Randomized trial of breast self-examination in Shanghai: methodology and preliminary results

BACKGROUND: The efficacy of breast self-examination in helping to reduce mortality from breast cancer has not been rigorously demonstrated. PURPOSE: To assess efficacy, a large, randomized trial was initiated in Shanghai, China. METHODS: From October 1989 to October 1991, 267040 current and retired female employees associated with 520 factories in the Shanghai Textile Industry Bureau were randomly assigned on the basis of factory to either a self-examination instruction group (133375 women) or a control group (133665 women). The women were born within the period from 1925 through 1958. Women in the instruction group were given intensive training in breast self-examination, including the use of silicone breast models and personalized instruction, plus two subsequent reinforcement sessions and multiple reminders to practice the technique. Women in the control group were asked to attend training sessions on the prevention of low back pain. All women have been followed for the development of breast diseases and for death from breast cancer. RESULTS: A high level of participation during the first 4-5 years of the trial was documented among women in the instruction group. Randomly sampled women in this group demonstrated greater proficiency in detecting lumps in breast models than did randomly sampled women in the control group. Approximately equal numbers of breast cancers were detected in the two groups (331 in the instruction group and 322 in the control group) through 1994, which is the last year for which case-finding efforts have been completed. The breast cancers detected in the instruction group were not diagnosed at an appreciably earlier stage or smaller size than those in the control group. More benign breast lesions were detected in the instruction group than in the control group (1457 versus 623, respectively), suggesting a higher index of suspicion for women who received training. Cumulative breast cancer mortality rates through 5 years from entry into the study were nearly equivalent for the two groups. CONCLUSIONS: Breast self-examination has not led to a reduction in mortality from breast cancer in this study cohort in the first several years since the trial began. A shift toward the diagnosis of disease at a less advanced stage in women given instruction has also not been demonstrated. Longer follow-up of participants in this trial is required before final assessment can be made of the efficacy of breast self-examination. IMPLICATIONS: At this time, there is insufficient evidence to recommend for or against the teaching of breast self-examination.     

ZAP-70 association with T cell receptor zeta (TCRzeta): fluorescence imaging of dynamic changes upon cellular stimulation

The nonreceptor protein tyrosine kinase ZAP-70 is a critical enzyme required for successful T lymphocyte activation. After antigenic stimulation, ZAP-70 rapidly associates with T cell receptor (TCR) subunits. The kinetics of its translocation to the cell surface, the properties of its specific interaction with the TCRzeta chain expressed as a chimeric protein (TTzeta and Tzetazeta), and its mobility in different intracellular compartments were studied in individual live HeLa cells, using ZAP-70 and Tzetazeta fused to green fluorescent protein (ZAP-70 GFP and Tzetazeta-GFP, respectively). Time-lapse imaging using confocal microscopy indicated that the activation-induced redistribution of ZAP-70 to the plasma membrane, after a delayed onset, is of long duration. The presence of the TCRzeta chain is critical for the redistribution, which is enhanced when an active form of the protein tyrosine kinase Lck is coexpressed. Binding specificity to TTzeta was indicated using mutant ZAP-70 GFPs and a truncated zeta chimera. Photobleaching techniques revealed that ZAP-70 GFP has decreased mobility at the plasma membrane, in contrast to its rapid mobility in the cytosol and nucleus. Tzetazeta- GFP is relatively immobile, while peripherally located ZAP-70 in stimulated cells is less mobile than cytosolic ZAP-70 in unstimulated cells, a phenotype confirmed by determining the respective diffusion constants. Examination of the specific molecular association of signaling proteins using these approaches has provided new insights into the TCRzeta-ZAP-70 interaction and will be a powerful tool for continuing studies of lymphocyte activation.     

