identification strategy relies on scheduled macroeconomic announcements and professional economic forecasts. An important advantage of using these variables to model suicide rates is that they can efficiently capture the elements of 'surprise or shock' via the observed difference between how the economy actually performed and how it was expected to perform. Provided that professional forecasts are unbiased and efficient, the estimated 'surprises or shocks' are 'as good as random', and therefore are exogenous. We employ time series regressions and present robust evidence that these exogenous macroeconomic shocks affect the suicide rate. Overall, our results are consistent with economic theory that shocks that reduce estimated permanent income, and therefore expected lifetime utility, can propel suicide rates. Specifically, at the population level, negative shocks to consumer confidence and house prices accelerate the suicide rate. However, there is evidence of behavioural heterogeneity between sexes, states of the economy, and levels of public trust in government. Negative shocks to the retail price index (RPI) raise the suicide rate for males. Negative shocks to the growth rate in gross domestic product (GDP) raise the population suicide rate when the economy is doing poorly. When public trust in government is low, increases in the unemployment rate increase the suicide rate for females.

Pharmacological Gq inhibition induces strong pulmonary vasorelaxation and reverses pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease with limited survival. Herein, we propose the pharmacological inhibition of Gq proteins as a novel concept to counteract pulmonary vasoconstriction and proliferation/migration of pulmonary artery smooth muscle cells (PASMCs) in PAH. We demonstrate that the specific pan-Gq inhibitor FR900359 (FR) induced a strong vasorelaxation in large and small pulmonary arteries in mouse, pig, and human subjects ex vivo. Vasorelaxation by FR proved at least as potent as the currently used triple therapy. We also provide in vivo evidence that local pulmonary application of FR prevented right ventricular systolic pressure increase in healthy mice as well as in mice suffering from hypoxia (Hx)-induced pulmonary hypertension (PH). In addition, we demonstrate that chronic application of FR prevented and also reversed Sugen (Su)Hx-induced PH in mice. We also demonstrate that Gq inhibition reduces proliferation and migration of PASMCs in vitro. Thus, our work illustrates a dominant role of Gq proteins for pulmonary vasoconstriction as well as remodeling and proposes direct Gq inhibition as a powerful pharmacological strategy in PH.

Structural response of G protein binding to the cyclodepsipeptide inhibitor FR900359 probed by NMR spectroscopy.

The cyclodepsipeptide FR900359 (FR) and its analogs are able to selectively inhibit the class of Gq proteins by blocking GDP/GTP exchange. The inhibitor binding site of Gq has been characterized by X-ray crystallography, and various binding and functional studies have determined binding kinetics and mode of inhibition. Here we investigate isotope-labeled FR bound to the membrane-anchored G protein heterotrimer by solid-state nuclear magnetic resonance (ssNMR) and in solution by liquid-state NMR. The resulting data allowed us to identify regions of the inhibitor which show especially pronounced effects upon binding and revealed a generally rigid binding mode in the cis conformation under native-like conditions. The inclusion of the membrane environment allowed us to show a deep penetration of FR into the lipid bilayer illustrating a possible access mode of FR into the cell. Dynamic nuclear polarization (DNP)-enhanced ssNMR was used to observe the structural response of specific segments of the Gα subunit to inhibitor binding. This revealed rigidification of the switch I binding site and an allosteric response in the α5 helix as well as suppression of structural changes induced by nucleotide exchange due to inhibition by FR. Our NMR studies of the FR-G protein complex conducted directly within a native membrane environment provide important insights into the inhibitors access via the lipid membrane, binding mode, and structural allosteric effects.

GRK specificity and Gßγ dependency determines the potential of a GPCR for arrestin-biased agonism.

G protein-coupled receptors (GPCRs) are mainly regulated by GPCR kinase (GRK) phosphorylation and subsequent ß-arrestin recruitment. The ubiquitously expressed GRKs are classified into cytosolic GRK2/3 and membrane-tethered GRK5/6 subfamilies. GRK2/3 interact with activated G protein ßγ-subunits to translocate to the membrane. Yet, this need was not linked as a factor for bias, influencing the effectiveness of ß-arrestin-biased agonist creation. Using multiple approaches such as GRK2/3 mutants unable to interact with Gßγ, membrane-tethered GRKs and G protein inhibitors in GRK2/3/5/6 knockout cells, we show that G protein activation will precede GRK2/3-mediated ß-arrestin2 recruitment to activated receptors. This was independent of the source of free Gßγ and observable for Gs-, Gi- and Gq-coupled GPCRs. Thus, ß-arrestin interaction for GRK2/3-regulated receptors is inseparably connected with G protein activation. We outline a theoretical framework of how GRK dependence on free Gßγ can determine a GPCR's potential for biased agonism. Due to this inherent cellular mechanism for GRK2/3 recruitment and receptor phosphorylation, we anticipate generation of ß-arrestin-biased ligands to be mechanistically challenging for the subgroup of GPCRs exclusively regulated by GRK2/3, but achievable for GRK5/6-regulated receptors, that do not demand liberated Gßγ. Accordingly, GRK specificity of any GPCR is foundational for developing arrestin-biased ligands.

Avaliação da qualidade de amostras comerciais de chás na cidade de Vitória da Conquista-Bahia

Análises que comprovem a qualidade de manejo, produção e armazenamento dos chás comercializados são importantes para a saúde da população, pois garantem aos usuários um produto com boas condições físicas e biológicas, além de fornecer informações que contribuam para o uso correto, seguro e eficaz. Este estudo avaliou a qualidade de amostras comerciais de chás na cidade de Vitória da Conquista ­ Bahia, pela análise microbiológica, presença de impurezas e análise de rótulo. Foram analisados chás de espécies vegetais como Piptadenia macrocarpa, Myracrodrum urundeuva, Ziziphus joazeiro, Sideroxylon obtusifolium, Amburana cearensis e Matricaria recutita. Pelas análises microbiológicas não se pôde determinar a seguridade dos chás para o consumo, uma vez que, houve contradição entre os valores de referências adotados. Na análise de rótulos, os resultados mostraram que nenhuma amostra apresentou todos os requisitos exigidos pela Agência Nacional de Vigilância Sanitária-ANVISA. Os resultados obtidos demonstraram a falta de informações básicas necessárias ao consumidor, ficando evidente a necessidade de uma fiscalização mais rigorosa e efetiva por parte da Vigilância Sanitária para essas empresas que processam e embalam esses produtos naturais.