Clinical and histologic characteristics of breast cancers in women with previous pathologic diagnosis of benign breast disease in Spain

Women with a benign breast disease (BBD) have an increased risk of subsequent breast carcinoma. Information is scarce regarding the characteristics of breast carcinomas diagnosed after a BBD. Our aim was to point out the differences in clinical and histologic characteristics of breast carcinomas diagnosed in women with and without a previous pathologic diagnosis of BBD in the context of population‐based mammography screening. Retrospective cohort study of all women aged 50‐69 years who were screened at least once in a population‐based screening program in Spain, between 1994 and 2011 and followed up until December 2012. The mean follow‐up was 6.1 years. We analyzed 6645 breast carcinomas, of whom 238 had a previous pathologic diagnosis of BBD. Information on clinical and histologic characteristics was collected from pathology reports. Logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (95%CI) of occurrence of selected histologic characteristics of breast carcinomas in women with and without a previous BBD. Women with a previous BBD had a higher proportion of ductal carcinoma in situ (DCIS) compared with women without a BBD (22.1% and 13.6%, respectively). Among those diagnosed with an invasive breast carcinoma, women with previous BBD were more likely to be diagnosed with carcinomas sized >2 cm (OR = 1.46; 95%CI = 1.03‐2.08), metastatic positive (OR = 2.66; 95%CI = 1.21‐5.86), and with a high Ki‐67 proliferation rate (OR = 1.93; 95%CI = 1.24‐2.99). No differences were found across histologic subtypes of BBD. Screening participants with a previous pathologic diagnosis of BBD had a higher proportion of DCIS. However, invasive carcinomas detected in women with a BBD were associated with clinical and histologic characteristics conferring a worst prognosis.     

Impacto de la utilización de stents colónicos como puente a la cirugía de neoplasias colorrectales oclusivas potencialmente curables sobre los resultados quirúrgicos y oncológicos

Introduction

The outcomes of patients treated with colonic stents as a bridge to surgery (BTS) have recently been questioned in terms of safety and long-term oncologic outcomes. The aim of this study is to evaluate the effects on surgical and oncologic outcomes of colonic stents as a BTS for potentially resectable obstructive colorectal cancer.

Evaluation of Safety Management and Leadership Training Using Mobile Technologies among Logging Supervisors

ABSTRACT

Background: Logging is recognized as one of the most dangerous industries in the United States (US), ranking among those with the highest occupational injury and fatality rates. Although logging operations in the Southeastern US have lower rates of injuries and fatalities compared to other regions of the US, due in part to the use of large machinery to fell timber as opposed to chainsaw felling, safety hazards continue to persist. The hazards present in the logging cut sites in which loggers operate may result in worker injury, illness, or fatality. Our objective was to develop, deliver, and evaluate a safety management and leadership training among logging contractors and supervisors using mobile tablets as a personal learning environment.

Methods: A safety leadership and management training vignette was developed based on previously collected focus group needs assessment data. A non-random sample of 31 male logging supervisors received the safety leadership and management training on a mobile tablet. Kirkpatrick Levels 1, 2, and 3 training effectiveness evaluations were performed.

Results: A statistically significant large effect size suggests safety knowledge was gained among training participants when comparing post-test scores to pre-test scores (Level-2). Participants rated their training experience favorably (Level-1), and applied knowledge gained from the training throughout their weekly work activities three months after training (Level-3).

Conclusion: Our findings suggest the utilization of mobile learning techniques can be an effective means to deliver safety management and leadership training content to logging contractors and supervisors. Future trainings should be linguistically and literacy-level appropriate, as well as comprehensive in nature, including meaningful and relevant content. Our observations support the use of mobile devices as just one component of a more comprehensive health and safety management program for workers in the logging industry.     

Bipolar I patients with and without a history of psychotic symptoms: Do they differ in their cognitive functioning?