Kinetic analysis of secretory protein traffic and characterization of golgi to plasma membrane transport intermediates in living cells

Quantitative time-lapse imaging data of single cells expressing the transmembrane protein, vesicular stomatitis virus ts045 G protein fused to green fluorescent protein (VSVG-GFP), were used for kinetic modeling of protein traffic through the various compartments of the secretory pathway. A series of first order rate laws was sufficient to accurately describe VSVG-GFP transport, and provided compartment residence times and rate constants for transport into and out of the Golgi complex and delivery to the plasma membrane. For ER to Golgi transport the mean rate constant (i.e., the fraction of VSVG-GFP moved per unit of time) was 2.8% per min, for Golgi to plasma membrane transport it was 3.0% per min, and for transport from the plasma membrane to a degradative site it was 0.25% per min. Because these rate constants did not change as the concentration of VSVG-GFP in different compartments went from high (early in the experiment) to low (late in the experiment), secretory transport machinery was never saturated during the experiments. The processes of budding, translocation, and fusion of post-Golgi transport intermediates carrying VSVG- GFP to the plasma membrane were also analyzed using quantitative imaging techniques. Large pleiomorphic tubular structures, rather than small vesicles, were found to be the primary vehicles for Golgi to plasma membrane transport of VSVG-GFP. These structures budded as entire domains from the Golgi complex and underwent dynamic shape changes as they moved along microtubule tracks to the cell periphery. They carried up to 10,000 VSVG-GFP molecules and had a mean life time in COS cells of 3.8 min. In addition, they fused with the plasma membrane without intersecting other membrane transport pathways in the cell. These properties suggest that the post-Golgi intermediates represent a unique transport organelle for conveying large quantities of protein cargo from the Golgi complex directly to the plasma membrane.     

Interactions of Lipid Droplets with the Intracellular Transport Machinery

Historically, studies of intracellular membrane trafficking have focused on the secretory and endocytic pathways and their major organelles. However, these pathways are also directly implicated in the biogenesis and function of other important intracellular organelles, the best studied of which are peroxisomes and lipid droplets. There is a large recent body of work on these organelles, which have resulted in the introduction of new paradigms regarding the roles of membrane trafficking organelles. In this review, we discuss the roles of membrane trafficking in the life cycle of lipid droplets. This includes the complementary roles of lipid phase separation and proteins in the biogenesis of lipid droplets from endoplasmic reticulum (ER) membranes, and the attachment of mature lipid droplets to membranes by lipidic bridges and by more conventional protein tethers. We also discuss the catabolism of neutral lipids, which in part results from the interaction of lipid droplets with cytosolic molecules, but with important roles for both macroautophagy and microautophagy. Finally, we address their eventual demise, which involves interactions with the autophagocytotic machinery. We pay particular attention to the roles of small GTPases, particularly Rab18, in these processes.     

Sintered electrospun poly(ɛ-caprolactone)–poly(ethylene terephthalate) for drug delivery

Electrospinning has the inherent advantage of being able to achieve molecular mixing of polymers having substantially different melting points. Electrospun poly(ɛ-caprolactone)–poly(ethylene terephthalate) (PCL:PET) capsules are densified by sintering to enable drug encapsulation. Proton and diffusive nuclear magnetic resonance, as well as a selective dissolution, suggest an absence of reaction between the two polymers. Sintering at 100 °C successfully densifies 88.89:11.11 and 75:25 PCL:PET blends. Following sintering, the otherwise dense 75:25 composition retains electrospun features and exhibits some “memory” of its previous state. Sintering increases UTS approximately eightfold versus as-spun values for 88.89:11.11 and 75:25. Elongation increases sixfold and twofold and modulus 44- and 69-fold for the 75:25 and 88.89:11.11 samples, respectively. Differential scanning calorimetry suggests a postsintering structure of nanoscale PET dispersed in PCL along the original fiber directions. Selective PCL removal from dense blends shows that fibrous characteristics remain. An internal shish–kebab-like structure is also present in as-spun 75:25 PCL:PET. Water absorption of hydrophobic oil-containing capsules is approximately zero after 49 days. In contrast, hydrophilic (HPI) oils allow substantial water uptake. Unsurprisingly, there is no release of a model drug from the hydrophobic carrier. HPI oil provides linear (zero-order) release inversely proportional to PET from the 88.89:11.11 and 75:25 ratios. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47731.     

