Pulsatility index (PI) is a hemodynamic parameter determined using Doppler sonography; it reflects the degree of peripheral vascular resistance. Moreover, researchers have reported significant relationships between an increase in the PI of the common carotid artery (CCA) and ischemic stroke. This cross-sectional study aimed to clarify the relationships between cardio-ankle vascular index (CAVI) as a marker of arterial stiffness and the PI of the CCA in patients with cardiovascular risk factors for the primary prevention of ischemic stroke.

Recent studies have demonstrated that hepatectomy in patients with synchronous hepatic gastric metastases may improve survival in certain patients. This study aimed to evaluate survival benefits of gastrectomy plus hepatectomy versus gastrectomy alone in patients with hepatic gastric metastases.

Over 95% of pancreatic adenocarcinomas (PDACs), as well as a large fraction of other tumor types, such as colorectal adenocarcinoma, are driven by KRAS activation. However, no direct RAS inhibitors exist for cancer therapy. Furthermore, the delivery of therapeutic agents of any kind to PDAC in particular has been hindered by the extensive desmoplasia and resultant drug delivery challenges that accompanies these tumors. Small interfering RNA (siRNA) is a promising modality for anti-neoplastic therapy due to its precision and wide range of potential therapeutic targets. Unfortunately, siRNA therapy is limited by low serum half-life, vulnerability to intracellular digestion, and transient therapeutic effect. We assessed the ability of a peptide based, oligonucleotide condensing, endosomolytic nanoparticle (NP) system to deliver siRNA to KRAS-driven cancers. We show that this peptide-based NP is avidly taken up by cancer cells in vitro, can deliver KRAS-specific siRNA, inhibit KRAS expression, and reduce cell viability. We further demonstrate that this system can deliver siRNA to the tumor microenvironment, reduce KRAS expression, and inhibit pancreatic cancer growth in vivo. In a spontaneous KPPC model of PDAC, this system effectively delivers siRNA to stroma-rich tumors. This model has the potential for translational relevance for patients with KRAS driven solid tumors.

Nosocomial sepsis is the main problem that preterms have to face during their stay at neonatal intensive care units (NICU). Serratia marcescens is an emerging cause of preterm sepsis but its epidemiology is still largely unknown. Consequently, the aims of this study were to know the rate of preterms colonized by S. marcescens during their stay at the NICU and the characteristics and evolution of the S. marcescens population, including the susceptibility to clinically relevant antibiotics.

Lupus is a complex, heterogeneous autoimmune disease that has yet to see significant progress towards more timely diagnosis, improved treatment options for short-term and long-term outcomes, and appropriate access to care. The Addressing Lupus Pillars for Health Advancement (ALPHA) project is the first step in establishing global consensus and developing concrete strategies to address the challenges limiting progress.

In vitro assays that evaluate CD8+ T cell-mediated cytotoxicity are important to aid in the development of novel therapeutic approaches to enhance anti-tumor immune responses. Here, we describe a novel cytotoxicity co-culture assay that circumvents the problem of highly variable allogeneic responses and obviates the constraints of HLA-restriction between effector and target cells. We show that this assay can be easily applied to a panel of tumor cell lines to provide additional insights into intrinsic drivers of sensitivity/resistance to T cell-mediated killing, and to evaluate the impact of targeted therapies on both tumor and T cell compartments.

As cancer immunotherapy gains importance, the determination of a patient's ability to react to his/her tumor is unquestionably relevant. Though the presence of T cells that recognize specific tumor antigens is well established, the total frequency of tumor-reactive T cells in humans is difficult to assess, especially due to the lack of broad analysis techniques. Here, we describe a strategy that allows this determination, in both CD4 and CD8 compartments, using T cell proliferation induced by tumor cell-lysate pulsed dendritic cells as the readout. All 12 healthy donor tested had circulating CD4 and CD8 tumor cell-reactive T cells. The detection of these T cells, not only in the naïve but also in the memory compartment, can be seen as an evidence of tumor immunosurveillance in humans. As expected, breast cancer patients had higher frequencies of blood tumor-reactive T cells, but with differences among breast cancer subtypes. Interestingly, the frequency of blood tumor-reactive T cells in patients did not correlate to the frequency of infiltrating tumor-reactive T cells, highlighting the danger of implying a local tumor response from blood obtained data. In conclusion, these data add T cell evidence to immunosurveillance in humans, confirm that immune parameters in blood may be misleading and describe a tool to follow the tumor-specific immune response in patients and, thus, to design better immunotherapeutic approaches.