Recently, many reports have consistently demonstrated cognitive deficits in patients with bipolar disorder (BD), but their relationship with symptomatology, specifically psychotic symptoms, remains unclear. Our main hypothesis was that a history of hallucinations and/or delusions in the course of BD-I is associated with severe cognitive deficits. We investigated several cognitive functions (memory, attention, verbal fluency and executive functions) in 18 BD-I patients with a history of psychotic symptoms (HPS+), 17 BD-I patients without a history of psychotic symptoms (HPS-), 33 schizophrenic patients and 26 healthy control subjects. Both groups of BD-I patients were more impaired than the normal controls in attention, verbal memory, verbal fluency and executive functions. Only HPS+ BD-I patients showed more difficulties in completing the Stroop test than nonpsychotic bipolar patients. Nevertheless, after adjustment for the effects of current psychopathology, this difference disappeared. Schizophrenic subjects showed worse performance than BD-I subjects in verbal memory and verbal fluency. These results suggest that a history of psychotic symptoms in bipolar I disorder may not be associated with more cognitive deficits. Further research on euthymic bipolar patients with and without HPS is required to confirm these findings.     

In vivo functional analysis of the counterbalance of hyperactive phosphatidylinositol 3-kinase p110 catalytic oncoproteins by the tumor suppressor PTEN

The signaling pathways involving class I phosphatidylinositol 3-kinases (PI3K) and the phosphatidylinositol-(3,4,5)-trisphosphate phosphatase PTEN regulate cell proliferation and survival. Thus, mutations in the corresponding genes are associated to a wide variety of human tumors. Heterologous expression of hyperactive forms of mammalian p110alpha and p110beta in Saccharomyces cerevisiae leads to growth arrest, which is counterbalanced by coexpression of mammalian PTEN. Using this in vivo yeast-based system, we have done an extensive functional analysis of germ-line and somatic human PTEN mutations, as well as a directed mutational analysis of discrete PTEN functional domains. A distinctive penetrance of the PTEN rescue phenotype was observed depending on the levels of PTEN expression in yeast and on the combinations of the inactivating PTEN mutations and the activating p110alpha or p110beta mutations analyzed, which may reflect pathologic differences found in tumors with distinct alterations at the p110 and PTEN genes or proteins. We also define the minimum length of the PTEN protein required for stability and function in vivo. In addition, a random mutagenesis screen on PTEN based on this system allowed both the reisolation of known clinically relevant PTEN mutants and the identification of novel PTEN loss-of-function mutations, which were validated in mammalian cells. Our results show that the PI3K/PTEN yeast-based system is a sensitive tool to test in vivo the pathologic properties and the functionality of mutations in the human p110 proto-oncogenes and the PTEN tumor suppressor and provide a framework for comprehensive functional studies of these tumor-related enzymes.     

Pyridoxal kinase inhibition by artemisinins down-regulates inhibitory neurotransmission

The antimalarial artemisinins have also been implicated in the regulation of various cellular pathways including immunomodulation of cancers and regulation of pancreatic cell signaling in mammals. Despite their widespread application, the cellular specificities and molecular mechanisms of target recognition by artemisinins remain poorly characterized. We recently demonstrated how these drugs modulate inhibitory postsynaptic signaling by direct binding to the postsynaptic scaffolding protein gephyrin. Here, we report the crystal structure of the central metabolic enzyme pyridoxal kinase (PDXK), which catalyzes the production of the active form of vitamin B6 (also known as pyridoxal 5′-phosphate [PLP]), in complex with artesunate at 2.4-Å resolution. Partially overlapping binding of artemisinins with the substrate pyridoxal inhibits PLP biosynthesis as demonstrated by kinetic measurements. Electrophysiological recordings from hippocampal slices and activity measurements of glutamic acid decarboxylase (GAD), a PLP-dependent enzyme synthesizing the neurotransmitter γ-aminobutyric acid (GABA), define how artemisinins also interfere presynaptically with GABAergic signaling. Our data provide a comprehensive picture of artemisinin-induced effects on inhibitory signaling in the brain.