Metal distributions in New Orleans following hurricanes Katrina and Rita: A continuation study

In late October 2005, twenty-seven metals were determined in soils and sediment layers deposited by floodwaters (flood sediments) within New Orleans, Louisiana. Samples originated from 43 sites along four transects, at an industrial canal, and near the Superdome. The sampling design encompassed flooded and nonflooded areas as well as differing economic strata within the city. Results from this effort confirmed findings of our previous study designed to quantify contaminant profiles in the aftermath of Hurricane Katrina. The expanded sampling from this most recent investigation revealed that arsenic (As) and lead (Pb) concentrations exceeded United States Environmental Protection Agency (USEPA) soil screening criteria indiscriminately throughout the city. However, As and Pb concentrations were lower along St. Charles Avenue, an area largely unaffected by hurricane related flooding. Toxicant concentrations did not exceed soil screening criteria values for lead within any flood sediments or for 32 of 37 soil samples, but arsenic concentrations in 40 of 43 samples exceeded screening criteria.     

Motor,Visual and Emotional Deficits in Mice after Closed-Head Mild Traumatic Brain Injury Are Alleviated by the Novel CB2 Inverse Agonist SMM-189

We have developed a focal blast model of closed-head mild traumatic brain injury (TBI) in mice. As true for individuals that have experienced mild TBI, mice subjected to 50–60 psi blast show motor, visual and emotional deficits, diffuse axonal injury and microglial activation, but no overt neuron loss. Because microglial activation can worsen brain damage after a concussive event and because microglia can be modulated by their cannabinoid type 2 receptors (CB2), we evaluated the effectiveness of the novel CB2 receptor inverse agonist SMM-189 in altering microglial activation and mitigating deficits after mild TBI. In vitro analysis indicated that SMM-189 converted human microglia from the pro-inflammatory M1 phenotype to the pro-healing M2 phenotype. Studies in mice showed that daily administration of SMM-189 for two weeks beginning shortly after blast greatly reduced the motor, visual, and emotional deficits otherwise evident after 50–60 psi blasts, and prevented brain injury that may contribute to these deficits. Our results suggest that treatment with the CB2 inverse agonist SMM-189 after a mild TBI event can reduce its adverse consequences by beneficially modulating microglial activation. These findings recommend further evaluation of CB2 inverse agonists as a novel therapeutic approach for treating mild TBI.     

Engineering the Virtual Enterprise: An Architecture-Driven Modeling Approach

The managerial and organization practices required by an increasingly dynamic competitive manufacturing, business, and industrial environment include the formation of virtual enterprises. A major concern in the management of virtual enterprises is the integration and coordination of business processes contributed by partner enterprises. The traditional methods of process modeling currently used for the design of business processes do not fully support the needs of the virtual enterprise. The design of these virtual enterprises imposes requirements that make it more complex than conventional intraorganizational business process design. This paper first describes an architecture that assists in the design of the virtual enterprise. Then it discusses business process reengineering (BPR) as a methodology for modeling and designing virtual organizations. While BPR presents many useful tools, the approach itself and the modeling tools commonly used for redesign have fundamental shortcomings when dealing with the virtual enterprise. However, several innovative modeling approaches provide promise for this problem. The paper discusses some of these innovative modeling approaches, such as object-oriented modeling of business processes, agent modeling of organizational players, and the use of ontological modeling to capture and manipulate knowledge about the players and processes. The paper concludes with a conceptual modeling methodology that combines these approaches under the enterprise architecture for the design of virtual enterprises.     

Dissimilar Impact Welding of 6111-T4, 5052-H32 Aluminum Alloys to 22MnB5, DP980 Steels and the Structure–Property Relationship of a Strongly Bonded Interface

Metallurgical and Materials Transactions A - The ability to weld high-strength aluminum to high-strength steel is highly desired for vehicle lightweighting but difficult to attain by conventional...