Immunotherapies such as adoptive cell therapy (ACT) are promising treatments for solid cancers. However, relapsing disease remains a problem and the molecular mechanisms underlying resistance are poorly defined. We postulated that the deregulated epigenetic landscape in cancer cells could underpin the acquisition of resistance to immunotherapy. To address this question, two preclinical models of ACT were employed to study transcriptional and epigenetic regulatory processes within ACT-treated cancer cells. In these models ACT consistently causes robust tumor regression, but resistance develops and tumors relapse. We identified down-regulated expression of immunogenic antigens at the mRNA level correlated with escape from immune control. To determine whether this down-regulation was under epigenetic control, we treated escaped tumor cells with DNA demethylating agents, azacytidine (AZA) and decitabine (DEC). AZA or DEC treatment restored antigen expression in a proportion of the tumor population. To explore the importance of other epigenetic modifications we isolated tumor cells refractory to DNA demethylation and screened clones against a panel of 19 different epigenetic modifying agents (EMAs). The library of EMAs included inhibitors of a range of chromosomal and transcription regulatory protein complexes, however, when tested as single agents none restored further antigen expression. These findings suggest that tumor cells employ multiple epigenetic and genetic mechanisms to evade immune control, and a combinatorial approach employing several EMAs targeting transcription and genome stability may be required to overcome tumor resistance to immunotherapy.

The value of a clinical quality registry is contingent on the quality of its data. This study aims to pilot methodology for data quality audits of the Australian and New Zealand Hip Fracture Registry, a clinical quality registry of hip fracture clinical care and secondary fracture prevention.

Medical diagnoses and assessed need for care are the prerequisites for planning and delivery of care to residents of care homes. Assessing the effectiveness of care is difficult. The aim of this study was to test the practicality and construct validity of the howRu health status measure using secondary analysis of a large data set.

Identification of the mechanisms that control lead (Pb) concentration in plants is a prerequisite for minimizing dietary uptake of Pb from contaminated crops. This study examines how nitrate uptake by roots affects Pb uptake and reveals a new resistance strategy for plants to cope with Pb contamination. We investigated the interaction between nitrate transporter (NRT)-mediated NO3- uptake and exposure to Pb in Arabidopsis using NRT-related mutants. Exposure to Pb specifically stimulated NRT1.1-mediated nitrate uptake. Loss of function of NRT1.1 in nrt1.1-knockout mutants resulted in greater Pb toxicity and higher Pb accumulation in nitrate-sufficient growth medium, whereas no difference was seen between wild-type plants and null-mutants for NRT1.2, NRT2.1, NRT2.2, NRT2.4, and NRT2.5. These results indicate that only NRT1.1-mediated NO3- uptake alleviated Pb toxicity in the plants. Further examination indicated that rhizosphere acidification, which favors Pb entry to roots by increasing its availability, is prevented when NRT1.1 is functional and both NO3- and NH4+ are present in the medium.

Hirschsprung's disease (HSCR) is a developmental defect of the enteric nervous system. Transanal endorectal pullthrough (TERPT) is one of the surgical procedures for HSCR. Clavien-Dindo is an objective classification system, used worldwide, to describe postoperative complications. The aim of this study was to use Clavien-Dindo grading for short-term complication after TERPT.

Spinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if infiltration of the spinal cord or dissemination throughout the central nervous system (CNS) occurs and, in these cases, clinical outcome remains poor. Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma. Copy number variation plots derived from DNA methylation arrays showed MYCN amplification as a characteristic genetic alteration in all cases of our cohort (n = 13), which was subsequently validated using fluorescence in situ hybridization. The histological diagnosis was anaplastic ependymoma (WHO Grade III) in ten cases and classic ependymoma (WHO Grade II) in three cases. Histological re-evaluation in five primary tumors and seven relapses showed characteristic histological features of ependymoma, namely pseudorosettes, GFAP- and EMA positivity. Electron microscopy revealed cilia, complex intercellular junctions and intermediate filaments in a representative sample. Taking these findings into account, we suggest to designate this molecular subgroup spinal ependymoma with MYCN amplification, SP-EPN-MYCN. SP-EPN-MYCN tumors showed distinct growth patterns with intradural, extramedullary localization mostly within the thoracic and cervical spine, diffuse leptomeningeal spread throughout the whole CNS and infiltrative invasion of the spinal cord. Dissemination was observed in 100% of cases. Despite high-intensity treatment, SP-EPN-MYCN showed significantly worse median progression free survival (PFS) (17 months) and median overall survival (OS) (87 months) than all other previously described molecular spinal ependymoma subgroups. OS and PFS were similar to supratentorial ependymoma with RELA-fusion (ST-EPN-RELA) and posterior fossa ependymoma A (PF-EPN-A), further highlighting the aggressiveness of this distinct new subgroup. We, therefore, propose to establish SP-EPN-MYCN as a new molecular subgroup in ependymoma and advocate for testing newly diagnosed spinal ependymal tumors for MYCN amplification.

Outside of the photosynthetic machinery, high-valent manganese cofactors are rare in biology. It was proposed that a recently discovered subclass of ribonucleotide reductase (RNR), class Id, is dependent on a Mn2(IV,III) cofactor for catalysis. Class I RNRs consist of a substrate-binding component (NrdA) and a metal-containing radical-generating component (NrdB). Herein we utilize a combination of EPR spectroscopy and enzyme assays to underscore the enzymatic relevance of the Mn2(IV,III) cofactor in class Id NrdB from Facklamia ignava. Once formed, the Mn2(IV,III) cofactor confers enzyme activity that correlates well with cofactor quantity. Moreover, we present the X-ray structure of the apo- and aerobically Mn-loaded forms of the homologous class Id NrdB from Leeuwenhoekiella blandensis, revealing a dimanganese centre typical of the subclass, with a tyrosine residue maintained at distance from the metal centre and a lysine residue projected towards the metals. Structural comparison of the apo- and metal-loaded forms of the protein reveals a refolding of the loop containing the conserved lysine and an unusual shift in the orientation of helices within a monomer, leading to the opening of a channel towards the metal site. Such major conformational changes have not been observed in NrdB proteins before. Finally, in vitro reconstitution experiments reveal that the high-valent manganese cofactor is not formed spontaneously from oxygen, but can be generated from at least two different reduced oxygen species, i.e. H2O2 and superoxide (O 2·- ). Considering the observed differences in the efficiency of these two activating reagents, we propose that the physiologically relevant mechanism involves superoxide.

The aim of this analysis was to study the impact of marital status on inflammatory breast cancer (IBC) patients, as the prognostic impact is yet to be studied in detail.

The domestication process of Asian rice (Oryza sativa L.) is complicated. It's well established that Oryza rufipogon is the ancestor of Asian rice, although the number of domestication events still controversial. Recently, numerous types of studies based on rice nuclear genome have been conducted, but the results are quite different. Chloroplasts (cp) are also part of the rice genome and have a conserved cyclic structure that is valuable for plant genetics and evolutionary studies. Therefore, we conducted chloroplast-based studies, aiming to provide more evidence for the domestication of Asian rice.

The PLANET trials showed that atorvastatin 80 mg but not rosuvastatin at either 10 or 40 mg reduced urinary protein to creatinine ratio (UPCR) at similar effects on LDL-cholesterol. However, individual changes in both UPCR and LDL-cholesterol during treatment with these statins varied widely between patients. This inter-individual variability could not be explained by patients' physical or biochemical characteristics. We assessed whether the plasma concentrations of both statins were associated with LDL-cholesterol and UPCR response.

Adherence reflects the extent to which individuals experience or engage with the content of online interventions and poses a major challenge. Neglecting to examine and report adherence and its relation to outcomes can compromise the interpretation of research findings.

To provide a concise review of the literature and data pertaining to the use of nurse practitioners and physician assistants, collectively called advanced practice providers, in ICU and acute care settings.

Current treatments for diabetic retinopathy (DR) have considerable limitations, underpinning the need for new therapeutic options. In this article, the ability of an engineered angiopoietin-1 variant (COMP-Ang1) to ameliorate the injurious effects of hyperglycemia on barrier integrity in a human retinal microvascular endothelial cell (HRMvEC) model is comprehensively investigated.