Pyridoxal 5′-phosphate (PLP) is the active form of vitamin B6. In humans, PLP biosynthesis is catalyzed by pyridoxal kinase (PDXK), a member of the ribokinase superfamily. PDXK utilizes inactive forms of vitamin B6 (pyridoxal [PL], pyridoxine, and pyridoxamine) and ATP as substrates, producing PLP along with the byproduct ADP. The corresponding reaction proceeds via a random substrate addition reaction mechanism (1) in which PLP biosynthesis takes place by transferring the γ-phosphate of ATP to the 5′-OH group of the B6 vitamers, in a process assisted by divalent metal ions such as Zn²⁺ and Mg²⁺ (2) (Fig. 1A). PLP serves as the essential active site component for more than 160 distinct human enzymatic activities (3) catalyzing crucial cellular processes such as detoxification reactions and multiple metabolic processes including amino acid, carbohydrate, and lipid metabolism. PLP-dependent enzymes also participate in neurotransmitter biosynthesis including the inhibitory neurotransmitters γ-aminobutyric acid (GABA) and glycine (4–6), which are synthesized by glutamic acid decarboxylase (GAD) and serine hydroxymethyl transferase (SHMT), respectively. Vitamin B6 deficiency has been implicated in multiple neurological, psychiatric, and internal disorders possibly including even diabetes, cancer, and autism (3), thus underpinning the importance of a finely tuned PLP biosynthesis.Open in a separate windowFig. 1.Biochemical basis of PDXK inhibition by artemisinins. (A) Schematic representation of the reaction catalyzed by PDXK. (B) Michaelis–Menten curve derived for the enzymatic activity of recombinantly purified PDXK. (C and D) Chemical structures of artemisinin (C) and artesunate (D). (E) Enzymatic activity of wild-type PDXK (WT-PDXK) in the absence and presence of artemisinin derivatives at a concentration of 1.5 mM (artesunate) and 156 µM (artemisinin), respectively. Data are presented as mean ± SEM (P values are *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001) (one-way ANOVA test). (F) Inhibition curves of PDXK by artemisinin and artesunate used to derive the corresponding IC₅₀ values.Recently, PDXK was identified as one of the mammalian targets of the antimalarial drug artemisinin (7). Artemisinin-containing plant extracts have been used in traditional Chinese medicine for the treatment of malaria (8). Chemically, these small molecules are sesquiterpene lactones with an unusual endoperoxide bridge. Artemisinin and its semisynthetic derivatives artemether and artesunate (collectively referred to as artemisinins), in combination with quinones such as mefloquine and lumefantrine, nowadays represent the standard drug combinations used to treat malaria caused by Plasmodium falciparum (9). In addition to their antiprotozoan activities, these drugs have also been pharmacologically observed to regulate the activities of a variety of mammalian cellular processes, some of which are deregulated in various types of cancer (10, 11). Recently, it was discovered that artemisinins also modulate the differentiation of pancreatic Tα cells by inducing the transdifferentiation of glucagon-producing Tα cells into insulin-secreting Tβ cells, thus suggesting an antidiabetic activity of artemisinins (7). However, two subsequent studies contradicted this observation, thus questioning the potential clinical application of these compounds in the treatment of diabetes (12, 13).Until recently, in the absence of a single protein crystal structure in complex with artemisinins (neither a plasmodial nor a mammalian protein), the detailed framework describing the target recognition by these small molecules remained enigmatic. The first molecular insights into artemisinin recognition by a target protein were derived by us from crystal structures of the C-terminal domain of the moonlighting protein gephyrin (GephE) in complex with two artemisinin derivatives, artesunate and artemether (14). Gephyrin is the principal scaffolding protein at inhibitory postsynaptic specializations and also catalyzes the final two steps of the evolutionarily conserved molybdenum cofactor (Moco) biosynthesis (15–17). Structures of the GephE–artemisinin complexes demonstrated that artemisinins specifically target the universal receptor binding pocket of this moonlighting protein, without altering its enzymatic activity, thus inhibiting critical interactions of gephyrin with GABA type A receptors (GABA_ARs) and glycine receptors (GlyRs). As an important functional consequence, artemisinins modulate inhibitory neurotransmission in a gephyrin-dependent manner. In addition to gephyrin, various proteins were identified as putative targets of artemisinins in pancreatic cells, including the central metabolic enzyme PDXK (7), yet the molecular mechanisms underlying the modulation of these targets by artemisinins remained unknown.Here, we determined the 2.4-Å resolution crystal structure of mouse pyridoxal kinase (mPDXK) in complex with artesunate, a succinate derivative of artemisinin. The artesunate binding site partially overlaps with the substrate (PL)/product (PLP) binding site, thus suggesting a drug-induced inhibitory effect. Enzymatic activity assays in vitro indeed revealed a significant inhibition of PLP production in the presence of artemisinins with K_i values in the high micromolar range. Electrophysiological recordings and measurements of GABA biosynthesis suggest that artemisinins exert their effect by down-regulating the activity of PLP-dependent enzymes such as GAD. Taken together, our data define the molecular basis for the inhibition of PDXK by artemisinins and their consequences at the presynaptic terminals of inhibitory postsynapses and extend our current understanding of the artemisinin-induced modulation of inhibitory neurotransmission beyond gephyrin.